Ruthenium-Catalysed Hydrogenation of Aromatic Ketones using Monodentate Phosphoramidite Ligands

A ruthenium pre-catalyst containing two equivalents of the bulky monodentate phosphoramidite 3,3’-dimethyl-PipPhos and one equivalent of a chiral diamine such as 1,2-diphenylethylenediamine or 1,2-diaminocyclohexane was used for the asymmetric hydrogenation of aromatic ketones. A range of substituted and unsubstituted aryl alkyl ketones was hydrogenated using only 0.1 mol% of this catalyst with full conversions and enantioselectivities up to 97%. The phosphoramidite and diamine ligands matched when both had the same configuration, i.e., S-phosphoramidite with S,S-diamine. In that case the product was obtained with high enantioselectivity and the R-configuration. The mismatched case produced the product in lower ee. The product configuration was determined by the configuration of the diamine ligand. A mechanistic proposal was made.

Rapidly Measuring the Speed of Unconscious Learning: Amnesics Learn Quickly and Happy People Slowly

BACKGROUND We introduce a method for quickly determining the rate of implicit learning. METHODOLOGY/PRINCIPAL FINDINGS The task involves making a binary prediction for a probabilistic sequence over 10 minutes; from this it is possible to determine the influence of events of a different number of trials in the past on the current decision. This profile directly reflects the learning rate parameter of a large class of learning algorithms including the delta and Rescorla-Wagner rules. To illustrate the use of the method, we compare a person with amnesia with normal controls and we compare people with induced happy and sad moods. CONCLUSIONS/SIGNIFICANCE Learning on the task is likely both associative and implicit. We argue theoretically and demonstrate empirically that both amnesia and also transient negative moods can be associated with an especially large learning rate: People with amnesia can learn quickly and happy people slowl

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome

Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world’s countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome

Cold Ischemia Time and Graft Fibrosis Are Associated with Autoantibodies after Pediatric Liver Transplantation: A Retrospective Cohort Study of the European Reference Network TransplantChild

The reported prevalence of autoantibodies (AAB) (ANA, SMA, LKM, SLA) after pediatric liver transplantation (pLTX) varies considerably from 26–75%, but their clinical impact on outcome is uncertain. We aimed to study the prevalence of AAB after pLTX, their association with donor-, transplant-, and recipient-characteristics, and their relation to outcome. In our multicenter retrospective study, we aimed to clarify conflicting results from earlier studies. Six ERN TransplantChild centers reported data on 242 patients, of whom 61% were AAB positive. Prevalence varied across these centers. Independent of the interval between pLTX and AAB analysis, a one-hour increase in CIT resulted in an odds ratio (OR) of 1.37 (95% CI 1.11–1.69) for SMA positivity and an OR of 1.42 (95%CI 1.18–1.72) for ANA positivity. Steroid-free immunosuppression (IS) versus steroid-including IS (OR 5.28; 95% CI 1.45–19.28) was a risk factor for SMA positivity. Liver enzymes were not associated with ANA or SMA positivity. We did not observe an association of rejection activity index with ANA or SMA. However, the liver fibrosis score in follow-up biopsies was associated with ANA titer and donor age. In conclusion, this first multicenter study on AAB after pLTX showed high AAB prevalence and varied widely between centers. Longer CIT and prednisolone-free-IS were associated with AAB positivity, whereas AAB were not indicative of rejection, but instead were associated with graft fibrosis. The detection of AAB may be a marker of liver fibrosis and may be taken into consideration when indications for liver biopsy and immunosuppressive regimes, or reduction of immunosuppression in long-term follow-up, are being discussed. Prospective immunological profiling of pLTX patients, including AAB, is important to further improve our understanding of transplant immunology and silent graft fibrosis

Besteht eine Assoziation zwischen früh-postoperativer Genexpression der Chemokine IP10 und MIG sowie deren Rezeptor CXCR3 und der Entwicklung von Abstoßungen nach Lebertransplantation?

