Nanomaterials (NMs) have gained prominence in technological advancements due to their tunable physical, chemical and biological properties with enhanced performance over their bulk counterparts. NMs ...are categorized depending on their size, composition, shape, and origin. The ability to predict the unique properties of NMs increases the value of each classification. Due to increased growth of production of NMs and their industrial applications, issues relating to toxicity are inevitable. The aim of this review is to compare synthetic (engineered) and naturally occurring nanoparticles (NPs) and nanostructured materials (NSMs) to identify their nanoscale properties and to define the specific knowledge gaps related to the risk assessment of NPs and NSMs in the environment. The review presents an overview of the history and classifications of NMs and gives an overview of the various sources of NPs and NSMs, from natural to synthetic, and their toxic effects towards mammalian cells and tissue. Additionally, the types of toxic reactions associated with NPs and NSMs and the regulations implemented by different countries to reduce the associated risks are also discussed.
The proteolysis-assisted protein quality control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous defective proteins are specifically eliminated and which ...molecular characteristics direct them for removal are fundamental questions. We reveal a mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase uses interchangeable substrate receptors to recognize the unusual C termini of abnormal proteins (i.e., C-end degrons). C-end degrons are mostly less than ten residues in length and comprise a few indispensable residues along with some rather degenerate ones. The C-terminal end position is essential for C-end degron function. Truncated selenoproteins generated by translation errors and the USP1 N-terminal fragment from post-translational cleavage are eliminated by DesCEND. DesCEND also targets full-length proteins with naturally occurring C-end degrons. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” as indicators for protein elimination.
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•CRL2 ubiquitin ligase functions in protein quality control•CRL2 recognizes the unusual C-termini of aberrant proteins (i.e., C-end degrons)•CRL2 recognizes various C-end degrons through interchangeable substrate receptors•CRL2 also targets full-length proteins with naturally occurring C-end degrons
Lin et al. uncover a protein degradation mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase recognizes and eliminates proteins with exposed C-end degrons through interchangeable substrate receptors. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” in directing protein elimination.
Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts and ...perivascular stromal cells including endothelial cells, CXCL12-abundant reticular cells, leptin-receptor-positive stromal cells, and nestin-green fluorescent protein (GFP)-positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C-X-C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B-lymphoid progenitors, but HSC function is normal. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 from nestin-negative mesenchymal progenitors using Prx1-cre (Prx1 also known as Prrx1) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs.
Background and purpose
The pharmacologic effects of pioglitazone on the incidence of Parkinson disease (PD) are not clear. No study has examined the interaction between pioglitazone and statin ...treatment on prevention of PD. This study analyzed the associations between pioglitazone, statins, and the incidence of PD in patients with diabetes mellitus (DM) in Taiwan.
Methods
We used the National Health Insurance database from 1996 to 2013. DM and PD were diagnosed according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes. We used the propensity score‐matching method to match the study groups. Cox regression analyses were employed to calculate the relative risk of the incidence of PD.
Results
There were 48 828 patients matched and categorized equally into the pioglitazone group and the non‐pioglitazone group. The number of PD patients in the pioglitazone group and the non‐pioglitazone group was 275 (1.1%) and 417 (1.7%), respectively. The pioglitazone group had a lower incidence of PD, with an adjusted hazard ratio (aHR) of 0.66 95% confidence interval (CI): 0.57–0.78, and this benefit was dose‐dependent. Of note, as compared with either pioglitazone or statin treatment, our results first showed that the combination of pioglitazone and statins further lowered the risk of PD, with an aHR of 0.78 (95% CI: 0.64–0.94; P = 0.010).
Conclusions
Our study results suggested that pioglitazone could be a promising agent for reducing the incidence of PD in patients with DM, and works synergistically with statins.
Pioglitazone and statins may lower the indidence of Parkinsion disease independently and synergistically in patients with diabetes mellitus.
The lysosome is an acidic multi-functional organelle with roles in macromolecular digestion, nutrient sensing, and signaling. However, why cells require acidic lysosomes to proliferate and which ...nutrients become limiting under lysosomal dysfunction are unclear. To address this, we performed CRISPR-Cas9-based genetic screens and identified cholesterol biosynthesis and iron uptake as essential metabolic pathways when lysosomal pH is altered. While cholesterol synthesis is only necessary, iron is both necessary and sufficient for cell proliferation under lysosomal dysfunction. Remarkably, iron supplementation restores cell proliferation under both pharmacologic and genetic-mediated lysosomal dysfunction. The rescue was independent of metabolic or signaling changes classically associated with increased lysosomal pH, uncoupling lysosomal function from cell proliferation. Finally, our experiments revealed that lysosomal dysfunction dramatically alters mitochondrial metabolism and hypoxia inducible factor (HIF) signaling due to iron depletion. Altogether, these findings identify iron homeostasis as the key function of lysosomal acidity for cell proliferation.
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•Cells starve for cholesterol and iron under lysosomal dysfunction•Upon increased lysosomal pH, only iron addition enables cell proliferation•Iron does not restore lysosomal pH-related catabolic and signaling functions•Iron reverses other cellular processes related to depleted cellular iron
The lysosome is a multi-functional organelle whose low pH is required for cell viability. Weber et al. identified iron as necessary and sufficient for cell proliferation under lysosomal dysfunction. While iron addition uncouples lysosomal acidity from cell viability, iron chelation combined with lysosome-targeting compounds represents a potential cancer therapeutic strategy.
