Migraine-Asthma Comorbidity and Risk of Hypertensive Disorders of Pregnancy

Background: To evaluate the association of migraine and asthma and to estimate the risk of hypertensive disorders of pregnancy in relation to maternal comorbid migraine and asthma. Methods: Reproductive age women (N = 3.731) were interviewed during early pregnancy. At the time of interview, we ascertained participants' migraine and asthma status. From medical records, we collected information to allow the diagnosis of pregnancy-induced hypertension (PIH) and preeclampsia. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression procedures. Results: After adjusting for confounders, migraineurs had 1.38-fold increased odds of asthma as compared with nonmigraineurs (95% CI 1.09–1.38). The odds of hypertensive disorders of pregnancy were highest among women with comorbid migraine-asthma. The ORs for PIH preeclampsia and the two disorders combined were 2.53 (95% CI 1.39–4.61), 3.53 (95% CI 1.51–8.24), and 2.64 (95% CI 1.56–4.47), respectively, for women with comorbid migraine-asthma as compared with those who had neither disorder. Conclusion: These findings confirm prior reports and extend the literature by documenting particularly high odds of pregnancy-induced hypertension and preeclampsia among women with comorbid migraine-asthma. Increased knowledge about the prevalence and sequelae of comorbidities during pregnancy may lead to improved symptom management and perinatal outcomes

Room temperature deformation mechanisms of the C14 Laves Phase in the Mg‐Al‐Ca system

In order to improve the creep resistance of magnesium alloys and thereby increase their operating temperature, hard intermetallic phases can be incorporated in the microstructure. In particular the addition of Al or Ca to Mg results in the formation of a skeleton-like intermetallic structure at the grain boundaries. This structure consists predominately of Laves phases, which reduces the minimum creep rate by a few orders of magnitude. In bulk, these Laves phases are extremely brittle at low temperatures, limiting our understanding of the underlying mechanisms of plasticity. Additionally, the small size of the microstructural features in technical alloys make bulk-scale tests unsuitable for studying these phases. Using nanomechanical testing (nanoindentation and microcompression) in individual grains, cracking can be suppressed and plastic deformation can be observed [1]. Micropillars were milled using FIB in individual grains of a polycrystalline specimen, and orientations determined by EBSD to activate and interrogate slip systems. These data have then been combined with slip line analysis around indents. Such an approach reveals the presence of pyramidal, prismatic and basal slip at ambient conditions, with pyramidal 1st order being the predominant slip plane. Critical resolved shear stresses for these slip systems have been calculated, and TEM analysis of the deformation microstructure performed. This work therefore exemplifies how nanomechanical testing in conjunction with electron microscopy can extend the current knowledge of plasticity in macroscopically brittle crystals. [1] S. Korte, W.J. Clegg, Studying Plasticity in Hard and Soft Nb–Co Intermetallics, Advanced Engineering Materials, 14, No. 11 (2012), 991-99

Migraine-Asthma Comorbidity and Risk of Hypertensive Disorders of Pregnancy

Background. To evaluate the association of migraine and asthma and to estimate the risk of hypertensive disorders of pregnancy in relation to maternal comorbid migraine and asthma. Methods. Reproductive age women (N = 3.731) were interviewed during early pregnancy. At the time of interview, we ascertained participants' migraine and asthma status. From medical records, we collected information to allow the diagnosis of pregnancy-induced hypertension (PIH) and preeclampsia. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression procedures. Results. After adjusting for confounders, migraineurs had 1.38-fold increased odds of asthma as compared with nonmigraineurs (95% CI 1.09-1.38). The odds of hypertensive disorders of pregnancy were highest among women with comorbid migraine-asthma. The ORs for PIH preeclampsia and the two disorders combined were 2.53 (95% CI 1.39-4.61), 3.53 (95% CI 1.51-8.24), and 2.64 (95% CI 1.56-4.47), respectively, for women with comorbid migraine-asthma as compared with those who had neither disorder. Conclusion. These findings confirm prior reports and extend the literature by documenting particularly high odds of pregnancy-induced hypertension and preeclampsia among women with comorbid migraine-asthma. Increased knowledge about the prevalence and sequelae of comorbidities during pregnancy may lead to improved symptom management and perinatal outcomes

Evolutionary repurposing of a sulfatase: A new Michaelis complex leads to efficient transition state charge offset

The recruitment and evolutionary optimization of promiscuous enzymes is key to the rapid adaptation of organisms to changing environments. Our understanding of the precise mechanisms underlying enzyme repurposing is, however, limited: What are the active-site features that enable the molecular recognition of multiple substrates with contrasting catalytic requirements? To gain insights into the molecular determinants of adaptation in promiscuous enzymes, we performed the laboratory evolution of an arylsulfatase to improve its initially weak phenylphosphonate hydrolase activity. The evolutionary trajectory led to a 100,000-fold enhancement of phenylphosphonate hydrolysis, while the native sulfate and promiscuous phosphate mono-and diester hydrolyses were only marginally affected (<= 50-fold). Structural, kinetic, and in silico characterizations of the evolutionary intermediates revealed that two key mutations, T50A and M72V, locally reshaped the active site, improving access to the catalytic machinery for the phosphonate. Measured transition state (TS) charge changes along the trajectory suggest the creation of a new Michaelis complex (E.S, enzyme-substrate), with enhanced leaving group stabilization in the TS for the promiscuous phosphonate (beta(leaving) (group) from -1.08 to -0.42). Rather than altering the catalytic machinery, evolutionary repurposing was achieved by fine-tuning the molecular recognition of the phosphonate in the Michaelis complex, and by extension, also in the TS. This molecular scenario constitutes a mechanistic alternative to adaptation solely based on enzyme flexibility and conformational selection. Instead, rapid functional transitions between distinct chemical reactions rely on the high reactivity of permissive active-site architectures that allow multiple substrate binding modes

