Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the ...lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs,
. In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure,
. Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to ...cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.
High species diversity may result from recent rapid speciation in a 'cradle' and/or the gradual accumulation and preservation of species over time in a 'museum'. China harbours nearly 10% of ...angiosperm species worldwide and has long been considered as both a museum, owing to the presence of many species with hypothesized ancient origins, and a cradle, as many lineages have originated as recent topographic changes and climatic shifts-such as the formation of the Qinghai-Tibetan Plateau and the development of the monsoon-provided new habitats that promoted remarkable radiation. However, no detailed phylogenetic study has addressed when and how the major components of the Chinese angiosperm flora assembled to form the present-day vegetation. Here we investigate the spatio-temporal divergence patterns of the Chinese flora using a dated phylogeny of 92% of the angiosperm genera for the region, a nearly complete species-level tree comprising 26,978 species and detailed spatial distribution data. We found that 66% of the angiosperm genera in China did not originate until early in the Miocene epoch (23 million years ago (Mya)). The flora of eastern China bears a signature of older divergence (mean divergence times of 22.04-25.39 Mya), phylogenetic overdispersion (spatial co-occurrence of distant relatives) and higher phylogenetic diversity. In western China, the flora shows more recent divergence (mean divergence times of 15.29-18.86 Mya), pronounced phylogenetic clustering (co-occurrence of close relatives) and lower phylogenetic diversity. Analyses of species-level phylogenetic diversity using simulated branch lengths yielded results similar to genus-level patterns. Our analyses indicate that eastern China represents a floristic museum, and western China an evolutionary cradle, for herbaceous genera; eastern China has served as both a museum and a cradle for woody genera. These results identify areas of high species richness and phylogenetic diversity, and provide a foundation on which to build conservation efforts in China.
Hepatocytic ballooning is a key histological feature in the diagnosis of non‐alcoholic steatohepatitis (NASH) and is an essential component of the two most widely used histological scoring systems ...for diagnosing and staging non‐alcoholic fatty liver disease (NAFLD) namely, the NAFLD activity score (NAS), and the steatosis, activity and fibrosis (SAF) scoring system. As a result of the increasing incidence of NASH globally, the diagnostic challenges of hepatocytic ballooning are unprecedented. Despite the clear pathological concept of hepatocytic ballooning, there are still challenges in assessing hepatocytic ballooning in ‘real life’ situations. Hepatocytic ballooning can be confused with cellular oedema and microvesicular steatosis. Significant inter‐observer variability does exist in assessing the presence and severity of hepatocytic ballooning. In this review article, we describe the underlying mechanisms associated with hepatocytic ballooning. Specifically, we discuss the increased endoplasmic reticulum stress and the unfolded protein response, as well as the rearrangement of the intermediate filament cytoskeleton, the appearance of Mallory‐Denk bodies and activation of the sonic Hedgehog pathway. We also discuss the use of artificial intelligence in the detection and interpretation of hepatocytic ballooning, which may provide new possibilities for future diagnosis and treatment.
Poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA‐deficient tumors. However, over 40% of BRCA‐deficient patients fail to respond to PARPi. Here, we ...report that thioparib, a next‐generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi‐sensitive and ‐resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1‐dependent DNA damage and replication stress, causing S‐phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR‐mediated DNA repair while increasing RAD51 foci formation. Notably, the on‐target inhibition of PARP7 by thioparib‐activated STING/TBK1‐dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome‐scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next‐generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier‐generation PARPi.
Synopsis
PARP inhibitors (PARPi) resistance is ubiquitous in the clinic. A newly discovered pan‐PARP inhibitor, thioparib, is highly effective against olaparib‐resistant cancer models, which suggests that therapeutic vulnerabilities still exist in PARPi‐resistant tumors.
Thioparib is a novel, potent, and orally bioavailable pan‐PARP inhibitor.
Thioparib overcomes primary and acquired olaparib resistance in vitro and in vivo.
Thioparib suppresses HR‐mediated DNA repair.
Thioparib induces a robust type I interferon response.
PARP inhibitors (PARPi) resistance is ubiquitous in the clinic. A newly discovered pan‐PARP inhibitor, thioparib, is highly effective against olaparib‐resistant cancer models, which suggests that therapeutic vulnerabilities still exist in PARPi‐resistant tumors.
The current outbreak of coronavirus disease (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, spreads across national and international ...borders. The overall death rate of COVID-19 pneumonia in the Chinese population was 4%.
To describe the process of hospitalization and critical care of patients who died of COVID-19 pneumonia.
This was a multicenter observational study of 109 decedents with COVID-19 pneumonia from three hospitals in Wuhan. Demographic, clinical, laboratory, and treatment data were collected and analyzed, and the final date of follow-up was February 24, 2020.
The mean age of 109 decedents with COVID-19 pneumonia was 70.7 years, 35 patients (32.1%) were female, and 85 patients (78.0%) suffered from one or more underlying comorbidities. Multiple organ failure, especially respiratory failure and heart failure, appeared in all patients even at the early stage of disease. Overall, the mean time from onset of symptoms to death was 22.3 days. All 109 hospitalized patients needed admission to an intensive care unit (ICU); however, because of limited availability, only 51 (46.8%) could be admitted. The period from hospitalization to death in the ICU group and non-ICU group was 15.9 days (standard deviation = 8.8 d) and 12.5 days (8.6 d,
= 0.044), respectively.
