Differences in metal sequestration between zebra mussels from clean and polluted field locations

Organisms are able to detoxify accumulated metals by, e.g. binding them to metallothionein (MT) and/or sequestering them in metal-rich granules (MRG). The different factors involved in determining the capacity or efficiency with which metals are detoxified are not yet known.In this work we studied how the sub-cellular distribution pattern of cadmium, copper and zinc in whole tissue of zebra mussels from clean and polluted surface waters is influenced by the total accumulated metal concentration and by its physiological condition. Additionally we measured the metallothionein concentration in the mussel tissue. Metal concentration increased gradually in the metal-sensitive and detoxified sub-cellular fractions with increasing whole tissue concentrations. However, metal concentrations in the sensitive fractions did not increase to the same extent as metal concentrations in whole tissues. In more polluted mussels the contribution of MRG and MT became more important. Nevertheless, metal detoxification was not sufficient to prevent metal binding to heat-sensitive low molecular weight proteins (HDP fraction). Finally we found an indication that metal detoxification was influenced by the condition of the zebra mussels. MT content could be explained for up to 83% by variations in Zn concentration and physiological condition of the mussels

An investigation of motor memory deficits in Parkinson’s disease

People with Parkinson’s disease (PD) display motor memory deficits when tested on motor adaptation tasks involving visuomotor rotations, while the process of adaptation itself seems largely unaffected. Other forms of adaptation are unexplored and the mechanisms underlying their motor memory deficits unknown. Previous research has suggested reinforcement mechanisms to be affected in PD, but whether defective reinforcement is underlying motor memory impairments has never been directly investigated. Firstly, we investigated if the motor memory deficits shown by earlier studies also hold for force-field adaptation, where the participant learns to compensate for a perturbation caused by an external force acting on the limb. We then explored if adaptation to such force-fields was possible when adaptation was dependent on contextual cues, i.e. if people with PD were able to make context-motor associations, and in addition we investigated whether augmentation of reward and punishment improved reinforcement in PD. To increase our understanding of the effect of reward and punishment feedback on context-dependent motor learning their separate effects were investigated in a group of young adults. Results showed intact recall of the learned adapted state in people with PD, suggesting intact consolidation, but motor memory as tested with interference, where memory of the initial adaptation impairs learning of an opposite adaptation, to be strongly reduced in PD. We found evidence that people with PD were less able to learn context-motor associations in comparison to older Controls and these deficits became more pronounced when success-based feedback was strengthened suggesting reduced sensitivity to augmentation of reward and/or punishment. In young adults, reward and punishment feedback did not influence context-dependent motor adaptation itself, but it had some effect on movement velocity. We conclude that PD pathology leads to weaker context-motor associations and defective reinforcement processes, which may be underlying impaired recall of certain motor states

The lethal response to Cdk1 inhibition depends on sister chromatid alignment errors generated by KIF4 and isoform 1 of PRC1

Cyclin-dependent kinase 1 (Cdk1) is absolutely essential for cell division. Complete ablation of Cdk1 precludes the entry of G2 phase cells into mitosis, and is early embryonic lethal in mice. Dampening Cdk1 activation, by reducing gene expression or upon treatment with cell-permeable Cdk1 inhibitors, is also detrimental for proliferating cells, but has been associated with defects in mitotic progression, and the formation of aneuploid daughter cells. Here, we used a large-scale RNAi screen to identify the human genes that critically determine the cellular toxicity of Cdk1 inhibition. We show that Cdk1 inhibition leads to fatal sister chromatid alignment errors and mitotic arrest in the spindle checkpoint. These problems start early in mitosis and are alleviated by depletion of isoform 1 of PRC1 (PRC1-1), by gene ablation of its binding partner KIF4, or by abrogation of KIF4 motor activity. Our results show that, normally, Cdk1 activity must rise above the level required for mitotic entry. This prevents KIF4-dependent PRC1-1 translocation to astral microtubule tips and safeguards proper chromosome congression. We conclude that cell death in response to Cdk1 inhibitors directly relates to chromosome alignment defects generated by insufficient repression of PRC1-1 and KIF4 during prometaphase

Munc18-1 promotes larger dense-core vesicle docking.

AbstractSecretory vesicles dock at the plasma membrane before Ca2+ triggers their exocytosis. Exocytosis requires the assembly of SNARE complexes formed by the vesicle protein Synaptobrevin and the membrane proteins Syntaxin-1 and SNAP-25. We analyzed the role of Munc18-1, a cytosolic binding partner of Syntaxin-1, in large dense-core vesicle (LDCV) secretion. Calcium-dependent LDCV exocytosis was reduced 10-fold in mouse chromaffin cells lacking Munc18-1, but the kinetic properties of the remaining release, including single fusion events, were not different from controls. Concomitantly, mutant cells displayed a 10-fold reduction in morphologically docked LDCVs. Moreover, acute overexpression of Munc18-1 in bovine chromaffin cells increased the amount of releasable vesicles and accelerated vesicle supply. We conclude that Munc18-1 functions upstream of SNARE complex formation and promotes LDCV docking

