30 research outputs found
Yersinia pestis DNA from Skeletal Remains from the 6(th) Century AD Reveals Insights into Justinianic Plague.
No full textYersinia pestis, the etiologic agent of the disease plague, has been implicated in three historical pandemics. These include the third pandemic of the 19(th) and 20(th) centuries, during which plague was spread around the world, and the second pandemic of the 14(th)-17(th) centuries, which included the infamous epidemic known as the Black Death. Previous studies have confirmed that Y. pestis caused these two more recent pandemics. However, a highly spirited debate still continues as to whether Y. pestis caused the so-called Justinianic Plague of the 6(th)-8(th) centuries AD. By analyzing ancient DNA in two independent ancient DNA laboratories, we confirmed unambiguously the presence of Y. pestis DNA in human skeletal remains from an Early Medieval cemetery. In addition, we narrowed the phylogenetic position of the responsible strain down to major branch 0 on the Y. pestis phylogeny, specifically between nodes N03 and N05. Our findings confirm that Y. pestis was responsible for the Justinianic Plague, which should end the controversy regarding the etiology of this pandemic. The first genotype of a Y. pestis strain that caused the Late Antique plague provides important information about the history of the plague bacillus and suggests that the first pandemic also originated in Asia, similar to the other two plague pandemics
Gene loss and lineage specific restriction-modification systems associated with niche differentiation in the Campylobacter jejuni Sequence Type 403 clonal complex
No full textCampylobacter jejuni is a highly diverse species of bacteria commonly associated with infectious intestinal disease of humans and zoonotic carriage in poultry, cattle, pigs, and other animals. The species contains a large number of distinct clonal complexes that vary from host generalist lineages commonly found in poultry, livestock, and human disease cases to host-adapted specialized lineages primarily associated with livestock or poultry. Here, we present novel data on the ST403 clonal complex of C. jejuni, a lineage that has not been reported in avian hosts. Our data show that the lineage exhibits a distinctive pattern of intralineage recombination that is accompanied by the presence of lineage-specific restriction-modification systems. Furthermore, we show that the ST403 complex has undergone gene decay at a number of loci. Our data provide a putative link between the lack of association with avian hosts of C. jejuni ST403 and both gene gain and gene loss through nonsense mutations in coding sequences of genes, resulting in pseudogene formation
Control of cellular Bcl-xL levels by deamidation-regulated degradation
No full textThe cellular concentration of Bcl-xL is among the most important determinants of treatment response and overall prognosis in a broad range of tumors as well as an important determinant of the cellular response to several forms of tissue injury. We and others have previously shown that human Bcl-xL undergoes deamidation at two asparaginyl residues and that DNA-damaging antineoplastic agents as well as other stimuli can increase the rate of deamidation. Deamidation results in the replacement of asparginyl residues with aspartyl or isoaspartyl residues. Thus deamidation, like phosphorylation, introduces a negative charge into proteins. Here we show that the level of human Bcl-xL is constantly modulated by deamidation because deamidation, like phosphorylation in other proteins, activates a conditional PEST sequence to target Bcl-xL for degradation. Additionally, we show that degradation of deamidated Bcl-xL is mediated at least in part by calpain. Notably, we present sequence and biochemical data that suggest that deamidation has been conserved from the simplest extant metazoans through the human form of Bcl-xL, underscoring its importance in Bcl-xL regulation. Our findings strongly suggest that deamidation-regulated Bcl-xL degradation is an important component of the cellular rheostat that determines susceptibility to DNA-damaging agents and other death stimuli
Die Epidemiologie der Pestvektoren und die Verteilung und Charakterisierung von Yersinia pestis in der Mongolei
No full textIm Rahmen dieser Arbeit wurden die epidemiologischen Bedingungen in den natürlichen Pestherden der Mongolei untersucht. Die untersuchten Vektoren schlossen sowohl Ektoparasiten wie Flöhe, Zecken und Läuse, als auch die assoziierten Wirtstiere wie Murmeltiere und Ziesel ein. Parasit-Wirt Beziehungen, die bei der Verbreitung und Persistenz der Pest in der Mongolei eine wichtige Rolle spielen, wurden erfolgreich einzelnen Pestherden und Pestherd-Typen zugeordnet und nach Bedeutung eingestuft. Die vektorbasierten Wechselwirkungen der mongolischen
