Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection.

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.

Genetic adaptation of skin pigmentation in highland Tibetans.

Strong ultraviolet (UV) radiation at high altitude imposes a serious selective pressure, which may induce skin pigmentation adaptation of indigenous populations. We conducted skin pigmentation phenotyping and genome-wide analysis of Tibetans in order to understand the underlying mechanism of adaptation to UV radiation. We observe that Tibetans have darker baseline skin color compared with lowland Han Chinese, as well as an improved tanning ability, suggesting a two-level adaptation to boost their melanin production. A genome-wide search for the responsible genes identifies GNPAT showing strong signals of positive selection in Tibetans. An enhancer mutation (rs75356281) located in GNPAT intron 2 is enriched in Tibetans (58%) but rare in other world populations (0 to 18%). The adaptive allele of rs75356281 is associated with darker skin in Tibetans and, under UVB treatment, it displays higher enhancer activities compared with the wild-type allele in in vitro luciferase assays. Transcriptome analyses of gene-edited cells clearly show that with UVB treatment, the adaptive variant of GNPAT promotes melanin synthesis, likely through the interactions of CAT and ACAA1 in peroxisomes with other pigmentation genes, and they act synergistically, leading to an improved tanning ability in Tibetans for UV protection.

Comparative plastome analysis of the sister genera Ceratocephala and Myosurus (Ranunculaceae) reveals signals of adaptive evolution to arid and aquatic environments.

BACKGROUND: Expansion and contraction of inverted repeats can cause considerable variation of plastid genomes (plastomes) in angiosperms. However, little is known about whether structural variations of plastomes are associated with adaptation to or occupancy of new environments. Moreover, adaptive evolution of angiosperm plastid genes remains poorly understood. Here, we sequenced the complete plastomes for four species of xerophytic Ceratocephala and hydrophytic Myosurus, as well as Ficaria verna. By an integration of phylogenomic, comparative genomic, and selection pressure analyses, we investigated evolutionary patterns of plastomes in Ranunculeae and their relationships with adaptation to dry and aquatic habitats. RESULTS: Owing to the significant contraction of the boundary of IRA/LSC towards the IRA, plastome sizes and IR lengths of Myosurus and Ceratocephala are smaller within Ranunculeae. Compared to other Ranunculeae, the Myosurus plastome lost clpP and rps16, one copy of rpl2 and rpl23, and one intron of rpoC1 and rpl16, and the Ceratocephala plastome added an infA gene and lost one copy of rpl2 and two introns of clpP. A total of 11 plastid genes (14%) showed positive selection, two genes common to Myosurus and Ceratocephala, seven in Ceratocephala only, and two in Myosurus only. Four genes showed strong signals of episodic positive selection. The rps7 gene of Ceratocephala and the rpl32 and ycf4 genes of Myosurus showed an increase in the rate of variation close to 3.3 Ma. CONCLUSIONS: The plastomic structure variations as well as the positive selection of two plastid genes might be related to the colonization of new environments by the common ancestor of Ceratocephala and Myosurus. The seven and two genes under positive selection might be related to the adaptation to dry and aquatic habitats in Ceratocephala and Myosurus, respectively. Moreover, intensified aridity and frequent sea-level fluctuations, as well as global cooling, might have favored an increased rate of change in some genes at about 3.3 Ma, associated with adaptation to dry and aquatic environments, respectively. These findings suggest that changing environments might have influenced structural variations of plastomes and fixed new mutations arising on some plastid genes owing to adaptation to specific habitats.

Genetically predicted gut microbiome and risk of oral cancer.

PURPOSE: Mounting evidence suggests a possible link between gut microbiome and oral cancer, pointing to some potential modifiable targets for disease prevention. In the present study, Mendelian randomization (MR) was used to explore whether there was a causal link between gut microbiome and oral cancer. METHODS: The single nucleotide polymorphisms (SNPs) significantly associated with gut microbiome were served as instrumental variables. MR analyses were performed using genetic approaches such as inverse variance weighting (IVW), MR Egger and weighted median, with IVW as the primary approach, supplemented by MR Egger and weighted median. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were used to detect the presence of horizontal pleiotropy and identify outlier SNPs. RESULTS: Causal effect estimates indicated that genetically predicted abundance of Prevotellaceae was associated with higher risk of oral cancer (odds ratio (OR) 1.80, 95% confidence interval (CI) 1.16-2.81, p = 0.009). There was no evidence of notable heterogeneity and horizontal pleiotropy. CONCLUSION: Genetically derived estimates suggest that Prevotellaceae may be associated with the risk of oral cancer. Such robust evidence should be given priority in future studies and explore the underlying mechanisms.

Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis.

BACKGROUND AND AIMS: Liver fibrosis results from the accumulation of myofibroblasts (MFs) derived from quiescent HSCs, and yes-associated protein (YAP) controls this state transition. Although fibrosis is also influenced by HSC death and senescence, whether YAP regulates these processes and whether this could be leveraged to treat liver fibrosis are unknown. APPROACH AND RESULTS: YAP activity was manipulated in MF-HSCs to determine how YAP impacts susceptibility to pro-apoptotic senolytic agents or ferroptosis. Effects of senescence on YAP activity and susceptibility to apoptosis versus ferroptosis were also examined. CCl 4 -treated mice were treated with a ferroptosis inducer or pro-apoptotic senolytic to determine the effects on liver fibrosis. YAP was conditionally disrupted in MFs to determine how YAP activity in MF-HSC affects liver fibrosis in mouse models. Silencing YAP in cultured MF-HSCs induced HSC senescence and vulnerability to senolytics, and promoted ferroptosis resistance. Conversely, inducing HSC senescence suppressed YAP activity, increased sensitivity to senolytics, and decreased sensitivity to ferroptosis. Single-cell analysis of HSCs from fibrotic livers revealed heterogeneous sensitivity to ferroptosis, apoptosis, and senescence. In mice with chronic liver injury, neither the ferroptosis inducer nor senolytic improved fibrosis. However, selectively depleting YAP in MF-HSCs induced senescence and decreased liver injury and fibrosis. CONCLUSION: YAP determines whether MF-HSCs remain activated or become senescent. By regulating this state transition, Yap controls both HSC fibrogenic activity and susceptibility to distinct mechanisms for cell death. MF-HSC-specific YAP depletion induces senescence and protects injured livers from fibrosis. Clarifying determinants of HSC YAP activity may facilitate the development of novel anti-fibrotic therapies.

Association of lifestyle behaviors and oral health care needs: Mediating effects of inflammatory markers.

OBJECTIVE: Mounting evidence indicates that modifiable risk factors such as lifestyle behaviors may be involved in the occurrence of oral diseases. However, existing research doesn't come to a unanimous consent. This study aims to evaluate the association between lifestyle behaviors and oral health care needs. METHODS: This study used the nationally representative dataset from the National Health and Nutrition Examination Survey (NHANES) from March 2017 to 2020 pre-pandemic. Binary logistic regression analysis was used to evaluate lifestyle behavioral factors that influence oral health care needs. Mediation analysis was performed to explore the roles of inflammatory markers in the relationship between physical activities and oral problems. RESULTS: After adjusting for covariates, multivariate analysis indicated that flossing (OR = 0.590, 95% CI, 0.510-0.682, P < 0.001), moderate alcohol consumption (per week: OR = 0.717, 95% CI, 0.588-0.873, P < 0.001; per month/year: OR = 0.794, 95% CI, 0.669-0.942, P = 0.008) and participation in recreational activities (vigorous recreational activities: OR = 0.548, 95% CI, 0.462-0.648, P < 0.001; moderate recreational activities: OR = 0.629, 95% CI, 0.549-0.721, P < 0.001) significantly reduced oral health care needs. In addition, sleep duration of 7-9 h was associated with lower oral health care needs compared to less or more sleep duration (<7 h or > 9 h) (OR = 0.851, 95% CI, 0.741-0.976, P = 0.021). Mediation analysis suggested that white blood cell (WBC) counts and high-sensitivity C-reactive protein (hs-CRP) concentrations acted significant mediating roles in the association between recreational activities and oral problems. CONCLUSIONS: The possible beneficial effects of healthy lifestyle behaviors on oral health will guide individuals to develop good habits, thereby reducing the burden of oral diseases.

Evolutionary history of the angiosperm flora of China.

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.

Machine learning analysis of socioeconomic drivers in urban ozone pollution in Chinese cities.

