-
The Journal of Organic Chemistry Jul 2024Construction of the core structure of akuammiline alkaloids with three-dimensional cage-like structures for their diversity-oriented synthesis was investigated....
Construction of the core structure of akuammiline alkaloids with three-dimensional cage-like structures for their diversity-oriented synthesis was investigated. Extensive exploration centered around the introduction of nitrogen functional groups and construction of the E-ring in an intramolecular or intermolecular manner revealed that a Claisen rearrangement approach involving intramolecular amination provided a common precursor, potentially facilitating divergent access to various types of akuammiline alkaloids.
PubMed: 38952036
DOI: 10.1021/acs.joc.4c01105 -
The Journal of Eukaryotic Microbiology Jul 2024Glaucophytes, an enigmatic group of freshwater algae, occupy a pivotal position within the Archaeplastida, providing insights into the early evolutionary history of...
Glaucophytes, an enigmatic group of freshwater algae, occupy a pivotal position within the Archaeplastida, providing insights into the early evolutionary history of plastids and their host cells. These algae possess unique plastids, known as cyanelles that retain certain ancestral features, enabling a better understanding of the plastid transition from cyanobacteria. In this study, we investigated the role of ethylene, a potent hormone used by land plants to coordinate stress responses, in the glaucophyte alga Cyanophora paradoxa. We demonstrate that C. paradoxa produces gaseous ethylene when supplied with exogenous 1-aminocyclopropane-1-carboxylic acid (ACC), the ethylene precursor in land plants. In addition, we show that cells produce ethylene natively in response to abiotic stress, and that another plant hormone, abscisic acid (ABA), interferes with ethylene synthesis from exogenously supplied ACC, while positively regulating reactive oxygen species (ROS) accumulation. ROS synthesis also occurred following abiotic stress and ACC treatment, possibly acting as a second messenger in stress responses. A physiological response of C. paradoxa to ACC treatment is growth inhibition. Using transcriptomics, we reveal that ACC treatment induces the upregulation of senescence-associated proteases, consistent with the observation of growth inhibition. This is the first report of hormone usage in a glaucophyte alga, extending our understanding of hormone-mediated stress response coordination into the Glaucophyta, with implications for the evolution of signaling modalities across Archaeplastida.
PubMed: 38952030
DOI: 10.1111/jeu.13041 -
The Journal of Organic Chemistry Jul 2024We have successfully synthesized a series of bidentate ligands by utilizing 2-(trimethylsilyl)phenyl trifluorosulfonate as a precursor for the benzyl group. This method...
We have successfully synthesized a series of bidentate ligands by utilizing 2-(trimethylsilyl)phenyl trifluorosulfonate as a precursor for the benzyl group. This method proceeded by inserting a polythiourea into the C═S π-bond, intramolecular ring proton migration, and ring opening. Salient features of this strategy are mild reaction conditions, a novel product structure, excellent stereochemistry, and a good functional group tolerance. Furthermore, a series of density functional theory calculations were performed to gain insights into the transfer mechanism.
PubMed: 38951997
DOI: 10.1021/acs.joc.4c00894 -
Alzheimer's Research & Therapy Jun 2024The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the... (Review)
Review
The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the main constituent of amyloid plaques in Alzheimer's Disease (AD). The physiological functions of APP in the human adult brain are very diverse including intracellular signaling, synaptic and neuronal plasticity, and cell adhesion, among others. There is growing evidence that APP becomes dysfunctional in AD and that this dyshomeostasis may impact several APP functions beyond Aβ generation. The vast majority of current anti-amyloid approaches in AD have focused on reducing the synthesis of Aβ or increasing the clearance of brain Aβ aggregates following a paradigm in which Aβ plays a solo in APP dyshomeostasis. A wider view places APP at the center stage in which Aβ is an important, but not the only, factor involved in APP dyshomeostasis. Under this paradigm, APP dysfunction is universal in AD, but with some differences across different subtypes. Little is known about how to approach APP dysfunction therapeutically beyond anti-Aβ strategies. In this review, we will describe the role of APP dyshomeostasis in AD beyond Aβ and the potential therapeutic strategies targeting APP.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Amyloid beta-Peptides; Brain
PubMed: 38951839
DOI: 10.1186/s13195-024-01504-w -
Scientific Reports Jul 2024Proline 4-hydroxylase 2 (P4HA2) is known for its hydroxylase activity, primarily involved in hydroxylating collagen precursors and promoting collagen cross-linking under...
