Structural RNA components supervise the sequential DNA cleavage in R2 retrotransposon.

Retroelements are the widespread jumping elements considered as major drivers for genome evolution, which can also be repurposed as gene-editing tools. Here, we determine the cryo-EM structures of eukaryotic R2 retrotransposon with ribosomal DNA target and regulatory RNAs. Combined with biochemical and sequencing analysis, we reveal two essential DNA regions, Drr and Dcr, required for recognition and cleavage. The association of 3' regulatory RNA with R2 protein accelerates the first-strand cleavage, blocks the second-strand cleavage, and initiates the reverse transcription starting from the 3'-tail. Removing 3' regulatory RNA by reverse transcription allows the association of 5' regulatory RNA and initiates the second-strand cleavage. Taken together, our work explains the DNA recognition and RNA supervised sequential retrotransposition mechanisms by R2 machinery, providing insights into the retrotransposon and application reprogramming.

Maintenance of persistent transmission of a plant arbovirus in its insect vector mediated by the Toll-Dorsal immune pathway.

Throughout evolution, arboviruses have developed various strategies to counteract the host's innate immune defenses to maintain persistent transmission. Recent studies have shown that, in addition to bacteria and fungi, the innate Toll-Dorsal immune system also plays an essential role in preventing viral infections in invertebrates. However, whether the classical Toll immune pathway is involved in maintaining the homeostatic process to ensure the persistent and propagative transmission of arboviruses in insect vectors remain unclear. In this study, we revealed that the transcription factor Dorsal is actively involved in the antiviral defense of an insect vector (Laodelphax striatellus) by regulating the target gene, zinc finger protein 708 (LsZN708), which mediates downstream immune-related effectors against infection with the plant virus (Rice stripe virus, RSV). In contrast, an antidefense strategy involving the use of the nonstructural-protein (NS4) to antagonize host antiviral defense through competitive binding to Dorsal from the MSK2 kinase was employed by RSV; this competitive binding inhibited Dorsal phosphorylation and reduced the antiviral response of the host insect. Our study revealed the molecular mechanism through which Toll-Dorsal-ZN708 mediates the maintenance of an arbovirus homeostasis in insect vectors. Specifically, ZN708 is a newly documented zinc finger protein targeted by Dorsal that mediates the downstream antiviral response. This study will contribute to our understanding of the successful transmission and spread of arboviruses in plant or invertebrate hosts.

A dual role of human tRNA methyltransferase hTrmt13 in regulating translation and transcription.

Since numerous RNAs and RBPs prevalently localize to active chromatin regions, many RNA-binding proteins (RBPs) may be potential transcriptional regulators. RBPs are generally thought to regulate transcription via noncoding RNAs. Here, we describe a distinct, dual mechanism of transcriptional regulation by the previously uncharacterized tRNA-modifying enzyme, hTrmt13. On one hand, hTrmt13 acts in the cytoplasm to catalyze 2'-O-methylation of tRNAs, thus regulating translation in a manner depending on its tRNA-modification activity. On the other hand, nucleus-localized hTrmt13 directly binds DNA as a transcriptional co-activator of key epithelial-mesenchymal transition factors, thereby promoting cell migration independent of tRNA-modification activity. These dual functions of hTrmt13 are mutually exclusive, as it can bind either DNA or tRNA through its CHHC zinc finger domain. Finally, we find that hTrmt13 expression is tightly associated with poor prognosis and survival in diverse cancer patients. Our discovery of the noncatalytic roles of an RNA-modifying enzyme provides a new perspective for understanding epitranscriptomic regulation.

Cortical Tagged Synaptic Long-Term Depression in the Anterior Cingulate Cortex of Adult Mice.