Die fast ausschließliche Expression des Chemokinrezeptors CXCR3 auf TH1-Helferzellen legt eine Funktion dieses Rezeptors und seiner Liganden IP10 (CXCL10) und MIG (CXCL9) auch innerhalb von Abstoßungsreaktionen nach Organtransplantation nahe. Dies konnte in tierexperimentellen und klinischen Untersuchungen bestätigt werden. Die Ziele dieser Arbeit sind, die Real-Time-Taqman-PCR aus humanen Leberbiopsien als Methode zur quantitativen Bestimmung der Chemokinexpression nach und während orthotoper Lebertransplantation (OLT)zu etablieren. Des Weiteren soll die Studie prüfen, ob eine akute zelluläre Abstoßung (AR), der Ischiämie-Reperfusionsschaden (IRI) und die Organqualität mit einer vermehrten Genexpression von IP10, MIG und CXCR3 im Zusammenhang stehen. Die Genexpression wurde mittels PCR in Spenderleberproben von 21 Patienten (52,4% weiblich, 47,6% männlich, mittleres Alter zum Zeitpunkt der OLT 44 Jahre) unmittelbar vor Implantation, in der ersten Stunde nach Reperfusion und 10-18 Tage nach OLT gemessen und mit GAPDH als Housekeepinggen einer effizienzkorrigierten, semiquantitativen Auswertung zugeführt. Der klinische Verlauf der Patienten wurde über 24 Monate nach OLT beobachtet. Die gemessenen Genexpressionen sind reproduzierbar und korrelieren hoch signifikant miteinander. Die Gruppe der Patienten, die in den ersten 24 Monaten nach OLT mehr als eine Abstoßung entwickelt hat, hat vor Implantation in der Spenderleber signifikant höhere Genexpressionen für IP10 (p= 0,014), MIG (p= 0,014) und CXCR3 (p= 0,044), als Patienten, die höchstens eine Abstoßung entwickelt haben. Kurz nach Reperfusion ist die Genexpression von CXCR3 in der abstoßungsfreien Patientengruppe und in der Patientengruppe mit einer höchstens leichten Abstoßung signifikant (p= 0,047 bzw. 0,008) niedriger als in der Patentengruppe mit Abstoßung bzw. mindestens mäßiger Abstoßung. Für IP10 findet sich diese Signifikanz (p= 0,033) nur für den Vergleich höchstens leichte gegen mindestens mäßige Abstoßung. Für CXCR3 findet sich auch eine signifikante (p= 0,047) Zunahme der Genexpression mit Zunahme der kalten Ischiämiezeit (CIT). 10-18 Tage postoperativ ist die Genexpression von IP10, MIG und CXCR3 ein häufiges Ereignis und nicht signifikant mit Abstoßungsgeschehen assoziiert. Anhand der oben genannten Reproduzierbarkeit und Korrelation der Genexpressionen ist anzunehmen, dass die durchgeführte Methode geeignet ist. Die Genexpression vor Implantation spiegelt bisher nicht verifizierbare immunologische Reaktionen im Spenderorgan auf zellulärer Ebene wider, die eventuell ein immunologisches Milieu schaffen, welches wahrscheinlich den weitern klinischen Verlauf, insbesondere bezogen auf AR wesentlich beeinflussen kann. Somit können sie sowohl einen Marker für Organqualität auf zellulärer Ebene darstellen, als auch einen frühen Indikator für ein hohes Abstoßungsrisiko. Es ist anzunehmen, dass die intraoperative Expression von IP10 und CXCR3 durch den IRI bedingt ist. Aufgrund des oben genannten Zusammenhangs zwischen AR und der Expression von IP10 und CXCR3 zu diesem Zeitpunkt, kann man davon ausgehen, dass der IRI mit vermehrter Genexpression von IP10 und CXCR3 zu späteren AR prädisponiert und eine pharmakologische Intervention hier eventuell spätere Abstoßungen verhindern kann. Auch hier scheint die Genexpression von IP10 und CXCR3 prädiktiv für das Abstoßungsrisiko im weiteren Verlauf zu sein. Die Genexpression von IP10, MIG und CXCR3 10-18 Tage nach OLT scheint kein guter Marker für die Diagnose und Beurteilung einer Abstoßung zu sein