Unraveling structural and functional features of secondary transport proteins

Although xylosides are abundant in nature, knowledge about xyloside transporters is scarce. Recently, it has been shown that the xyloside isoprimeverose is the natural substrate of the XyIP protein of Lactobacillus pentosus, a secondary transport protein belonging to the GPH-family of major facilitators. To characterize this transport protein in more detail, a number of hurdles had to be taken, that is, the substrate had to be synthesized, a transport assay had to be developed and the protein had to be incorporated into an artificial membrane system. ... Zie: Chapter

Current Perspectives on Synthetic Compartments for Biomedical Applications

Nano- and micrometer-sized compartments composed of synthetic polymers are designed to mimic spatial and temporal divisions found in nature. Self-assembly of polymers into compartments such as polymersomes, giant unilamellar vesicles (GUVs), layer-by-layer (LbL) capsules, capsosomes, or polyion complex vesicles (PICsomes) allows for the separation of defined environments from the exterior. These compartments can be further engineered through the incorporation of (bio)molecules within the lumen or into the membrane, while the membrane can be decorated with functional moieties to produce catalytic compartments with defined structures and functions. Nanometer-sized compartments are used for imaging, theranostic, and therapeutic applications as a more mechanically stable alternative to liposomes, and through the encapsulation of catalytic molecules, i.e., enzymes, catalytic compartments can localize and act in vivo. On the micrometer scale, such biohybrid systems are used to encapsulate model proteins and form multicompartmentalized structures through the combination of multiple compartments, reaching closer to the creation of artificial organelles and cells. Significant progress in therapeutic applications and modeling strategies has been achieved through both the creation of polymers with tailored properties and functionalizations and novel techniques for their assembly

Hepcidin Is an Antibacterial, Stress-Inducible Peptide of the Biliary System

BACKGROUND/AIMS: Hepcidin (gene name HAMP), an IL-6-inducible acute phase peptide with antimicrobial properties, is the key negative regulator of iron metabolism. Liver is the primary source of HAMP synthesis, but it is also produced by other tissues such as kidney or heart and is found in body fluids such as urine or cerebrospinal fluid. While the role of hepcidin in biliary system is unknown, a recent study demonstrated that conditional gp130-knockout mice display diminished hepcidin levels and increased rate of biliary infections. METHODS: Expression and localization of HAMP in biliary system was analyzed by real time RT-PCR, in-situ hybridization, immunostaining and -blotting, while prohepcidin levels in human bile were determined by ELISA. RESULTS: Hepcidin was detected in mouse/human gallbladder and bile duct epithelia. Biliary HAMP is stress-inducible, in that it is increased in biliary cell lines upon IL-6 stimulation and in gallbladder mucosa of patients with acute cholecystitis. Hepcidin is also present in the bile and elevated prohepcidin levels were observed in bile of primary sclerosing cholangitis (PSC) patients with concurrent bacterial cholangitis compared to PSC subjects without bacterial infection (median values 22.3 vs. 8.9; p = 0.03). In PSC-cholangitis subjects, bile prohepcidin levels positively correlated with C-reactive protein and bilirubin levels (r = 0.48 and r = 0.71, respectively). In vitro, hepcidin enhanced the antimicrobial capacity of human bile (p<0.05). CONCLUSION: Hepcidin is a stress-inducible peptide of the biliary epithelia and a potential marker of biliary stress. In the bile, hepcidin may serve local functions such as protection from bacterial infections

Usability of the Video Head Impulse Test: Lessons From the Population-Based Prospective KORA Study

