Regulation der Mikrofilamente im Malariaerreger Plasmodium

Im Zentrum mannigfaltiger Bewegungen auf makroskopischer und mikroskopischer Ebene steht ein Protein und dessen Eigenschaft Polymere zu formen: Actin. Um diese fundamentale Funktion erfüllen zu können, muss die Polymerisation von Actin und die Lebensdauer der Mikrofilamente präzise reguliert werden. Heute sind viele Proteine bekannt, die mit Actinmonomeren und / oder -polymeren interagieren. Ein großer Teil unseres Wissens über Actin, Zellmotilität und weitere motile Prozesse stammt von einfachen Modellorganismen, zu denen auch Arten der Gattung Plasmodium zählen. Diese obligat parasitär lebenden Einzeller stehen als Erreger der Malaria seit langem im Fokus der Forschung. Auf der Suche nach Interventionsstrategien wurde auch deren einzigartige actinabhängige Bewegung untersucht, die sog. gliding motility. Die Sequenzierung des Plasmodium Genoms unterstrich die Eigentümlichkeit dieser actinbasierten Bewegungsform. Anders als bei den meisten anderen Eukaryoten ist das Repertoire an actinbindenden Proteinen in Plasmodien erstaunlich klein: nur etwas mehr als ein Dutzend Proteine gehören dazu. Damit kann ein besseres Verständnis der Actinregulation in Plasmodium auch ganz neue Einblicke in altbekannte Prozesse liefern. Darüber hinaus könnten dringend benötigte neue Interventionsstrategien zur Bekämpfung von Malaria aufzeigt werden. Im Mittelpunkt dieser Arbeit stand das heterodimere capping protein und dessen Eigenschaft Actinfilamente durch die Interaktion mit dem + Ende zu stabilisieren. Angesichts der äußerst geringen intrinsischen Stabilität von Plasmodium Actin, könnte diese zelluläre Funktion besonders wichtig für den Parasiten sein. In dieser Arbeit konnte ich an P. berghei zeigen, dass beide Untereinheiten unterschiedliche vitale Zellfunktionen erfüllen. PbCP ist essentiell für die Proliferation in erythrozytären Stadien. Diese Funktion kann in vollem Umfang durch heterologes P. falciparum CP übernommen werden, ist aber untrennbar mit der Funktion des actinbindenden C-Terminus verknüpft. Möglicherweise moduliert CP Actin auch außerhalb des Parasiten, wie die unerwartete Lokalisierung andeutete. Die P. berghei CP erfüllt indes eine vitale Rolle für die Motilität von Parasitenstadien im Anopheles Vektor. Bereits cp(-) Ookineten sind nur eingeschränkt motil, was deren Infektivität drastisch herabsetzt. In cp(-) Sporozoiten manifestiert sich dieser Phänotyp weiter: sie sind nicht mehr zu produktiver Lokomotion in der Lage. Die Mehrzahl der Parasiten bleibt mit dem Mitteldarm assoziiert und eine Invasion der Speicheldrüsen findet nicht statt. cp(-) Sporozoiten sind damit auch nicht mehr infektiös für den Wirbeltierwirt. Eine vollständige Unterbrechung des Lebenszyklus ist die Folge. Auf andere Entwicklungsprozesse des Parasiten, u.a. Schizogonie, Gametogonie und Sporogonie, wirkte sich das Fehlen von PbCP jedoch nicht negativ aus. Meine genetische Analyse konnte damit den Erstnachweis für getrennte zelluläre Funktionen der P. berghei CP Untereinheiten liefern. Ich konnte diesen Befund in Actin-Polymerisationsversuchen mit den individuellen, aufgereinigten Untereinheiten belegen. Damit ist P. berghei CP das erste beschriebene capping protein, bei dem eine funktionelle Trennung der beiden Untereinheiten stattfand. Meine genetischen und biochemischen Daten stützen die These, dass die beiden P. berghei CP Untereinheiten ihre essentiellen Funktionen im Malaria-Parasiten als Homodimere erfüllen

Los números

128 páginas.La teoría de los números ocupa un peculiar y distinguido lugar entre las diversas ramas de las matemáticas. Que su objetivo principal sea el estudio de algo tan conocido y familiar como son los enteros, sus propiedades y sus relaciones, explica el interés que ha suscitado siempre entre muchos ciudadanos, quienes, aun careciendo de la formación matemática apropiada, se sienten fascinados por sus problemas, tan fáciles de enunciar y, sin embargo, tan difíciles a veces de resolver. Este libro no pretende ser, ni mucho menos, un tratado de la teoría de los números, sino tan sólo un vehículo que permita al lector pasear por algunos de sus parajes más asequibles. Una especie de guía turística para aritméticos aficionados y para todos aquellos que tengan curiosidad acerca de las propiedades de los números y aprecien el arte de engarzar las ideas que conlleva todo razonamiento matemático.Peer reviewe

Indications and Outcomes of Patients Receiving Therapeutic Plasma Exchange under Critical Care Conditions: A Retrospective Eleven-Year Single-Center Study at a Tertiary Care Center

