Three-dimensional structural analysis of eukaryotic flagella/cilia by electron cryo-tomography

Based on the molecular architecture revealed by electron cryo-tomography, the mechanism of the bending motion of eukaryotic flagella/cilia is discussed

Molecular architecture of inner dynein arms in situ in Chlamydomonas reinhardtii flagella

The inner dynein arm regulates axonemal bending motion in eukaryotes. We used cryo-electron tomography to reconstruct the three-dimensional structure of inner dynein arms from Chlamydomonas reinhardtii. All the eight different heavy chains were identified in one 96-nm periodic repeat, as expected from previous biochemical studies. Based on mutants, we identified the positions of the AAA rings and the N-terminal tails of all the eight heavy chains. The dynein f dimer is located close to the surface of the A-microtubule, whereas the other six heavy chain rings are roughly colinear at a larger distance to form three dyads. Each dyad consists of two heavy chains and has a corresponding radial spoke or a similar feature. In each of the six heavy chains (dynein a, b, c, d, e, and g), the N-terminal tail extends from the distal side of the ring. To interact with the B-microtubule through stalks, the inner-arm dyneins must have either different handedness or, more probably, the opposite orientation of the AAA rings compared with the outer-arm dyneins

α- and β-Tubulin Lattice of the Axonemal Microtubule Doublet and Binding Proteins Revealed by Single Particle Cryo-Electron Microscopy and Tomography

SummaryMicrotubule doublet (MTD) is the main skeleton of cilia/flagella. Many proteins, such as dyneins and radial spokes, bind to MTD, and generate or regulate force. While the structure of the reconstituted microtubule has been solved at atomic resolution, nature of the axonemal MTD is still unclear. There are a few hypotheses of the lattice arrangement of its α- and β-tubulins, but it has not been described how dyneins and radial spokes bind to MTD. In this study, we analyzed the three-dimensional structure of Tetrahymena MTD at ∼19 Å resolution by single particle cryo-electron microscopy. To identify α- and β-tubulins, we combined image analysis of MTD with specific kinesin decoration. This work reveals that α- and β-tubulins form a B-lattice arrangement in the entire MTD with a seam at the outer junction. We revealed the unique way in which inner arm dyneins, radial spokes, and proteins inside MTD bind and bridge protofilaments

Zero-shot Object-Level OOD Detection with Context-Aware Inpainting

Machine learning algorithms are increasingly provided as black-box cloud services or pre-trained models, without access to their training data. This motivates the problem of zero-shot out-of-distribution (OOD) detection. Concretely, we aim to detect OOD objects that do not belong to the classifier's label set but are erroneously classified as in-distribution (ID) objects. Our approach, RONIN, uses an off-the-shelf diffusion model to replace detected objects with inpainting. RONIN conditions the inpainting process with the predicted ID label, drawing the input object closer to the in-distribution domain. As a result, the reconstructed object is very close to the original in the ID cases and far in the OOD cases, allowing RONIN to effectively distinguish ID and OOD samples. Throughout extensive experiments, we demonstrate that RONIN achieves competitive results compared to previous approaches across several datasets, both in zero-shot and non-zero-shot settings

The amyloid-β1-42-oligomer interacting peptide D-AIP possesses favorable biostability, pharmacokinetics, and brain region distribution.

We have previously developed a unique 8-amino acid Aβ42 oligomer-Interacting Peptide (AIP) as a novel anti-amyloid strategy for the treatment of Alzheimer's disease. Our lead candidate has successfully progressed from test tubes (i.e., in vitro characterization of protease-resistant D-AIP) to transgenic flies (i.e., in vivo rescue of human Aβ42-mediated toxicity via D-AIP-supplemented food). In the present study, we examined D-AIP in terms of its stability in multiple biological matrices (i.e., ex-vivo mouse plasma, whole blood, and liver S9 fractions) using MALDI mass spectrometry, pharmacokinetics using a rapid and sensitive LC-MS method, and blood brain barrier (BBB) penetrance in WT C57LB/6 mice. D-AIP was found to be relatively stable over 3 h at 37 °C in all matrices tested. Finally, label-free MALDI imaging showed that orally administered D-AIP can readily penetrate the intact BBB in both male and female WT mice. Based upon the favorable stability, pharmacokinetics, and BBB penetration outcomes for orally administered D-AIP in WT mice, we then examined the effect of D-AIP on amyloid "seeding" in vitro (i.e., freshly monomerized versus preaggregated Aβ42). Complementary biophysical assays (ThT, TEM, and MALDI-TOF MS) showed that D-AIP can directly interact with synthetic Aβ42 aggregates to disrupt primary and/or secondary seeding events. Taken together, the unique mechanistic and desired therapeutic potential of our lead D-AIP candidate warrants further investigation, that is, testing of D-AIP efficacy on the altered amyloid/tau pathology in transgenic mouse models of Alzheimer's disease