Objective: The video head impulse test (vHIT) has become a common examination in the work-up for dizziness and vertigo. However, recent studies suggest a number of pitfalls, which seem to reduce vHIT usability. Within the framework of a population-based prospective study with naïve examiners, we investigated the relevance of previously described technical mistakes in vHIT testing, and the effect of experience and training.Methods: Data originates from the KORA (Cooperative Health Research in the Region of Augsburg) FF4 study, the second follow-up of the KORA S4 population-based health survey. 681 participants were selected in a case-control design. Three examiners without any prior experience were trained in video head impulse testing. VHIT quality was assessed weekly by an experienced neuro-otologist. Restrictive mistakes (insufficient technical quality restricting interpretation) were noted. Based on these results, examiners received further individual training.Results: Twenty-two of the 681 vHITs (3.2%) were not interpretable due to restrictive mistakes. Restrictive mistakes could be grouped into four categories: slippage, i.e., goggle movement relative to the head (63.6%), calibration problems (18.2%), noise (13.6%), and low velocity of the head impulse (4.6%). The overall rate of restrictive mistakes decreased significantly during the study (12% / examiner within the first 25 tested participants and 2.1% during the rest of the examinations, p &lt; 0.0001).Conclusion: Few categories suffice to explain restrictive mistakes in vHIT testing. With slippage being most important, trainers should emphasize the importance of tight goggles. Experience and training seem to be effective in improving vHIT quality, leading to high usability

Prevalence, Determinants, and Consequences of Vestibular Hypofunction. Results From the KORA-FF4 Survey

Objective: Uni- or bilateral vestibular hypofunction (VH) impairs balance and mobility, and may specifically lead to injury from falls and to disability. The extent of this problem in the general population is still unknown and most likely to be underestimated. Objective of this study was to determine the prevalence, determinants, and consequences of VH in the general population.Methods: Data originates from the cross-sectional second follow-up (FF4) in 2013/14 of the KORA (Cooperative Health Research in the Region of Augsburg)-S4 study (1999–2001) from Southern Germany. This was a random sample of the target population consisting of all residents of the region aged 25–74 years in 1999. We included all participants who reported moderate or severe vertigo or dizziness during the last 12 months and a random sub-sample of participants representative for the general population without vertigo or dizziness during the last 12 months were tested. VH was assessed with the Video-Head Impulse Test (vHIT). Trained examiners applied high-acceleration, small-amplitude passive head rotations (“head impulses”) to the left and right in the plane of the horizontal semicircular canals while participants fixated a target straight ahead. During head impulses, head movements were measured with inertial sensors, eye movements with video-oculography (EyeSeeCam vHIT).Results: A total of 2,279 participants were included (mean age 60.8 years, 51.6% female), 570 (25.0%) with moderate or severe vertigo or dizziness during the last 12 months. Of these, 450 were assessed with vHIT where 26 (5.8%) had unilateral VH, and 16 (3.6%) had bilateral VH. Likewise, 190 asymptomatic participants were tested. Of these 5 (2.6%) had unilateral VH, and 2 (1.1%) had bilateral VH. Prevalence of uni- or bilateral VH among tested symptomatic participants was 2.4% in those &lt; 48 years, and 32.1% in individuals aged 79 and over. Age-adjusted prevalence was 6.7% (95% CI 4.8%; 8.6%). VH was associated with worse health, falls, hearing loss, hearing impairment, and ear pressure.Conclusion: VH may affect between 53 and 95 million adults in Europe and the US. While not all affected persons will experience the full spectrum of symptoms and consequences, adequate diagnostic and therapeutic measures should become standard of care to decrease the burden of disease

Preventing opioid-induced nausea and vomiting: Rest your head and close your eyes?

Although opioid-induced nausea and vomiting (OINV) is common and debilitating, its mechanism is still unclear. Recently, we suggested that opioids affect semicircular canal function and that this leads to a mismatch between canal input and other sensory information during head motion, which triggers OINV. Here, we assess if visual input is relevant for this mismatch. In a randomized-controlled crossover study 14 healthy men (26.9 +/- 3.4 years, mean +/- SD) were tested twice, once blindfolded and once with eyes open, with at least one-day washout. The opioid remifentanil was administered intravenously (0.15 mu g/kg/min) for 60 minutes. After a thirty-minutes resting period, subjects' head and trunk were passively moved. Nausea was rated before remifentanil start (T-0), before the movement intervention (T-30) and after 60 minutes (T-60) of administration. At rest (T-0, T-30), median nausea ratings were zero whether subjects were blindfolded or not. Movement triggered nausea independently of visual input (nausea rating 1.5/3.0 (median/interquartile range) in the blindfolded, 2.5/6 in the eyes-open condition, chi(2) (1) = 1.3, p = 0.25). As movement exacerbates OINV independently of visual input, a clash between visual and semicircular canal information is not the relevant trigger for OINV. To prevent OINV, emphasis should be put on head-rest, eye-closure is less important

