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1.
PARP enzymes create ADP-ribose modifications to regulate multiple facets of human biology, and some prominent PARP family members are best known for the nucleic acid interactions that regulate their activities and functions. Recent structural studies have highlighted PARP interactions with nucleic acids, in particular for PARP enzymes that detect and respond to DNA strand break damage. These studies build on our understanding of how DNA break detection is linked to the catalysis of ADP-ribose modifications, provide insights into distinct modes of DNA interaction, and shed light on the mechanisms of PARP inhibitor action. PARP enzymes have several connections to RNA biology, including the detection of the genomes of RNA viruses, and recent structural work has highlighted how PARP13/ZAP specifically targets viral genomes enriched in CG dinucleotides. 相似文献
3.
《Genomics》2023,115(4):110647
Differences in the gut microbiota and metabolic processes between males and females may explain differences in the risk of liver injury; however, the sex-specific effects of antibiotics and probiotics on these relationships are not clear. We evaluated differences in the gut microbiota and the risk of liver injury between male and female rats after the oral administration of antibiotics or probiotics followed by a period of diethylnitrosamine treatment to chemically induce liver injuryusing high-throughput sequencing of fecal microbiota combined with histological analyses of liver and colon tissues. Our results suggest that the ratio of gram-positive to gram-negative bacteria in kanamycin-treated rats was significantly higher than that of other groups, and this difference persisted for the duration of the experiment. Antibiotics significantly changed the composition of the gut microbiota of experimental rats. Clindamycin caused more diethylnitrosamine-induced damage to livers of male rats. Probiotics did not influencethe gut microbiota; however, they hadprotective effects against liver injury induced by diethylnitrosamine, especially in female rats. These results strengthen our understanding of sex differences in the indirect effects of antibiotics or probiotics on metabolism and liver injury in hosts via the gut microbiota. 相似文献
4.
Metagenomic sequencing data provide a rich resource from which to expand our understanding of differential protein functions involved in human health. Here, we outline a pipeline that combines microbial whole genome sequencing with protein structure data to yield a structural metagenomics-informed atlas of microbial enzyme families of interest. Visualizing metagenomics data through a structural lens facilitates downstream studies including targeted inhibition and probe-based proteomics to define at the molecular level how different enzyme orthologs impact in vivo function. Application of this pipeline to gut microbial enzymes like glucuronidases, TMA lyases, and bile salt hydrolases is expected to pinpoint their involvement in health and disease and may aid in the development of therapeutics that target specific enzymes within the microbiome. 相似文献
5.
《Biochimica et Biophysica Acta (BBA)/General Subjects》2022,1866(5):130114
Amyloidogenic proteins form aggregates in cells, thereby leading to neurodegenerative disorders, including Alzheimer's and prion's disease, amyotrophic lateral sclerosis (ALS) in humans, and degenerative myelopathy (DM) and cognitive dysfunction in dogs. Hence, many small-molecule compounds have been screened to examine their inhibitory effects on amyloidogenic protein aggregation. However, no effective drug suitable for transition to clinical use has been found. Here we examined several novel oxindole compounds (GIF compounds) for their inhibitory effects on aggregate formation of the canine mutant superoxide dismutase 1 (cSOD1 E40K), a causative mutation resulting in DM, using Thioflavin-T fluorescence. Most GIF compounds inhibited the aggregation of cSOD1 E40K. Among the compounds, GIF-0854-r and GIF-0890-r were most effective. Their inhibitory effects were also observed in cSOD1 E40K-transfected cells. Additionally, GIF-0890-r effectively inhibited the aggregate formation of human SOD1 G93A, a causative mutation of ALS. GIF-0827-r and GIF-0856-r also effectively inhibited aggregate formation of human prion protein (hPrP). Subsequently, the correlation between their inhibitory effects on cSOD1 and hPrP aggregation was shown, indicating GIF compounds inhibited the aggregate formation of multiple amyloidogenic proteins. Conclusively, the novel oxindole compounds (GIF-0827-r, GIF-0854-r, GIF-0856-r, and GIF-0890-r) are proposed as useful therapeutic candidates for amyloidogenic neurodegenerative disorders. 相似文献
6.
