Long Chain Base Profiling with Multiple Reaction Monitoring Mass Spectrometry.

Sphingolipids (SLs) are essential lipids with important functions in membrane formation and cell signaling. The presence of a long chain base (LCB) structure is common to all SLs. De novo SL synthesis is initiated by the enzyme serine-palmitoyltransferase (SPT), which forms an LCB by the conjugation from serine and fatty acyl-CoAs. SPT can metabolize a variety of acyl-CoA substrates, which form diverse LCB structures within and across species. The LCB then undergoes further metabolic modifications resulting in an extraordinarily diverse spectrum of sphingolipids formed. SL analysis, using liquid chromatography-mass spectrometry (LC-MS)-based methods, poses challenges due to the diverse range of frequently isobaric species. This complexity complicates the identification of underlying LCB structures using standard lipidomics approaches. Here, we describe a simplified method to analyze the LCB profile in cells, tissue, and blood. The procedure involves chemical hydrolysis to remove the conjugated headgroups and N-acyl chains, allowing to specifically resolve the underlying LCB structures by LC-MS. This method can also be combined with an isotope labeling approach to determine in vivo SPT activity and total SL de novo synthesis over time.

Space Molecules in Superacidic Media─The Synthesis and Structure of Monoprotonated Cyanoacetylene and Diprotonated Dicyanoacetylene.

The molecules cyanoacetylene and dicyanoacetylene detected in the atmosphere of Saturn's largest moon Titan were investigated in superacidic media XF/MF5 (X = H, D; M = As, Sb), XF/GeF4, and XF/BF3. Cyanoacetylene is obtained as a monoprotonated salt, while only the diprotonated salt of dicyanoacetylene has been isolated. The salts were characterized by vibrational spectroscopy, NMR spectroscopy, and single-crystal X-ray diffraction. The protonations lead to a significant shortening of the C≡N bond. The salts of [C3HXN][SbF6] (X = H, D) show very rare coupled oscillations in vibrational spectroscopy. The experimental results are discussed together with quantum chemical calculations at the M062X/aug-cc-pVTZ level of theory. The -M and -I effects of the C≡N moiety decrease by protonation of the nitrile moiety.

Concordant inter-laboratory derived concentrations of ceramides in human plasma reference materials via authentic standards.

In this community effort, we compare measurements between 34 laboratories from 19 countries, utilizing mixtures of labelled authentic synthetic standards, to quantify by mass spectrometry four clinically used ceramide species in the NIST (National Institute of Standards and Technology) human blood plasma Standard Reference Material (SRM) 1950, as well as a set of candidate plasma reference materials (RM 8231). Participants either utilized a provided validated method and/or their method of choice. Mean concentration values, and intra- and inter-laboratory coefficients of variation (CV) were calculated using single-point and multi-point calibrations, respectively. These results are the most precise (intra-laboratory CVs ≤ 4.2%) and concordant (inter-laboratory CVs < 14%) community-derived absolute concentration values reported to date for four clinically used ceramides in the commonly analyzed SRM 1950. We demonstrate that calibration using authentic labelled standards dramatically reduces data variability. Furthermore, we show how the use of shared RM can correct systematic quantitative biases and help in harmonizing lipidomics. Collectively, the results from the present study provide a significant knowledge base for translation of lipidomic technologies to future clinical applications that might require the determination of reference intervals (RIs) in various human populations or might need to estimate reference change values (RCV), when analytical variability is a key factor for recall during multiple testing of individuals.

Associations between antagonistic SNPs for neuropsychiatric disorders and human brain structure.

A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.

Deoxyfluorination with superacids - synthesis and characterization of protonated α-fluorohydroxyacetic acid.

