Large Range of a High-Precision, Independent, Sub-Mirror Three-Dimensional Co-Phase Error Sensing and Correction Method via a Mask and Population Algorithm.

The emergence of segmented mirrors is expected to solve the design, processing, manufacturing, testing, and launching of space telescopes of large apertures. However, with the increase in the number of sub-mirrors, the sensing and correction of co-phase errors in segmented mirrors will be very difficult. In this paper, an independent three-dimensional method for sub-mirror co-phase error sensing and correction method is proposed. The method is based on a wide spectral modulation transfer function (MTF), mask, population optimization algorithm, and online model-free correction. In this method, the sensing and correction process of each sub-mirror co-phase error is independent of each other, so the increase in the number of sub-mirrors will not increase the difficulty of the method. This method can sense and correct the co-phase errors of three dimensions of the sub-mirror, including piston, tip, and tilt, even without modeling the optical system, and has a wide detection range and high precision. And the efficiency is high because the sub-mirrors can be corrected simultaneously in parallel. Simulation results show that the proposed method can effectively sense and correct the co-phase errors of the sub-mirrors in the range [-50λ, 50λ] in three dimensions with high precision. The average RMSE value in 100 experiments of the true co-phase error values and the experimental co-phase error values of one of the six sub-mirrors is 2.358 × 10-7λ.

Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+ T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

Metagenomic sequencing reveals swine lung microbial communities and metagenome-assembled genomes associated with lung lesions-a pilot study.

Low microbial biomass in the lungs, high host-DNA contamination and sampling difficulty limit the study on lung microbiome. Therefore, little is still known about lung microbial communities and their functions. Here, we perform a preliminary exploratory study to investigate the composition of swine lung microbial community using shotgun metagenomic sequencing and compare the microbial communities between healthy and severe-lesion lungs. We collected ten lavage-fluid samples from swine lungs (five from healthy lungs and five from severe-lesion lungs), and obtained their metagenomes by shotgun metagenomic sequencing. After filtering host genomic DNA contamination (93.5% ± 1.2%) in the lung metagenomic data, we annotated swine lung microbial communities ranging from four domains to 645 species. Compared with previous taxonomic annotation of the same samples by the 16S rRNA gene amplicon sequencing, it annotated the same number of family taxa but more genera and species. We next performed an association analysis between lung microbiome and host lung-lesion phenotype. We found three species (Mycoplasma hyopneumoniae, Ureaplasma diversum, and Mycoplasma hyorhinis) were associated with lung lesions, suggesting they might be the key species causing swine lung lesions. Furthermore, we successfully reconstructed the metagenome-assembled genomes (MAGs) of these three species using metagenomic binning. This pilot study showed us the feasibility and relevant limitations of shotgun metagenomic sequencing for the characterization of swine lung microbiome using lung lavage-fluid samples. The findings provided an enhanced understanding of the swine lung microbiome and its role in maintaining lung health and/or causing lung lesions.

Security Implications of AI Chatbots in Health Care.

Artificial intelligence (AI) chatbots like ChatGPT and Google Bard are computer programs that use AI and natural language processing to understand customer questions and generate natural, fluid, dialogue-like responses to their inputs. ChatGPT, an AI chatbot created by OpenAI, has rapidly become a widely used tool on the internet. AI chatbots have the potential to improve patient care and public health. However, they are trained on massive amounts of people's data, which may include sensitive patient data and business information. The increased use of chatbots introduces data security issues, which should be handled yet remain understudied. This paper aims to identify the most important security problems of AI chatbots and propose guidelines for protecting sensitive health information. It explores the impact of using ChatGPT in health care. It also identifies the principal security risks of ChatGPT and suggests key considerations for security risk mitigation. It concludes by discussing the policy implications of using AI chatbots in health care.

Channel Modeling and Characteristics Analysis under Different 3D Dynamic Trajectories for UAV-Assisted Emergency Communications.

This study involved channel modeling and characteristics analysis of unmanned aerial vehicles (UAVs) according to different operating trajectories. Based on the idea of standardized channel modeling, air-to-ground (AG) channel modeling of a UAV was carried out, taking into consideration that both the receiver (Rx) and the transmitter (Tx) ran along different types of trajectories. In addition, based on Markov chains and a smooth-turn (ST) mobility model, the influences of different operation trajectories on typical channel characteristics-including time-variant power delay profile (PDP), stationary interval, temporal autocorrelation function (ACF), root mean square (RMS) delay spread (DS), and spatial cross-correlation function (CCF)-were studied. The multi-mobility multi-trajectory UAV channel model matched well with actual operation scenarios, and the characteristics of the UAV AG channel could be analyzed more accurately, thus providing a reference for future system design and sensor network deployment of sixth-generation (6G) UAV-assisted emergency communications.

