Clinically suspected neurodegeneration in histiocytic neoplasms as causes of neurologic decline: a retrospective study.
ObjectivesThe aim of this study was to evaluate the causes of suspected neurodegeneration in adults with histiocytic neoplasms. MethodsPatients with histiocytic neoplasms were identified. Inclusion criteria were diagnosis of histiocytic neoplasm; the treating hematologist suspected neurodegeneration; and patients age 18 years or older. Active CNS histiocytic neoplasm was defined as new or enlarging T2 lesions, or gadolinium enhancing lesions on MRI.
To identify the critical mitochondrial protease regulating HSPC homeostasis, we performed real-time PCR to examine the expression levels of various mitochondrial proteases in EPCR+SLAM-HSCs from mouse bone marrow (BM). Among them, the m-AAA protease Afg3l2 was the most highly expressed (Figure S1 A),18 suggesting its potential significance in HSC regulation. Furthermore, we conducted a comprehensive analysis of Afg3l2 expression across the hematopoietic hierarchy by examining EPCR+ SLAM-HSCs, SLAM-LT-HSCs, SLAM-ST-HSCs, SLAM-MPPs (multipotent progenitors), LSK (Lin-Sca-1+c-Kit+) cells, Lin− cells, and mature blood cells (B cells, T cells, and myeloid cells). Our results demonstrate that Afg3l2 expression is highest in the most primitive EPCR+SLAM-HSC population and gradually decreases with differentiation, supporting its crucial role in hematopoietic stem cells (HSCs) (Figure S1 B). Afg3l2 dysfunction has been linked to neurodegenerative disorders such as spinocerebellar ataxia19,20,21; however, its role in hematopoietic cells and its broader metabolic implications remain unexplored. To systemically investigate the function of Afg3l2 in HSPCs, we generated a conditional knockout (KO) allele of the Afg3l2 gene (Afg3l2f/+), in which exons 4 and 5 were flanked by loxP sites (Figure S1 C). Afg3l2f/+ mice were then crossed with Mx1-Cre transgenic mice to obtain Afg3l2f/f;Mx1-Cre+ animals. Deletion of Afg3l2 in hematopoietic cells was induced by administering polyinosinic-polycytidylic acid (pIpC) to 6-to 8-week-old mice, and KO efficiency was confirmed by real-time PCR and western blot analysis (Figures S1 D–S1G). On day 14 after the final pIpC administration, complete blood count analysis revealed a significant reduction in white blood cell, lymphoid cell, and platelet counts in Afg3l2f/f mice (wild-type [WT]) compared to Afg3l2f/f;Mx1-Cre+ mice (KO) (Figures S1 H–S1J). Interestingly, red blood cell counts and hemoglobin levels remained comparable between WT and KO groups (Figures S1 K and S1L). Flow cytometry analysis of BM revealed a significant reduction in multiple hematopoietic populations in Afg3l2-KO mice, including LT-HSCs, ST-HSCs, MPPs, common myeloid progenitors, granulocytic/monocytic progenitors, and megakaryocyte/erythroid progenitors (Figures S1 M–S1P). Notably, the EPCR+SLAM-HSC population, a highly purified HSC subset, was also remarkably diminished (Figure S1 Q).
Consistently, functional colony-forming unit (CFU) assays showed that CFU-granulocyte, erythrocyte, macrophage, megakaryocyte (CFU-GEMM); CFU-granulocyte and macrophage (CFU-GM); and burst-forming unit-erythroid (BFU-E) were markedly decreased in Afg3l2-KO BM cells (Figures S1 R and S1S). These findings indicate that Afg3l2 deficiency causes leukopenia and impairs steady-state hematopoiesis.
To assess the in vivo function of Afg3l2 in HSPCs, we performed competitive BM transplantation. Lethally irradiated recipient mice (CD45.1) were transplanted with a 1:1 mixture of total BM cells from WT or Afg3l2-KO donor mice (CD45.2) and competitor BM cells (CD45.1/CD45.2) (Figure 1A). CD45 chimerism in peripheral blood (PB) was monitored every four weeks, and BM composition was analyzed 16 weeks post-transplantation. The percentage of donor-derived CD45.2+ cells in PB was significantly lower in recipients receiving Afg3l2-KO BM compared to those transplanted with WT BM (Figures 1B and 1C). The percentage of donor BM cells-derived CD45.2+ cells, HPCs, Lin−Sca-1+c-Kit+ (LSK) cells, HSCs, myeloid cells, B cells, and T cells was dramatically decreased in the BM of the Afg3l2-KO cell transplanted group 16 weeks after transplantation (Figures 1D and 1E).