Proline 4-hydroxylase 2 (P4HA2) is known for its hydroxylase activity, primarily involved in hydroxylating collagen precursors and promoting collagen cross-linking under physiological conditions. Although its overexpression influences a wide variety of malignant tumors' occurrence and development, its specific effects and mechanisms in oral squamous cell carcinoma (OSCC) remain unclear. This study focused on investigating the expression patterns, carcinogenic functions, and underlying mechanisms of P4HA2 in OSCC cells. Various databases, including TCGA, TIMER, UALCAN, GEPIA, and K-M plotter, along with paraffin-embedded samples, were used to ascertain P4HA2 expression in cancer and its correlation with clinicopathological features. P4HA2 knockdown and overexpression cell models were developed to assess its oncogenic roles and mechanisms. The results indicated that P4HA2 was overexpressed in OSCC and inversely correlated with patient survival. Knockdown of P4HA2 suppressed invasion, migration, and proliferation of OSCC cells both in vitro and in vivo, whereas overexpression of P4HA2 had the opposite effects. Mechanistically, the phosphorylation levels of the PI3K/AKT pathway were reduced following P4HA2 silencing. The study reveals that P4HA2 acts as a promising biomarker for predicting prognosis in OSCC and significantly affects metastasis, invasion, and proliferation of OSCC cells through the regulation of the PI3K/AKT signaling pathway.
Topics: Humans; Proto-Oncogene Proteins c-akt; Mouth Neoplasms; Cell Proliferation; Phosphatidylinositol 3-Kinases; Signal Transduction; Cell Line, Tumor; Neoplasm Invasiveness; Cell Movement; Procollagen-Proline Dioxygenase; Carcinoma, Squamous Cell; Gene Expression Regulation, Neoplastic; Animals; Mice; Female; Male; Neoplasm Metastasis; Middle Aged; Mice, Nude
PubMed: 38951593
DOI: 10.1038/s41598-024-64264-5 -
Scientific Reports Jul 2024The primary objective of analyzing the data obtained in a mass spectrometry-based proteomic experiment is peptide and protein identification, or correct assignment of...
The primary objective of analyzing the data obtained in a mass spectrometry-based proteomic experiment is peptide and protein identification, or correct assignment of the tandem mass spectrum to one amino acid sequence. Comparison of empirical fragment spectra with the theoretical predicted one or matching with the collected spectra library are commonly accepted strategies of proteins identification and defining of their amino acid sequences. Although these approaches are widely used and are appreciably efficient for the well-characterized model organisms or measured proteins, they cannot detect novel peptide sequences that have not been previously annotated or are rare. This study presents PowerNovo tool for de novo sequencing of proteins using tandem mass spectra acquired in a variety of types of mass analyzers and different fragmentation techniques. PowerNovo involves an ensemble of models for peptide sequencing: model for detecting regularities in tandem mass spectra, precursors, and fragment ions and a natural language processing model, which has a function of peptide sequence quality assessment and helps with reconstruction of noisy sequences. The results of testing showed that the performance of PowerNovo is comparable and even better than widely utilized PointNovo, DeepNovo, Casanovo, and Novor packages. Also, PowerNovo provides complete cycle of processing (pipeline) of mass spectrometry data and, along with predicting the peptide sequence, involves the peptide assembly and protein inference blocks.
Topics: Tandem Mass Spectrometry; Sequence Analysis, Protein; Peptides; Amino Acid Sequence; Software; Proteomics; Algorithms
PubMed: 38951578
DOI: 10.1038/s41598-024-65861-0 -
Nature Communications Jun 2024Argonaute proteins are the central effectors of RNA-guided RNA silencing pathways in eukaryotes, playing crucial roles in gene repression and defense against viruses and...
