A reassessment of the problematic Ediacaran genus Orbisiana Sokolov 1976

The genus Orbisiana was established in 1976 by B.S. Sokolov based on a collection of seven specimens within core material from a borehole drilled through the Ediacaran-age Gavrilov Yam Formation of the Moscow Basin, Russia. Here we reassess the original material for the type species Orbisiana simplexSokolov 1976, which was long considered to be lost; fix the holotype of the type species; and revise the original diagnosis of the genus and species. Pyritisation of the fossils, which are preserved in finely laminated shales, allows three-dimensional morphological characterisation of this taxon using X-ray microtomography (μCT). Morphological and taphonomic analyses of the type material and additional three-dimensionally preserved specimens from the Verkhovka Formation (Vendian of the White Sea area) suggest that Orbisiana simplex consisted of submillimetric to millimetric globular chambers arranged in compact, grape-like clusters, or forming sinuous to linear aggregates. Occasionally, aggregates can bifurcate, with no appreciable change in chamber dimensions or shape. The phylogenetic affinity of Orbisiana remains uncertain, but its chambered construction, putative agglutinated structure of the chamber walls, and compact, occasionally branching chamber arrangement are shared with agglutinated tests of the Ediacaran genus Palaeopascichnus. Our reassessment and systematic study of the genus Orbisiana sheds new light on one of the least studied members of the late Ediacaran macroscopic biota.NER

Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer.

Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies

Complexity without chaos: Plasticity within random recurrent networks generates robust timing and motor control

It is widely accepted that the complex dynamics characteristic of recurrent neural circuits contributes in a fundamental manner to brain function. Progress has been slow in understanding and exploiting the computational power of recurrent dynamics for two main reasons: nonlinear recurrent networks often exhibit chaotic behavior and most known learning rules do not work in robust fashion in recurrent networks. Here we address both these problems by demonstrating how random recurrent networks (RRN) that initially exhibit chaotic dynamics can be tuned through a supervised learning rule to generate locally stable neural patterns of activity that are both complex and robust to noise. The outcome is a novel neural network regime that exhibits both transiently stable and chaotic trajectories. We further show that the recurrent learning rule dramatically increases the ability of RRNs to generate complex spatiotemporal motor patterns, and accounts for recent experimental data showing a decrease in neural variability in response to stimulus onset

Critical change in the Fermi surface of iron arsenic superconductors at the onset of superconductivity

The phase diagram of a correlated material is the result of a complex interplay between several degrees of freedom, providing a map of the material's behavior. One can understand (and ultimately control) the material's ground state by associating features and regions of the phase diagram, with specific physical events or underlying quantum mechanical properties. The phase diagram of the newly discovered iron arsenic high temperature superconductors is particularly rich and interesting. In the AE(Fe1-xTx)2As2 class (AE being Ca, Sr, Ba, T being transition metals), the simultaneous structural/magnetic phase transition that occurs at elevated temperature in the undoped material, splits and is suppressed by carrier doping, the suppression being complete around optimal doping. A dome of superconductivity exists with apparent equal ease in the orthorhombic / antiferromagnetic (AFM) state as well as in the tetragonal state with no long range magnetic order. The question then is what determines the critical doping at which superconductivity emerges, if the AFM order is fully suppressed only at higher doping values. Here we report evidence from angle resolved photoemission spectroscopy (ARPES) that critical changes in the Fermi surface (FS) occur at the doping level that marks the onset of superconductivity. The presence of the AFM order leads to a reconstruction of the electronic structure, most significantly the appearance of the small hole pockets at the Fermi level. These hole pockets vanish, i. e. undergo a Lifshitz transition, at the onset of superconductivity. Superconductivity and magnetism are competing states in the iron arsenic superconductors. In the presence of the hole pockets superconductivity is fully suppressed, while in their absence the two states can coexist.Comment: Updated version accepted in Nature Physic

Navigation of Distinct Euclidean Particles via Hierarchical Clustering

We present a centralized online (completely reactive) hybrid navigation algorithm for bringing a swarm of n perfectly sensed and actuated point particles in Euclidean d space (for arbitrary n and d) to an arbitrary goal configuration with the guarantee of no collisions along the way. Our construction entails a discrete abstraction of configurations using cluster hierarchies, and relies upon two prior recent constructions: (i) a family of hierarchy-preserving control policies and (ii) an abstract discrete dynamical system for navigating through the space of cluster hierarchies. Here, we relate the (combinatorial) topology of hierarchical clusters to the (continuous) topology of configurations by constructing “portals” — open sets of configurations supporting two adjacent hierarchies. The resulting online sequential composition of hierarchy-invariant swarming followed by discrete selection of a hierarchy “closer” to that of the destination along with its continuous instantiation via an appropriate portal configuration yields a computationally effective construction for the desired navigation policy

Towards Safer Robot Motion: Using a Qualitative Motion Model to Classify Human-Robot Spatial Interaction