The anterior cingulate cortex (ACC) is a key cortical region for pain perception and emotion. Different forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), have been reported in the ACC. Synaptic tagging of LTP plays an important role in hippocampus-related associative memory. In this study, we demonstrate that synaptic tagging of LTD is detected in the ACC of adult male and female mice. This form of tagged LTD requires the activation of metabotropic glutamate receptor subtype 1 (mGluR1). The induction of tagged LTD is time-related with the strongest tagged LTD appearing when the interval between two independent stimuli is 30 min. Inhibitors of mGluR1 blocked the induction of tagged LTD; however, blocking N-methyl-d-aspartate receptors did not affect the induction of tagged LTD. Nimodipine, an inhibitor of L-type voltage-gated calcium channels, also blocked tagged LTD. In an animal model of amputation, we found that tagged LTD was either reduced or completely blocked. Together with our previous report of tagged LTP in the ACC, this study strongly suggests that excitatory synapses in the adult ACC are highly plastic. The biphasic tagging of synaptic transmission provides a new form of heterosynaptic plasticity in the ACC which has functional and pathophysiological significance in phantom pain.

Endogenous nege-like viral elements in arthropod genomes reveal virus-host coevolution and ancient history of two plant virus families.

Negevirus is a recently proposed taxon of arthropod-infecting virus, which is associated with plant viruses of two families (Virgaviridae and Kitaviridae). Nevertheless, the evolutionary history of negevirus-host and its relationship with plant viruses remain poorly understood. Endogenous nege-like viral elements (ENVEs) are ancient nege-like viral sequences integrated into the arthropod genomes, which can serve as the molecular fossil records of previous viral infection. In this study, 292 ENVEs were identified in 150 published arthropod genomes, revealing the evolutionary history of nege-like viruses and two related plant virus families. We discovered three novel and eight strains of nege-like viruses in 11 aphid species. Further analysis indicated that 10 ENVEs were detected in six aphid genomes, and they were divided into four types (ENVE1-ENVE4). Orthologous integration and phylogenetic analyses revealed that nege-like viruses had a history of infection of over 60 My and coexisted with aphid ancestors throughout the Cenozoic Era. Moreover, two nege-like viral proteins (CP and SP24) were highly homologous to those of plant viruses in the families Virgaviridae and Kitaviridae. CP- and SP24-derived ENVEs were widely integrated into numerous arthropod genomes. These results demonstrate that nege-like viruses have a long-term coexistence with arthropod hosts and plant viruses of the two families, Virgaviridae and Kitaviridae, which may have evolved from the nege-like virus ancestor through horizontal virus transfer events. These findings broaden our perspective on the history of viral infection in arthropods and the origins of plant viruses. IMPORTANCE: Although negevirus is phylogenetically related to plant virus, the evolutionary history of negevirus-host and its relationship with plant virus remain largely unknown. In this study, we used endogenous nege-like viral elements (ENVEs) as the molecular fossil records to investigate the history of nege-like viral infection in arthropod hosts and the evolution of two related plant virus families (Virgaviridae and Kitaviridae). Our results showed the infection of nege-like viruses for over 60 My during the arthropod evolution. ENVEs highly homologous to viral sequences in Virgaviridae and Kitaviridae were present in a wide range of arthropod genomes but were absent in plant genomes, indicating that plant viruses in these two families possibly evolved from the nege-like virus ancestor through cross-species horizontal virus transmission. Our findings provide a new perspective on the virus-host coevolution and the origins of plant viruses.

Passage of exogeneous fine particles from the lung into the brain in humans and animals.

There are still significant knowledge gaps in understanding the intrusion and retention of exogeneous particles into the central nervous system (CNS). Here, we uncovered various exogeneous fine particles in human cerebrospinal fluids (CSFs) and identified the ambient environmental or occupational exposure sources of these particles, including commonly found particles (e.g., Fe- and Ca-containing ones) and other compositions that have not been reported previously (such as malayaite and anatase TiO2), by mapping their chemical and structural fingerprints. Furthermore, using mouse and in vitro models, we unveiled a possible translocation pathway of various inhaled fine particles from the lung to the brain through blood circulation (via dedicated biodistribution and mechanistic studies). Importantly, with the aid of isotope labeling, we obtained the retention kinetics of inhaled fine particles in mice, indicating a much slower clearance rate of localized exogenous particles from the brain than from other main metabolic organs. Collectively, our results provide a piece of evidence on the intrusion of exogeneous particles into the CNS and support the association between the inhalation of exogenous particles and their transport into the brain tissues. This work thus provides additional insights for the continued investigation of the adverse effects of air pollution on the brain.

