Geometry and Mechanics

IASS-IACM 2008 Session: Geometry and Mechanics -- Session Organizers: Kai-Uwe BLETZINGER (TU Munich), Fehmi CIRAK (University of Cambridge) -- Keynote Lecture: "Modeling and computation of patient-specific vascular fluid-structure interaction using Isogeometric Analysis" by Yuri BAZILEVS , Victor M. CALO, Thomas J. R. HUGHES (University of Texas at Austin), Yongie ZHANG (Carnegie Mellon University) -- Keynote Lecture: "Optimal shapes of mechanically motivated surfaces" by Kai-Uwe BLETZINGER , Matthias FIRL, Johannes LINHARD, Roland WUCHNER (TU Munich) -- "Subdivision shells for nonsmooth and branching geometries" by Quan LONG, Fehmi CIRAK (University of Cambridge) -- "Water landing analyses with explicit finite element method" by John T. WANG (NASA Langley Research Center) -- "On a geometrically exact contact description for shells: From linear approximations for shells to high-order FEM" by Alexander KONYUKHOV, Karl SCHWEIZERHOF (University of Karlsruhe

Structural Role of Conformational Heterogeneity and Juxtamembrane Regions in the Ephrin A1 Interactions With the EphA2 Receptor Ligand-binding Domain

Ephrin growth factors are attached to the membrane by either GPI-anchor or transmembrane domains and are known to signal bi-directionally: cells, expressing the ephrins experience the downstream signaling in response to ephrin recognition by their receptor, Eph. This bidirectionality makes ephrins an interesting drug target. In the present work, we investigate the role played by conformational heterogeneity and juxtamembrane domains of Ephrin A1 in its interactions with the ligand-binding domain of EphA2 receptor by NMR spectroscopy. We show that ligand recognition occurs via a conformational selection mechanism and that the juxtamembrane regions are flexible, unstructured and are not involved in the binding

Motor and functional outcome of selective dorsal rhizotomy in children with spastic diplegia at 12 and 24 months of follow-up

Background: Selective dorsal rhizotomy (SDR) in ambulatory children affected by cerebral palsy (CP) is a surgical treatment option to lower spasticity and thereby improve gait and ambulation. The aim of the current study is to investigate the outcome of children with respect to spasticity, muscle strength, and overall function after SDR. Methods: All children who underwent SDR via a single-level laminotomy in the time period from January 2007 to April 2015 at our center were enrolled in this study. Within a standardized evaluation process, the following was assessed routinely pre-operatively and 12 and 24 months following surgery: extent of spasticity at hip adductors and hamstrings as characterized by the Modified Ashworth Scale (MAS), maximal muscle strength as characterized by the Medical Council Research Scale (MRC), overall function regarding ambulation as characterized by the Gross Motors Function Classification System (GFMCS), and overall function as characterized by the Gross Motor Function Measure (GMFM-88). Results: Matching sets of pre- and post-operative assessments of the chosen outcome parameters were available for 109 of the 150 children who underwent SDR within the observation period. After 24 months, the MAS scores of hip adductors (n = 59) improved in 71% and 76% of children on the right and left side, respectively. In 20% and 19%, it remained unchanged and worsened in 9% and 5% of children on the right and left side, respectively (p < 0.00625). For hamstrings, the rates for the right and left sides were 81% and 79% improvement, 16% and 16% unchanged, and 4% and 5% worsened, respectively (p < 0.00625). Muscle strength of ankle dorsiflexion and knee extension significantly improved after 24 months. Overall function assessed by GMFM-88 improved significantly by 4% after 12 months (n = 77) and by 7% after 24 months (n = 56, p < 0.0001). Conclusions: The presented data underlines the benefit of SDR in a pediatric patient collective with bilateral spastic CP. The procedure resulted in an effective and permanent reduction of spasticity and improved overall function without causing relevant weakness of the lower extremities

The MECP2 TRD domain interacts with the DNMT3A ADD domain at the H3 tail binding site

The DNMT3A DNA methyltransferase and MECP2 methylation reader are highly expressed in neurons. Both proteins interact via their DNMT3A ADD and MECP2 TRD domains, and the MECP2 interaction regulates the activity and subnuclear localization of DNMT3A. Here, we mapped the interface of both domains using peptide SPOT array binding, protein pull down, equilibrium peptide binding assays, and structural analyses. The region D529 D531 on the surface of the ADD domain was identified as interaction point with the TRD domain. This includes important residues of the histone H3 N terminal tail binding site to the ADD domain, explaining why TRD and H3 binding to the ADD domain is competitive. On the TRD domain, residues 214 228 containing K219 and K223 were found to be essential for the ADD interaction. This part represents a folded patch within the otherwise largely disordered TRD domain. A crystal structure analysis of ADD revealed that the identified H3 TDR lysine binding pocket is occupied by an arginine residue from a crystallographic neighbor in the ADD apoprotein structure. Finally, we show that mutations in the interface of ADD and TRD domains disrupt the cellular interaction of both proteins in NIH3T3 cells. In summary, our data show that the H3 peptide binding cleft of the ADD domain also mediates the interaction with the MECP2 TRD domain suggesting that this binding site may have a broader role also in the interaction of DNMT3A with other proteins leading to complex regulation options by competitive and PTM specific bindin

Unexpected Course of Nonlinear Cardiac Interbeat Interval Dynamics during Childhood and Adolescence

