Secondary biochemical and morphological consequences in lysosomal storage diseases

More than 50 hereditary lysosomal storage disorders (LSDs) are currently described. Most of these disorders are due to a deficiency of certain hydrolases/glycosidases and subsequent accumulation of nonhydrolyzable carbohydrate-containing compounds in lysosomes. Such accumulation causing hypertrophy of the lysosomal compartment is a characteristic feature of affected cells in LSDs. The investigation of biochemical and cellular parameters is of particular interest for understanding “life” of lysosomes in the normal state and in LSDs. This review highlights the wide spectrum of biochemical and morphological changes during developing LSDs that are extremely critical for many metabolic processes inside the various cells and tissues of affected persons. The data presented will help establish new complex strategies for metabolic correction of LSDs.     

μOrgano: A Lego?-Like Plug & Play System for Modular Multi-Organ-Chips

Human organ-on-a-chip systems for drug screening have evolved as feasible alternatives to animal models, which are unreliable, expensive, and at times erroneous. While chips featuring single organs can be of great use for both pharmaceutical testing and basic organ-level studies, the huge potential of the organ-on-a-chip technology is revealed by connecting multiple organs on one chip to create a single integrated system for sophisticated fundamental biological studies and devising therapies for disease. Furthermore, since most organ-on-a-chip systems require special protocols with organ-specific media for the differentiation and maturation of the tissues, multi-organ systems will need to be temporally customizable and flexible in terms of the time point of connection of the individual organ units. We present a customizable Lego^®-like plug & play system, μOrgano, which enables initial individual culture of single organ-on-a-chip systems and subsequent connection to create integrated multi-organ microphysiological systems. As a proof of concept, the μOrgano system was used to connect multiple heart chips in series with excellent cell viability and spontaneously physiological beat rates.     

Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity

L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin—Frankfurt—Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01–0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09–0.53); p = 8.48E-04 and OR = 3.02 (1.36–6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect.     

The cochlea of the enigmatic pygmy right whale Caperea marginata informs mysticete phylogeny

The pygmy right whale, Caperea marginata , is the least understood extant baleen whale (Cetacea, Mysticeti). Knowledge on its basic anatomy, ecology, and fossil record is limited, even though its singular position outside both balaenids (right whales) and balaenopteroids (rorquals + grey whales) gives Caperea a pivotal role in mysticete evolution. Recent investigations of the cetacean cochlea have provided new insights into sensory capabilities and phylogeny. Here, we extend this advance to Caperea by describing, for the first time, the inner ear of this enigmatic species. The cochlea is large and appears to be sensitive to low‐frequency sounds, but its hearing limit is relatively high. The presence of a well‐developed tympanal recess links Caperea with cetotheriids and balaenopteroids, rather than balaenids, contrary to the traditional morphological view of a close Caperea‐balaenid relationship. Nevertheless, a broader sample of the cetotheriid Herpetocetus demonstrates that the presence of a tympanal recess can be variable at the specific and possibly even the intraspecific level.     

A Dynamic Gene Regulatory Network Model That Recovers the Cyclic Behavior of Arabidopsis thaliana Cell Cycle

Cell cycle control is fundamental in eukaryotic development. Several modeling efforts have been used to integrate the complex network of interacting molecular components involved in cell cycle dynamics. In this paper, we aimed at recovering the regulatory logic upstream of previously known components of cell cycle control, with the aim of understanding the mechanisms underlying the emergence of the cyclic behavior of such components. We focus on Arabidopsis thaliana, but given that many components of cell cycle regulation are conserved among eukaryotes, when experimental data for this system was not available, we considered experimental results from yeast and animal systems. We are proposing a Boolean gene regulatory network (GRN) that converges into only one robust limit cycle attractor that closely resembles the cyclic behavior of the key cell-cycle molecular components and other regulators considered here. We validate the model by comparing our in silico configurations with data from loss- and gain-of-function mutants, where the endocyclic behavior also was recovered. Additionally, we approximate a continuous model and recovered the temporal periodic expression profiles of the cell-cycle molecular components involved, thus suggesting that the single limit cycle attractor recovered with the Boolean model is not an artifact of its discrete and synchronous nature, but rather an emergent consequence of the inherent characteristics of the regulatory logic proposed here. This dynamical model, hence provides a novel theoretical framework to address cell cycle regulation in plants, and it can also be used to propose novel predictions regarding cell cycle regulation in other eukaryotes.