Marine anoxia linked to abrupt global warming during Earth's penultimate icehouse.

Piecing together the history of carbon (C) perturbation events throughout Earth's history has provided key insights into how the Earth system responds to abrupt warming. Previous studies, however, focused on short-term warming events that were superimposed on longer-term greenhouse climate states. Here, we present an integrated proxy (C and uranium [U] isotopes and paleo CO2) and multicomponent modeling approach to investigate an abrupt C perturbation and global warming event (∼304 Ma) that occurred during a paleo-glacial state. We report pronounced negative C and U isotopic excursions coincident with a doubling of atmospheric CO2 partial pressure and a biodiversity nadir. The isotopic excursions can be linked to an injection of ∼9,000 Gt of organic matter­derived C over ∼300 kyr and to near 20% of areal extent of seafloor anoxia. Earth system modeling indicates that widespread anoxic conditions can be linked to enhanced thermocline stratification and increased nutrient fluxes during this global warming within an icehouse.

Loss of threonyl-tRNA synthetase-like protein Tarsl2 has little impact on protein synthesis but affects mouse development.

Aminoacyl-tRNA synthetases (aaRSs) are essential components for mRNA translation. Two sets of aaRSs are required for cytoplasmic and mitochondrial translation in vertebrates. Interestingly, TARSL2 is a recently evolved duplicated gene of TARS1 (encoding cytoplasmic threonyl-tRNA synthetase) and represents the only duplicated aaRS gene in vertebrates. Although TARSL2 retains the canonical aminoacylation and editing activities in vitro, whether it is a true tRNA synthetase for mRNA translation in vivo is unclear. In this study, we showed that Tars1 is an essential gene since homozygous Tars1 KO mice were lethal. In contrast, when Tarsl2 was deleted in mice and zebrafish, neither the abundance nor the charging levels of tRNAThrs were changed, indicating that cells relied on Tars1 but not on Tarsl2 for mRNA translation. Furthermore, Tarsl2 deletion did not influence the integrity of the multiple tRNA synthetase complex, suggesting that Tarsl2 is a peripheral member of the multiple tRNA synthetase complex. Finally, we observed that Tarsl2-deleted mice exhibited severe developmental retardation, elevated metabolic capacity, and abnormal bone and muscle development after 3 weeks. Collectively, these data suggest that, despite its intrinsic activity, loss of Tarsl2 has little influence on protein synthesis but does affect mouse development.

Insight into the Rate-Determining Step in Photocatalytic Z-Scheme Overall Water Splitting by Employing A Series of Perovskite RTaON2 (R = Pr, Nd, Sm, and Gd) as Model Photocatalysts.

Photocatalysis is an intricate process that involves a multitude of physical and chemical factors operating across diverse temporal and spatial scales. Identifying the dominant factors that influence photocatalyst performance is one of the central challenges in the field. Here, we synthesized a series of perovskite RTaON2 semiconductors with different A-site rare earth atoms (R = Pr, Nd, Sm, and Gd) as model photocatalysts to discuss the influence of the A-site modulation on their local structures as well as both physical and chemical properties and to get insight into the rate-determining step in photocatalytic Z-scheme overall water splitting (OWS). It is interesting to find that, with a decreasing ionic radius of the A-site cations, the RTaON2 compounds exhibit continuous blue shift of light absorption and a concomitant reduction in the lifetime of photogenerated carriers, revealing a significant influence of A-site atoms on the light absorption and charge separation processes. On the other hand, the A-site atomic substitution was revealed to significantly modulate the valence band positions as well as surface oxidation kinetics. By employing the Pt-modified RTaON2 as H2-evolving photocatalysts, the activity of photocatalytic Z-scheme OWS for hydrogen production on them is found to be determined by its surface oxidation process instead of light absorption or charge separation. Our results give the first experimental demonstration of the rate-determining step during the photocatalytic Z-scheme OWS processes, as should be instructive for the design and development of other efficient solar-to-chemical energy conversion systems.