While aggression is often conceptualized as a highly stereotyped, innate behavior, individuals within a species exhibit a surprising amount of variability in the frequency, intensity, and targets of their aggression. While differences in genetics are a source of some of this variation across individuals (estimates place the heritability of behavior at around 25–30%), a critical driver of variability is previous life experience. A wide variety of social experiences, including sexual, parental, and housing experiences can facilitate “persistent” aggressive states, suggesting that these experiences engage a common set of synaptic and molecular mechanisms that act on dedicated neural circuits for aggression. It has long been known that sex steroid hormones are powerful modulators of behavior, and also, that levels of these hormones are themselves modulated by experience. Several recent studies have started to unravel how experience-dependent hormonal changes during adulthood can create a cascade of molecular, synaptic, and circuit changes that enable behavioral persistence through circuit level remodeling. Here, we propose that sex steroid hormones facilitate persistent aggressive states by changing the relationship between neural activity and an aggression “threshold”. 相似文献
7.
Hippocampal inhibitory interneurons exert a powerful influence on learning and memory. Inhibitory interneurons are known to play a major role in many diseases that affect memory, and to strongly influence brain functions required for memory-related tasks. While previous studies involving genetic, optogenetic, and pharmacological manipulations have shown that hippocampal interneurons play essential roles in spatial and episodic learning and memory, exactly how interneurons affect local circuit computations during spatial navigation is not well understood. Given the significant anatomical, morphological, and functional heterogeneity in hippocampal interneurons, one may suspect cell-type specific roles in circuit computations. Here, we review emerging evidence of CA1 hippocampal interneurons’ role in local circuit computations that support spatial learning and memory and discuss open questions about CA1 interneurons in spatial learning. 相似文献
8.
Serum-free culturing of patient-derived glioblastoma biopsies enrich for glioblastoma stem cells (GSCs) and is recognized as a disease-relevant model system in glioblastoma (GBM). We hypothesized that the temozolomide (TMZ) drug sensitivity of patient-derived GSC cultures correlates to clinical sensitivity patterns and has clinical predictive value in a cohort of GBM patients. To this aim, we established 51 individual GSC cultures from surgical biopsies from both treatment-naïve primary and pretreated recurrent GBM patients. The cultures were evaluated for sensitivity to TMZ over a dosing range achievable in normal clinical practice. Drug efficacy was quantified by the drug sensitivity score. MGMT-methylation status was investigated by pyrosequencing. Correlative, contingency, and survival analyses were performed for associations between experimental and clinical data. We found a heterogeneous response to temozolomide in the GSC culture cohort. There were significant differences in the sensitivity to TMZ between the newly diagnosed and the TMZ-treated recurrent disease (p <0.01). There was a moderate correlation between MGMT-status and sensitivity to TMZ (r=0.459, p=0.0009). The relationship between MGMT status and TMZ efficacy was statistically significant on multivariate analyses (p=0.0051). We found a predictive value of TMZ sensitivity in individual GSC cultures to patient survival (p=0.0089). We conclude that GSC-enriched cultures hold clinical and translational relevance by their ability to reflect the clinical heterogeneity in TMZ-sensitivity, substantiate the association between TMZ-sensitivity and MGMT-promotor methylation status and appear to have a stronger predictive value than MGMT-promotor methylation on clinical responses to TMZ. 相似文献
9.
Long-lasting synaptic changes within the neuronal network mediate memory. Neurons bearing such physical traces of memory (memory engram cells) are often equated with neurons expressing immediate early genes (IEGs) during a specific experience. However, past studies observed the expression of different IEGs in non-overlapping neurons or synaptic plasticity in neurons that do not express a particular IEG. Importantly, recent studies revealed that distinct subsets of neurons expressing different IEGs or even IEG negative-(yet active) neurons support different aspects of memory or computation, suggesting a more complex nature of memory engram cells than previously thought. In this short review, we introduce studies revealing such heterogeneous composition of the memory engram and discuss how the memory system benefits from it. 相似文献
10.
