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Abstract The core of many cryptocurrencies is the decentralised validation network operating on proof-of-work technology. In these systems, validation is done by so-called miners who can digitally sign blocks once they solve a computationally-hard problem. Conventional wisdom generally considers this protocol as secure and stable as miners are incentivised to follow the behaviour of the majority. However, whether some strategic mining behaviours occur in practice is still a major concern. In this paper we target this question by focusing on a security threat: a selfish mining attack in which malicious miners deviate from protocol by not immediately revealing their newly mined blocks. We propose a statistical test to analyse each miner’s behaviour in five popular cryptocurrencies: Bitcoin, Litecoin, Monacoin, Ethereum and Bitcoin Cash. Our method is based on the realisation that selfish mining behaviour will cause identifiable anomalies in the statistics of miner’s successive blocks discovery. Secondly, we apply heuristics-based address clustering to improve the detectability of this kind of behaviour. We find a marked presence of abnormal miners in Monacoin and Bitcoin Cash, and, to a lesser extent, in Ethereum. Finally, we extend our method to detect coordinated selfish mining attacks, finding mining cartels in Monacoin where miners might secretly share information about newly mined blocks in advance. Our analysis contributes to the research on security in cryptocurrency systems by providing the first empirical evidence that the aforementioned strategic mining behaviours do take place in practice.

Abstract Background Recent research shows that tumor-associated macrophages (TAMs) are the primary consumers of glucose in tumor tissue, surpassing that of tumor cells. Our previous studies revealed that inhibiting glucose uptake impairs the survival and tumor-promoting function of hypoxic TAMs, suggesting that glucose reduction by energy restriction (calorie restriction or short-term fasting) may has a significant impact on TAMs. The purpose of this study is to verify the effect of fasting-mimicking diet (FMD) on TAMs, and to determine whether FMD synergizes with anti-angiogenic drug apatinib via TAMs. Methods The effect of FMD on TAMs and its synergistic effects with apatinib were observed using an orthotopic mouse breast cancer model. An in vitro cell model, utilizing M2 macrophages derived from THP-1 cell line, was intended to assess the effects of low glucose on TAMs under hypoxic and normoxic conditions. Bioinformatics was used to screen for potential mechanisms of action, which were then validated both in vivo and in vitro. Results FMD significantly inhibit the pro-tumor function of TAMs in vivo and in vitro, with the inhibitory effect being more pronounced under hypoxic conditions. Additionally, the combination of FMD-mediated TAMs inhibition with apatinib results in synergistic anti-tumor activity. This effect is partially mediated by the downregulation of CCL8 expression and secretion by the mTOR-HIF-1α signaling pathway. Conclusions These results support further clinical combination studies of FMD and anti-angiogenic therapy as potential anti-tumor strategies. Graphical Abstract

Abstract Obesity is characterized by chronic inflammation, insulin resistance, and gut microbiota dysbiosis. Dioscorea opposita Thunb. is a traditional food and medicine homolog from China. In the present study, polysaccharides isolated from a water extract of Dioscorea opposita Thunb. (DOTPs) were prepared. We showed that DOTPs reduced body weight, accumulation of fat tissues, insulin resistance, and inflammation in high‐fat diet (HFD)‐fed mice. Further experiments showed that DOTPs could regulate the composition of the gut microbiota in HFD mice. DOTPs supplementation in HFD‐fed mice resulted in the reduction of the Firmicutes‐to‐Bacteroidetes ratio. We further demonstrated that DOTPs supplementation enhanced bacterial levels of Akkermansia and reduced levels of Ruminiclostridium_9. A significant reduction of glycolysis metabolism related to obesity and gut microbiota dysbiosis was also observed upon administration of DOTPs. Our results suggest that DOTPs can produce significant anti‐obesity effects, by inhibiting systematic inflammation and ameliorating gut microbiota dysbiosis in diet‐induced obese mice.