Pestherde untereinander sowie ihr Einfluß auf die Pestherde in den angrenzenden
Ländern konnten ebenfalls bestätigt werden. Aus den untersuchten Vektoren isolierte Peststämme wurden mittels verfügbarer diagnostischer Verfahren zur Charakterisierung des Pesterregers Y. pestis untersucht. Diese Analysen verdeutlichten die Heterogenität der mongolischen Peststämme, zeigten jedoch auch, dass klassische biochemische Testsysteme wie der API® 20E ® Test für die Identifizierung von mongolischen Y. pestis Stämmen herangezogen werden können. Mittels des BWY in house Systems konnte zusätzlich eine Differenzierung auf der Biovar-Ebene durchgeführt werden. Das Vorkommen eines multiresistenten Peststammes aus einem Wildisolat ist das erste seiner Art in Zentralasien und besonders aus humanmedizinischer Sicht äußerst besorgniserregend. Die Ergebnisse dieser Untersuchungen verdeutlichen die Notwendigkeit steter Überwachung von Vektoren, um auf Veränderungen in den natürlichen Pestherden der Mongolei reagieren zu können. Von ebenso großer Wichtigkeit ist die kontinuierliche Überwachung von Antibiotika-Resistenzen der Peststämme in diesem Gebiet
Aminosäuren – Leitlinie Parenterale Ernährung, Kapitel 4
No full textProtein catabolism should be reduced and protein synthesis promoted with parenteral nutrion (PN). Amino acid (AA) solutions should always be infused with PN. Standard AA solutions are generally used, whereas specially adapted AA solutions may be required in certain conditions such as severe disorders of AA utilisation or in inborn errors of AA metabolism. An AA intake of 0.8 g/kg/day is generally recommended for adult patients with a normal metabolism, which may be increased to 1.2–1.5 g/kg/day, or to 2.0 or 2.5 g/kg/day in exceptional cases. Sufficient non-nitrogen energy sources should be added in order to assure adequate utilisation of AA. A nitrogen calorie ratio of 1:130 to 1:170 (g N/kcal) or 1:21 to 1:27 (g AA/kcal) is recommended under normal metabolic conditions. In critically ill patients glutamine should be administered parenterally if indicated in the form of peptides, for example 0.3–0.4 g glutamine dipeptide/kg body weight/day (=0.2–0.26 g glutamine/kg body weight/day). No recommendation can be made for glutamine supplementation in PN for patients with acute pancreatitis or after bone marrow transplantation (BMT), and in newborns. The application of arginine is currently not warranted as a supplement in PN in adults. N-acetyl AA are only of limited use as alternative AA sources. There is currently no indication for use of AA solutions with an increased content of glycine, branched-chain AAs (BCAA) and ornithine-α-ketoglutarate (OKG) in all patients receiving PN. AA solutions with an increased proportion of BCAA are recommended in the treatment of hepatic encephalopathy (III–IV).Ein Proteinkatabolismus soll bei parenteraler Ernährung (PE) vermindert und anabole Stoffwechselprozesse gefördert werden. Standard-Aminosäure (AS)-Lösungen werden empfohlen, falls nicht in Sondersituationen z. B. bei schweren AS-Verwertungsstörungen oder bei angeborenen Stoffwechselstörungen spezifisch adaptierte AS-Lösungen eingesetzt werden müssen. Für erwachsene Patienten in ausgeglichenem Stoffwechselzustand wird eine AS-Zufuhr von 0,8 g/kg/Tag empfohlen, die auf 1,2–1,5 g/kg/Tag oder in Ausnahmefällen auch auf 2,0–2,5 g/kg/Tag gesteigert werden kann. Zur Gewährleistung einer angemessenen Utilisation von AS sollten ausreichend Nicht-Stickstoff-Energieträger zugegeben werden. Das angestrebte Verhältnis zwischen Stickstoff- und Energiezufuhr (Stickstoff-Kalorien-Verhältnis) sollte unter Normalbedingungen 1:100–1:130 (g N:kcal) bzw. 1:16–1:21 (g AS:kcal) betragen. Glutamin sollte parenteral bei kritisch Kranken, sofern indiziert, in Form von Peptiden verabreicht werden, wie z.B. 0,3–0,4 g Glutamin-Dipepetid/kg KG/Tag (entsprechend 0,2–0,26 g Glutamin/kg KG/Tag). Für Patienten mit akuter Pankreatitis, nach Knochenmarkstransplantation sowie für Neugeborene kann derzeit keine Empfehlung für eine Glutaminsupplementierung mit der PE ausgesprochen werden. Der Einsatz von Arginin als Supplement in der PE beim Erwachsenen ist derzeit nicht gerechtfertigt. Den N-azetylierten AS kommen als alternative Aminosäurenquellen zur Zeit nur eine begrenzte Bedeutung zu. Für eine generelle Verwendung von AS-Lösungen mit einem erhöhten Gehalt von Glyzin und verzweigtkettigten AS (VKAS) wie auch für Ornithin-α-Ketoglutarat (OKG) besteht keine gesicherte Indikation. Die Wirksamkeit von AS-Lösungen mit erhöhtem Anteil an VKAS in der Behandlung der hepatischen Enzephalopathie (III–IV) wird empfohlen
Management of imatinib-resistant CML patients
No full textImatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients
Do Investors Learn About Analyst Accuracy?