Channel Characterization and Modeling for 6G UAV-Assisted Emergency Communications in Complicated Mountainous Scenarios.

Regarding the new demands and challenges of sixth-generation (6G) mobile communications, wireless networks are undergoing a significant shift from traditional terrestrial networks to space-air-ground-sea-integrated networks. Unmanned aerial vehicle (UAV) communications in complicated mountainous scenarios are typical applications and have practical implications, especially in emergency communications. In this paper, the ray-tracing (RT) method was applied to reconstruct the propagation scenario and then acquire the wireless channel data. Channel measurements are also conducted in real mountainous scenarios for verification. By setting different flight positions, trajectories, and altitudes, channel data in the millimeter wave (mmWave) band was obtained. Important statistical properties, such as the power delay profile (PDP), Rician K-factor, path loss (PL), root mean square (RMS) delay spread (DS), RMS angular spreads (ASs), and channel capacity were compared and analyzed. The effects of different frequency bands on channel characteristics at 3.5 GHz, 4.9 GHz, 28 GHz, and 38 GHz bands in mountainous scenarios were considered. Furthermore, the effects of extreme weather, especially different precipitation, on the channel characteristics were analyzed. The related results can provide fundamental support for the design and performance evaluation of future 6G UAV-assisted sensor networks in complicated mountainous scenarios.

Spatio-temporal variation in water quality and phytoplankton community structure in Changwang, Meishe, and Wuyuan Rivers in Hainan Island, China.

For the first time, this study explored spatio-temporal variation in water quality and phytoplankton community structure in Changwang, Meishe, and Wuyuan Rivers in tropical Hainan Island, China. Phytoplankton samples and water were collected between March and December 2019 and analyzed using standard methods. Two-way ANOVA revealed significant spatial and seasonal variation in physico-chemical parameters (p < 0.05). Wuyuan had high TP (0.06 ± 0.04 mg L-1), TN (1.14 ± 0.71 mg L-1), NH4+-N (0.07 ± 0.09 mg L-1), Secchi depth (2.28 ± 3.79 m), salinity (3.60±5.50 ppt), and EC (332.50 ± 219.10 µS cm-1). At the same time, Meishe had high TP (0.07 ± 0.03 mg L-1), TN (1.04 ± 0.74 mg L-1), NH4+-N (0.07 ± 0.10 mg L-1), EC (327.61 ± 63.22 µS cm-1), and turbidity (40.25 ± 21.16 NTU). In terms of seasons, spring recorded high average TP, TN, NH4+-N, COD, and DO, while summer had a high temperature, Chl-a, salinity, and EC. Generally, the physico-chemical parameters met the China water quality standard limits (GB 3838-2002). Overall, 197 phytoplankton species belonging to Cyanophyta, Chlorophyta, Cryptophyta, Bacillariophyta, Pyrrophyta, Euglenophyta, Xanthophyta, and Chrysophyta were identified, with Cyanophyta being dominant. Phytoplankton density showed spatial changes varying from 18 × 106 cell L-1 to 84 × 106 cell L-1. The phytoplankton diversity ranged from 1.86 to 2.41, indicating a mesotrophic state. One-way ANOSIM showed no significant spatial dissimilarity in phytoplankton composition (R = 0.042, p = 0.771) but indicated a significant seasonal difference (R = 0.265, p = 0.001). Therefore, SIMPER analysis revealed that Lyngbya attenuata, Merismopedia tenuissima, Cyclotella sp., Merismopedia glauca, Merismopedia elegans, and Phormidium tenue contributed to the seasonal differences. Furthermore, CCA demonstrated that TP, TN, NH4+-N, COD, Chl-a, and Secchi depth greatly influenced the phytoplankton community. This study shows the spatio-temporal variation in water quality and phytoplankton communities, useful for managing riverine quality.

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/ß-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA.

BACKGROUND: Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined. METHODS: The TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNA STEAP3-AS1 in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation of STEAP3-AS1 mediated by HIF-1α. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role of STEAP3-AS1/STEAP3/Wnt/ß-catenin axis in CRC proliferation and metastasis. RESULTS: Here, we identified a hypoxia-induced antisense lncRNA STEAP3-AS1 that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNA STEAP3-AS1, which was induced by HIF-1α-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, STEAP3-AS1 interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N6-methyladenosine (m6A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m6A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe2+). Increased Fe2+ levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) and inhibited its kinase activity, thus releasing ß-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression. CONCLUSIONS: Taken together, our study highlights the mechanisms of lncRNA STEAP3-AS1 in facilitating CRC progression involving the STEAP3-AS1/STEAP3/Wnt/ß-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment. Hypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNA STEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability of STEAP3 and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe2+), which induces the Ser 9 phosphorylation and inactivation of GSK3ß, releasing ß-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression.