Proof-of-Stake (PoS) variants provide an energy-efficient alternative to Proof-of-Work (PoW). However, it is not clear whether practical PoS implementations are fair with respect to wealth, stake, and reward distribution. In this paper, we analyse the fairness of the four well-known PoS platforms Tezos, Polkadot, Cardano, and Casper through a data-driven approach. For this, we collect data on stakes and rewards for all the four platforms over several years. We then apply four measures to study the fairness along different dimensions. We calculate the Gini coefficient to explore the wealth inequality, the Nakamoto coefficient to investigate the degree of decentralization, and the expectational and robust fairness of the stake-reward proportions, i.e., if the validators receive their fair share of the rewards given their stake share. We can show that there are dynamics of high wealth inequalities and stake centralization in all the systems with Polkadot being the exception. With respect to stake-reward fairness, the platforms differ in the distributions of deviations from the fair share, i.e., in Cardano and Tezos, the differences have a lower magnitue as many small validators participate. However, by examining specific outcomes, we can show that platforms with a limited validator set such as Polkadot and Casper tend to be fairer regarding the reward payoffs, but it is not possible for smaller validators to participate. This mechanism sheds light on a trade-off that the platforms face: the more inclusive (open) the validation process is designed, the unfairer the reward distribution tends to be. Our results allow us to conclude that the way of how PoS is implemented matters greatly for its fairness.

In blockchain-based systems whose consensus mechanisms resort to Proof-of-Work (PoW), it is expected that a miner’s share of total block revenue is proportional to their share of hashing power with respect to the rest of the network. The protocol relies on the immediate broadcast of blocks by miners, to earn precedence in peers’ local blockchains. However, a deviation from this strategy named selfish mining (SM), may lead miners to earn more than their “fair share”. In this paper, we introduce an agent-based model to simulate the dynamics of SM behaviour by a single miner as well as mining pools to understand the influence of (a) mining power distribution, (b) overlay network topology, (c) positioning of the selfish nodes within the peer to peer network. Our minimalistic model allows us to find that in high levels of latency, SM is always a more profitable strategy; our results are very robust to different network topologies and mining nodes’ centrality in the network. Moreover, the power-law distribution of the miners’ hashing power can make it harder for a selfish miner to be profitable. In addition, we analyze the effect of SM on system global efficiency and fairness. Our analysis confirms that SM is always more profitable for hashing powers representing more than one-third of the total computing power. Further, it also confirms that SM behaviour could cause a statistically significant high probability of continuously mined blocks opening the door for empirical verification of the phenomenon.

Abstract The current study set out to clarify the role of miR‐424‐5p promoter methylation in epithelial mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. The findings of quantitative real‐time‐polymerase chain reaction and methylation‐sensitive high‐resolution melting assays elicited that miR‐424‐5p was poorly expressed in HCC tissues and cells while highly methylated. Meanwhile, upon demethylation, miR‐424‐5p expression levels were partly recovered in HCC cells. In addition, miR‐424‐5p upregulation reduced cell viability and elevated apoptosis of HCC cells, in parallel with increased N‐cadherin and decreased E‐cadherin levels. Dual‐luciferase reporter assay further validated that miR‐424‐5p bound to the kinesin family member 2A (KIF2A), and miR‐424‐5p overexpression downregulated KIF2A. In addition, KIF2A overexpression reversed the miR‐424‐5p‐driven changes in terms of cell viability, apoptosis and EMT‐related protein levels. Furthermore, xenograft tumors were established via injection of Huh7 cells, followed by miR‐424‐5p overexpression in vivo, which inhabited KIF2A downregulation and attenuated tumor growth along with decreased Ki67 positive expression, diminished N‐cadherin and elevated E‐cadherin levels. Overall, our findings supported the conclusion that miR‐424‐5p promoter methylation reduced miR‐424‐5p expression and upregulated KIF2A, thereby promoting HCC EMT.