Argonaute proteins are the central effectors of RNA-guided RNA silencing pathways in eukaryotes, playing crucial roles in gene repression and defense against viruses and transposons. Eukaryotic Argonautes are subdivided into two clades: AGOs generally facilitate miRNA- or siRNA-mediated silencing, while PIWIs generally facilitate piRNA-mediated silencing. It is currently unclear when and how Argonaute-based RNA silencing mechanisms arose and diverged during the emergence and early evolution of eukaryotes. Here, we show that in Asgard archaea, the closest prokaryotic relatives of eukaryotes, an evolutionary expansion of Argonaute proteins took place. In particular, a deep-branching PIWI protein (HrAgo1) encoded by the genome of the Lokiarchaeon 'Candidatus Harpocratesius repetitus' shares a common origin with eukaryotic PIWI proteins. Contrasting known prokaryotic Argonautes that use single-stranded DNA as guides and/or targets, HrAgo1 mediates RNA-guided RNA cleavage, and facilitates gene silencing when expressed in human cells and supplied with miRNA precursors. A cryo-EM structure of HrAgo1, combined with quantitative single-molecule experiments, reveals that the protein displays structural features and target-binding modes that are a mix of those of eukaryotic AGO and PIWI proteins. Thus, this deep-branching archaeal PIWI may have retained an ancestral molecular architecture that preceded the functional and mechanistic divergence of eukaryotic AGOs and PIWIs.
Topics: Argonaute Proteins; Humans; RNA Interference; Archaea; RNA, Small Interfering; Archaeal Proteins; Cryoelectron Microscopy; MicroRNAs; Evolution, Molecular; Phylogeny
PubMed: 38951509
DOI: 10.1038/s41467-024-49452-1 -
Annals of Biomedical Engineering Jun 2024Low back pain (LBP) is a common medical condition worldwide, though the etiology of injuries causing most LBP is unknown. Flexion and repeated compression increase...
Low back pain (LBP) is a common medical condition worldwide, though the etiology of injuries causing most LBP is unknown. Flexion and repeated compression increase lumbar injury risk, yet the complex viscoelastic behavior of the lumbar spine has not been characterized under this loading scheme. Characterizing the non-injurious primary creep behavior in the lumbar spine is necessary for understanding the biomechanical response preceding injury. Fifteen porcine lumbar spinal units were loaded in repeated flexion-compression with peak compressive stresses ranging from 1.41 to 4.68 MPa. Applied loading simulated real loading exposures experienced by high-speed watercraft occupants. The strain response in the primary creep region was modeled for all tests using a generalized Kelvin-Voigt model. A quasilinear viscoelastic (QLV) approach was used to separate time-dependent (creep) and stress-dependent (elastic) responses. Optimizations between the models and experimental data determined creep time constants, creep coefficients, and elastic constants associated with this tissue under repeated flexion-compression loading. Average R for all fifteen models was 0.997. Creep time constants optimized across all fifteen models were 24 s and 580 s and contributed to 20 ± 3% and 30 ± 3% of the overall strain response, respectively. The non-transient behavior contributed to 50 ± 0% of the overall response. Elastic behavior for this porcine population had an average standard deviation of 24.5% strain across the applied stress range. The presented primary creep characterization provides the response precursor to injurious behavior in the lumbar spine. Results from this study can further inform lumbar injury prediction and kinematic models.
PubMed: 38951421
DOI: 10.1007/s10439-024-03557-2 -
Journal of Molecular Modeling Jun 2024A nanocomposite photocatalyst consisting of polyaniline (PANI) and copper oxide (CuO) was successfully synthesized through an in-situ polymerization approach using...
CONTEXT AND RESULTS
A nanocomposite photocatalyst consisting of polyaniline (PANI) and copper oxide (CuO) was successfully synthesized through an in-situ polymerization approach using aniline as the precursor. The synthesized nanocomposite was characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), UV-visible spectroscopy (UV-Vis), determination of the point of zero charge (pHPZC), and scanning electron microscopy (SEM). The photocatalytic efficiency of the PANI-CuO nanocomposite was evaluated in the context of photodegrading Malachite Green (MG) dye under visible light. Malachite Green, a synthetic dye commonly used in the textile and aquaculture industries, is a significant contaminant due to its toxic, mutagenic, and carcinogenic properties, making its removal from water resources crucial for environmental and human health. Distilled water artificially contaminated with MG dye was used as the medium for testing. The parameters influencing the photodegradation efficiency were comprehensively investigated. These parameters included catalyst dosage, reaction time, initial dye concentration, and pH. The results of this study indicate that the degradation efficiency of MG dye displayed an upward trend with time, catalyst dosage, and pH while exhibiting a converse relationship with the initial dye concentration. A degradation rate of 97% was achieved with an initial concentration of 20 mg L, employing a catalyst dose of 1.6 g L at pH 6 for a reaction time of 180 min. Furthermore, the reusability of the catalyst was assessed, revealing consistent performance over five consecutive cycles.