No full textWe study the impact of analyst forecasts on prices to determine whether investors learn about analyst accuracy. Our test market is the crude oil futures market. Prices rise when analysts forecast a decrease (increase) in crude supplies. In the 15 minutes following supply realizations, prices rise (fall) when forecasts have been too high (low). In both the initial price action relative to forecasts and in the subsequent reaction relative to realized forecast errors, the price response is stronger for more accurate analysts. These price reactions imply that investors learn about analyst accuracy and trade accordingly.Financial Economics, Institutional and Behavioral Economics, Political Economy,
Poloxamer 188 decreases membrane toxicity of mutant SOD1 and ameliorates pathology observed in SOD1 mouse model for ALS
No full text<sup>18</sup>F-Fluorocholine PET and 4D-CT in Patients with Persistent and Recurrent Primary Hyperparathyroidism
No full textPatients with primary hyperparathyroidism (pHPT) can develop persistent (P-pHPT) or recurrent (R-pHPT) disease after parathyroidectomy. Before recommending reoperation, recurrence must be accurately identified because of the high risk of complications. Our study evaluates 18F-fluorocholine (18F-FCH) PET/CT and 4D-CT integrated in PET/4D-CT in patients with P-pHPT/R-pHPT. Patients with P-pHPT/R-pHPT investigated by 18F-FCH PET/4D-CT between May 2018 and March 2021 were retrospectively included. Forty-two patients were included, 37 of whom underwent 4D-CT. The sensitivity and detection rate (DR%) were 95% and 88% for 18F-FCH PET/CT and 70% and 63% for 4D-CT, respectively. PET/CT and 4D-CT were concordant in 18/24 glands and concordant and positive in 15/24 (63%) glands. Discordant results were obtained for 6/24 glands. The surgical success rate was 65%. PET/CT showed significantly higher sensitivity than 4D-CT. Dynamic CT allowed the identification of no additional glands missed by PET/CT, and the combination of the 2 techniques did not improve the sensitivity or DR%. 18F-FCH PET/CT appears to be a valuable technique to accurately detect hyperfunctioning parathyroid tissue in patients with P-pHPT/R-pHPT and is better than 4D-CT. Except for cases with doubtful locations of PET targets that may require 4D-CT for surgical guidance, standard nonenhanced 18F-FCH PET/CT can be effectively recommended in patients with P-pHPT/R-pHPT before reoperation
Deamidation activates a conditional PEST sequence to target Bcl-x<sub>L</sub> for degradation.
No full text<p>(A) Immunoblot of Bcl-x<sub>L</sub> in <i>bcl-x<sup>−/−</sup>/p53<sup>−/−</sup></i> MEFs infected with vectors for wild-type Bcl-x<sub>L</sub> or a form of Bcl-x<sub>L</sub> in which the PEST sequence is disrupted by substitution of alanines for three of the PEST sequence prolines, Bcl-x<sub>L</sub>(3P/A), that were treated with etoposide as indicated. Two different exposures of the immunoblot are shown to facilitate the visualization of deamidated forms of Bcl-x<sub>L</sub>. (B) Anti-HA and tubulin immunoblot of 2 µg/ml of cycloheximide-treated SAOS-2 cells expressing HA-tagged versions of wild-type Bcl-x<sub>L</sub> or Bcl-x<sub>L</sub>(3P/A) for the indicated times. (C) Survival assay of <i>bcl-x<sup>−/−</sup>/p53<sup>−/−</sup></i> MEFs expressing Bcl-x<sub>L</sub>(3P/3A) and wild-type Bcl-x<sub>L</sub>. MEFs were treated with etoposide or cisplatin as indicated and survival was assessed at 48 h.</p