Adaptive fuzzy-neural network effectively disturbance compensate in sliding mode control for dual arm robot

In this study, an Adaptive Backstepping Sliding Mode Controller (ABSMC) is introduced based on the Radial Basis Function (RBF) neural network and a fuzzy logic modifier. The proposed method is used to control a Dual-Arm Robot (DAR) – a nonlinear structure with unstable parameters and external disturbances. The control aims to track the motion trajectory of both arms in the flat surface coordinate within a short time, maintaining stability, and ensuring that the tracking error converges in finite time, especially when influenced by unforeseen external disturbances. The nonlinear Backstepping Sliding Mode Control (BSMC) is effective in trajectory tracking control; however, undesired phenomena may occur if there are uncertain disturbances affecting the system or model parameters change. It is proposed to use a neural network to estimate a nonlinear function to handle unknown uncertainties of the system. The neural network parameters can be adaptively adjusted to optimal values through adaptation rules derived from Lyapunov's theorem. Additionally, fuzzy logic theory is also employed to adjust the controller parameters to accommodate changes or unexpected impacts. The performance of the Fuzzy Neural Network Backstepping Sliding Mode Control (FNN-BSMC) is evaluated through simulation results using Matlab/Simulink software. Two simulation cases are conducted: the first case assumes stable model parameters without uncertain disturbances affecting the joints, while the second case considers a model with changing parameters and disturbances. Simulation results demonstrate the effective adaptability of the proposed method when the system model is affected by various types of uncertainties from the environmen

Anatomical Characteristics and Variants of Prostatic Artery in Patients of Benign Hyperplasia Prostate by Digital Subtraction Angiography

AIM: This work is aimed to describe anatomical features and variants of the prostatic artery (PA) using digital subtraction angiography (DSA). METHODS: This is a descriptive statistic study. We reviewed the DSA of 348 patients, who had a PA embolisation to reduce the benign prostatic hyperplasia (BPH) symptoms at Radiology Department of Bach Mai Hospital from Oct – 2014 to Oct – 2018. RESULTS: PA was found at 660 pelvic halves, of which 30 pelvic halves (4.5%) had two PAs, 630 pelvic halves had one PA. In terms of the origin of PA, in total 690 PAs, the percentage of type 1, 2, 3, 4 and 5 was successively 33.9%, 13.9%, 18.3%, 23.9% and 10.4%, respectively. Atherosclerosis of PA observed in 20.9%. The ‘corkscrew’ pattern was found in 30.4%. The average diameter of PA was 1.5 ± 0.34mm. The anastomosis of PA with surrounding arteries was common. PA may supply rectum (6.1%), seminal vesical (9.6%), bladder (5.2%), contralateral prostatic parenchyma (13.0%), surrounding soft-tissues (3.5%). CONCLUSION: The common trunk with SVA superior vesical artery was the most common origin of PA. Anastomoses of PA with surrounding tissues were complex

Structural basis for assembly and function of the Nup82 complex in the nuclear pore scaffold

Nuclear pore complexes (NPCs) are huge assemblies formed from ∼30 different nucleoporins, typically organized in subcomplexes. One module, the conserved Nup82 complex at the cytoplasmic face of NPCs, is crucial to terminate mRNA export. To gain insight into the structure, assembly, and function of the cytoplasmic pore filaments, we reconstituted in yeast the Nup82–Nup159–Nsp1–Dyn2 complex, which was suitable for biochemical, biophysical, and electron microscopy analyses. Our integrative approach revealed that the yeast Nup82 complex forms an unusual asymmetric structure with a dimeric array of subunits. Based on all these data, we developed a three-dimensional structural model of the Nup82 complex that depicts how this module might be anchored to the NPC scaffold and concomitantly can interact with the soluble nucleocytoplasmic transport machinery