Abstract Moderate autophagy can remove damaged proteins and organelles. In some inflammatory diseases, autophagy plays a protective role by inhibiting the NOD-like receptor family pyrin domain containing 3(NLRP3). (Pro)renin receptor (PRR, or ATP6AP2) is a critical component of the V-ATPase required for autophagy. It remains controversial about ATP6AP2 in the pathological process. The impact of ATP6AP2 on NLRP3 inflammasome and autophagic flux remains unknown under pressure overload stress. This research explores the potential link between ATP6AP2, autophagic flux, and NLRP3. There was upregulation of ATP6AP2 from 5-day post-TAC, and this expression remained at a high level until 8-weeks post-TAC in wild mice. Meanwhile, autophagic flux switched from early compensatory activation to blocking in the heart failure phase. NLRP3 activation can be seen at 8-week post-TAC. Adenovirus-mediated knockdown of ATP6AP2(shR-ATP6AP2) accelerated the progress of heart failure. After TAC was induced, shR-ATP6AP2 significantly deteriorated heart function and fibrosis compared with the shR-Scr group. Meanwhile, there was an elevated expression of NLRP3 and autophagic flux blockage. A transgenic mouse(Tg) with cardio-restricted ATP6AP2/(P)RR overexpression was constructed. Although high expression in cardiac tissue, there were no spontaneous functional abnormalities under the basal state. Cardiac function, fibrosis, hypertrophy remained identical to the control TAC group. However, SQSTM1/P62 was reduced, which indicated the relief of autophagic flux blockage. Further, Neonatal rat ventricular myocyte (NRVMs) transfected with shR-ATP6AP2 showed more susceptibility than sh-Scr NRVMs to phenylephrine-induced cell death. More reactive oxygen species (ROS) or mito-ROS accumulated in the shR-ATP6AP2 group when phenylephrine stimulation. Blocking NLRP3 activation in vivo partly rescued cardiac dysfunction and fibrosis. In conclusion, ATP6AP2 upregulation is a compensatory response to pressure overload. If not effectively compensated, it compromises autophagic flux, leads to dysfunctional mitochondria accumulation, further produces ROS to activate NLRP3, eventually accelerates heart failure.

Obstructive sleep apnea (OSA) accelerates the progression of chronic heart failure (CHF). OSA is characterized by chronic intermittent hypoxia (CIH), and CIH exposure accelerates cardiac systolic dysfunction and cardiac remodeling in a cardiac afterload stress mouse model. Mechanistic experiments showed that long-term CIH exposure activated hypoxia-inducible factor 1α (HIF-1α) expression in the mouse heart and upregulated miR-29c expression and that both HIF-1α and miR-29c simultaneously inhibited sarco-/endoplasmic reticulum calcium ATPase 2a (SERCA2a) expression in the mouse heart. Cardiac HIF-1α activation promoted cardiomyocyte hypertrophy. SERCA2a expression was suppressed in mouse heart in middle- and late-stage cardiac afterload stress, and CIH exposure further downregulated SERCA2a expression and accelerated cardiac systolic dysfunction. Prolyl hydroxylases (PHDs) are physiological inhibitors of HIF-1α, and PHD3 is most highly expressed in the heart. Overexpression of PHD3 inhibited CIH-induced HIF-1α activation in the mouse heart while decreasing miR-29c expression, stabilizing the level of SERCA2a. Although PHD3 overexpression did not reduce mortality in mice, it alleviated cardiac systolic dysfunction and cardiac remodeling induced by CIH exposure.

Cinnamon oil is a blend of secondary metabolites and is widely used as spice. Endophytic bacteria are always related to the secondary metabolites production. However, the potential of endophytic bacteria communities for cinnamon oil production during cinnamon shade-drying process is still not clear. In this study, we investigated the composition and metabolic function of endophytic bacterial community during 80-day shade-drying process. The temporal dynamics of essential oil content and its dominant constituents were analyzed. The succession of endophytic bacterial community from d0 to d80 was identified. The influence of endophytic bacterial community evolution on cinnamon oil is significant positive. Predictive functional analysis indicated that shade-drying process was rich in Saccharopolyspora that produce enzymes for the conversion of phenylalanine to cinnamaldehyde. These findings enhance our understanding of the functional bacterial genera and functional genes involved in the production of cinnamon oil during cinnamon shade-drying process.

