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Environment International Jun 2024Fusion energy investigation has stepped to a new stage adopting deuterium and tritium as fuels from the previous stage concentrating hydrogen plasma physics. Special... (Review)
Review
Fusion energy investigation has stepped to a new stage adopting deuterium and tritium as fuels from the previous stage concentrating hydrogen plasma physics. Special radiation safety issues would be introduced during this stage. In addition to industrial and military uses, tungsten is also regarded as the most promising plasma facing material for fusion reactors. During the operation of fusion reactors, tungsten-based plasma facing materials can be activated via neutron nuclear reaction. Meanwhile, activated tungsten dust can be produced when high-energy plasma interacts with the tungsten-based plasma facing materials, namely plasma wall interaction. Activated tungsten dust would be an emerging environmental pollutant with radiation toxicity containing various radionuclides in addition to the chemical toxicity of tungsten itself. Nonetheless, the historical underestimation of its environmental availability has led to limited research on tungsten compared to other environmental contaminants. This paper presents the first systematic review on the safety issue of emerging activated tungsten dust, encompassing source terms, environmental behaviors, and health effects. The key contents are as follows: 1) to detail the source terms of activated tungsten dust from aspects of tungsten basic properties, generation mechanism, physical morphology and chemical component, radioactivity, as well as potential release pathways, 2) to illustrate the environmental behaviors from aspects of atmospheric dispersion and deposition, transformation and migration in soil, as well as plant absorption and distribution, 3) to identify the toxicity and health effects from aspects of toxicity to plants, distribution in human body, as well as health effects by radiation and chemical toxicity, 4) based on the research progress, research and development issues needed are also pointed out to better knowledge of safety issue of activated tungsten dust, which would be beneficial to the area of fusion energy and ecological impact caused by the routine tungsten related industrial and military applications.
Topics: Tungsten; Dust; Humans
PubMed: 38810497
DOI: 10.1016/j.envint.2024.108774 -
Protein Science : a Publication of the... Jun 2024Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for obesity, diabetes, and certain types of cancer. In particular, allosteric inhibitors hold...
Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for obesity, diabetes, and certain types of cancer. In particular, allosteric inhibitors hold potential for therapeutic use, but an incomplete understanding of conformational dynamics and allostery in this protein has hindered their development. Here, we interrogate solution dynamics and allosteric responses in PTP1B using high-resolution hydrogen-deuterium exchange mass spectrometry (HDX-MS), an emerging and powerful biophysical technique. Using HDX-MS, we obtain a detailed map of backbone amide exchange that serves as a proxy for the solution dynamics of apo PTP1B, revealing several flexible loops interspersed among more constrained and rigid regions within the protein structure, as well as local regions that exchange faster than expected from their secondary structure and solvent accessibility. We demonstrate that our HDX rate data obtained in solution adds value to estimates of conformational heterogeneity derived from a pseudo-ensemble constructed from ~200 crystal structures of PTP1B. Furthermore, we report HDX-MS maps for PTP1B with active-site versus allosteric small-molecule inhibitors. These maps suggest distinct and widespread effects on protein dynamics relative to the apo form, including changes in locations distal (>35 Å) from the respective ligand binding sites. These results illuminate that allosteric inhibitors of PTP1B can induce unexpected changes in dynamics that extend beyond the previously understood allosteric network. Together, our data suggest a model of BB3 allostery in PTP1B that combines conformational restriction of active-site residues with compensatory liberation of distal residues that aid in entropic balancing. Overall, our work showcases the potential of HDX-MS for elucidating aspects of protein conformational dynamics and allosteric effects of small-molecule ligands and highlights the potential of integrating HDX-MS alongside other complementary methods, such as room-temperature X-ray crystallography, NMR spectroscopy, and molecular dynamics simulations, to guide the development of new therapeutics.
Topics: Protein Tyrosine Phosphatase, Non-Receptor Type 1; Allosteric Regulation; Humans; Hydrogen Deuterium Exchange-Mass Spectrometry; Molecular Dynamics Simulation; Protein Conformation; Models, Molecular; Catalytic Domain
PubMed: 38801229
DOI: 10.1002/pro.5024 -
Biomedicines Apr 2024The thymus provides maturation and migration of T cells to peripheral organs of immunity, where they recognize diverse antigens and maintain immunological memory and...