Functioning brain cells need a functioning system for picking up the trash and sorting the recycling. But when the cellular sanitation machines responsible for those tasks, called lysosomes, break down or get overwhelmed, it can increase the risk of Alzheimer’s, Parkinson’s, and other neurological disorders.
“Lysosomal function is essential for brain health, and mutations in lysosomal genes are risk factors for neurodegenerative diseases,” said Monther Abu-Remaileh, a Wu Tsai Neuro affiliate and an assistant professor of chemical engineering in the Stanford School of Engineering and an assistant professor of genetics in the Stanford School of Medicine.
The trouble is, scientists aren’t sure exactly how lysosomes do their work, what’s going wrong with lysosomes that leads to neurodegeneration—or even in which cell types neurodegenerative disease begins. There might even be other lysosomal disorders yet to be discovered.
Harnessing the power of artificial intelligence to study plant microbiomes—communities of microbes living in and around plants—could help improve soil health, boost crop yields, and restore degraded lands. But there’s a catch: AI needs massive amounts of reliable data to learn from, and that kind of consistent information about plant-microbe interactions has been hard to come by.
In a new paper in PLOS Biology, researchers in the Biosciences Area at Lawrence Berkeley National Laboratory (Berkeley Lab) led an international consortium of scientists to study whether small plastic growth chambers called EcoFABs could help solve this problem.
Building on their previous work with microbe-free plants, the scientists used the Berkeley Lab-developed devices to run identical plant–microbe experiments across labs on three continents and got matching results. The breakthrough shows that EcoFABs can remove one of the biggest barriers in microbiome research: the difficulty of reproducing experiments in different places.
Inserting, removing or swapping individual atoms from the core of a molecule is a long-standing challenge in chemistry. This process, called skeletal editing, can dramatically speed up drug discovery or be applied for upcycling of plastics. Consequently, the field is witnessing a surge of interest spanning from fundamental chemical research to applications in the pharmaceutical industry.
A group of researchers have now extended the scope of skeletal editing to the scale of just a single molecule. Such a level of precision in skeletal editing is unprecedented, and this may open a new route to obtain elusive molecules.
The team of researchers are active at Chalmers University of Technology, Sweden; IBM Research Europe—Zurich, Switzerland; and CiQUS at the University of Santiago de Compostela, Spain. In a recent article published in the Journal of the American Chemical Society, they demonstrate how, in a controlled manner, they can selectively remove a single oxygen atom from an organic molecule using the sharp tip of a scanning probe microscope.
Enzymes with specific functions are becoming increasingly important in industry, medicine and environmental protection. For example, they make it possible to synthesize chemicals in a more environmentally friendly way, produce active ingredients in a targeted manner or break down environmentally harmful substances.
Researchers from Gustav Oberdorfer’s working group at the Institute of Biochemistry at Graz University of Technology (TU Graz), together with colleagues from the University of Graz, have now published a study in Nature describing a new method for the design of customized enzymes.
The technology called Riff-Diff (Rotamer Inverted Fragment Finder–Diffusion) makes it possible to accurately and efficiently build the protein structure specifically around the active center instead of searching for a suitable structure from existing databases. The resulting enzymes are not only significantly more active than previous artificial enzymes, but also more stable.
Placental toxicology progress!
Commonly used in vitro and in vivo placental models capture key placental functions and toxicity mechanisms, but have significant limitations.
The physiological relevance of placental models varies, with a general hierarchy of simple in vitro complex in vitro/ organ-on-chip in vivo, but species-of origin considerations may alter their relevance to human physiology.
Cellular, rodent, human, and computational modeling systems provide insights into placental transport, physiology, and toxicology linked to maternal–fetal health.
Recent advances in 3D culture and microfluidic technologies offer more physiologically relevant models for studying the placenta.
Mathematical modeling approaches can integrate mechanistic physiological data and exposure assessments to define key toxicokinetic parameters.
Environmental chemical concentrations and omic data obtained from placental tissues can link toxicant influences on placental function to adverse birth outcomes.