Showing papers by "Free University of Berlin published in 2000"

Complex Phenotype of Mice Lacking Occludin, a Component of Tight Junction Strands

Abstract: Occludin is an integral membrane protein with four transmembrane domains that is exclusively localized at tight junction (TJ) strands. Here, we describe the generation and analysis of mice carrying a null mutation in the occludin gene. Occludin -/- mice were born with no gross phenotype in the expected Mendelian ratios, but they showed significant postnatal growth retardation. Occludin -/- males produced no litters with wild-type females, whereas occludin -/- females produced litters normally when mated with wild-type males but did not suckle them. In occludin -/- mice, TJs themselves did not appear to be affected morphologically, and the barrier function of intestinal epithelium was normal as far as examined electrophysiologically. However, histological abnormalities were found in several tissues, i.e., chronic inflammation and hyperplasia of the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in striated duct cells of the salivary gland, and thinning of the compact bone. These phenotypes suggested that the functions of TJs as well as occludin are more complex than previously supposed.

OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.

Abstract: Ca2+-permeable channels that are involved in the responses of mammalian cells to changes in extracellular osmolarity have not been characterized at the molecular level. Here we identify a new TRP (transient receptor potential)-like channel protein, OTRPC4, that is expressed at high levels in the kidney, liver and heart. OTRPC4 forms Ca2+-permeable, nonselective cation channels that exhibit spontaneous activity in isotonic media and are rapidly activated by decreases in, and are inhibited by increases in, extracellular osmolarity. Changes in osmolarity of as little as 10% result in significant changes in intracellular Ca2+ concentration. We propose that OTRPC4 is a candidate for a molecular sensor that confers osmosensitivity on mammalian cells.

Modeling the dynamics of strategic fit: a normative approach to strategic change

Abstract: This study develops and tests a dynamic perspective on strategic fit. Drawing from contingency and resource-based arguments in the strategy and organizational theory literatures, we propose a distinctive analytical approach to identify environmental and organizational contingencies that should predict changes in a firm's strategy and the performance implications of such changes. We test our model using extensive longitudinal data from over 4000 U.S. savings and loan institutions during a period when many S&Ls considered changing strategic direction. The findings support our model of dynamic strategic fit. Specifically, we find that (1) the timing, direction, and magnitude of strategic changes can be logically predicted based on differences in specific environmental forces and organizational resources, and (2) organizations that deviated from our model's prediction of dynamic strategic fit (i.e., changed more or changed less than our model prescribed) experienced negative performance consequences. We conclude by discussing the implications of our approach and findings for future research on strategic fit and strategic change. Copyright © 2000 John Wiley & Sons, Ltd.

The endothelial surface layer.

Abstract: The endothelial lining of blood vessels presents a large surface area for exchange of materials between blood and tissues, and is critically involved in many other processes such as regulation of blood flow, inflammatory responses and blood coagulation. It has long been known that the luminal surface of the endothelium is lined with a glycocalyx, a layer of membrane-bound macromolecules which has been determined by electron microscopy to be several tens of nanometers thick. However, investigations in vivo have indicated the presence of a much thicker endothelial surface layer (ESL), with an estimated thickness ranging from 0.5 µm to over 1 µm, that restricts the flow of plasma and can exclude red blood cells and some macromolecular solutes. The evidence for the existence of the ESL, hypotheses about its composition and biophysical properties, its relevance to physiological processes, and its possible clinical implications are considered in this review.

Fractional calculus and continuous-time finance

Abstract: In this paper we present a rather general phenomenological theory of tick-by-tick dynamics in financial markets Many well-known aspects, such as the Levy scaling form, follow as particular cases of the theory The theory fully takes into account the non-Markovian and non-local character of financial time series Predictions on the long-time behaviour of the waiting-time probability density are presented Finally, a general scaling form is given, based on the solution of the fractional diffusion equation

Inducing all steps of a chemical reaction with the scanning tunneling microscope tip: towards single molecule engineering

Abstract: All elementary steps of a chemical reaction have been successfully induced on individual molecules with a scanning tunneling microscope (STM) in a controlled step-by-step manner utilizing a variety of manipulation techniques. The reaction steps involve the separation of iodine from iodobenzene by using tunneling electrons, bringing together two resultant phenyls mechanically by lateral manipulation and, finally, their chemical association to form a biphenyl molecule mediated by excitation with tunneling electrons. The procedures presented here constitute an important step towards the assembly of individual molecules out of simple building blocks in situ on the atomic scale.