Electron microscopy in three dimensions (3D) of cells and tissues can be essential for understanding the ultrastructural aspects of biological processes. The quest for 3D information reveals challenges at many stages of the workflow, from sample preparation, to imaging, data analysis and segmentation. Here, we outline several available methods, including volume SEM imaging, cryo-TEM and cryo-STEM tomography, each one occupying a different domain in the basic tradeoff between field-of-view and resolution. We discuss the considerations for choosing a suitable method depending on research needs and highlight recent developments that are essential for making 3D volume imaging of cells and tissues a standard tool for cellular and structural biologists. 相似文献
11.
《Journal of structural biology》2023,215(1):107941
As structural determination of protein complexes approaches atomic resolution, there is an increasing focus on conformational dynamics. Here we conceptualize the combination of two techniques which have become established in recent years: microcrystal electron diffraction and ultrafast electron microscopy. We show that the extremely low dose of pulsed photoemission still enables microED due to the strength of the electron bunching from diffraction of the protein crystals. Indeed, ultrafast electron diffraction experiments on protein crystals have already been demonstrated to be effective in measuring intermolecular forces in protein microcrystals. We discuss difficulties that may arise in the acquisition and processing of data and the overall feasibility of the experiment, paying specific attention to dose and signal-to-noise ratio. In doing so, we outline a detailed workflow that may be effective in minimizing the dose on the specimen. A series of model systems that would be good candidates for initial experiments is provided. 相似文献
12.
《Genomics》2022,114(2):110302
The genetic origins of novelty are of central interest in evolutionary biology. ISG15 and UBA7 are present only in vertebrates. The emergence and evolution of them are not clear. Phylogenetic comparisons revealed that UBA7 descends from gene duplication, and ISG15 and UBA7 arose from UBB/UBC and UBA1, respectively. Uba7 exhibits ubiquitin-activation activity in fish but not tetrapods, suggesting that the relationship of ISG15/Uba7 was promiscuous in origin but was later coopted toward higher specificity. Zebrafish Uba7 is capable of activating the ubiquitin cascade in vitro and in vivo, and it displays distinct specificity preference toward substrates and E2 enzymes compared to zebrafish Uba1. These results together provide a framework for understanding the origin and diversification of ISG15/Uba7 and may serve as a paradigmatic example in which an originally minor functionality in an old gene is made into a new high-specificity protein through random mutations and natural selection. 相似文献
13.
Autophagy regulates cell survival (or cell death in several cases), whereas apoptosis regulates cell death. However, the relationship between autophagy and apoptosis and the regulative mechanism is unclear. We report that steroid hormone 20-hydroxyecdysone (20E) promotes switching from autophagy to apoptosis by increasing intracellular calcium levels in the midgut of the lepidopteran insect Helicoverpa armigera. Autophagy and apoptosis sequentially occurred during midgut programmed cell death under 20E regulation, in which lower concentrations of 20E induced microtubule-associated protein 1 light chain 3–phosphatidylethanolamine (LC3–II, also known as autophagy-related gene 8, ATG8) expression and autophagy. High concentrations of 20E induced cleavage of ATG5 to NtATG5 and pro-caspase-3 to active caspase-3, which led to a switch from autophagy to apoptosis. Blocking autophagy by knockdown of ATG5, ATG7, or ATG12, or with the autophagy inhibitor 3-methyladenine, inhibited 20E-induced autophagy and apoptosis. Blocking apoptosis by using the apoptosis inhibitor Ac-DEVD-CHO did not prevent 20E-induced autophagy, suggesting that apoptosis relies on autophagy. ATG5 knockdown resulted in abnormal pupation and delayed pupation time. High concentrations of 20E induced high levels of intracellular Ca2+, NtATG5, and active caspase-3, which mediated the switch from autophagy to apoptosis. Blocking 20E-mediated increase of cellular Ca2+ caused a decrease of NtATG5 and active caspase-3 and repressed the transformation from autophagy to apoptosis, thereby promoting cell survival. 20E induces an increase in the concentration of intracellular Ca2+, thereby switching autophagic cell survival to apoptotic cell death. 相似文献
14.
