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BMC Genomics Dec 2023As an economically important tree, Gleditsia sinensis Lam. is widely planted. A lack of background genetic information on G. sinensis hinders molecular breeding. Based...
As an economically important tree, Gleditsia sinensis Lam. is widely planted. A lack of background genetic information on G. sinensis hinders molecular breeding. Based on PacBio single-molecule real-time (SMRT) sequencing and analysis of G. sinensis, a total of 95,183 non-redundant transcript sequences were obtained, of which 93,668 contained complete open reading frames (ORFs), 2,858 were long non-coding RNAs (LncRNAs) and 18,855 alternative splicing (AS) events were identified. Genes orthologous to different Gleditsia species pairs were identified, stress-related genes had been positively selected during the evolution. AGA, AGG, and CCA were identified as the universal optimal codon in the genus of Gleditsia. EIF5A was selected as a suitable fluorescent quantitative reference gene. 315 Cytochrome P450 monooxygenases (CYP450s) and 147 uridine diphosphate (UDP)-glycosyltransferases (UGTs) were recognized through the PacBio SMRT transcriptome. Randomized selection of GsIAA14 for cloning verified the reliability of the PacBio SMRT transcriptome assembly sequence. In conclusion, the research data lay the foundation for further analysis of the evolutionary mechanism and molecular breeding of Gleditsia.
Topics: Transcriptome; Gleditsia; Reproducibility of Results; Alternative Splicing
PubMed: 38066414
DOI: 10.1186/s12864-023-09843-y -
BioRxiv : the Preprint Server For... Nov 2023Brain somatic variants in are associated with clinically drug-resistant epilepsy and developmental brain malformations, including mild malformation of cortical...
Brain somatic variants in are associated with clinically drug-resistant epilepsy and developmental brain malformations, including mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). encodes a uridine diphosphate galactose translocator that is essential for protein glycosylation; however, the neurodevelopmental mechanisms by which disruption leads to clinical and histopathological features remain unspecified. We hypothesized that focal knockout (KO) or knockdown (KD) of in the developing mouse cortex would disrupt cerebral cortical development through altered neuronal migration and cause changes in network excitability. We used electroporation (IUE) to introduce CRISPR/Cas9 and targeted guide RNAs or short-hairpin RNAs to achieve KO or KD, respectively, during early corticogenesis. Following KO or KD, we observed disrupted radial migration of transfected neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. KO in neurons did not induce changes in oligodendrocyte number, suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects. Spontaneous seizures were not observed, but intracranial EEG recordings after focal KO showed a reduced seizure threshold following pentylenetetrazol injection. These results demonstrate that KO or KD disrupts corticogenesis through altered neuronal migration.
PubMed: 38077069
DOI: 10.1101/2023.11.29.569243 -
Cell Death & Disease Jul 2023Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate...
Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an important role in tissue mineralization. However, the function of ANK in intervertebral disc has not been fully explored. Herein we analyzed the spinal phenotype of Ank mutant mice (ank/ank) with attenuated ANK function. Micro-computed tomography and histological analysis showed that loss of ANK function results in the aberrant annulus fibrosus mineralization and peripheral disc fusions with cranial to caudal progression in the spine. Vertebrae in ank mice exhibit elevated cortical bone mass and increased tissue non-specific alkaline phosphatase-positive endplate chondrocytes with decreased subchondral endplate porosity. The acellular dystrophic mineral inclusions in the annulus fibrosus were localized adjacent to apoptotic cells and cells that acquired osteoblast-like phenotype. Fourier transform infrared spectral imaging showed that the apatite mineral in the outer annulus fibrosus had similar chemical composition to that of vertebral bone. Transcriptomic analysis of annulus fibrosus and nucleus pulposus tissues showed changes in several biological themes with a prominent dysregulation of BMAL1/CLOCK circadian regulation. The present study provides new insights into the role of ANK in the disc tissue compartments and highlights the importance of local inorganic pyrophosphate metabolism in inhibiting the mineralization of this important connective tissue.
Topics: Animals; Humans; Mice; Calcinosis; Diphosphates; Intervertebral Disc; Intervertebral Disc Degeneration; Loss of Function Mutation; Phenotype; X-Ray Microtomography
PubMed: 37468461
DOI: 10.1038/s41419-023-05893-y -
Cell Surface (Amsterdam, Netherlands) Dec 2023•Xylan is an abundant carbohydrate component of plant cell walls that is vital for proper cell wall structure and vascular tissue development.•Xylan structure is... (Review)
Review
•Xylan is an abundant carbohydrate component of plant cell walls that is vital for proper cell wall structure and vascular tissue development.•Xylan structure is known to vary between different tissues and species.•The role of xylan in the plant cell wall is to interact with cellulose, lignin, and hemicelluloses.•Xylan synthesis is directed by several types of Golgi-localized enzymes.•Xylan is being explored as an eco-friendly resource for diverse commercial applications.