Background: In reproductive-aged women, the incidence of atypical endometrial hyperplasia (AEH) or endometrioid endometrial carcinoma (EEC) is rising globally. The study aimed to investigate the effectiveness of hysteroscopic curettage followed by megestrol acetate (MA) plus metformin as conservative treatment in AEH and early EEC. Methods: We retrospectively studied AEH and stage IA, grade 1 EEC patients treated with hysteroscopic curettage followed by MA (160 mg/d) plus metformin (1500 mg/d) from January 2010 to December 2020 at Fudan University Shanghai Cancer Center. Treatment outcomes were assessed by complete response (CR) rate, recurrence rate, and pregnancy outcomes. Univariate and multivariate analyses were performed via the logistic regression model. Results: The study included 79 patients, 31 (39.2%) with AEH and 48 (60.8%) with EEC. The medians of age (years) and follow-up time (months) were 30 and 39.5, respectively. Seventy-six patients (96.2%) finally achieved CR. The median time to CR was 3.6 (3.0-20.6) months. The CR rate after 3 months, 6 months, and 1 year was 55 (69.6%), 67 (84.8%), and 72 (91.1%), respectively. Recurrence occurred in 26 (34.2%) patients. Treatment duration ⩾9 months was associated with a lower recurrence rate after CR ( P = .012). Fourteen (93.3%) of the 15 recurrent patients who received progestin re-treatment achieved CR again. Finally, 29 patients delivered live births. Conclusions: Hysteroscopy followed by MA plus metformin can achieve CR in short time and is overall safe. Consolidation treatment should be prolonged to decrease the recurrence rate, despite a shorter time to CR.

Quantum dot light-emitting diodes (QLEDs) have been identified as a next-generation display technology owing to their low-cost manufacturing, wide color gamut, and electrically driven self-emission properties. However, the efficiency and stability of blue QLEDs still pose a significant challenge, limiting their production and potential application. This review aims to analyse the factors leading to the failure of blue QLEDs and presents a roadmap to accelerate their development based on the progress made in the synthesis of II-VI (CdSe, ZnSe) quantum dots (QDs), III-V (InP) QDs, carbon dots, and perovskite QDs. The proposed analysis will include discussions on material synthesis, core-shell structures, ligand interactions, and device fabrication, providing a comprehensive overview of these materials and their development.

The complete mitochondrial genome of Aucklandia lappa was sequenced for the first time. The mitochondrial genome length was 320,439 bp, with 45.05% GC contents. There were 67 genes annotated, including 31 known protein-coding genes, 25 tRNAs, and six rRNAs. The maximum likelihood method was used to establish the phylogenetic tree of 37 species. Results have shown that A. lappa and Arctium lappa were sister groups. It reveals the genetic relationship between different species and provides a theoretical basis for the establishment of a classification system.

Abstract Adipocytes arising from mesenchymal stem cells (MSCs) requires MSC adipocyte commitment and differentiation of preadipocytes to mature adipocytes. Several signaling and some cytokines affect the adipogenesis of MSCs. This review focuses on the roles of TGF-β/SMAD signaling in adipocyte commitment of MSCs. BMP4 and BMP7 signaling are sufficient to induce adipocyte lineage determination of MSCs. The roles of BMP2, TGF-β, and myostatin signaling in this process are unclear. Other TGF-β/SMAD signaling such as BMP3 and BMP6 signaling have almost no effect on commitment because of limited research available, while GDF11 signaling inhibits adipocyte commitment in human MSCs. In this review, we summarize the available information on TGF-β/SMAD signaling regulation of MSCs in adipocyte commitment. Deeper study of this commitment mechanism will offer new approaches in treating obesity, diabetes mellitus, and obesity-related metabolism syndrome.

Aconitum kusnezoffii Rchb. is a medicinal plant in the Ranunculaceae family. In this study, we report the first complete mitochondrial genome of A. kusnezoffii. The total length of the mitochondrial genome of A. kusnezoffii is 440,720 bp and the GC content of 46.85%. The mitochondrial genome contained 37 protein-coding genes, 29 tRNAs, and three rRNAs. These data will provide the basis for the systematic evolutionary analysis of Ranunculaceae.

The complete mitochondrial genome of an important medicinal plant Glycyrrhiza uralensis Fisch. is reported for the first time. The mitochondrial genome sequence of G. uralensis was 463,869 bp in length and had a GC content of 45.19%. The genome contained 40 protein-coding genes (PCGs), 30 transfer RNAs (tRNAs), and three ribosomal RNAs (rRNAs). The phylogenetic tree was built based on 25 plants, using the maximum-likelihood method. These data will provide certain help to determine the taxonomic status of G. uralensis.