Mortality due to COVID-19 pneumonia was concentrated in patients above the age of 65 years, especially those with major comorbidities. Patients who were admitted to the ICU lived longer than those who were not. Our findings should aid in the recognition and clinical management of such infections, especially with regard to ICU resource allocation.
Agricultural greenhouses (AGs) are an important facility for the development of modern agriculture. Accurately and effectively detecting AGs is a necessity for the strategic planning of modern ...agriculture. With the advent of deep learning algorithms, various convolutional neural network (CNN)-based models have been proposed for object detection with high spatial resolution images. In this paper, we conducted a comparative assessment of the three well-established CNN-based models, which are Faster R-CNN, You Look Only Once-v3 (YOLO v3), and Single Shot Multi-Box Detector (SSD) for detecting AGs. The transfer learning and fine-tuning approaches were implemented to train models. Accuracy and efficiency evaluation results show that YOLO v3 achieved the best performance according to the average precision (mAP), frames per second (FPS) metrics and visual inspection. The SSD demonstrated an advantage in detection speed with an FPS twice higher than Faster R-CNN, although their mAP is close on the test set. The trained models were also applied to two independent test sets, which proved that these models have a certain transability and the higher resolution images are significant for accuracy improvement. Our study suggests YOLO v3 with superiorities in both accuracy and computational efficiency can be applied to detect AGs using high-resolution satellite images operationally.
T-helper (Th) 22 is involved in the pathogenesis of inflammatory diseases. The roles of Th22 cells in the pathophysiological of ankylosing spondylitis (AS) and rheumatoid arthritis (RA) remain ...unsettled. So we examined the frequencies of Th22 cells, Th17 cells and Th1 cells in peripheral blood (PB) from patients with AS and patients with RA compared with both healthy controls as well as patients with osteoarthritis.
We studied 32 AS patients, 20 RA patients, 10 OA patients and 20 healthy controls. The expression of IL-22, IL-17 and IFN-γ were examined in AS, RA, OA patients and healthy controls by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay.
Th22 cells, Th17 cells and interleukin-22 were significantly elevated in AS and RA patients compared with OA patients and healthy controls. Moreover, Th22 cells showed positive correlation with Th17 cells as well as interleukin-22 in AS and RA patients. However, positive correlation between IL-22 and Th17 cells was only found in AS patients not in RA patients. In addition, the percentages of both Th22 cells and Th17 cells correlated positively with disease activity only in RA patients not in AS patients.
The frequencies of both Th22 cells and Th17 cells were elevated in PB from patients with AS and patients with RA. These findings suggest that Th22 cells and Th17 cells may be implicated in the pathogenesis of AS and RA, and Th22 cells and Th17 cells may be reasonable cellular targets for therapeutic intervention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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The gut microbiota decomposes the ingredients in TCM into secondary metabolites with high biological activity, promotes the entry of medicines into the circulation, and has a ...beneficial effect on pathological sites. At the same time, the ingredient of TCM can well change the composition and structure of the gut microbiota, thereby realising the function of diseased organ/tissues through the systemic action of the gut microbiota.
In recent years, the interaction between the bioactive ingredients of traditional Chinese medicine (TCM) and gut microbiota has been a focus of many studies. When TCM enters the digestive tract, some bioactive ingredients are not absorbed into the gut well thus leading to low bioavailability. Ingredients of TCM are metabolised, or biotransformed by gut microbiota, thereby producing new bioactive molecules, and promote medicine absorption into the circulation. At the same time, the ingredients of TCM effect the composition and structure of gut microbiota, thereby influencing the remote function of diseased organs / tissues through the systemic action of the gut microbiota. In this review, we summarise the gut microbiota-mediated metabolism of flavonoids, alkaloids, terpenoids, saponins, polysaccharides, phenylpropanoids, and organic acids, along with a discussion on the metabolites formed and the biotransformation pathways involving various enzymes. We also highlight the importance of bioactive ingredients of TCM in regulating gut microbiota.
Single atomic Pt catalysts exhibit particularly high hydrogen evolution reaction (HER) activity compared to conventional nanomaterial‐based catalysts. However, the enhanced mechanisms between Pt and ...their coordination environment are not understood in detail. Hence, a systematic study examining the different types of N in the support is essential to clearly demonstrate the relationship between Pt single atoms and N‐doped support. Herein, three types of carbon nanotubes with varying types of N (pyridine‐like N, pyrrole‐like N, and quaternary N) are used as carbon support for Pt single atom atomic layer deposition. The detailed coordination environment of the Pt single atom catalyst is carefully studied by electron microscope and X‐ray absorption spectra (XAS). Interestingly, with the increase of pyrrole‐like N in the CNT support, the HER activity of the Pt catalyst also improves. First principle calculations results indicate that the interaction between the dyz and s orbitals of H and sp3 hybrid orbital of N should be the origin of the superior HER performance of these Pt single atom catalysts (SACs).
The precisely controlled electronic structure of Pt single atoms by pyrrole‐like nitrogen in the support is achieved by atomic layer deposition method. The Pt single atoms anchored on pyrrole‐like nitrogen in the nitrogen‐doped carbon nanotube support show much higher mass activity and excellent stability compared to commercial Pt/C catalysts for hydrogen evolution reaction.
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