Recruitment of cortical silent responses by forskolin in the anterior cingulate cortex of adult mice.

Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.

Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of pain and anxiety symptoms in Parkinson's disease mice model.

Pain and anxiety are two common and undertreated non-motor symptoms in Parkinson's disease (PD), which affect the life quality of PD patients, and the underlying mechanisms remain unclear. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical long-term potentiation (LTP) and injury induced synaptic potentiation in the cortical areas including anterior cingulate cortex (ACC) and insular cortex (IC). Genetic deletion of AC1 or pharmacological inhibition of AC1 improved chronic pain and anxiety in different animal models. In this study, we proved the motor deficit, pain and anxiety symptoms of PD in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model. As a lead candidate AC1 inhibitor, oral administration (1 dose and seven doses) of NB001 (20 and 40 mg/kg) showed significant analgesic effect in MPTP-treated mice, and the anxiety behavior was also reduced (40 mg/kg). By using genetic knockout mice, we found that AC1 knockout mice showed reduced pain and anxiety symptoms after MPTP administration, but not AC8 knockout mice. In summary, genetic deletion of AC1 or pharmacological inhibition of AC1 improved pain and anxiety symptoms in PD model mice, but didn't affect motor function. These results suggest that NB001 is a potential drug for the treatment of pain and anxiety symptoms in PD patients by inhibiting AC1 target.

How well do neural signatures of resting-state EEG detect consciousness? A large-scale clinical study.

The assessment of consciousness states, especially distinguishing minimally conscious states (MCS) from unresponsive wakefulness states (UWS), constitutes a pivotal role in clinical therapies. Despite that numerous neural signatures of consciousness have been proposed, the effectiveness and reliability of such signatures for clinical consciousness assessment still remains an intense debate. Through a comprehensive review of the literature, inconsistent findings are observed about the effectiveness of diverse neural signatures. Notably, the majority of existing studies have evaluated neural signatures on a limited number of subjects (usually below 30), which may result in uncertain conclusions due to small data bias. This study presents a systematic evaluation of neural signatures with large-scale clinical resting-state electroencephalography (EEG) signals containing 99 UWS, 129 MCS, 36 emergence from the minimally conscious state, and 32 healthy subjects (296 total) collected over 3 years. A total of 380 EEG-based metrics for consciousness detection, including spectrum features, nonlinear measures, functional connectivity, and graph-based measures, are summarized and evaluated. To further mitigate the effect of data bias, the evaluation is performed with bootstrap sampling so that reliable measures can be obtained. The results of this study suggest that relative power in alpha and delta serve as dependable indicators of consciousness. With the MCS group, there is a notable increase in the phase lag index-related connectivity measures and enhanced functional connectivity between brain regions in comparison to the UWS group. A combination of features enables the development of an automatic detector of conscious states.

Integrative analyses of bulk and single-cell RNA-seq reveals the correlation between SPP1+ macrophages and resistance to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma.