The fluctuations of the cardiac interbeat series contain rich information because they reflect variations of other functions on different time scales (e.g., respiration or blood pressure control). Nonlinear measures such as complexity and fractal scaling properties derived from 24 h heart rate dynamics of healthy subjects vary from childhood to old age. In this study, the age-related variations during childhood and adolescence were addressed. In particular, the cardiac interbeat interval series was quantified with respect to complexity and fractal scaling properties. The R-R interval series of 409 healthy children and adolescents (age range: 1 to 22 years, 220 females) was analyzed with respect to complexity (Approximate Entropy, ApEn) and fractal scaling properties on three time scales: long-term (slope β of the power spectrum, log power vs. log frequency, in the frequency range 10−4 to 10−2 Hz) intermediate-term (DFA, detrended fluctuation analysis, α2) and short-term (DFA α1). Unexpectedly, during age 7 to 13 years β and ApEn were higher compared to the age <7 years and age >13 years (β: −1.06 vs. −1.21; ApEn: 0.88 vs. 0.74). Hence, the heart rate dynamics were closer to a 1/f power law and most complex between 7 and 13 years. However, DFA α1 and α2 increased with progressing age similar to measures reflecting linear properties. In conclusion, the course of long-term fractal scaling properties and complexity of heart rate dynamics during childhood and adolescence indicates that these measures reflect complex changes possibly linked to hormonal changes during pre-puberty and puberty

Optimization of the Lead Compound NVP BHG712 as Colorectal Cancer Inhibitor

The ephrin type A receptor 2 EPHA2 kinase belongs to the largest family of receptor tyrosine kinases. There are several indications of an involvement of EPHA2 in the development of infectious diseases and cancer. Despite pharmacological potential, EPHA2 is an under examined target protein. In this study, we synthesized a series of derivatives of the inhibitor NVP BHG712 and triazine based compounds. These compounds were evaluated to determine their potential as kinase inhibitors of EPHA2, including elucidation of their binding mode X ray crystallography , affinity microscale thermophoresis , and selectivity Kinobeads assay . Eight inhibitors showed affinities in the low nanomolar regime K D lt;10 nM . Testing in up to seven colon cancer cell lines that express EPHA2 reveals that several derivatives feature promising effects for the control of human colon carcinoma. Thus, we have developed a set of powerful tool compounds for fundamental new research on the interplay of EPH receptors in a cellular contex

¹H, ¹³C, and ¹⁵N backbone chemical shift assignments of coronavirus-2 non-structural protein Nsp10

The international Covid19-NMR consortium aims at the comprehensive spectroscopic characterization of SARS-CoV-2 RNA elements and proteins and will provide NMR chemical shift assignments of the molecular components of this virus. The SARS-CoV-2 genome encodes approximately 30 different proteins. Four of these proteins are involved in forming the viral envelope or in the packaging of the RNA genome and are therefore called structural proteins. The other proteins fulfill a variety of functions during the viral life cycle and comprise the so-called non-structural proteins (nsps). Here, we report the near-complete NMR resonance assignment for the backbone chemical shifts of the non-structural protein 10 (nsp10). Nsp10 is part of the viral replication-transcription complex (RTC). It aids in synthesizing and modifying the genomic and subgenomic RNAs. Via its interaction with nsp14, it ensures transcriptional fidelity of the RNA-dependent RNA polymerase, and through its stimulation of the methyltransferase activity of nsp16, it aids in synthesizing the RNA cap structures which protect the viral RNAs from being recognized by the innate immune system. Both of these functions can be potentially targeted by drugs. Our data will aid in performing additional NMR-based characterizations, and provide a basis for the identification of possible small molecule ligands interfering with nsp10 exerting its essential role in viral replication

¹H, ¹³C, and ¹⁵N backbone chemical shift assignments of the apo and the ADP-ribose bound forms of the macrodomain of SARS-CoV-2 non-structural protein 3b

The SARS-CoV-2 genome encodes for approximately 30 proteins. Within the international project COVID19-NMR, we distribute the spectroscopic analysis of the viral proteins and RNA. Here, we report NMR chemical shift assignments for the protein Nsp3b, a domain of Nsp3. The 217-kDa large Nsp3 protein contains multiple structurally independent, yet functionally related domains including the viral papain-like protease and Nsp3b, a macrodomain (MD). In general, the MDs of SARS-CoV and MERS-CoV were suggested to play a key role in viral replication by modulating the immune response of the host. The MDs are structurally conserved. They most likely remove ADP-ribose, a common posttranslational modification, from protein side chains. This de-ADP ribosylating function has potentially evolved to protect the virus from the anti-viral ADP-ribosylation catalyzed by poly-ADP-ribose polymerases (PARPs), which in turn are triggered by pathogen-associated sensing of the host immune system. This renders the SARS-CoV-2 Nsp3b a highly relevant drug target in the viral replication process. We here report the near-complete NMR backbone resonance assignment (¹H, ¹³C, ¹⁵N) of the putative Nsp3b MD in its apo form and in complex with ADP-ribose. Furthermore, we derive the secondary structure of Nsp3b in solution. In addition, ¹⁵N-relaxation data suggest an ordered, rigid core of the MD structure. These data will provide a basis for NMR investigations targeted at obtaining small-molecule inhibitors interfering with the catalytic activity of Nsp3b