The escalation of ground-level ozone (O3) pollution presents a significant challenge to the sustainable growth of Chinese cities. This study utilizes advanced machine learning algorithms to investigate the intricate interplay between urban socioeconomic growth and O3 levels. Surpassing traditional environmental chemistry, it assesses the effectiveness of these algorithms in interpreting socioeconomic and environmental data, while elucidating urban development's environmental impacts from a novel socioeconomic perspective. Key findings indicate that factors such as urban infrastructure, industrial activities, and demographic dynamics significantly influence O3 pollution. The study highlights the particular sensitivity of urban public transportation and population density, each exerting a unique and substantial effect on O3 levels. Additionally, the research identifies nuanced interactions among these factors, indicating a complex web of influences on urban O3 pollution. These interactions suggest that the impact of individual socioeconomic elements on O3 pollution is interdependent, being either amplified or mitigated by other factors. The study emphasizes the crucial need to integrate socioeconomic variables into urban O3 pollution strategies, advocating for policies tailored to each city's distinct characteristics, informed by the detailed analysis provided by machine learning. This approach is essential for developing effective and nuanced urban pollution management strategies.

Tailoring Advanced N-Defective and S-Doped g-C3 N4 for Photocatalytic H2 Evolution.

Although challenges remain, synergistic adjusting various microstructures and photo/electrochemical parameters of graphitic carbon nitride (g-C3 N4 ) in photocatalytic hydrogen evolution reaction (HER) are the keys to alleviating the energy crisis and environmental pollution. In this work, a novel nitrogen-defective and sulfur-doped g-C3 N4 (S-g-C3 N4 -D) is designed elaborately. Subsequent physical and chemical characterization proved that the developed S-g-C3 N4 -D not only displays well-defined 2D lamellar morphology with a large porosity and a high specific surface area but also has an efficient light utilization and carriers-separation and transfer. Moreover, the calculated optimal Gibbs free energy of adsorbed hydrogen (ΔGH* ) for S-g-C3 N4 -D at the S active sites is close to zero (≈0.24 eV) on the basis of first-principle density functional theory (DFT). Accordingly, the developed S-g-C3 N4 -D catalyst shows a high H2 evolution rate of 5651.5 µmol g-1  h-1 . Both DFT calculations and experimental results reveal that a memorable defective g-C3 N4 /S-doped g-C3 N4 step-scheme heterojunction is constructed between S-doped domains and N-defective domains in the structural configuration of S-g-C3 N4 -D. This work exhibits a significant guidance for the design and fabrication of high-efficiency photocatalysts.

A complete genus-level phylogeny reveals the Cretaceous biogeographic diversification of the poppy family.

Angiosperms, a trigger for the Cretaceous Terrestrial Revolution (KTR), underwent a rapid expansion and occupied all the environments during the Mid-Upper Cretaceous. Yet, Cretaceous biogeographic patterns and processes underlying the distribution of angiosperm diversity in the Northern Hemisphere are still poorly known. Here, we elucidated the biogeographic diversification of the angiosperm family Papaveraceae, an ancient Northern Hemisphere clade characterized by poor dispersal ability and high level of regional endemism. Based on both plastome and multi-locus datasets, we reconstructed a robust time-calibrated phylogeny that includes all currently recognized 45 genera of this family. Within the time-calibrated phylogenetic framework, we conducted 72 biogeographic analyses by testing the sensitivity of uncertainties of area delimitation, maxarea constraints, and the parameters of the model, i.e., j (describing jump-dispersal events) and w (modifying dispersal multiplier matrices), to ancestral range estimations. We also inferred ancestral habitat and ecological niches. Phylogenetic analyses strongly support Papaveraceae as monophyletic. Pteridophylloideae is strongly supported as sister to Hypecoideae-Fumarioideae. Our results indicate that the j parameter and number of predefined areas strongly affect ancestral range estimates, generating questionable ancestral ranges, whereas maxarea constraint and w parameter have no effect and improve model fit. After accounting for these uncertainties, our results indicate that Papaveraceae differentiated in Asian wet forests during the Lower Cretaceous and subsequently occupied the Asian and western North American arid and open areas. Three dispersals from Asia to western North America via the Bering land bridge occurred in the Mid-Upper Cretaceous, largely in agreement with the KTR. Habitat shift and ecological niche divergence resulted in the subsequent disjunctions between Asia and western North America. These findings suggest that the interplay of range expansion and niche divergence-driven vicariance might have shaped Cretaceous biogeographic patterns of angiosperms with Papaveraceae-like ecological requirements and dispersal abilities in the Northern Hemisphere, hence contributing to the knowledge on the geographic expansion of angiosperms during the KTR.

The synergy of abiotic and biotic factors correlated with diversification of Fumarioideae (Papaveraceae) in the Cenozoic.