Background: Therapeutic plasma exchange (TPE) is frequently performed in critical care settings for heterogenous indications. However, specific intensive care unit (ICU) data regarding TPE indications, patient characteristics and technical details are sparse. Methods: We performed a retrospective, single-center study using data from January 2010 until August 2021 for patients treated with TPE in an ICU setting at the University Hospital Zurich. Data collected included patient characteristics and outcomes, ICU-specific parameters, as well as apheresis-specific technical parameters and complications. Results: We identified n = 105 patients receiving n = 408 TPEs for n = 24 indications during the study period. The most common was thrombotic microangiopathies (TMA) (38%), transplant-associated complications (16.3%) and vasculitis (14%). One-third of indications (35.2%) could not be classified according to ASFA. Anaphylaxis was the most common TPE-related complication (6.7%), while bleeding complications were rare (1%). The median duration of ICU stay was 8 ± 14 days. Ventilator support, renal replacement therapy or vasopressors were required in 59 (56.2%), 26 (24.8%), and 35 (33.3%) patients, respectively, and 6 (5.7%) patients required extracorporeal membrane oxygenation. The overall hospital survival rate was 88.6%. Conclusion: Our study provides valuable real-world data on heterogenous TPE indications for patients in the ICU setting, potentially supporting decision-making

A Plasmodium falciparum Histone Deacetylase Regulates Antigenic Variation and Gametocyte Conversion

SummaryThe asexual forms of the malaria parasite Plasmodium falciparum are adapted for chronic persistence in human red blood cells, continuously evading host immunity using epigenetically regulated antigenic variation of virulence-associated genes. Parasite survival on a population level also requires differentiation into sexual forms, an obligatory step for further human transmission. We reveal that the essential nuclear gene, P. falciparum histone deacetylase 2 (PfHda2), is a global silencer of virulence gene expression and controls the frequency of switching from the asexual cycle to sexual development. PfHda2 depletion leads to dysregulated expression of both virulence-associated var genes and PfAP2-g, a transcription factor controlling sexual conversion, and is accompanied by increases in gametocytogenesis. Mathematical modeling further indicates that PfHda2 has likely evolved to optimize the parasite’s infectious period by achieving low frequencies of virulence gene expression switching and sexual conversion. This common regulation of cellular transcriptional programs mechanistically links parasite transmissibility and virulence

NT-proBNP or Self-Reported Functional Capacity in Estimating Risk of Cardiovascular Events After Noncardiac Surgery

ImportanceNearly 16 million surgical procedures are conducted in North America yearly, and postoperative cardiovascular events are frequent. Guidelines suggest functional capacity or B-type natriuretic peptides (BNP) to guide perioperative management. Data comparing the performance of these approaches are scarce.ObjectiveTo compare the addition of either N-terminal pro-BNP (NT-proBNP) or self-reported functional capacity to clinical scores to estimate the risk of major adverse cardiac events (MACE).Design, Setting, and ParticipantsThis cohort study included patients undergoing inpatient, elective, noncardiac surgery at 25 tertiary care hospitals in Europe between June 2017 and April 2020. Analysis was conducted in January 2023. Eligible patients were either aged 45 years or older with a Revised Cardiac Risk Index (RCRI) of 2 or higher or a National Surgical Quality Improvement Program, Risk Calculator for Myocardial Infarction and Cardiac (NSQIP MICA) above 1%, or they were aged 65 years or older and underwent intermediate or high-risk procedures.ExposuresPreoperative NT-proBNP and the following self-reported measures of functional capacity were the exposures: (1) questionnaire-estimated metabolic equivalents (METs), (2) ability to climb 1 floor, and (3) level of regular physical activity.Main Outcome and MeasuresMACE was defined as a composite end point of in-hospital cardiovascular mortality, cardiac arrest, myocardial infarction, stroke, and congestive heart failure requiring transfer to a higher unit of care.ResultsA total of 3731 eligible patients undergoing noncardiac surgery were analyzed; 3597 patients had complete data (1258 women [35.0%]; 1463 (40.7%) aged 75 years or older; 86 [2.4%] experienced a MACE). Discrimination of NT-proBNP or functional capacity measures added to clinical scores did not significantly differ (Area under the receiver operating curve: RCRI, age, and 4MET, 0.704; 95% CI, 0.646-0.763; RCRI, age, and 4MET plus floor climbing, 0.702; 95% CI, 0.645-0.760; RCRI, age, and 4MET plus physical activity, 0.724; 95% CI, 0.672-0.775; RCRI, age, and 4MET plus NT-proBNP, 0.736; 95% CI, 0.682-0.790). Benefit analysis favored NT-proBNP at a threshold of 5% or below, ie, if true positives were valued 20 times or more compared with false positives. The findings were similar for NSQIP MICA as baseline clinical scores.Conclusions and relevanceIn this cohort study of nearly 3600 patients with elevated cardiovascular risk undergoing noncardiac surgery, there was no conclusive evidence of a difference between a NT-proBNP–based and a self-reported functional capacity–based estimate of MACE risk.Trial RegistrationClinicalTrials.gov Identifier: NCT0301693

Free backbone carbonyls mediate rhodopsin activation

Conserved prolines in the transmembrane helices of G-protein-coupled receptors (GPCRs) are often considered to function as hinges that divide the helix into two segments capable of independent motion. Depending on their potential to hydrogen-bond, the free C=O groups associated with these prolines can facilitate conformational flexibility, conformational switching or stabilization of the receptor structure. To address the role of conserved prolines in family A GPCRs through solid-state NMR spectroscopy, we focus on bovine rhodopsin, a GPCR in the visual receptor subfamily. The free backbone C=O groups on helices H5 and H7 stabilize the inactive rhodopsin structure through hydrogen-bonds to residues on adjacent helices. In response to light-induced isomerization of the retinal chromophore, hydrogen-bonding interactions involving these C=O groups are released, thus facilitating repacking of H5 and H7 onto the transmembrane core of the receptor. These results provide insights into the multiple structural and functional roles of prolines in membrane proteins

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

State of the climate in 2018

In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and $25 billion (U.S. dollars) in damages. In the western North Pacific, Super Typhoon Mangkhut led to 160 fatalities and$6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)