Neoadjuvant chemoimmunotherapy (NACI) has significant implications for the treatment of esophageal cancer. However, its clinical efficacy varies considerably among patients, necessitating further investigation into the underlying mechanisms. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology facilitates the analysis of patient heterogeneity at the cellular level, particularly regarding treatment outcomes. In this study, we first analyzed scRNA-seq data of esophageal squamous cell carcinoma (ESCC) following NACI, obtained from the Gene Expression Omnibus (GEO) database. After performing dimensionality reduction, clustering, and annotation on the scRNA-seq data, we employed CellChat to investigate differences in cell-cell communication among samples from distinct efficacy groups. The results indicated that macrophages in the non-responder exhibited stronger cell communication intensity compared to those in responders, with SPP1 and GALECTIN signals showing the most significant differences between the two groups. This finding underscores the crucial role of macrophages in the efficacy of NACI. Subsequently, reclustering of macrophages revealed that Mac-SPP1 may be primarily responsible for treatment resistance, while Mac-C1QC appears to promote T cell activation. Finally, we conducted transcriptome sequencing on ESCC tissues obtained from 32 patients who underwent surgery following NACI. Utilizing CIBERSORT, CIBERSORTx, and WGCNA, we analyzed the heterogeneity of tumor microenvironment among different efficacy groups and validated the correlation between SPP1+ macrophages and resistance to NACI in ESCC using publicly available transcriptome sequencing datasets. These findings suggest that SPP1+ macrophages may represent a key factor contributing to resistance against NACI in ESCC.

The Polo-Like Kinase 1-Mammalian Target of Rapamycin Axis Regulates Autophagy to Prevent Intestinal Barrier Dysfunction During Sepsis.

The intestines play a crucial role in the development of sepsis. The balance between autophagy and apoptosis in intestinal epithelial cells is dynamic and determines intestinal permeability. The present study focused on the potential role of autophagy in sepsis-induced intestinal barrier dysfunction and explored the mechanisms in vivo and in vitro. Excessive apoptosis in intestinal epithelia and a disrupted intestinal barrier were observed in septic mice. Promoting autophagy with rapamycin reduced intestinal epithelial apoptosis and restored intestinal barrier function, presenting as decreased serum diamine oxidase (DAO) and fluorescein isothiocyanate-dextran 40 (FD40) levels and increased expression of zonula occludens-1 (ZO-1) and Occludin. Polo-like kinase 1 (PLK1) knockdown in mice ameliorated intestinal epithelial apoptosis and the intestinal barrier during sepsis, whereas these effects were reduced with chloroquine and enhanced with rapamycin. PLK1 also promoted cell autophagy and improved lipopolysaccharide-induced apoptosis and high permeability in vitro. Moreover, PLK1 physically interacted with mammalian target of rapamycin (mTOR) and participated in reciprocal regulatory crosstalk in intestinal epithelial cells during sepsis. This study provides novel insight into the role of autophagy in sepsis-induced intestinal barrier dysfunction and indicates that the PLK1-mTOR axis may be a promising therapeutic target for sepsis.

Comparing genomes of Fructus Amomi-producing species reveals genetic basis of volatile terpenoid divergence.

Wurfbainia longiligularis and Wurfbainia villosa are both rich in volatile terpenoids and are 2 primary plant sources of Fructus Amomi used for curing gastrointestinal diseases. Metabolomic profiling has demonstrated that bornyl diphosphate (BPP)-related terpenoids are more abundant in the W. villosa seeds and have a wider tissue distribution in W. longiligularis. To explore the genetic mechanisms underlying the volatile terpenoid divergence, a high-quality chromosome-level genome of W. longiligularis (2.29 Gb, contig N50 of 80.39 Mb) was assembled. Functional characterization of 17 terpene synthases (WlTPSs) revealed that WlBPPS, along with WlTPS 24/26/28 with bornyl diphosphate synthase (BPPS) activity, contributes to the wider tissue distribution of BPP-related terpenoids in W. longiligularis compared to W. villosa. Furthermore, transgenic Nicotiana tabacum showed that the GCN4-motif element positively regulates seed expression of WvBPPS and thus promotes the enrichment of BPP-related terpenoids in W. villosa seeds. Systematic identification and analysis of candidate TPS in 29 monocot plants from 16 families indicated that substantial expansion of TPS-a and TPS-b subfamily genes in Zingiberaceae may have driven increased diversity and production of volatile terpenoids. Evolutionary analysis and functional identification of BPPS genes showed that BPP-related terpenoids may be distributed only in the Zingiberaceae of monocot plants. This research provides valuable genomic resources for breeding and improving Fructus Amomi with medicinal and edible value and sheds light on the evolution of terpenoid biosynthesis in Zingiberaceae.