Rapid diversification of a group is often associated with exploiting an ecological opportunity and/or the evolution of a key innovation. However, how the interplay of such abiotic and biotic factors correlates with organismal diversification has been rarely documented in empirical studies, especially for organisms inhabiting drylands. Fumarioideae is the largest subfamily in Papaveraceae and is mainly distributed in temperate regions of the Northern Hemisphere. Here, we used one nuclear (ITS) and six plastid (rbcL, atpB, matK, rps16, trnL-F, and trnG) DNA sequences to investigate the spatio-temporal patterns of diversification and potential related factors of this subfamily. We first present the most comprehensive phylogenetic analysis of Fumarioideae to date. The results of our integrated molecular dating and biogeographic analyses indicate that the most recent common ancestor of Fumarioideae started to diversify in Asia during the Upper Cretaceous, and then dispersed multiple times out of Asia in the Cenozoic. In particular, we discover two independent dispersal events from Eurasia to East Africa in the late Miocene, suggesting that the Arabian Peninsula might be an important exchange corridor between Eurasia and East Africa in the late Miocene. Within the Fumarioideae, increased speciation rates were detected in two groups, Corydalis and Fumariinae. Corydalis first experienced a burst of diversification in its crown group at âˆ¼ 42 Ma, and further accelerated diversification from the mid-Miocene onwards. During these two periods, Corydalis had evolved diverse life history types, which could have facilitated the colonization of diverse habitats originating from extensive orogenesis in the Northern Hemisphere as well as Asian interior desertification. Fumariinae underwent a burst of diversification at âˆ¼ 15 Ma, which temporally coincides with the increasing aridification in central Eurasia, but is markedly posterior to the shifts in habitat (from moist to arid) and in life history (from perennial to annual) and to range expansion from Asia to Europe, suggesting that Fumariinae species may have been pre-adapted to invade European arid habitats by the acquisition of annual life history. Our study provides an empirical case that documents the importance of pre-adaptation on organismal diversification in drylands and highlights the significant roles of the synergy of abiotic and biotic factors in promoting plant diversification.

Biogeographic diversification of Actaea (Ranunculaceae): Insights into the historical assembly of deciduous broad-leaved forests in the Northern Hemisphere.

The deciduous broad-leaved forests (DBLFs) cover large temperate and subtropical high-altitude regions in the Northern Hemisphere. They are home to rich biodiversity, especially to numerous endemic and relict species. However, we know little about how this vegetation in the Northern Hemisphere has developed through time. Here, we used Actaea (Ranunculaceae), an herbaceous genus almost exclusively growing in the understory of the Northern Hemisphere DBLFs, to shed light on the historical assembly of this biome in the Northern Hemisphere. We present a complete species-level phylogenetic analysis of Actaea based on five plastid and nuclear loci. Using the phylogenetic framework, we estimated divergence times, ancestral ranges, and diversification rates. Phylogenetic analyses strongly support Actaea as monophyletic. Sections Podocarpae and Oligocarpae compose a clade, sister to all other Actaea. The sister relationship between sections Chloranthae and Souliea is strongly supported. Section Dichanthera is not monophyletic unless section Cimicifuga is included. Actaea originated in East Asia, likely the Qinghai-Tibet Plateau, in the late Paleocene (c. 57 Ma), and subsequently dispersed into North America in the middle Eocene (c. 43 Ma) via the Thulean bridge. Actaea reached Europe twice, Japan twice, and Taiwan once, and all these five colonization events occurred in the late Miocene-early Pliocene, a period when sea level dropped. Actaea began to diversify at c. 43 Ma. The section-level diversification took place at c. 27-37 Ma and the species-level diversification experienced accelerations twice, which occurred at c. 15 Ma and c. 5 Ma, respectively. Our findings suggest that the Northern Hemisphere DBLFs might have risen in the middle Eocene and further diversified in the late Eocene-Oligocene, middle Miocene and early Pliocene, in association with climatic deterioration during these four periods.

Role of Left-Hand Cut Contributions on Pole Extractions from Lattice Data: Case Study for T_{cc}(3875)

We discuss recent lattice data for the T_{cc}(3875)^{+} state to stress, for the first time, a potentially strong impact of left-hand cuts from the one-pion exchange on the pole extraction for near-threshold exotic states. In particular, if the left-hand cut is located close to the two-particle threshold, which happens naturally in the DD^{*} system for the pion mass exceeding its physical value, the effective-range expansion is valid only in a very limited energy range up to the cut and as such is of little use to reliably extract the poles. Then, an accurate extraction of the pole locations requires the one-pion exchange to be implemented explicitly into the scattering amplitudes. Our findings are general and potentially relevant for a wide class of hadronic near-threshold states.