The complete mitochondrial genome of medicinal plant, Euonymus alatus, was sequenced for the first time. The genome sequence is 1,045,106 bp in length (GenBank accession number MW009108), with 44.98% GC contents. There are 72 genes in the genome, including 41 known protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), and three ribosomal RNAs (rRNAs). The phylogenetic trees of 28 species are constructed using the maximum-likelihood method. The information will provide references for phylogenetic research.

Complete mitogenome sequence of an important medicinal plant, Arctium lappa, was determined for the first time. The entire circular genome is 312,598 bp in length (GenBank accession number SRX7565441), with 45.43% GC contents. The genome has 131genes, including 33 known protein-coding genes (PCGs), 25 transfer RNAs (tRNAs), and 6 ribosomal RNAs (rRNAs). The phylogenetic trees are built based on 32 plants, using the maximum-likelihood method. The data will provide certain help to subsequent botany for classifying plants

Spinal cord edema, mainly including vasogenic and cytotoxic edema, influences neurological outcome after spinal cord contusion (SCC). Aquaporin 4 (AQP4) is the most ubiquitous water channel in the central nervous system (CNS), which is a rate-limiting factor in vasogenic edema expressing in brain injury, and it contributes to the formation of cytotoxic edema locating in astrocytes. However, little is known about the regulatory mechanism of AQP4 within vasogenic and cytotoxic edema in SCC, and whether the regulation mechanism of AQP4 is related to Cytochrome coxidase (COX5A) affecting energy metabolism. Therefore, the SCC model is established by Allen’s method, and the degree of edema and neuronal area is measured. The motor function of rats is evaluated by the Basso, Beattie, and Bresnahan (BBB) scoring system. Meanwhile, AQP4 and COX5A are detected by real-time quantitative PCR (qRT-PCR) and western blot (WB). The localization of targeted protein is exhibited by immunohistochemical staining (IHC) and immunofluorescence (IF). Additionally, the methodology of AQP4 lentivirus-mediated RNA interference (AQP4-RNAi) is used to reveal the effect on edema of SCC and the regulating molecular mechanism. Firstly, we observe that the tissue water content increases after SCC and decreases after the peak value of tissue water content at 3 days (P < 0.05) with abundant expression of AQP4 protein locating around vascular endothelial cells (VECs), which suggests that the increasing AQP4 promotes water reabsorption and improves vasogenic edema in the early stage of SCC. However, the neuronal area is larger than in the sham group in the 7 days (P < 0.05) with the total water content of spinal cord decrease. Meanwhile, AQP4 migrates from VECs to neuronal cytomembrane, which indicates that AQP4 plays a crucial role in aggravating the formation and development of cytotoxic edema in the middle stages of SCC. Secondly, AQP4-RNAi is used to elucidate the mechanism of AQP4 to edema of SCC. The neuronal area shrinks and the area of cytotoxic edema reduces after AQP4 downregulation. The BBB scores are significantly higher than in the vector group after AQP4-RNAi at 5, 7, and 14 (P < 0.05). There is a relationship between AQP4 and COX5A shown by bioinformatics analysis. After AQP4 inhibition, the expression of COX5A is significantly upregulated in the swelling astrocytes. Therefore, the inhibition of AQP4 expression reduces cytotoxic edema in SCC and improves motor function, which may be associated with upregulation of COX5A via affecting energy metabolism. Moreover, it is not clear how the inhibition of AQP4 directly causes the upregulation of COX5A.