α-Fluoroalcohols describe a rare and unstable class of compounds, accessible mainly by fluorination of highly electrophilic carbonyl compounds. In this work, we report the syntheses of α-fluorohydroxyacetic acid (FHA) and its acyl fluoride (FHA-F) by reacting the dihydroxy species glyoxylic acid monohydrate (GAM) with SF4. Surprisingly, only one of the geminal hydroxy groups is substituted when excess SF4 is employed. Implementing GAM with the binary superacid HF/AsF5 also leads to a single yet quantitative deoxyfluorination at the diol group. The reaction pathways are discussed based on NMR experiments, the characterization was carried out using NMR and vibrational spectroscopy as well as single-crystal X-ray diffraction.

On-Surface Atomic Scale Qubit Platform.

Recent advances in scanning probe microscopy combined with electron spin resonance have revealed that localized electron spins on or near surfaces can be utilized as building blocks for the bottom-up assembly of functional quantum-coherent nanostructures. In this perspective, we review the recent advances, lay out advantages of this platform and outline the challenges that lie ahead on the way to the application of on-surface atomic spins to quantum information science and quantum computing.

The human gut microbiome in health and disease: time for a new chapter?

The gut microbiome, composed of the colonic microbiota and their host environment, is important for many aspects of human health. A gut microbiome imbalance (gut dysbiosis) is associated with major causes of human morbidity and mortality. Despite the central part our gut microbiome plays in health and disease, mechanisms that maintain homeostasis and properties that demarcate dysbiosis remain largely undefined. Here we discuss that sorting taxa into meaningful ecological units reveals that the availability of respiratory electron acceptors, such as oxygen, in the host environment has a dominant influence on gut microbiome health. During homeostasis, host functions that limit the diffusion of oxygen into the colonic lumen shelter a microbial community dominated by primary fermenters from atmospheric oxygen. In turn, primary fermenters break down unabsorbed nutrients into fermentation products that support host nutrition. This symbiotic relationship is disrupted when host functions that limit the luminal availability of host-derived electron acceptors become weakened. The resulting changes in the host environment drive alterations in the microbiota composition, which feature an elevated abundance of facultatively anaerobic microbes. Thus, the part of the gut microbiome that becomes imbalanced during dysbiosis is the host environment, whereas changes in the microbiota composition are secondary to this underlying cause. This shift in our understanding of dysbiosis provides a novel starting point for therapeutic strategies to restore microbiome health. Such strategies can either target the microbes through metabolism-based editing or strengthen the host functions that control their environment.

Rhodium/Trialkylamines Catalyzed Reductive Hydroformylation in Ionic Liquid/Heptane Medium: An Unexpected Concept for Catalyst Recycling in Batch and Continuous Flow Processes.

We report here the rhodium catalyzed reductive hydroformylation of methyl 10-undecenoate. Our approach is based on an ionic liquid/heptane biphasic system associated with commercially available trialkylamines. The effects of various reaction parameters such as amine type, amine amount, temperature, syngas pressure and composition were studied in order to minimize the rhodium leaching and increase the production of primary alcohols. Although the amine is less soluble in the ionic liquid than in heptane, the catalytic system is efficiently maintained in the ionic liquid phase. For the optimized conditions, the catalytic ionic liquid layer can be recycled at least nine times by keeping an alcohol yield over 50% and by limiting the rhodium leaching. As an extension of this system and to examine the long-term stability, this batch system was transferred to a miniplant for a continuous flow process. A pilot plant was operated for 45 h of total reaction time, reaching a TTON of 232 for alcohol production.

The coming microbial crisis: Our antibiotic bubble is about to burst.

This month, the United Nations (UN) General Assembly will convene its second High-Level Meeting on antimicrobial resistance, urging UN member states to take decisive action against this growing threat. The US Centers for Disease Control and Prevention (CDC) has released a list of the drug-resistant bacterial and fungal infections that pose the greatest concern to public health. Yet, despite increasing warnings from infectious disease experts, the public remains largely unaware of the true scale of the problem. In a world where antibiotics still protect us from bacterial infections, we are shielded from experiencing antimicrobial resistance as an immediate threat to our daily lives.

Protein persulfidation in plants: mechanisms and functions beyond a simple stress response.