For adoption of Autonomous Mobile Robots (AMR) across a breadth of industries, they must navigate around humans in a way which is safe and which humans perceive as safe, but without greatly compromising efficiency. This work aims to classify the Human-Robot Spatial Interaction (HRSI) situation of an interacting human and robot, to be applied in Human-Aware Navigation (HAN) to account for situational context. We develop qualitative probabilistic models of relative human and robot movements in various HRSI situations to classify situations, and explain our plan to develop per-situation probabilistic models of socially legible HRSI to predict human and robot movement. In future work we aim to use these predictions to generate qualitative constraints in the form of metric cost-maps for local robot motion planners, enforcing more efficient and socially legible trajectories which are both physically safe and perceived as safe

Ultrathin 2 nm gold as ideal impedance-matched absorber for infrared light

Thermal detectors are a cornerstone of infrared (IR) and terahertz (THz) technology due to their broad spectral range. These detectors call for suitable broad spectral absorbers with minimalthermal mass. Often this is realized by plasmonic absorbers, which ensure a high absorptivity butonly for a narrow spectral band. Alternativly, a common approach is based on impedance-matching the sheet resistance of a thin metallic film to half the free-space impedance. Thereby, it is possible to achieve a wavelength-independent absorptivity of up to 50 %, depending on the dielectric properties of the underlying substrate. However, existing absorber films typicallyrequire a thickness of the order of tens of nanometers, such as titanium nitride (14 nm), whichcan significantly deteriorate the response of a thermal transducers. Here, we present the application of ultrathin gold (2 nm) on top of a 1.2 nm copper oxide seed layer as an effective IR absorber. An almost wavelength-independent and long-time stable absorptivity of 47(3) %, ranging from 2 $\mu$m to 20 $\mu$m, could be obtained and is further discussed. The presented gold thin-film represents analmost ideal impedance-matched IR absorber that allows a significant improvement of state-of-the-art thermal detector technology

Immunodepletion of high-abundant proteins from acute and chronic wound fluids to elucidate low-abundant regulators in wound healing

<p>Abstract</p> <p>Background</p> <p>The process of wound healing consists of several well distinguishable and finely tuned phases. For most of these phases specific proteins have been characterized, although the underlying mechanisms of regulation are not yet fully understood. It is an open question as to whether deficits in wound healing can be traced back to chronic illnesses such as diabetes mellitus. Previous research efforts in this field focus largely on a restricted set of marker proteins due to the limitations detection by antibodies imposes. For mechanistic purposes the elucidation of differences in acute and chronic wounds can be addressed by a less restricted proteome study. Mass spectrometric (MS) methods, e.g. multi dimensional protein identification technology (MudPIT), are well suitable for this complex theme of interest. The human wound fluid proteome is extremely complex, as is human plasma. Therefore, high-abundant proteins often mask the mass spectrometric detection of lower-abundant ones, which makes a depletion step of such predominant proteins inevitable.</p> <p>Findings</p> <p>In this study a commercially available immunodepletion kit was evaluated for the detection of low-abundant proteins from wound fluids. The dynamic range of the entire workflow was significantly increased to 5-6 orders of magnitude, which makes low-abundant regulatory proteins involved in wound healing accessible for MS detection.</p> <p>Conclusion</p> <p>The depletion of abundant proteins is absolutely necessary in order to analyze highly complex protein mixtures such as wound fluids using mass spectrometry. For this the used immunodepletion kit is a first but important step in order to represent the entire dynamic range of highly complex protein mixtures in the future.</p

LZAP Inhibits p38 MAPK (p38) Phosphorylation and Activity by Facilitating p38 Association with the Wild-Type p53 Induced Phosphatase 1 (WIP1)

LZAP (Cdk5rap3, C53) is a putative tumor suppressor that inhibits RelA, Chk1 and Chk2 and activates p53. LZAP is lost in a portion of human head and neck squamous cell carcinoma and experimental loss of LZAP expression is associated with enhanced invasion, xenograft tumor growth and angiogenesis. p38 MAPK can increase or decrease proliferation and cell death depending on cellular context. LZAP has no known enzymatic activity, implying that its biological functions are likely mediated by its protein-protein interactions. To gain further insight into LZAP activities, we searched for LZAP-associated proteins (LAPs). Here we show that the LZAP binds p38, alters p38 cellular localization, and inhibits basal and cytokine-stimulated p38 activity. Expression of LZAP inhibits p38 phosphorylation in a dose-dependent fashion while loss of LZAP enhances phosphorylation and activation with resultant phosphorylation of p38 downstream targets. Mechanistically, the ability of LZAP to alter p38 phosphorylation depended, at least partially, on the p38 phosphatase, Wip1. Expression of LZAP increased both LZAP and Wip1 binding to p38. Taken together, these data suggest that LZAP activity includes inhibition of p38 phosphorylation and activation

A randomized phase 3 study of ixazomib–dexamethasone versus physician’s choice in relapsed or refractory AL amyloidosis

In the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1–2 prior lines were randomized to ixazomib (4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician’s choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib–dexamethasone vs 51% with physician’s choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32–0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib–dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options