The thymus provides maturation and migration of T cells to peripheral organs of immunity, where they recognize diverse antigens and maintain immunological memory and self-tolerance. The thymus is known to be involved with age and in response to stress factors. Therefore, the search for approaches to the restoration of thymopoiesis is of great interest. The present investigation was aimed at evaluating how prolonged deuterium depletion affects morphogenetic processes and the physiological transition of the thymus to age-related involution. The study was performed on 60 male Wistar rats subjected to consumption of deuterium-depleted water with a 10 ppm deuterium content for 28 days. The control rats consumed distilled water with a normal deuterium content of 150 ppm. The examination found no significant differences in body weight gain or the amount of water consumed. The exposed rats exhibited similar to control dynamics of the thymus weight but significant changes in thymic cell maturation according to cytofluorimetric analysis of thymic subpopulations. Changes in T cell production were not monotonic and differentially engaged morphogenetic processes of cell proliferation, differentiation, and migration. The reactive response to deuterium depletion was a sharp increase in the number of progenitor CD4CD8 cells and their differentiation into T cells. The compensatory reaction was inhibition of thymopoiesis with more pronounced suppression of differentiation of T-cytotoxic lymphocytes, followed by intensification of emigration of mature T cells to the bloodstream. This period lasts from 3 to 14 days, then differentiation of thymic lymphocytes is restored, later cell proliferation is activated, and finally the thymopoiesis rate exceeds the control values. The increase in the number of thymic progenitor cells after 3-4 weeks suggests consideration of deuterium elimination as a novel approach to prevent thymus involution.
PubMed: 38790918
DOI: 10.3390/biomedicines12050956 -
Biochemistry Jun 2024The active form of the murine urokinase-type plasminogen activator (muPA) is formed by a 27-residue disordered light chain connecting the amino-terminal fragment (ATF)...
The active form of the murine urokinase-type plasminogen activator (muPA) is formed by a 27-residue disordered light chain connecting the amino-terminal fragment (ATF) with the serine protease domain. The two chains are tethered by a disulfide bond between C1 in the disordered light chain and C122 in the protease domain. Previous work showed that the presence of the disordered light chain affected the inhibition of the protease domain by antibodies. Here we show that the disordered light chain induced a 3.7-fold increase in of the protease domain of muPA. In addition, hydrogen-deuterium exchange mass spectrometry (HDX-MS) and accelerated molecular dynamics (AMD) were performed to identify the interactions between the disordered light chain and the protease domain. HDX-MS revealed that the light chain is contacting the 110s, the turn between the β10- and β11-strand, and the β7-strand. A reduction in deuterium uptake was also observed in the activation loop, the 140s loop and the 220s loop, which forms the S1-specificty pocket where the substrate binds. These loops are further away from where the light chain seems to be interacting with the protease domain. Our results suggest that the light chain most likely increases the activity of muPA by allosterically favoring conformations in which the specificity pocket is formed. We propose a model by which the allostery would be transmitted through the β-strands of the β-barrels to the loops on the other side of the protease domain.
Topics: Animals; Mice; Urokinase-Type Plasminogen Activator; Allosteric Regulation; Molecular Dynamics Simulation; Hydrogen Deuterium Exchange-Mass Spectrometry; Kinetics
PubMed: 38780522
DOI: 10.1021/acs.biochem.4c00071 -
The Journal of Biological Chemistry May 2024Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug...
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 posttranslational regulation. Here, we characterize a phosphorylation site at Ser situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function. In human T cells, Ser is phosphorylated by glycogen synthase kinase-3 (GSK3) following TCR stimulation, which promotes its TCR-inhibitory activity. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9-mediated suppression of Ser phosphorylation and inhibited by mimicking it via glutamic acid substitution. Global phospho-mass spectrometry showed Ser phosphorylation state alters downstream transcriptional activity through enrichment of Swi3p, Rsc8p, and Moira domain binding proteins, and next-generation sequencing revealed it differentially regulates the expression of chemokines and T cell activation pathways. Moreover, in vitro kinetic data suggest the modulation of activity depends on a cellular context. Finally, we begin to address the structural and mechanistic basis for the influence of Ser phosphorylation on the protein's properties by deuterium exchange mass spectrometry and NMR spectroscopy. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling and provides details that might inform the future development of allosteric modulators of PTPN22.
PubMed: 38777143
DOI: 10.1016/j.jbc.2024.107393 -
Antiviral Research Jul 2024Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic...
Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.
Topics: Antiviral Agents; Respiratory Syncytial Virus Infections; Animals; Humans; Virus Replication; Respiratory Syncytial Virus, Human; Sheep; Drug Resistance, Viral; Viral Proteins; Lung
PubMed: 38772503
DOI: 10.1016/j.antiviral.2024.105907 -
Scientific Reports May 2024Possibility of nuclear reactions in solid state is intriguing for two reasons: (1) It provides a means of studying nuclear processes in conditions that are much...