Posttranslational modifications (PTMs) can modulate the activity, localization and interactions of proteins and (re)define their biological function. Understanding how changing environments can alter cellular processes thus requires detailed knowledge about the dynamics of PTMs in time and space. A PTM that gained increasing attention in the last decades is protein persulfidation, where a cysteine thiol (-SH) is covalently bound to sulfane sulfur to form a persulfide (-SSH). The precise cellular mechanisms underlying the presumed persulfide signaling in plants are, however, only beginning to emerge. In the mitochondrial matrix, strict regulation of persulfidation and H2S homeostasis is of prime importance for maintaining mitochondrial bioenergetic processes because H2S is a highly potent poison for cytochrome c oxidase. This review summarizes the current knowledge about protein persulfidation and corresponding processes in mitochondria of the model plant Arabidopsis. These processes will be compared to the respective processes in non-plant models to underpin similarities or highlight apparent differences. We provide an overview of mitochondrial pathways that contribute to H2S and protein persulfide generation and mechanisms for H2S fixation and de-persulfidation. Based on current proteomic data, we compile a plant mitochondrial persulfidome and discuss how persulfidation may regulate protein function.

[Genetic diagnostics of mental health disorders in adulthood]. / Genetische Diagnostik bei psychischen Erkrankungen im Erwachsenenalter.

This review article provides insights into the role of genetic diagnostics in adult mental health disorders. The importance of genetic factors in the development of mental illnesses, from rare genetic syndromes to common complex genetic disorders, is described. Current clinical characteristics that may warrant a genetic diagnostic work-up are highlighted, including intellectual disability, autism spectrum disorders and severe psychiatric conditions with specific comorbidities, such as organ malformations or epilepsy. The review discusses when genetic diagnostics are recommended according to current guidelines as well as situations where they might be considered even in the absence of explicit guideline recommendations. This is followed by an overview of the procedures and the currently used diagnostic methods. Current limitations and possible developments in the field of genetic diagnostics in psychiatry are discussed, including the fact that, for many mental health conditions, genetic testing is not yet part of standard clinical practice; however, in summary genetic causes should be considered more frequently in certain clinical constellations, and genetic diagnostics and counselling should be offered where appropriate.

[Organ-preserving treatment for urothelial carcinoma of the upper urinary tract]. / Organerhaltende Therapien beim Urothelkarzinom des oberen Harntrakts.

Urothelial carcinoma of the upper urinary tract is rare but the incidence is currently increasing in western countries. Radical nephroureterectomy has long been the standard treatment; however, it can lead to chronic kidney failure and also the necessity for dialysis. Therefore, organ-preserving treatment is now recommended for selected patients with low-risk tumors. The choice of treatment depends on the tumor characteristics, comorbidities and individual risk factors. Surgical options for organ preservation include ureterorenoscopy (URS), percutaneous treatment and partial ureteral resection. The URS is the most frequently used method for organ preservation. Photodynamic diagnostics (PDD) and narrow band imaging (NBI) can potentially also be used for tumor detection in the upper urinary tract. Conservative options such as topical treatment with mitomycin C or Bacillus Calmette-Guérin (BCG) and systemic treatment options are also possible.

Synthesis and Stabilization of Highly Reactive Haloacetylium Ions.

The reactions of selected haloacetyl fluorides with the strong Lewis acids AsF5 and SbF5 were investigated in the aprotic solvent SO2ClF. Depending on the stoichiometric ratio of AsF5 or SbF5 and the haloacetyl fluorides, either O-coordinated adducts or the respective haloacetylium ions were isolated as solids. The compounds were characterized by low-temperature vibrational spectroscopy and single-crystal X-ray diffraction. [CClH2CO][Sb2F11] and [CH2FCO][Sb2F11] crystallize in the monoclinic space group P21 with two formula units per unit cell. The reactivity of the haloacetyl fluorides under Lewis acidic conditions is discussed based on quantum chemical calculations of fluoride ion affinities on the BP/def2SVPP level of theory. The haloacetylium ions are stabilized in the solid-state phase by intermolecular C···F contacts and electron donation of the fluorine ligands of the anions as well as intramolecular hyperconjugation.