Shape modulation of squaramide-based supramolecular polymer nanoparticles

We report the synthesis and self-assembly of a library of squaramide-based bolaamphiphiles with variable hydrophobic and hydrophilic domain sizes, consisting of varied aliphatic chains (n = 2 to 12 methylene repeat units) and linear oligo(ethylene glycol) (m = 11 to 36 repeat units), to understand their effect on the formation of supramolecular polymer nanoparticles. Systematic variation of the hydrophobic chain length show that a minimum hydrophobic domain is required to shield the squaramide units from water when a constant hydrophilic domain is maintained for self-assembly. By contrast, significant increases to the hydrophilic chain length of the bolaamphiphile, while keeping the hydrophobic domain constant, results in a transition from fibrillar to spherical nanoscale objects with an alteration in the aggregation mode of the monomers likely due to steric constraints of the oligo(ethylene glycol) chains. By understanding the self-assembly space achievable for these squaramide-based bolaamphiphiles through examining the interplay between various monomer features, we show their distinct effects on the formation of self-assembled nanoparticles with possibilities to modulate their shape and size in water for future applications in the biomedical area.</p

Effect of H-Bonding on Order Amplification in the Growth of a Supramolecular Polymer in Water

While a great deal of knowledge on the roles of hydrogen bonding and hydrophobicity in proteins has resulted in the creation of rationally designed and functional peptidic structures, the roles of these forces on purely synthetic supramolecular architectures in water have proven difficult to ascertain. Focusing on a 1,3,5-benzenetricarboxamide (BTA)-based supramolecular polymer, we have designed a molecular modeling strategy to dissect the energetic contributions involved in the self-assembly (electrostatic, hydrophobic, etc.) upon growth of both ordered BTA stacks and random BTA aggregates. Utilizing this set of simulations, we have unraveled the cooperative mechanism for polymer growth, where a critical size must be reached in the aggregates before emergence and amplification of order into the experimentally observed fibers. Furthermore, we have found that the formation of ordered fibers is favored over disordered aggregates solely on the basis of electrostatic interactions. Detailed analysis of the simulation data suggests that H-bonding is a major source of this stabilization energy. Experimental and computational comparison with a newly synthesized 1,3,5-benzenetricarboxyester (BTE) derivative, lacking the ability to form the H-bonding network, demonstrated that this BTE variant is also capable of fiber formation, albeit at a reduced persistence length. This work provides unambiguous evidence for the key 1D driving force of hydrogen bonding in enhancing the persistency of monomer stacking and amplifying the level of order into the growing supramolecular polymer in water. Our computational approach provides an important relationship directly linking the structure of the monomer to the structure and properties of the supramolecular polymer

Hybrid Deep Learning Gaussian Process for Diabetic Retinopathy Diagnosis and Uncertainty Quantification

Diabetic Retinopathy (DR) is one of the microvascular complications of Diabetes Mellitus, which remains as one of the leading causes of blindness worldwide. Computational models based on Convolutional Neural Networks represent the state of the art for the automatic detection of DR using eye fundus images. Most of the current work address this problem as a binary classification task. However, including the grade estimation and quantification of predictions uncertainty can potentially increase the robustness of the model. In this paper, a hybrid Deep Learning-Gaussian process method for DR diagnosis and uncertainty quantification is presented. This method combines the representational power of deep learning, with the ability to generalize from small datasets of Gaussian process models. The results show that uncertainty quantification in the predictions improves the interpretability of the method as a diagnostic support tool. The source code to replicate the experiments is publicly available at https://github.com/stoledoc/DLGP-DR-Diagnosis

Efficacy of simultaneous vaccination with Enterisol® Ileitis and Ingelvac® CircoFLEXTM in a Swiss breeding farm

This study explores administration of two piglet vaccines as compared to the mono- and adjuvant-application. A vaccine against the Porcine Circovirus Type 2 (PCV2) cap protein subunit and a vaccine with attenuated live culture against Lawsonia (L.) intracellularis were applied to piglets aged 23.5 days on average. 1'405 animals were divided randomly into four groups. One piglet group was immunized with both vaccines while two other groups were immunized with a combination of one vaccine and adjuvants of alternate vaccination protocol and vice versa. These piglet groups were also compared to a control group supplemented with both adjuvants only. During fattening, pigs, which were simultaneously immunized with Enterisol(®) Ileitis and Ingelvac(®) CircoFLEX(TM) vaccine, gained significantly more weight (792 g/day) when compared to piglet groups mono-vaccinated with Ingelvac® CircoFLEXTM (772 g/day) or either with Enterisol® Ileitis (774 g/day). Moreover, immunized piglet groups showed significantly higher daily weight gain when compared to adjuvants only inoculated control group (751 g/day). Additionally, during fattening the control group displayed higher mortality (6,3 %) than the three vaccinated groups (Ingelvac(®) CircoFLEX(TM) 2,5 %, Enterisol(®) Ileitis 2,3 % and the combination of both vaccines 1,1 %). These data imply that simultaneous immunization with PCV2- and L. intracellularis specific vaccines positively benefit piglet growth observed by an additive effect on growth parameters in farms harboring both pathogens. Return of investment was calculated of 2.10 on the additional Enterisol(®) Ileitis vaccination

CAPS1 Regulates Catecholamine Loading of Large Dense-Core Vesicles

SummaryCAPS1 is thought to play an essential role in mediating exocytosis from large dense-core vesicles (LDCVs). We generated CAPS1-deficient (KO) mice and studied exocytosis in a model system for Ca2+-dependent LDCV secretion, the adrenal chromaffin cell. Adult heterozygous CAPS1 KO cells display a gene dosage-dependent decrease of CAPS1 expression and a concomitant reduction in the number of docked vesicles and secretion. Embryonic homozygous CAPS1 KO cells show a strong reduction in the frequency of amperometrically detectable release events of transmitter-filled vesicles, while the total number of fusing vesicles, as judged by capacitance recordings or total internal reflection microscopy, remains unchanged. We conclude that CAPS1 is required for an essential step in the uptake or storage of catecholamines in LDCVs