Possibility of nuclear reactions in solid state is intriguing for two reasons: (1) It provides a means of studying nuclear processes in conditions that are much different from traditional plasma-filled reactors or particle accelerators; (2) it dramatically lowers the cost and complexity of the experimental setups by eliminating the highly capital intensive components such as plasma/vacuum systems and particle accelerators. In this article we report the observation of neutron emission coincident with acoustic cavitation of deuterated titanium powder suspended in mineral oil. The resulting neutron emission was detected using an assembly of He proportional neutron counters. The peak neutron count rate was in excess of 6500 CPM, more than 10,000 times in excess of background. The observed neutron emission was coincident with the application of acoustic influence. The neutrons were present only when secondary acoustic waves originating from the complex bubble interactions inside the reactor constructively interfered resulting in massive, sharp pressure peaks on the order of a few thousand psi. We were able to sustain the neutron production for several hours and repeated the experiment multiple times under various conditions. We hypothesize that the observed neutrons originate from nuclear fusion of deuterium ions dissolved in titanium lattice due to the mechanical action of the impinging cavitation jets, although other processes (such as spallation) still need to be ruled out.
PubMed: 38769316
DOI: 10.1038/s41598-024-62055-6 -
BioRxiv : the Preprint Server For... Apr 2024The lipid kinase phosphatidylinositol 4 kinase III alpha (PI4KIIIα/PI4KA) is a master regulator of the lipid composition and asymmetry of the plasma membrane. PI4KA...
The lipid kinase phosphatidylinositol 4 kinase III alpha (PI4KIIIα/PI4KA) is a master regulator of the lipid composition and asymmetry of the plasma membrane. PI4KA exists primarily in a heterotrimeric complex with its regulatory proteins TTC7 and FAM126. Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B. Here, we report a cryo-EM structure of the C-terminus of EFR3A bound to the PI4KA-TTC7B-FAM126A complex, with extensive validation using both hydrogen deuterium exchange mass spectrometry (HDX-MS), and mutational analysis. The EFR3A C-terminus undergoes a disorder-order transition upon binding to the PI4KA complex, with an unexpected direct interaction with both TTC7B and FAM126A. Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane. Multiple post-translational modifications and disease linked mutations map to this site, providing insight into how PI4KA membrane recruitment can be regulated and disrupted in human disease.
PubMed: 38746453
DOI: 10.1101/2024.04.30.587787 -
BioRxiv : the Preprint Server For... May 2024Lyme disease is a tick-borne, multisystem infection caused by the spirochete, . Although antibodies have been implicated in the resolution of Lyme disease, the specific...
Lyme disease is a tick-borne, multisystem infection caused by the spirochete, . Although antibodies have been implicated in the resolution of Lyme disease, the specific B cell epitopes targeted during human infections remain largely unknown. In this study, we characterized and defined the structural epitope of a patient-derived bactericidal monoclonal IgG ("B11") against Outer surface protein C (OspC), a homodimeric lipoprotein necessary for tick-mediated transmission and early-stage colonization of vertebrate hosts. High-resolution epitope mapping was accomplished through hydrogen deuterium exchange-mass spectrometry (HDX-MS) and X-ray crystallography. Structural analysis of B11 Fab-OspC complexes revealed the B11 Fabs associated in a 1:1 stoichiometry with the lateral faces of OspC homodimers such that the antibodies are essentially positioned perpendicular to the spirochete's outer surface. B11's primary contacts reside within the membrane proximal regions of α-helices 1 and 6 and adjacent loops 5 and 6 in one OspC monomer. In addition, B11 spans the OspC dimer interface, engaging opposing α-helix 1', α-helix 2', and loop 2-3' in the second OspC monomer. The B11-OspC structure is reminiscent of the recently solved mouse transmission blocking monoclonal IgG B5 in complex with OspC , indicating a mode of engagement with OspC that is conserved across species. In conclusion, we provide the first detailed insight into the interaction between a functional human antibody and an immunodominant Lyme disease antigen long considered an important vaccine target.
PubMed: 38746285
DOI: 10.1101/2024.04.29.591597 -
Chemoselective Hydrogenation of α,β-Unsaturated Ketones Catalyzed by a Manganese(I) Hydride Complex.Organic Letters May 2024Here, we report the chemoselective hydrogenation of α,β-unsaturated ketones catalyzed by a well-defined Mn(I) PCP pincer complex [(PCP)Mn(CO)H] (). The reaction is...
Here, we report the chemoselective hydrogenation of α,β-unsaturated ketones catalyzed by a well-defined Mn(I) PCP pincer complex [(PCP)Mn(CO)H] (). The reaction is compatible with a wide variety of functional groups that include halides, esters, amides, nitriles, nitro, alkynes, and alkenes, and for most substrates occurs readily at ambient hydrogen pressure (1-2 bar). Mechanistic studies and deuterium labeling experiments reveal a non-cooperative mechanism, which is further discussed in this report.
PubMed: 38738936
DOI: 10.1021/acs.orglett.4c00277