Foraminiferan tests and dasycladalean thalli as cryptic microhabitats for thaumatoporellacean algae from Mesozoic (Late Triassic–Late Cretaceous) platform carbonates

Thaumatoporellacean algae are widespread constituents in Middle Triassic–Cretaceous shallow-marine carbonates of the Tethyan realm. Based on various examples from Mesozoic limestones of Mediterranean platforms (e.g., Dinaric, Apenninic, Apulia) and rare records of Iberia (Pyrenees), Saudi Arabia and Mexico, it is shown that thaumatoporellaceans commonly dwelt as cryptoendoliths in the tests of larger benthic foraminifera and the thalli of dasycladalean algae. Their high morphological plasticity allowed the test invasion and the adaptation to the available interior spaces (chambers, apertures). The temporal distribution of cryptoendolithic thaumatoporellaceans with first records in the Late Triassic, shows acme intervals in Early–Middle Jurassic and Early–Late Cretaceous times. Within the foraminiferans, the thaumatoporellaceans were erroneously considered as an integral part of the test, respectively, phrenoteca-like structures (species Biokovina gradacensis) in the Lower Jurassic and trematophore (species Scandonea? mediterranea) in the Upper Cretaceous. Therefore, the presence of phrenoteca-like structures in the Biokovinidae, being part of the family diagnosis, is challenged. The comparably thin walls of the cryptoendolithic thaumatoporellacean algae are interpreted as an adaptation to the poorly illuminated microhabitats (photoadaptation) in order to maximize light capture for photosynthesis.     

Structural insights into the neutralization mechanism of a higher primate antibody against dengue virus

The four serotypes of dengue virus (DENV-1 to -4) cause the most important emerging viral disease. Protein E, the principal viral envelope glycoprotein, mediates fusion of the viral and endosomal membranes during virus entry and is the target of neutralizing antibodies. However, the epitopes of strongly neutralizing human antibodies have not been described despite their importance to vaccine development. The chimpanzee Mab 5H2 potently neutralizes DENV-4 by binding to domain I of E. The crystal structure of Fab 5H2 bound to E from DENV-4 shows that antibody binding prevents formation of the fusogenic hairpin conformation of E, which together with in-vitro assays, demonstrates that 5H2 neutralizes by blocking membrane fusion in the endosome. Furthermore, we show that human sera from patients recovering from DENV-4 infection contain antibodies that bind to the 5H2 epitope region on domain I. This study, thus, provides new information and tools for effective vaccine design to prevent dengue disease.     

Familial hemiplegic migraine type 1 mutations W1684R and V1696I alter G protein-mediated regulation of CaV2.1 voltage-gated calcium channels

Familial hemiplegic migraine type 1 (FHM-1) is a monogenic form of migraine with aura that is characterized by recurrent attacks of a typical migraine headache with transient hemiparesis during the aura phase. In a subset of patients, additional symptoms such as epilepsy and cerebellar ataxia are part of the clinical phenotype. FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the pore-forming subunit of Ca_V2.1 voltage-gated Ca^2 + channels. Although the functional effects of an increasing number of FHM-1 mutations have been characterized, knowledge on the influence of most of these mutations on G protein regulation of channel function is lacking. Here, we explored the effects of G protein-dependent modulation on mutations W1684R and V1696I which cause FHM-1 with and without cerebellar ataxia, respectively. Both mutations were introduced into the human Ca_V2.1α₁ subunit and their functional consequences investigated after heterologous expression in human embryonic kidney 293 (HEK‐293) cells using patch-clamp recordings. When co-expressed along with the human μ-opioid receptor, application of the agonist [d‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin (DAMGO) inhibited currents through both wild-type (WT) and mutant Ca_V2.1 channels, which is consistent with the known modulation of these channels by G protein-coupled receptors. Prepulse facilitation, which is a way to characterize the relief of direct voltage-dependent G protein regulation, was reduced by both FHM-1 mutations. Moreover, the kinetic analysis of the onset and decay of facilitation showed that the W1684R and V1696I mutations affect the apparent dissociation and reassociation rates of the Gβγ dimer from the channel complex, suggesting that the G protein-Ca^2 + channel affinity may be altered by the mutations. These biophysical studies may shed new light on the pathophysiology underlying FHM-1.     

A catalytic defect in mitochondrial respiratory chain complex I due to a mutation in NDUFS2 in a patient with Leigh syndrome

In this study, we investigated the pathogenicity of a homozygous Asp446Asn mutation in the NDUFS2 gene of a patient with a mitochondrial respiratory chain complex I deficiency. The clinical, biochemical, and genetic features of the NDUFS2 patient were compared with those of 4 patients with previously identified NDUFS2 mutations. All 5 patients presented with Leigh syndrome. In addition, 3 out of 5 showed hypertrophic cardiomyopathy. Complex I amounts in the patient carrying the Asp446Asn mutation were normal, while the complex I activity was strongly reduced, showing that the NDUFS2 mutation affects complex I enzymatic function. By contrast, the 4 other NDUFS2 patients showed both a reduced amount and activity of complex I. The enzymatic defect in fibroblasts of the patient carrying the Asp446Asn mutation was rescued by transduction of wild type NDUFS2. A 3-D model of the catalytic core of complex I showed that the mutated amino acid residue resides near the coenzyme Q binding pocket. However, the K_M of complex I for coenzyme Q analogs of the Asp446Asn mutated complex I was similar to the K_M observed in other complex I defects and in controls. We propose that the mutation interferes with the reduction of coenzyme Q or with the coupling of coenzyme Q reduction with the conformational changes involved in proton pumping of complex I.     

Elastic properties of an intact and ACL-ruptured knee joint: measurement, mathematical modelling, and haptic rendering

An analytical, dynamic model of the human knee joint has been developed to simulate the unloaded knee joint behaviour in 6 degrees of freedom. It is based on extensive robot-based measurements of the elastic properties of a human cadaver knee joint. The measured data are compared with data from the literature to ensure that a proper database for modelling is used. The analytical modelling of the passive elastic joint properties is done with Local Linear Model Trees. The deduced knee joint model incorporates passive elastic properties of the internal knee joint structures, passive elastic muscle forces, damping forces, gravitational forces, and external forces. There are two sets of parameters, one simulating the movement of the intact knee joint, and a second simulating the knee joint with ruptured anterior cruciate ligament. The dynamic model can be easily processed in real-time. It is implemented in the haptic display of the Munich Knee Joint Simulator (MKS), which enables a person to move a plastic leg driven by a robot manipulator and feel the simulated knee joint force. Orthopaedic physicians judged the performance of the dynamic knee joint model by executing physical knee joint tests at the MKS.