COMPUTATIONAL AND THEORETICAL TECHNIQUES
Density functional theory (DFT) was employed to optimize the structures of PANI, PANI-CuO, and their respective complexes formed through dye interaction, employing Gaussian software. These calculations employed the B3LYP/6-311G + + (d,p) basis set in an aqueous environment with water serving as the solvent. The kinetics of Malachite Green degradation were analyzed using both first and second-order kinetic models.
PubMed: 38951276
DOI: 10.1007/s00894-024-06039-3 -
Scientific Reports Jul 2024The formation of planets in our solar system encompassed various stages of accretion of planetesimals that formed in the protoplanetary disk within the first few million...
The formation of planets in our solar system encompassed various stages of accretion of planetesimals that formed in the protoplanetary disk within the first few million years at different distances to the sun. Their chemical diversity is reflected by compositionally variable meteorite groups from different parent bodies. There is general consensus that their formation location is roughly constrained by a dichotomy of nucleosynthetic isotope anomalies, relating carbonaceous (C) meteorite parent bodies to the outer protoplanetary disk and the non-carbonaceous (NC) parent bodies to an origin closer to the sun. It is a common idea, that in these inner parts of the protoplanetary disks, planetesimal accretion processes were faster. Testing such scenarios requires constraining formation ages of meteorite parent bodies. Although isotopic age dating can yield precise formation ages of individual mineral constituents of meteorites, such ages frequently represent mineral cooling ages that can postdate planetesimal formation by millions or tens of millions of years, depending on the cooling history of individual planetesimals at different depths. Nevertheless, such cooling ages provide a detailed thermal history which can be fitted by thermal evolution models that constrain the formation age of individual parent bodies. Here we apply state-of-the-art thermal evolution models to constrain planetesimal formation times particular in the outer solar system formation region of C meteorites. We infer a temporally distributed accretion of various parent bodies from Ma to Ma after solar system formation, with 3.7 Ma and Ma for the parent bodies of CR1-3 chondrites and the Flensburg carbonaceous chondrite, and and Ma for the parent bodies of differentiated achondrites NWA 6704 and NWA 011, respectively. This implies that accretion processes in the C reservoir started as early as in the NC reservoir and were operating throughout typical protoplanetary disk lifetimes, thereby producing differentiated parent bodies with carbonaceous compositions in addition to undifferentiated C chondrite parent bodies. The accretion times correlate inversely with the degree of the meteorites' alteration, metamorphism, or differentiation. The accretion times for the CM, CI, Ryugu, and Tafassite parent bodies of 3.8 Ma, 3.8 Ma, Ma, and 1.1 Ma, respectively, fit well into this correlation in agreement with the thermal and alteration conditions suggested by these meteorites. Our results indicate that individual planetesimals formed rapidly (i.e., within Ma), however, distinct planetesimals formed recurrently throughout the total lifetime of the protoplanetary disk. Rapid individual formation is consistent with streaming instabilities assisted by gravitational collapse. However, obviously not the total dust inventory was consumed at early disk evolution stages, so there must have been some delay mechanisms, e.g. collisional destruction of precursor aggregates due to high impact velocities induced by radial drift phenomena. This counterbalance enabled late ( Ma) accretion of C planetesimals beyond the snow line which escaped severe planetesimal heating and volatile loss, hence, preserving their volatiles, especially water. Only this delayed formation of water-rich planetesimals allowed Earth to accrete sufficient water to become a habitable planet, preventing it from being a bone dry planet.
PubMed: 38951135
DOI: 10.1038/s41598-024-63768-4