OER-Policy Kit

Homp F, Czerwinski S, Dreyer A, Hörmann I, Legler S, Loose Y. OER-Policy Kit. twillo; 2024.Das OER-Policy Kit ist als Leitfaden zum Policy-Prozess an Hochschulen zu verstehen und umfasst sieben Schritte, die mit weiteren Materialien ergänzt werden, wie z.B. einer Muster OER-Policy oder Mailvorlagen. Das OER-Policy Kit wird über Liascript realisiert. Die dazugehörige Markdown-Datei sowie alle anderen Bild- und Textdateien finden sich im Github-Repository. Immer mehr Hochschulen bekennen sich zu Openness und wollen durch eine Richtlinie das Signal für Lehrende und andere Hochschulangehörige setzen, dass sie das Erstellen und Teilen von OER unterstützen. Obwohl diese Richtlinie – zumeist als OER-Policy bezeichnet – nicht unbedingt rechtlich verbindlich ist, wie z.B. eine Dienstanweisung, schafft sie einen hohen Grad an Verbindlichkeit für das Thema OER und öffnet damit viele Türen hin zu einer anerkannten und gelebten offenen Bildung. Das Policy Kit stellt keinen Gold-Standard-Weg hin zu einer OER-Policy dar, sondern soll an die spezifische Situation Ihrer Hochschule angepasst werden. Da der konkrete Ablauf sehr unterschiedlich sein kann, ist die Reihenfolge der Schritte nicht strikt einzuhalten. Im Policy-Prozess ist eine Linearität nicht unbedingt gegeben, so dass es einige Schleifen im Policy-Prozess geben kann und mehrere Schritte wiederholt werden bzw. zwischen den Schritten hin und her gesprungen wird

Innate and adaptive immunity associated with resolution of acute woodchuck hepatitis virus infection in adult woodchucks.

Viral and/or host factors that are directly responsible for the acute versus chronic outcome of hepatitis B virus (HBV) infection have not been identified yet. Information on immune response during the early stages of HBV infection in humans is mainly derived from blood samples of patients with acute hepatitis B (AHB), which are usually obtained after the onset of clinical symptoms. Features of intrahepatic immune response in these patients are less studied due to the difficulty of obtaining multiple liver biopsies. Woodchuck hepatitis virus (WHV) infection in woodchucks is a model for HBV infection in humans. In the present study, five adult woodchucks were experimentally infected with WHV and then followed for 18 weeks. Blood and liver tissues were frequently collected for assaying markers of WHV replication and innate and adaptive immune responses. Liver tissues were further analyzed for pathological changes and stained for important immune cell subsets and cytokines. The increase and subsequent decline of viral replication markers in serum and liver, the elicitation of antibodies against viral proteins, and the induction of virus-specific T-cell responses indicated eventual resolution of acute WHV infection in all animals. Intrahepatic innate immune makers stayed unchanged immediately after the infection, but increased markedly during resolution, as determined by changes in transcript levels. The presence of interferon-gamma and expression of natural killer (NK) cell markers suggested that a non-cytolytic response mechanism is involved in the initial viral control in liver. This was followed by the expression of T-cell markers and cytolytic effector molecules, indicating the induction of a cytolytic response mechanism. Parallel increases in regulatory T-cell markers suggested that this cell subset participates in the overall immune cell infiltration in liver and/or has a role in regulating AHB induced by the cytolytic response mechanism. Since the transcript levels of immune cell markers in blood, when detectable, were lower than in liver, and the kinetics, except for NK-cells and interferon-gamma, did not correlate well with their intrahepatic expression, this further indicated enrichment of immune cells within liver. Conclusion: The coordinated interplay of innate and adaptive immunity mediates viral clearance in the woodchuck animal model of HBV infection. The initial presence of NK-cell associated interferon-gamma response points to an important role of this cytokine in HBV resolution

Antiviral Efficacy and Host Innate Immunity Associated with SB 9200 Treatment in the Woodchuck Model of Chronic Hepatitis B.

SB 9200, an oral prodrug of the dinucleotide SB 9000, is being developed for the treatment of chronic hepatitis B virus (HBV) infection and represents a novel class of antivirals. SB 9200 is thought to activate the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) resulting in interferon (IFN) mediated antiviral immune responses in virus-infected cells. Additionally, the binding of SB 9200 to these sensor proteins could also sterically block the ability of the viral polymerase to access pre-genomic RNA for nucleic acid synthesis. The immune stimulating and direct antiviral properties of SB 9200 were evaluated in woodchucks chronically infected with woodchuck hepatitis virus (WHV) by daily, oral dosing at 15 and 30 mg/kg for 12 weeks. Prolonged treatment resulted in 2.2 and 3.7 log10 reductions in serum WHV DNA and in 0.5 and 1.6 log10 declines in serum WHV surface antigen from pretreatment level with the lower or higher dose of SB 9200, respectively. SB 9200 treatment also resulted in lower hepatic levels of WHV nucleic acids and antigen and reduced liver inflammation. Following treatment cessation, recrudescence of viral replication was observed but with dose-dependent delays in viral relapse. The antiviral effects were associated with dose-dependent and long-lasting induction of IFN-α, IFN-β and IFN-stimulated genes in blood and liver, which correlated with the prolonged activation of the RIG-I/NOD2 pathway and hepatic presence of elevated RIG-I protein levels. These results suggest that in addition to a direct antiviral activity, SB 9200 induces antiviral immunity during chronic hepadnaviral infection via activation of the viral sensor pathway