Mechanisms of cancer cell killing by metformin: a review on different cell death pathways.

Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.

Comprehensive analysis of candidate signatures of long non-coding RNA LINC01116 and related protein-coding genes in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a long-term malignancy that causes high morbidities and mortalities worldwide. Notably, long non-coding RNAs (LncRNAs) have been identified as candidate targets for malignancy treatments. METHODS: LncRNA LINC01116 and its Pearson-correlated genes (PCGs) were identified and analyzed in HCC patients. The diagnostic and prognostic value of the lncRNA was evaluated using data from The Cancer Genome Atlas (TCGA). Further, we explored the target drugs of LINC01116 for clinical application. Relationships between immune infiltration and PCGs, methylation and PCGs were explored. The diagnostic potentials were then validated by Oncomine cohorts. RESULTS: LINC01116 and the PCG OLFML2B are differentially and highly expressed in tumor tissues (both P ≤ 0.050). We found that LINC01116, TMSB15A, PLAU, OLFML2B, and MRC2 have diagnostic potentials (all AUC ≥ 0.700, all P ≤ 0.050) while LINC01116 and TMSB15A have prognostic significance (both adjusted P ≤ 0.050). LINC01116 was enriched in the vascular endothelial growth factor (VEGF) receptor signaling pathway, mesenchyme morphogenesis, etc. After that, candidate target drugs with potential clinical significance were identified: Thiamine, Cromolyn, Rilmenidine, Chlorhexidine, Sulindac_sulfone, Chloropyrazine, and Meprylcaine. Analysis of immune infiltration revealed that MRC2, OLFML2B, PLAU, and TMSB15A are negatively associated with the purity but positively associated with the specific cell types (all P < 0.050). Analysis of promoter methylation demonstrated that MRC2, OLFML2B, and PLAU have differential and high methylation levels in primary tumors (all P < 0.050). Validation results of the differential expressions and diagnostic potential of OLFML2B (Oncomine) were consistent with those obtained in the TCGA cohort (P < 0.050, AUC > 0.700). CONCLUSIONS: Differentially expressed LINC01116 could be a candidate diagnostic and an independent prognostic signature in HCC. Besides, its target drugs may work for HCC therapy via the VEGF receptor signaling pathway. Differentially expressed OLFML2B could be a diagnostic signature involved in HCC via immune infiltrates.

Oxygen defect-mediated NiCo2O4 nanosheets as the electrode for pseudocapacitors with improved rate capability.

Transition metal oxide-based supercapacitors have attracted much attention due to their high theoretical specific capacitances. However, due to an insufficient utilization ratio and poor intrinsic conductivity of active materials, the rate performance of these electrodes is usually low. Herein, oxygen defect-mediated NiCo2O4 nanosheets with enhanced electrical conductivity (1.9 S m-1vs. 0.2 S m-1 of original NiCo2O4 NSs) are fabricated using a post NaBH4 reduction strategy (denoted as r-NiCo2O4 NSs). The derived r-NiCo2O4 materials have sheet-like morphology, increased oxygen defects and low valence metal species, and an unprecedented rate capability comparable to that of carbon-based electrode materials, with a satisfactory capacitance of 1812 F g-1 and 91.5% retention at 20 A g-1. The general strategy can be extended to other transition metal oxides to construct enhanced conductivity electrodes for related energy storage and conversion devices.

DARE: Distill and Reinforce Ensemble Neural Networks for Climate-Domain Processing.

Natural-language processing is well positioned to help stakeholders study the dynamics of ambiguous Climate Change-related (CC) information. Recently, deep neural networks have achieved good results on a variety of NLP tasks depending on high-quality training data and complex and exquisite frameworks. This raises two dilemmas: (1) the networks are highly reliant on powerful hardware devices and processing is time-consuming, which is not only inconducive to execution on edge devices but also leads to resource consumption. (2) Obtaining large-scale effective annotated data is difficult and laborious, especially when it comes to a special domain such as CC. In this paper, we propose a CC-domain-adapted BERT distillation and reinforcement ensemble (DARE) model for tackling the problems above. Specifically, we propose a novel data-augmentation strategy which is a Generator-Reinforced Selector collaboration network for countering the dilemma of CC-related data scarcity. Extensive experimental results demonstrate that our proposed method outperforms baselines with a maximum of 26.83% on SoTA and 50.65× inference time speed-up. Furthermore, as a remedy for the lack of CC-related analysis in the NLP community, we also provide some interpretable conclusions for this global concern.