Sickle cell disease (SCD) is caused by a mutation in the β-globin gene HBB
. We used a custom adenine base editor (ABE8e-NRCH)
to convert the SCD allele (HBB
) into Makassar β-globin (HBB
), a ...non-pathogenic variant
. Ex vivo delivery of mRNA encoding the base editor with a targeting guide RNA into haematopoietic stem and progenitor cells (HSPCs) from patients with SCD resulted in 80% conversion of HBB
to HBB
. Sixteen weeks after transplantation of edited human HSPCs into immunodeficient mice, the frequency of HBB
was 68% and hypoxia-induced sickling of bone marrow reticulocytes had decreased fivefold, indicating durable gene editing. To assess the physiological effects of HBB
base editing, we delivered ABE8e-NRCH and guide RNA into HSPCs from a humanized SCD mouse
and then transplanted these cells into irradiated mice. After sixteen weeks, Makassar β-globin represented 79% of β-globin protein in blood, and hypoxia-induced sickling was reduced threefold. Mice that received base-edited HSPCs showed near-normal haematological parameters and reduced splenic pathology compared to mice that received unedited cells. Secondary transplantation of edited bone marrow confirmed that the gene editing was durable in long-term haematopoietic stem cells and showed that HBB
-to-HBB
editing of 20% or more is sufficient for phenotypic rescue. Base editing of human HSPCs avoided the p53 activation and larger deletions that have been observed following Cas9 nuclease treatment. These findings point towards a one-time autologous treatment for SCD that eliminates pathogenic HBB
, generates benign HBB
, and minimizes the undesired consequences of double-strand DNA breaks.
Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism
. Mitochondria, as the major site of oxidative reactions, must maintain ...sufficient levels of GSH to perform protective and biosynthetic functions
. GSH is synthesized exclusively in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remains unknown. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, as a regulator of GSH transport into mitochondria. Loss of SLC25A39 reduces mitochondrial GSH import and abundance without affecting cellular GSH levels. Cells lacking both SLC25A39 and its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron-sulfur clusters. We find that mitochondrial GSH import is necessary for cell proliferation in vitro and red blood cell development in mice. Heterologous expression of an engineered bifunctional bacterial GSH biosynthetic enzyme (GshF) in mitochondria enables mitochondrial GSH production and ameliorates the metabolic and proliferative defects caused by its depletion. Finally, GSH availability negatively regulates SLC25A39 protein abundance, coupling redox homeostasis to mitochondrial GSH import in mammalian cells. Our work identifies SLC25A39 as an essential and regulated component of the mitochondrial GSH-import machinery.
Adoptive transfer of high-affinity chimeric antigen receptor (CAR) T cells targeting hematological cancers has yielded impressive clinical results. However, safety concerns regarding target ...expression on healthy tissue and poor efficacy have hampered application to solid tumors. Here, a panel of affinity-variant CARs were constructed targeting overexpressed ICAM-1, a broad tumor biomarker, using its physiological ligand, LFA-1. Anti-tumor T cell potency in vitro was directly proportional to CAR affinity and ICAM-1 density. In a solid tumor mouse model allowing simultaneous monitoring of anti-tumor potency and systemic off-tumor toxicity, micromolar affinity CAR T cells demonstrated superior anti-tumor efficacy and safety compared to their nanomolar counterparts. Longitudinal T cell tracking by PET/CT and concurrent cytokine measurement revealed superior expansion and contraction kinetics of micromolar affinity CAR T cells. Therefore, we developed an ICAM-1 specific CAR with broad anti-tumor applicability that utilized a reduced affinity targeting strategy to significantly boost efficacy and safety.
Rationale
Methicillin‐resistant Staphylococcus aureus (MRSA) is one of major clinical pathogens responsible for both hospital‐ and community‐acquired infections worldwide. A delay in targeted ...antibiotic treatment contributes to longer hospitalization stay, higher costs, and increasing in‐hospital mortality. Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) has been integrated into the routine workflow for microbial identification over the past decade, and it has also shown promising functions in the detection of bacterial resistance. Therefore, we describe a rapid MALDI‐TOF MS‐based methodology for MRSA screening with machine‐learning algorithms.
Methods
A total of 452 clinical S. aureus isolates were included in this study, of which 194 were MRSA and 258 were methicillin‐sensitive S. aureus (MSSA). The mass‐to‐charge ratio (m/z) features from MRSA and MSSA strains were binned and selected through Lasso regression. These features were then used to train a non‐linear support vector machine (SVM) with radial basis function (RBF) kernels to evaluate the discrimination performance. The classifiers' accuracy, sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) were evaluated and compared with those from the random forest (RF) model.
Results
A total of 2601 unique spectral peaks of all isolates were identified and 38 m/z features were selected for the classifying model. The AUCs of the non‐linear RBF‐SVM model and the RF model were 0.89 and 0.87, respectively, and the accuracy ranged between 0.86 (RBF‐SVM) and 0.82 (RF).
Conclusions
Our study demonstrates that MALDI‐TOF MS coupled with machine‐learning algorithms could be used to develop a rapid and easy‐to‐use method to discriminate MRSA from MSSA. Considering that this method is easy to implement in routine microbiology laboratories, it suggests a cost‐effective and time‐efficient alternative to conventional resistance detection in the future to improve clinical treatment.
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