Generative molecular design for drug discovery and development has seen a recent resurgence promising to improve the efficiency of the design-make-test-analyse cycle; by computationally exploring much larger chemical spaces than traditional virtual screening techniques. However, most generative models thus far have only utilized small-molecule information to train and condition de novo molecule generators. Here, we instead focus on recent approaches that incorporate protein structure into de novo molecule optimization in an attempt to maximize the predicted on-target binding affinity of generated molecules. We summarize these structure integration principles into either distribution learning or goal-directed optimization and for each case whether the approach is protein structure-explicit or implicit with respect to the generative model. We discuss recent approaches in the context of this categorization and provide our perspective on the future direction of the field. 相似文献
15.
《Biochimica et Biophysica Acta - Proteins and Proteomics》2022,1870(10):140826
The deposition of α-synuclein (αS) aggregates in the gut and the brain is ever present in cases of Parkinson's disease. While the central non-amyloidogenic-component (NAC) region of αS plays a critical role in fibrilization, recent studies have identified a specific sequence from within the N-terminal region (NTR, residues 36–42) as a key modulator of αS fibrilization. Due to the lack of effective therapeutics which specifically target αS aggregates, we have developed a strategy to prevent the aggregation and subsequent toxicity attributed to αS fibrilization utilizing NTR targeting peptides. In this study, L- and D-isoforms of a hexa- (VAQKTV-Aib, 77–82 NAC) and heptapeptide (GVLYVGS-Aib, 36–42 NTR) containing a self-recognition component unique to αS, as well as a C-terminal disruption element, were synthesized to target primary sequence regions of αS that modulate fibrilization. The D-peptide that targets the NTR (NTR-TP-D) was shown by ThT fluorescence assays and TEM to be the most effective at preventing fibril formation and elongation, as well as increasing the abundance of soluble monomeric αS. In addition, NTR-TP-D alters the conformation of destabilised monomers into a less aggregation-prone state and reduces the hydrophobicity of αS fibrils via fibril remodelling. Furthermore, both NTR-TP isoforms alleviate the cytotoxic effects of αS aggregates in both Neuro-2a and Caco-2 cells. Together, this study highlights how targeting the NTR of αS using D-isoform peptide inhibitors may effectively combat the deleterious effects of αS fibrilization and paves the way for future drug design to utilise such an approach to treat Parkinson's disease. 相似文献
16.
《生物化学与生物物理学报:癌评论》2022,1877(4):188738
Small-molecule kinase inhibitors have been well established and successfully developed in the last decades for cancer target therapies. However, intrinsic or acquired drug resistance is becoming the major barrier for their clinical application. With the development of immunotherapies, in particular the discovery of immune checkpoint inhibitors (ICIs), the combination of ICIs with other therapies have recently been extensively explored, among which combination of ICIs with kinase inhibitors achieves promising clinical outcome in a plethora of cancer types. Here we comprehensively summarize the potent roles of protein kinases in modulating immune checkpoints both in tumor and immune cells, and reshaping tumor immune microenvironments by evoking innate immune response and neoantigen generation or presentation. Moreover, the clinical trial and approval of combined administration of kinase inhibitors with ICIs are collected, highlighting the precise strategies to benefit cancer immune therapies. 相似文献
17.
《Genomics》2022,114(4):110400
Endive (Cichorium endivia L.) is a leafy vegetable in the Asteraceae family. Sesquiterpene lactones (STLs) in endive leaves bring a bitter taste that varies between varieties. Despite their importance in breeding varieties with unique flavours, sesquiterpenoid biosynthesis pathways in endive are poorly understood. We assembled a chromosome-scale endive genome of 641 Mb with a contig N50 of 5.16 Mb and annotated 46,711 protein-coding genes. Several gene families, especially terpene synthases (TPS) genes, expanded significantly in the C. endivia genome. STLs biosynthesis-related genes and TPS genes in more bitter varieties have shown a higher level of expression, which could be attributed to genomic variations. Our results penetrate the origin and diversity of bitter taste and facilitate the molecular breeding of endive varieties with unique bitter tastes. The high-quality endive assembly would provide a reference genome for studying the evolution and diversity of Asteraceae. 相似文献
18.