Global Insights into Chronic Obstructive Pulmonary Disease and Coronary Artery Disease: A Systematic Review and Meta-Analysis of 6,400,000 Patients.

Background: The high prevalence of chronic obstructive pulmonary disease (COPD) in coronary artery disease (CAD) has been acknowledged over the past decade, although the cause/s remain uncertain due to differences in diagnoses. COPD has also become a leading CAD comorbidity, although again little is known about its interactions. This meta-analysis explored COPD prevalence in the global CAD population, as well as the influence of COPD on CAD. Methods: PubMed, Web of Science, Embase, and grey literature were searched until 26th November 2021. The prevalence of COPD was calculated, and data were grouped according to COPD diagnostic methods, interventions, region, economic status, etc. Outcomes including all-cause death, cardiac death, myocardial infarction, revascularization, stroke, heart failure, and respiratory failure were analyzed. This study was registered with PROSPERO (CRD No.42021293270). Results: There was an average prevalence of 14.2% for COPD in CAD patients (95% CI: 13.3-15.1), with diagnostics of COPD through spirometry, International Classification of the Diseases (ICD codes), and self-reported methods. Comorbid COPD-CAD patients were more likely to be smokers and suffer from cardiovascular and respiratory complications (all odds ratios [OR] > 1). COPD-CAD has higher mortality (hazard ratio [HR] 2.81, 95% CI: 2.40-3.29), and myocardial infarction, stroke, and respiratory failure rates (all HR > 1). Coronary artery bypass graft (CABG) reduces the need for revascularization (HR 0.43, 95% CI: 0.20-0.94) compared to percutaneous coronary intervention (PCI), without increasing mortality. Conclusions: The global prevalence of COPD is particularly high in CAD patients. COPD-CAD patients are more likely to encounter cardiovascular and respiratory complications and endure poorer outcomes. Limited evidence suggests that CABG may reduce the need for revascularization without increasing mortality, although further research is required to confirm these observations.

Single-Cell Transcriptomic Analysis Revealed the Cell Population Changes and Cell-Cell Communication in the Liver of a Carnivorous Fish in Response to High-Carbohydrate Diet.

BACKGROUND: Carnivorous fish have a low carbohydrate utilization ability, and the physiologic and molecular basis of glucose intolerance has not been fully illustrated. OBJECTIVES: This study aimed to use largemouth bass as a model to investigate the possible mechanism of glucose intolerance in carnivorous fish with the help of single-nuclei RNA sequencing (snRNA-seq). METHODS: Two diets were formulated, a low-carbohydrate (LC) diet and a high-carbohydrate (HC) diet. The feeding trial lasted for 6 wk, and then, growth performance, biochemical parameters, liver histology, and snRNA-seq were performed. RESULTS: Growth performance of fish was not affected by the HC diet, while liver glucolipid metabolism disorder and liver injury were observed. A total of 13,247 and 12,848 cells from the liver derived from 2 groups were isolated and sequenced, and 7 major liver cell types were annotated by the marker genes. Hepatocytes and cholangiocytes were lower and hepatic stellate cells (HSCs) and immune cells were higher in the HC group than those in the LC group. Reclustering analysis identified 7 subtypes of hepatocytes and immune cells, respectively. The HSCs showed more cell communication with other cell types, and periportal hepatocytes showed more cell communication with other hepatocyte subtypes. Cell-cell communication mainly focused on cell junction-related signaling pathways. Uncovered by the pseudotime analysis, midzonal hepatocytes were differentiated into 2 major branches-biliary epithelial hepatocytes and hepatobiliary hybrid progenitor. Cell junction and liver fibrosis-related genes were highly expressed in the HC group. HC diet induced the activation of HSCs and, therefore, led to the liver fibrosis of largemouth bass. CONCLUSIONS: HC diet induces liver glucolipid metabolism disorder and liver injury of largemouth bass. The increase and activation of HSCs might be the main reason for the liver injury. In adaption to HC diet, midzonal hepatocytes differentiates into 2 major branches-biliary epithelial hepatocytes and hepatobiliary hybrid progenitors.