Dendronized Polymers: Synthesis, Characterization, Assembly at Interfaces, and Manipulation

Abstract: Dendrimers are presently one of the most intensely studied classes of compounds because of their unusual structure. They can be described as a jungle of entangled branches traversed by winding trails which lead to sweet fruits and bright blossoms. On these trails one can reach the thicket's interior as well as find a way out. Expressed less lyrically, this thicket stands for regularly branched, densely packed structures, and the trails represent voids and channels not filled by bent back branches but by solvent. The fruit and blossoms are photochemically, electrochemically, or synthetically addressable units, catalytically active sites, etc., and the back and forth on the trails stands for transport processes. In a mathematical sense dendrimers are enveloped by an interface, which defines what is either in or out. This interface is shaped like a sphere if the trails are filled to bursting. Otherwise dendrimers are more flattened like amoeba, especially if in contact with a surface. The high density of the functional groups, the expansion of these compounds to a range of several nanometers, the existence of usable "surface" and transport possibilities in and with them have made dendrimers interesting candidates for many applications. This review describes how dendrimer construction and polymer synthesis were combined and used to move from fully or flattened spherical shapes to cylindrical ones. The shape-inducing influence of dendritic substituents can be driven to create nanoobjects with a cylindrical shape, which not only considerably widens the range of applications for the dendrimer class but also opens up new perspectives for supramolecular and polymer chemistry. Because of the sheer size of the described objects and complexity of shape-related properties, research in this area must necessarily be interdisciplinary. This article tries to mirror this by giving special attention not only to synthesis but also the characterization and behavior of these compounds in bulk and at interfaces. Furthermore, potential application fields are described.

When inverted faces are recognized: the role of configural information in face recognition.

Abstract: The identification of upright faces seems to involve a special sensitivity to “configural” information, the processing of which is less effective when the face is inverted. However the precise meaning of “configural” remains unclear. Five experiments are presented, which showed that the disruption of the processing of relational, rather than holistic, information largely determines the occurrence as well as the size of the face-inversion effect. In Experiment 1, faces could be identified either by unique combinations of local information (e.g. a specific eye colour plus hair colour) or by unique relational information (e.g. nose-mouth distance). The former showed no inversion effect, whereas the latter did. A combination of local and relational information (Experiment 2) again produced an inversion effect, although this effect was smaller than that found when only relational information was used. The results were replicated in Experiment 3 when differences in the brightness of local features were used ins...

Successful treatment of active ankylosing spondylitis with the anti–tumor necrosis factor α monoclonal antibody infliximab

Abstract: Objective Tumor necrosis factor α (TNFα) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFα monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS). Methods Eleven patients with AS of short duration (median 5 years, range 0.5–13 years) that had been active for at least 3 months (range 3–72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted >1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients. Results One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2–6 weeks after the third infusion revealed improvement in 2. Improvement of ≥50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41–94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6–90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0–28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts. Conclusion These data suggest that anti-TNFα therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.

Acute physiological effects of exhaustive whole‐body vibration exercise in man

Abstract: Summary Vibration exercise (VE) is a new neuromuscular training method which is applied in athletes as well as in prevention and therapy of osteoporosis. The present study explored the physiological mechanisms of fatigue by VE in 37 young healthy subjects. Exercise and cardiovascular data were compared to progressive bicycle ergometry until exhaustion. VE was performed in two sessions, with a 26 Hz vibration on a ground plate, in combination with squatting plus additional load (40% of body weight). After VE, subjectively perceived exertion on Borg’s scale was 18, and thus as high as after bicycle ergometry. Heart rate after VE increased to 128 min ‐1 , blood pressure to 132/ 52 mmHg, and lactate to 3AE 5m M. Oxygen uptake in VE was 48AE8% of VO2max in bicycle ergometry. After VE, voluntary force in knee extension was reduced by 9AE2%, jump height by 9AE1%, and the decrease of EMG median frequency during maximal voluntary contraction was attenuated. The reproducibility in the two VE sessions was quite good: for heart rate, oxygen uptake and reduction in jump height, correlation coefficients of values from session 1 and from session 2 were between 0AE67 and 0AE7. Thus, VE can be well controlled in terms of these parameters. Surprisingly, an itching erythema was found in about half of the individuals, and an increase in cutaneous blood flow. It follows that exhaustive whole-body VE elicits a mild cardiovascular exertion, and that neural as well as muscular mechanisms of fatigue may play a role.

High constitutive activity of native H3 receptors regulates histamine neurons in brain.