Genetic analysis of potential biomarkers and therapeutic targets in ferroptosis from coronary artery disease.

Ferroptosis plays a key role in the death of cells including cardiomyocytes, and it is related to a variety of cardiac diseases. However, the role of ferroptosis-related genes (FRGs) in coronary artery disease (CAD) is not well characterized. We downloaded CAD-related information and FRGs from the gene expression omnibus (GEO) database and Ferroptosis Database (FerrDb) respectively. A total of 10 CAD-related DE-FRGs were obtained, which were closely linked to autophagy regulation and immune response. Subsequently, CA9, CBS, CEBPG, HSPB1, SLC1A4, STMN1 and TRIB3 among the 10 DE-FRGs were identified as marker genes by LASSO and SVM-RFE algorithms, which had tolerable diagnostic capabilities. Subsequent functional enrichment analysis showed that these marker genes may play a corresponding role in CAD by participating in the regulation of immune response, amino acid metabolism, cell cycle and multiple pathways related to the pathogenesis of CAD. Furthermore, a total of 58 drugs targeting 7 marker genes had been obtained. On the contrary, the ceRNA network revealed a complex regulatory relationship based on the marker genes. Also, CIBERSORT analysis showed that the changes in the immune microenvironment of CAD patients may be related to CBS, HSPB1 and CEBPG. We developed a diagnostic potency and provided an insight for exploring the mechanism for CAD. Before clinical application, further research is needed to test its diagnostic value for CAD.

Exosomes in atrial fibrillation: therapeutic potential and role as clinical biomarkers.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is a global epidemic. AF can cause heart failure and myocardial infarction and increase the risk of stroke, disability, and thromboembolic events. AF is becoming increasingly ubiquitous and is associated with increased morbidity and mortality at higher ages, resulting in an increasing threat to human health as well as substantial medical and social costs. Currently, treatment strategies for AF focus on controlling heart rate and rhythm with medications to restore and maintain sinus rhythm, but this approach has limitations. Catheter ablation is not entirely satisfactory and does not address the issues underlying AF. Research exploring the mechanisms causing AF is urgently needed for improved prevention, diagnosis, and treatment of AF. Exosomes are small vesicles (30-150 nm) released by cells that transmit information between cells. MicroRNAs in exosomes play an important role in the pathogenesis of AF and are established as a biomarker for AF. In this review, a summary of the role of exosomes in AF is presented. The role of exosomes and microRNAs in AF occurrence, their therapeutic potential, and their potential role as clinical biomarkers is considered. A better understanding of exosomes has the potential to improve the prognosis of AF patients worldwide, reducing the global medical burden of this disease.

Individualized right ventricular outflow tract reconstruction using autologous pulmonary tissue in situ for the treatment of pulmonary atresia with ventricular septum defect.

OBJECTIVE: The study aims to evaluate the feasibility and effectiveness of an individualized procedure for right ventricular outflow tract (RVOT) reconstruction in pulmonary atresia with ventricular septal defect (PA-VSD). METHODS: RVOT was reconstructed using autologous pulmonary artery tissue preserved in situ as the posterior wall and a bovine jugular vein patch (BJVP) as the anterior wall in patients with PA-VSD (observation group). The size of the BJVP made from a bovine jugular vein conduit (BJVC) was individually calculated using a formula based on the child's weight and the size of the autologous pulmonary artery (the diameter of BJVC DB⁢J⁢V⁢C = Dt⁢h⁢e⁢o⁢r⁢e⁢t⁢i⁢c⁢a⁢l-W⁢z^-4π). Its effect was then compared with the conventional modified Rastelli procedure based on the BJVC (control group). RESULTS: A total of 22 patients that underwent the new procedure were simultaneously compared with the 25 patients in the control group. No deaths occurred in both groups. Notably, there were no significant differences in mechanical ventilation, ICU and postoperative residence, cardiopulmonary bypass, and aortic cross-clamp time. In the follow-up, which spanned for 8-12 years (mean 9.2 years), only four cases with moderate regurgitation were noted in the observation group without obstruction. In the control group, two patients had a conduit replacement. Three patients suffered from anastomotic stenosis, which was corrected by balloon dilatation. CONCLUSION: Individualized RVOT reconstruction with autologous pulmonary tissue preserved in situ as the posterior wall is adequate for treating PA-VSD.