Stanniocalcin-2 promotes cell EMT and glycolysis via activating ITGB2/FAK/SOX6 signaling pathway in nasopharyngeal carcinoma.

Stanniocalcin-2 (STC2) has been proved to regulate a variety of signaling pathways including cell growth, metastasis, and therapeutic resistance. However, the role of STC2 in the regulation of nasopharyngeal carcinoma (NPC) remains poorly understood. In this study, we investigated the regulatory function of STC2 on epithelial-mesenchymal transition (EMT) and glycolysis traits in NPC and revealed the underlying molecular mechanisms. We found that STC2 was highly expressed in primary nasopharyngeal carcinoma tissues and lymph node metastatic tissues. Silencing of STC2 inhibited cell proliferation, invasion, and glycolysis. Further analyses for the clinical samples demonstrated that STC2 expression was associated with the poor clinical progression. Moreover, we demonstrated the interaction of ITGB2 with STC2 and its involvement in STC2-mediated ITGB2/FAK/SOX6 axis. Collectively, our results provide new insights into understanding the regulatory mechanism of STC2 and suggest that the STC2/ITGB2/FAK/SOX6 signaling axis may be a potential therapeutic target for NPC.

Mutagenic Characteristics of Six Heavy Metals in Escherichia coli: The Commonality and Specificity.

The history of long-term environmental exposure to heavy metals can be recorded in the genome as sporadic and specific mutations. Variable environments introduce diverse and adaptive mutations to organisms. To reveal the information hidden in genomes about environmental exposure to heavy metals, we performed long-term mutation accumulation (MA) experiments with Escherichia coli, analyzed genomes from 36 populations across 1650 generations with 6 heavy metal exposure regimes (arsenic, cadmium, chromium, copper, nickel, and lead), and inferred metal-specific evolution modes at the genomic level. All heavy metals induced genetic mutations with a mean rate of 3.459 × 10-9 per nucleotide per generation. The mutational spectrum exhibited distinct signatures; however, heavy metals also shared common mutation signatures prominently associated with all cancer types. The mutated genes showed an average similarity of 54.4% within the same exposure regime, whereas only 38.8% between exposure regimes. In terms of biological insights, mutated genes were enriched to fundamental cellular processes such as metabolism, motility, and transport. Our study elucidates the mutagenic commonality and specificity of environmental heavy metals, which are highly specific at mutational features and locus, but conserved at gene and functional levels, and may play crucial roles in the convergence of adaptation to heavy metals.

Epigenetic silencing of microRNA-204 by Helicobacter pylori augments the NF-κB signaling pathway in gastric cancer development and progression.

Helicobacter pylori infection induces gastric cancer (GC) development through a progressive cascade; however, the roles of the microRNAs that are involved in the cascade and the underlying mechanisms are still unclear. Here, we found that microRNA-204 was suppressed in gastric mucosal cells in response to H.pylori infection and downregulated in GC tissues due to aberrant methylation of the promoter of its host gene, TRPM3. Helicobacter pylori induced a progressive downregulation of microRNA-204 from superficial gastritis to intestinal metaplasia, with an accompanying increment of the methylated levels of CpG sites in the TRPM3 promoter. With the GC cellular models of AGS, MGC-803 or BGC-823, we found that microRNA-204 suppressed the tumor necrosis factor (TNF)-α-induced activation of NF-κB signaling pathways and, in animal models, inhibited tumor growth and metastasis. The conditional supernatant of microRNA-204 overexpression GC cells led to reduced tube formation of human umbilical vein endothelial cells. A target gene for microRNA-204 was BIRC2, and in GC cells, BIRC2 knockdown recapitulated the biological phenotype of microRNA-204 overexpression. BIRC2 overexpression promoted the metastasis of GC cells and rescued the inhibition activities of microRNA-204 on cell migration and the NF-κB signaling pathway. Moreover, lower microRNA-204 and higher BIRC2 expression levels were associated with a poorer prognosis of GC patients. These results demonstrate that epigenetic silencing of microRNA-204 induced by H.pylori infection augments the NF-κB signaling pathway in H.pylori-induced gastritis and GC, potentially providing novel intervention targets for these diseases. MicroRNA-204 was epigenetically down-regulated by H. pylori infection in gastric mucosal cells. It led to enhanced BIRC2 expression level and BIRC2/TNF-a/NF-kB signaling pathway activities, which promoted angiogenesis and metastasis of gastric cancer cells.

Electrospun LiFePO4/C Composite Fiber Membrane as a Binder-Free, Self-Standing Cathode for Power Lithium-Ion Battery.