Aberrant neuronal connectivity and network activity of neurons derived from patients with idiopathic schizophrenia.

Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and E-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization.

Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis.

Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2-4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.

Biphasic Production of 5-hydroxymethylfurfural (HMF) in a Recyclable Deep Eutectic Solvent-based System Catalyzed by H4SiW12O40.

The reaction with in situ extraction to yield 5-hydroxymethylfurfural (HMF) from Fru was investigated using a biphasic system based on a self-consuming deep eutectic solvent (DES) as reaction phase. The significance of choline chloride (ChCl), a cost-effective and safe quaternary ammonium salt, was evident in enhancing 5-HMF yield through fructose dehydration and concurrently suppressing side reactions. The DES system demonstrated fast reactions with high selecivities and recyclability across five cycles. The observed decline in H4SiW12O40 activity, primarily due to proton leaching, was successfully restored with the addition of HCl. Furthermore, ChCl exhibited ease of recrystallization in the presence of acetonitrile. This research proposes an environmentally friendly approach for 5-HMF production through a reusable-biphasic process. The presented reaction system suppresses completely the formation of levulinic and formic acid leading to HMF yields of up to 84% of selectivities of up to 88% after 30 minutes at 80 °C. The system was recycled over 16 runs and after an initial slight loss of activity the system in the run 0-5, run 6-15 has shown a constant HMF output as in the first recycling run.

The electrophilic methylating agent [SO2Me]+ parent of two cationic species.

Methylfluoride and hydrogen fluoride react with powerful methylating agent [SO2Me]+ in a temperature-dependent addition reaction to form methylated fluorosulfuric acid [FS(OMe)2][Sb2F11] and methylated fluorosulfuric acid methyl ester [FS(OH)(OMe)][SbF6], respectively. The obtained methylated fluorosulfinic acid and methylated fluorosulfinic acid methyl ester were characterized by single X-ray structure analysis and vibrational spectroscopy.

'The mirror of the soul?' Inferring sadness in the eyes.

The eyes are widely regarded as the mirror of the soul, providing reliable nonverbal information about drives, feelings, and intentions of others. However, it is unclear how accurate emotion recognition is when only the eyes are visible and whether inferring of emotions is altered across healthy adulthood. To fill this gap, the present piece of research was directed at comparing the ability to infer basic emotions in two groups of typically developing females that differed in age. We set a focus on females seeking group homogeneity. In a face-to-face study, in a two-alternative forced choice paradigm (2AFC), participants had to indicate emotions for faces covered by masks. The outcome reveals that although the recognition pattern is similar in both groups, inferring sadness in the eyes substantially improves with age. Inference of sadness is not only more accurate and less variable in older participants, but also positively correlates with age from early through mid-adulthood. Moreover, reading sadness (and anger) is more challenging in the eyes of male posers. A possible impact of poser gender and cultural background, both in expressing and inferring sadness in the eyes, is highlighted.

The genomic landscape of 2,023 colorectal cancers.

Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

[Follow-up after urinary diversion]. / Nachsorge nach Harnableitung.

Radical cystectomy is currently the standard of care for muscle-invasive bladder cancer. Different parts of the small and large intestines can be utilized for continent and incontinent urinary diversion. The postoperative follow-up after urinary diversion should consider functional, metabolic and oncological aspects. The functional follow-up of (continent) urinary diversion includes stenosis, emptying disorders or incontinence. The oncological follow-up should focus on the detection of local, urethral and upper tract recurrences as well as distant metastases. As 90% of the tumor recurrences occur during the first 3 years, a close follow-up should be carried out during this period. Metabolic disturbances, such as vitamin B12 and bile acid deficits, acidosis and disorders of calcium metabolism can also occur during long-term follow-up. The metabolic follow-up should consider the metabolic consequences of the parts of the intestines utilized for the urinary diversion.