Abstract: Some G-protein-coupled receptors display ‘constitutive activity’, that is, spontaneous activity in the absence of agonist1,2,3,4. This means that a proportion of the receptor population spontaneously undergoes an allosteric transition, leading to a conformation that can bind G proteins3. The process has been shown to occur with recombinant receptors expressed at high density, and/or mutated, but also non-mutated recombinant receptors expressed at physiological concentrations5,6,7. Transgenic mice that express a constitutively active mutant of the β 2-adrenergic receptor display cardiac anomalies8; and spontaneous receptor mutations leading to constitutive activity are at the origin of some human diseases9,10. Nevertheless, this process has not previously been found to occur in animals expressing normal levels of receptor3,4. Here we show that two isoforms of the recombinant rat H3 receptor11,12 display high constitutive activity. Using drugs that abrogate this activity (‘inverse agonists’) and a drug that opposes both agonists and inverse agonists (‘neutral antagonist’), we show that constitutive activity of native H3 receptors is present in rodent brain and that it controls histaminergic neuron activity in vivo . Inverse agonists may therefore find therapeutic applications, even in the case of diseases involving non-mutated receptors expressed at normal levels.

Fractional calculus and continuous-time finance II: the waiting-time distribution

Abstract: We complement the theory of tick-by-tick dynamics of financial markets based on a continuous-time random walk (CTRW) model recently proposed by Scalas et al [4], and we point out its consistency with the behaviour observed in the waiting-time distribution for BUND future prices traded at LIFFE, London.

Physiology and Pathophysiology of the Adipose Tissue Renin-Angiotensin System

Abstract: The renin-angiotensin system has long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis, and local renin-angiotensin systems have also been implicated in pathological changes of organ structure and function by modulation of gene expression, growth, fibrosis, and inflammatory response. Recently, substantial data have been accumulated in support of the notion that adipose tissue, besides other endocrine functions, also hosts a local renin-angiotensin system. In the first part of this review, we describe the components of the adipose tissue renin-angiotensin system in human and rodent animal models with respect to regulation of angiotensinogen expression and secretion, formation of angiotensin peptides, and the existence of angiotensin II receptors. In the second part, we describe the role of the adipose tissue renin-angiotensin system in the process of adipogenic differentiation and in the regulation of body weight. We also detail the differential regulation of the adipose tissue renin-angiotensin system in obesity and hypertension and thereby also speculate on its possible role in the development of obesity-associated hypertension. Although some findings on the adipose tissue renin-angiotensin system appear to be confusing, its involvement in the physiology and pathophysiology of adipose tissue has been confirmed by several functional studies. Nevertheless, future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest.

Structural basis of gene regulation by the tetracycline inducible Tet repressor-operator system.

Abstract: The tetracycline repressor (TetR) regulates the most abundant resistance mechanism against the antibiotic tetracycline in grain-negative bacteria. The TetR protein and its mutants are commonly used as control elements to regulate gene expression in higher eukaryotes. We present the crystal structure of the TetR homodimer in complex with its palindromic DNA operator at 2.5 A resolution. Comparison to the structure of TetR in complex with the inducer tetracycline-Mg2+ allows the mechanism of induction to be deduced. Inducer binding in the repressor core initiates conformational changes starting with C-terminal unwinding and shifting of the short helix a6 in each monomer. This forces a pendulum-like motion of helix a4, which increases the separation of the attached DNA binding domains by 3 A, abolishing the affinity of TetR for its operator DNA.

Central Bank Independence: An Update of Theory and Evidence

Abstract: This paper reviews recent research on central bank independence (CBI). After we have distinguished between independence and conservativeness, the literature on optimal inflation contracts is discussed, followed by research in which the inflationary bias is endogenised. Finally, the various challenges that have been raised against previous empirical findings on CBI are reviewed. We conclude that the negative relationship between CBI and inflation is quite robust.

A mechanized gait trainer for restoration of gait.

Abstract: The newly developed gait trainer allows wheel-chair-bound subjects the repetitive practice of a gait-like movement without overstressing therapists. The device simulates the phases of gait, supports the subjects according to their abilities, and controls the center of mass (CoM) in the vertical and horizontal directions. The patterns of sagittal lower limb joint kinematics and of muscle activation for a normal subject were similar when using the mechanized trainer and when walking on a treadmill. A non-ambulatory hemiparetic subject required little help from one therapist on the gait trainer, while two therapists were required to support treadmill walking. Gait movements on the trainer were highly symmetrical, impact free, and less spastic. The vertical displacement of the CoM was bi-phasic instead of mono-phasic during each gait cycle on the new device. Two cases of non-ambulatory patients, who regained their walking ability after 4 weeks of daily training on the gait trainer, are reported.