Coinactivation of the Switch/Sucrose Nonfermenting Complex SMARCA4/BRG1 and SMARCB1/INI1 in a Cervical Mixed Carcinoma: A Case Report.

SMARCB1/SMARCA4-deficient malignancies of the female genital tract are rare entities, characterized by similar histologic features, such as sheet-like growth patterns and rhabdoid cells. Previous studies have shown mutually exclusive loss of SMARCA4/BRG1 and SMARCB1/INI1. Herein, we describe a unique cervical mixed carcinoma in a 77-year-old patient. The tumor consisted of 3 components, gastric-type adenocarcinoma, squamous carcinoma, and undifferentiated carcinoma. While the undifferentiated carcinoma was negtive for CK7, CK5/6 and p63, it was positive for pan-CK. DNA-based next-generation sequencing revealed a nonsense mutation in SMARCA4, copy number loss in SMARCB1, and a nonsense mutation in ARID1A. Different molecular alterations of the switch/sucrose nonfermenting complex subunits in the present case may provide further insights into the functions of the switch/sucrose nonfermenting complex in the progression of tumors.

Cytotoxicity and Epithelial Barrier Toxicity of Fine Particles from Residential Biomass Pellet Burning.

Rising environmental concerns associated with the domestic use of solid biofuels have driven the search for clean energy alternatives. This study investigated the in vitro toxicological characteristics of PM2.5 emissions from residential biomass pellet burning using the A549 epithelial cell line. The potential of modern pellet applications to reduce PM2.5 emissions was evaluated by considering both mass reduction and toxicity modification. PM2.5 emissions from raw and pelletized biomass combustion reduced cell viability, indicative of acute toxicity, and also protein expression associated with epithelial barrier integrity, implying further systemic toxicity, potentially via an oxidative stress mechanism. Toxicity varied between PM2.5 emissions from raw biomass and pellets, with pelletized straw and wood inducing cytotoxicity by factors of 0.54 and 1.30, and causing epithelial barrier damage by factors of 1.76 and 2.08, respectively, compared to their raw counterparts. Factoring in both mass reduction and toxicity modifications, PM2.5 emissions from pelletized straw and wood dropped to 1.83 and 5.07 g/kg, respectively, from 30.1 to 9.32 g/kg for raw biomass combustion. This study underscores the effectiveness of pelletized biomass, particularly straw pellets, as a sustainable alternative to traditional biofuels and highlights the necessity of considering changes in toxicity when assessing the potential of clean fuels to mitigate emissions of the PM2.5 complex.

Enhanced Intrusion of Exogenous Airborne Fine Particles toward Eyes in Humans and Animals: Where Damaged Blood-Ocular Barrier Plays a Crucial Role.

Emerging data suggest a close correlation between ambient fine particle (AFP) exposure and eye disorders and pinpoint potential threats of AFPs to eye health in humans. However, the possible passage (including direct intrusion) and the interactions of AFPs with the eye microenvironment in addition to morphological and physiological injuries remain elusive. To this end, the likely transport of AFPs into the eyes via blood-ocular barrier (BOB) in humans and animals was investigated herein. Exogenous particles were recognized inside human eyes with detailed structural and chemical fingerprints. Importantly, comparable AFPs were found in sera with constant structural and chemical fingerprints, hinting at the translocation pathway from blood circulation into the eye. Furthermore, we found that the particle concentrations in human eyes from patients with diabetic retinopathy were much higher than those from patients with no fundus pathological changes (i.e., myopia), indicating that the damaged BOB increased the possibility of particle entrance. Our diseased animal model further corroborated these findings. Collectively, our results offer a new piece of evidence on the intrusion of exogenous particles into human eyes and provide an explanation for AFP-induced eye disorders, with substantially increased risk in susceptible individuals with BOB injuries.