Prognostische Bedeutung von TP53-Mutationen beim Mantelzell-Lymphom

Das Mantelzell-Lymphom (MCL) ist eine klinisch heterogene Erkrankung. Eine Mutation des TP53-Gens (lokalisiert auf 17p13.1) gilt als negativer Prognoseparameter, wurde aber bislang noch nicht in einem multivariaten Modell bestätigt. Die Auswirkung einer 17p13-Deletion auf das Gesamtüberleben ist umstritten. In der vorliegenden Dissertation wird die prognostische Bedeutung von TP53-Mutationen und 17p13-Deletionen beim MCL untersucht und differenziert. Bei 108 MCL-Patienten wurde durch DHPLC-Analyse nach TP53-Mutationen gesucht (Exon 4-10) und diese durch direkte Sequenzierung bestätigt. Chromosomale Aberrationen wurden mittels FISH- oder MCGH-Analyse untersucht. Eine TP53-Mutation zeigen 25 % der Patienten, eine 17p13-Deletion tritt bei 19 % auf. Das mittlere Gesamtüberleben sowie das Ansprechen auf Therapie (komplette sowie partielle Remission) sind in der Gruppe mit TP53-Mutation reduziert (32,0 vs. 61,4 Monate; p<0,001 und 39 % vs. 77 %; p<0,05). In einem multivariaten Modell mit anderen chromosomalen Aberrationen zeigt sich ein Trend für die TP53-Mutation als unabhängiger Prognosefaktor (p=0,06). 17p13-Deletionen sind nicht signifikant mit dem Gesamtüberleben assoziiert. Auch die Differenzierung in alleinige TP53-Mutationen (n=11) und alleinige 17p13-Deletionen (n=7) zeigt nur für erstere ein geringeres Gesamtüberleben im Vergleich zu Patienten ohne TP53-Aberrationen (n=41; p<0,05). Weitere chromosomale Aberrationen, die das Gesamtüberleben verkürzen, sind eine 9p21-Deletion und eine 13q14-Deletion (36,1 vs. 53,2 Monate; p<0,05 und 37,1 vs. 61,4 Monate; p<0,05). Interessanterweise korrelieren diese beiden Aberrationen untereinander sowie mit TP53-Mutationen (jeweils p<0,05), nicht aber mit 17p13-Deletionen. Insgesamt zeigt sich ein eindeutiger Trend für die TP53-Mutation als unabhängiger Prognosefaktor und sie kann zur 17p13-Deletion bezüglich der Prognoserelevanz sowie der Assoziation mit anderen chromosomalen Aberrationen differenziert werden

Minimality of the Hamming Weight of the τ-NAF for Koblitz Curves and Improved Combination with Point Halving

Abstract. In order to efficiently perform scalar multiplications on elliptic Koblitz curves, expansions of the scalar to a complex base associated with the Frobenius endomorphism are commonly used. One such expansion is the τ-adic NAF, introduced by Solinas. Some properties of this expansion, such as the average weight, are well known, but in the literature there is no proof of its optimality, i.e. that it always has minimal weight. In this paper we provide the first proof of this fact. Point halving, being faster than doubling, is also used to perform fast scalar multiplications on generic elliptic curves over binary fields. Since its computation is more expensive than that of the Frobenius, halving was thought to be uninteresting for Koblitz curves. At PKC 2004, Avanzi, Ciet, and Sica combined Frobenius operations with one point halving to compute scalar multiplications on Koblitz curves using on average 14 % less group additions than with the usual τ-and-add method without increasing memory usage. The second result of this paper is an improvement over their expansion. The new representation, called the widedouble-NAF, is not only simpler to compute, but it is also optimal in a suitable sense. In fact, it has minimal Hamming weight among all τ-adic expansions with digits {0, ±1} that allow one halving to be inserted in the corresponding scalar multiplication algorithm. The resulting scalar multiplication requires on average 25 % less group operations than th