PubMed: 36748082
DOI: 10.1016/j.tcsw.2023.100101 -
World Journal of Emergency Medicine 2024Chlorfenapyr is used to kill insects that are resistant to organophosphorus insecticides. Chlorfenapyr poisoning has a high mortality rate and is difficult to treat.... (Review)
Review
BACKGROUND
Chlorfenapyr is used to kill insects that are resistant to organophosphorus insecticides. Chlorfenapyr poisoning has a high mortality rate and is difficult to treat. This article aims to review the mechanisms, clinical presentations, and treatment strategies for chlorfenapyr poisoning.
DATA RESOURCES
We conducted a review of the literature using PubMed, Web of Science, and SpringerLink from their beginnings to the end of October 2023. The inclusion criteria were systematic reviews, clinical guidelines, retrospective studies, and case reports on chlorfenapyr poisoning that focused on its mechanisms, clinical presentations, and treatment strategies. The references in the included studies were also examined to identify additional sources.
RESULTS
We included 57 studies in this review. Chlorfenapyr can be degraded into tralopyril, which is more toxic and reduces energy production by inhibiting the conversion of adenosine diphosphate to adenosine triphosphate. High fever and altered mental status are characteristic clinical presentations of chlorfenapyr poisoning. Once it occurs, respiratory failure occurs immediately, ultimately leading to cardiac arrest and death. Chlorfenapyr poisoning is difficult to treat, and there is no specific antidote.
CONCLUSION
Chlorfenapyr is a new pyrrole pesticide. Although it has been identified as a moderately toxic pesticide by the World Health Organization (WHO), the mortality rate of poisoned patients is extremely high. There is no specific antidote for chlorfenapyr poisoning. Therefore, based on the literature review, future efforts to explore rapid and effective detoxification methods, reconstitute intracellular oxidative phosphorylation couplings, identify early biomarkers of chlorfenapyr poisoning, and block the conversion of chlorfenapyr to tralopyril may be helpful for emergency physicians in the diagnosis and treatment of this disease.
PubMed: 38855374
DOI: 10.5847/wjem.j.1920-8642.2024.046 -
Cell Reports Oct 2023PARP-1 activation at DNA damage sites leads to the synthesis of long poly(ADP-ribose) (PAR) chains, which serve as a signal for DNA repair. Here we show that FUS, an...
PARP-1 activation at DNA damage sites leads to the synthesis of long poly(ADP-ribose) (PAR) chains, which serve as a signal for DNA repair. Here we show that FUS, an RNA-binding protein, is specifically directed to PAR through its RNA recognition motif (RRM) to increase PAR synthesis by PARP-1 in HeLa cells after genotoxic stress. Using a structural approach, we also identify specific residues located in the FUS RRM, which can be PARylated by PARP-1 to control the level of PAR synthesis. Based on the results of this work, we propose a model in which, following a transcriptional arrest that releases FUS from nascent mRNA, FUS can be recruited by PARP-1 activated by DNA damage to stimulate PAR synthesis. We anticipate that this model offers new perspectives to understand the role of FET proteins in cancers and in certain neurodegenerative diseases such as amyotrophic lateral sclerosis.
Topics: Humans; DNA Damage; DNA Repair; HeLa Cells; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; RNA Recognition Motif; RNA-Binding Protein FUS
PubMed: 37804508
DOI: 10.1016/j.celrep.2023.113199 -
Journal of Lipid Research Dec 2023Accurate intracellular cholesterol traffic plays crucial roles. Niemann Pick type C (NPC) proteins NPC1 and NPC2, are two lysosomal cholesterol transporters that mediate...
Accurate intracellular cholesterol traffic plays crucial roles. Niemann Pick type C (NPC) proteins NPC1 and NPC2, are two lysosomal cholesterol transporters that mediate the cholesterol exit from lysosomes. However, other proteins involved in this process remain poorly defined. Here, we find that the previously unannotated protein TMEM241 is required for cholesterol egressing from lysosomes through amphotericin B-based genome-wide CRISPR-Cas9 KO screening. Ablation of TMEM241 caused impaired sorting of NPC2, a protein utilizes the mannose-6-phosphate (M6P) modification for lysosomal targeting, resulting in cholesterol accumulation in the lysosomes. TMEM241 is a member of solute transporters 35 nucleotide sugar transporters family and localizes on the cis-Golgi network. Our data indicate that TMEM241 transports UDP-N-acetylglucosamine (UDP-GlcNAc) into Golgi lumen and UDP-GlcNAc is used for the M6P modification of proteins including NPC2. Furthermore, Tmem241-deficient mice display cholesterol accumulation in pulmonary cells and behave pulmonary injury and hypokinesia. Taken together, we demonstrate that TMEM241 is a Golgi-localized UDP-GlcNAc transporter and loss of TMEM241 causes cholesterol accumulation in lysosomes because of the impaired M6P-dependent lysosomal targeting of NPC2.