《Journal of molecular biology》2023,435(3):167920
Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) has been identified as a nuclear DNA sensor. Upon viral infection, hnRNP A2/B1 recognizes pathogen-derived DNA as a homodimer, which is a prerequisite for its translocation to the cytoplasm to activate the interferon response. However, the DNA binding mechanism inducing hnRNP A2/B1 homodimerization is unknown. Here, we show the crystal structure of the RNA recognition motif (RRM) of hnRNP A2/B1 in complex with a U-shaped ssDNA, which mediates the formation of a newly observed protein dimer. Our biochemical assays and mutagenesis studies confirm that the hnRNP A2/B1 homodimer forms in solution by binding to pre-generated ssDNA or dsDNA with a U-shaped bulge. These results depict a potential functional state of hnRNP A2/B1 in antiviral immunity and other cellular processes. 相似文献
19.
《Saudi Journal of Biological Sciences》2023,30(6):103646
In current study the pharmaceutically active herbs was used against coccidiosis, caused by a protozoan: Eimeria, lead to $ 3 billion loss annually. The aqueous and methanolic extracts of whole plants were applied in-vitro to assess sporulation inhibition (spi) assay and calculated the inhibitory concentration (IC50). For in-vivo study 9 groups of 14 day old broiler chicks were infected with Eimeria tenella and three groups were treated different concentrations of methanolic extracts of Verbena officinalis and Polygonum glabrum post infection. The mean weight gain, oocyst count, diarrhea, biochemical tests, hematology, and histopathology of all groups were analyzed. The herbs were characterized by antioxidant assay, phytochemical screening, Fourier transmission and infrared (FT-IR), Ultra Violet-visible (UV–Vis) spectroscopy and Gas chromatography and mass spectroscopy (GC–MS). The GC–MS identified phyto-compounds of V. officinalis were docked with S-Adenosyl methionine (SAM) synthetase. The in-vitro study revealed that V. officinalis and P. glabrum have minimum IC50 of 0.14 and 12 mg/ml respectively. The in-vivo experiment showed that V. officinalis had significantly high anticoccidial potential with significant hematological profile like drug treated controls. The histology of treated chicks also showed recovery in the studied tissues. The antioxidant assay showed that V. officinalis have 4.19U/mg Superoxide dismutase (SOD) and 33.96 µM/mg Glutathione (GSH) quantities. The chemical characterization confirmed the presence of large number of organic compounds, however Flavonoids found only in V. officinalis, which suggests the anticoccidial potential of V. officinalis because flavonoids as antagonist of thiamine (Prinzo, 1999), because it promotes the carbohydrate synthesis required. Strychane, 1-acetyl-20a-hydroxy-16-methylene has best binding of with target protein with lowest binding score (-6.4 Kcal/mol), suggests its anticoccidial potential in poultry. 相似文献
20.
A causal role for mitochondrial dysfunction in mammalian aging is supported by recent studies of the mtDNA mutator mouse (“PolG” mouse), which harbors a defect in the proofreading-exonuclease activity of mitochondrial DNA polymerase gamma. These mice exhibit accelerated aging phenotypes characteristic of human aging, including systemic mitochondrial dysfunction, exercise intolerance, alopecia and graying of hair, curvature of the spine, and premature mortality. While mitochondrial dysfunction has been shown to cause increased oxidative stress in many systems, several groups have suggested that PolG mutator mice show no markers of oxidative damage. These mice have been presented as proof that mitochondrial dysfunction is sufficient to accelerate aging without oxidative stress. In this study, by normalizing to mitochondrial content in enriched fractions we detected increased oxidative modification of protein and DNA in PolG skeletal muscle mitochondria. We separately developed novel methods that allow simultaneous direct measurement of mtDNA replication defects and oxidative damage. Using this approach, we find evidence that suggests PolG muscle mtDNA is indeed oxidatively damaged. We also observed a significant decrease in antioxidants and expression of mitochondrial biogenesis pathway components and DNA repair enzymes in these mice, indicating an association of maladaptive gene expression with the phenotypes observed in PolG mice. Together, these findings demonstrate the presence of oxidative damage associated with the premature aging-like phenotypes induced by mitochondrial dysfunction. 相似文献