In this study, the influence of fly ash (FA) content (0%, 10%, 20%, and 30%) on the alteration in the physical and mechanical parameters of loess is investigated. The influences of curing time (0, 14, and 28 days) and submergence and non-submergence conditions are analyzed as well. Analysis considers the variation in Atterberg limits (liquid limit, plastic limit, and plasticity index), compaction parameters (optimum moisture content (OMC), and maximum dry density (MDD)), unconfined compressive strength (UCS) stress, UCS strain, California bearing ratio (CBR) value, and swell potential. Results show that the application of FA-stabilized loess (FASL) is effective. Specifically, the MDD decreases and the OMC increases, the UCS stress increases and the UCS strain decreases, the CBR value improves and the swell potential declines, but Atterberg limits are insignificantly changed by the increase in the FA ratio compared with those of untreated loess. The UCS stress and CBR value are improved with the increase in curing time, whereas the UCS strain is negligible. FASL under submergence condition plays an important role in improving the effect of FA on the UCS stress and CBR value compared with that under non-submergence condition. The UCS stress and CBR value are more increased and more decreased than the UCS strain in submerged samples. Therefore, the application of FASL in flood areas is important for obtaining sustainable construction materials and ensuring environmental protection.

The non-noble metal modified sulfated zirconia was found easy to deactivate. Herein, highly active and highly stable non-noble core-shell Ni-S2O82-/Al2O3@ZrO2 catalysts (Ni-SA@Z-x, x = Al content in wt%) have been successfully prepared and investigated for n-pentane isomerization. The results showed that the core-shell Ni-SA@Z-30 provided a sustained high isopentane yield (63.1%) with little or no deactivation within 5000 min at a mild reaction pressure of 2.0 MPa, which can be attributed to the following factors: (i) carbon deposition was greatly suppressed by the large pore size and huge pore volume; (ii) the loss of sulfur entities was suppressed because the small and highly dispersed tetragonal ZrO2 particles can bond with the S species strongly; (iii) strong Brønsted acidity can be maintained well after the isomerization. The pore structures and acid nature of the core-shell Ni-SA@Z-x are entirely different from those of the normal structure Ni-S2O82-/ZrO2-Al2O3, even though the Al content and the compositions of the individual components are the same. The Al2O3 cores endow the catalysts with high internal surface area and high mechanical strength. Meanwhile, the ZrO2 shell, which consists of more and smaller tetragonal ZrO2 particles because of the large surface area of the Al2O3 core, promotes the formation of more stable sulfur species and stronger binding sites. [ABSTRACT FROM AUTHOR]

AIM: To describe the multimodal imaging features, treatment, and outcomes of patients diagnosed with adult-onset Coats disease. METHODS: This retrospective study included patients first diagnosed with Coats disease at ≥18 years of age between September 2017 and September 2021. Some patients received anti-vascular endothelial growth factor (VEGF) therapy (conbercept, 0.5 mg) as the initial treatment, which was combined with laser photocoagulation as needed. All the patients underwent best corrected visual acuity (BCVA) and intraocular pressure examinations, fundus color photography, spontaneous fluorescence tests, fundus fluorescein angiography, optical coherence tomography (OCT), OCT angiography, and other examinations. BCVA alterations and multimodal image findings in the affected eyes following treatment were compared and the prognostic factors were analyzed. RESULTS: The study included 15 patients who were aged 24-72 (57.33±12.61)y at presentation. Systemic hypertension was the most common associated systemic condition, occurring in 13 (86.7%) patients. Baseline BCVA ranged from 2.0 to 5.0 (4.0±1.1), which showed improvement following treatment (4.2±1.0). Multimodal imaging revealed retinal telangiectasis in 13 patients (86.7%), patchy hemorrhage in 5 patients (33.3%), and stage 2B disease (Shield's staging criteria) in 11 patients (73.3%). OCT revealed that the baseline central macular thickness (CMT) ranged from 129 to 964 µm (473.0±230.1 µm), with 13 patients (86.7%) exhibiting a baseline CMT exceeding 250 µm. Furthermore, 8 patients (53.3%) presented with an epiretinal membrane at baseline or during follow-up. Hyper-reflective scars were observed on OCT in five patients (33.3%) with poor visual prognosis. Vision deteriorated in one patient who did not receive treatment. Final vision was stable in three patients who received laser treatment, whereas improvement was observed in one of two patients who received anti-VEGF therapy alone. In addition, 8 of 9 patients (88.9%) who received laser treatment and conbercept exhibited stable or improved BCVA. CONCLUSION: Multimodal imaging can help diagnose adult-onset Coats disease. Anti-VEGF treatment combined with laser therapy can be an option for improving or maintaining BCVA and resolving macular edema. The final visual outcome depends on macular involvement and the disease stage.