Topics: Animals; Mice; Vesicular Transport Proteins; Cholesterol; Uridine Diphosphate; Lysosomes
PubMed: 37890669
DOI: 10.1016/j.jlr.2023.100465 -
The Journal of Biological Chemistry Dec 2023ADP-ribose is a versatile modification that plays a critical role in diverse cellular processes. The addition of this modification is catalyzed by... (Review)
Review
ADP-ribose is a versatile modification that plays a critical role in diverse cellular processes. The addition of this modification is catalyzed by ADP-ribosyltransferases, among which notable poly(ADP-ribose) polymerase (PARP) enzymes are intimately involved in the maintenance of genome integrity. The role of ADP-ribose modifications during DNA damage repair is of significant interest for the proper development of PARP inhibitors targeted toward the treatment of diseases caused by genomic instability. More specifically, inhibitors promoting PARP persistence on DNA lesions, termed PARP "trapping," is considered a desirable characteristic. In this review, we discuss key classes of proteins involved in ADP-ribose signaling (writers, readers, and erasers) with a focus on those involved in the maintenance of genome integrity. An overview of factors that modulate PARP1 and PARP2 persistence at sites of DNA lesions is also discussed. Finally, we clarify aspects of the PARP trapping model in light of recent studies that characterize the kinetics of PARP1 and PARP2 recruitment at sites of lesions. These findings suggest that PARP trapping could be considered as the continuous recruitment of PARP molecules to sites of lesions, rather than the physical stalling of molecules. Recent studies and novel research tools have elevated the level of understanding of ADP-ribosylation, marking a coming-of-age for this interesting modification.
Topics: Humans; Adenosine Diphosphate Ribose; DNA Damage; DNA Repair; Genomic Instability; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Animals
PubMed: 37898399
DOI: 10.1016/j.jbc.2023.105397 -
Journal of the American Chemical Society Feb 2024Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane...
Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphosphosugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). The two distinct superfamilies of PGT enzymes (polytopic and monotopic) show striking differences in their structure and mechanism. We designed and synthesized a series of uridine bisphosphonates (UBPs), wherein the diphosphate of the UDP and UDP-sugar is replaced by a substituted methylene bisphosphonate (CXY-BPs; X/Y = F/F, Cl/Cl, ()-H/F, ()-H/F, H/H, CH/CH). UBPs and UBPs incorporating an -acetylglucosamine (GlcNAc) substituent at the β-phosphonate were evaluated as inhibitors of a polytopic PGT (WecA from ) and a monotopic PGT (PglC from ). Although CHF-BP most closely mimics diphosphate with respect to its acid/base properties, the less basic CF-BP conjugate more strongly inhibited PglC, whereas the more basic CH-BP analogue was the strongest inhibitor of WecA. These surprising differences indicate different modes of ligand binding for the different PGT superfamilies, implicating a modified P-O interaction with the structural Mg. For the monoPGT enzyme, the two diastereomeric CHF-BP conjugates, which feature a chiral center at the P-CHF-P carbon, also exhibited strikingly different binding affinities and the inclusion of GlcNAc with the native α-anomer configuration significantly improved binding affinity. UBP-sugars are thus revealed as informative new mechanistic probes of PGTs that may aid development of novel antibiotic agents for the exclusively prokaryotic monoPGT superfamily.
Topics: Humans; Transferases; Uridine; Diphosphates; Glycoconjugates; Diphosphonates; Sugars; Uridine Diphosphate
PubMed: 38271668
DOI: 10.1021/jacs.3c11402 -
International Journal of Molecular... Dec 2023Androgen receptor pathway inhibitors (ARPI) and polyadenosine diphosphate-ribose inhibitors (PARPi) are part of the standard of care in patients with metastatic... (Review)
Review
Androgen receptor pathway inhibitors (ARPI) and polyadenosine diphosphate-ribose inhibitors (PARPi) are part of the standard of care in patients with metastatic castration-resistant prostate cancer (mCRPC). There is biological evidence that the association of ARPI and PARPi could have a synergistic effect; therefore, several ongoing clinical trials are investigating the efficacy of this combination with preliminary results that are not perfectly concordant in identifying patients who can obtain the most benefit from this therapeutic option. The purpose of this review is to describe the PARPi mechanisms of action and to analyze the biological mechanisms behind the interplay between the androgen receptor and the PARPi system to better understand the rationale of the ARPI + PARPi combinations. Furthermore, we will summarize the preliminary results of the ongoing studies on these combinations, trying to understand in which patients to apply. Finally, we will discuss the clinical implications of this combination and its possible future perspectives.
Topics: Male; Humans; Receptors, Androgen; Synthetic Lethal Mutations; Diphosphates; Ribose; Prostatic Neoplasms; Androgen Receptor Antagonists; Adenosine; Polymers
PubMed: 38203248
DOI: 10.3390/ijms25010078