A LiFePO4/C composite fiber membrane was fabricated by the electrospinning method and subsequent thermal treatment. The thermal decomposition process was analyzed by TG/DSC, the morphology, microstructure and composition were studied using SEM, TEM, XRD, Raman, respectively. The results indicated that the prepared LiFePO4/C composite fibers were composed of nanosized LiFePO4 crystals and amorphous carbon coatings, which formed a three dimensional (3D) long-range networks, greatly enhanced the electronic conductivity of LiFePO4 electrode up to 3.59× 10-2 S · cm-2. The 3D LiFePO4/C fiber membrane could be directly used as a binder-free, self-standing cathode for lithium-ion battery, and exhibited an improved capacity and rate performance. The LiFePO4/C composite electrode delivered a discharge capacity of 116 mAh·g-1, 109 mAh·g-1, 103 mAh·g-1, 91 mAh·g-1, 80 mAh·g-1 at 0.1 C, 0.5 C, 1 C, 3 C, 5 C, respectively. And a stable cycling performance was also achieved that the specific capacity could retain 75 mA·g-1 after 500 cycles at 5 C. Therefore, this LiFePO4/C composite fiber membrane was promising to be used as a cathode for power lithium ion battery.

Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumour-infiltrating macrophages, in the HCC tumour microenvironment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC. We investigated the feasibility of CCL2/CCR2 as a therapeutic target against HCC. DESIGN: CCL2 expression was analysed in two independent HCC cohorts. Growth of three murine HCC cells was evaluated in an orthotopic model, a postsurgical recurrence model and a subcutaneous model in mice after blocking CCL2/CCR2 axis by a novel CCR2 antagonist or knocking out of host CCR2. In vivo macrophage or T cell depletion and in vitro cell coculture were further conducted to investigate CCL2/CCR2-mediated crosstalk between tumour-associated macrophages (TAMs) and tumour cells. RESULT: CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8+ T cell response. CONCLUSIONS: In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.

Systematic network assessment of the carcinogenic activities of cadmium.

Cadmium has been defined as type I carcinogen for humans, but the underlying mechanisms of its carcinogenic activity and its influence on protein-protein interactions in cells are not fully elucidated. The aim of the current study was to evaluate, systematically, the carcinogenic activity of cadmium with systems biology approaches. From a literature search of 209 studies that performed with cellular models, 208 proteins influenced by cadmium exposure were identified. All of these were assessed by Western blotting and were recognized as key nodes in network analyses. The protein-protein functional interaction networks were constructed with NetBox software and visualized with Cytoscape software. These cadmium-rewired genes were used to construct a scale-free, highly connected biological protein interaction network with 850 nodes and 8770 edges. Of the network, nine key modules were identified and 60 key signaling pathways, including the estrogen, RAS, PI3K-Akt, NF-κB, HIF-1α, Jak-STAT, and TGF-ß signaling pathways, were significantly enriched. With breast cancer, colorectal and prostate cancer cellular models, we validated the key node genes in the network that had been previously reported or inferred form the network by Western blotting methods, including STAT3, JNK, p38, SMAD2/3, P65, AKT1, and HIF-1α. These results suggested the established network was robust and provided a systematic view of the carcinogenic activities of cadmium in human.

Pharmacokinetics and effects of demographic factors on blood 25(OH)D3 levels after a single orally administered high dose of vitamin D3.

AIM: To examine the biological consequences and demographic factors that might affect the pharmacokinetics of vitamin D3 after a single high dose intervention in a young Chinese population with vitamin D insufficiency status. METHODS: A total of 28 young subjects (25 to 35 years old) with vitamin D insufficiency status [serum 25(OH)D <30 ng/mL] was recruited in Shanghai, China. The subjects were orally administered a single high dose of vitamin D3 (300 000 IU). Baseline characteristics and blood samples were collected at d 0, 1, 2, 3, 7, 28, 56, 84 and 112 after the intervention. The blood biomarker levels were determined with standardized methods. RESULTS: The intervention markedly increased the blood 25(OH)D3 levels within the first five days (mean Tmax=5.1±2.1 d) and sustained an optimal circulating level of 25(OH)D3 (≥30 ng/mL) for 56 d. After the intervention, body weight and baseline 25(OH)D3 levels were significantly correlated with circulating 25(OH)D3 levels. No adverse events and no consistently significant changes in serum calcium, creatinine, glucose, parathyroid hormone, vitamin D binding protein, or the urinary calcium/reatinine ratio were observed. However, there was a significant increase in phosphorus after the vitamin D3 intervention. Total cholesterol and triglyceride levels were decreased at the end of the trial. CONCLUSION: The pharmacokinetics of vitamin D after intervention were influenced by baseline 25(OH)D3 levels and the body weight of the subjects. The results suggest that a single high oral vitamin D3 intervention is safe and efficient for improving the vitamin D status of young Chinese people with vitamin D insufficiency.

Topological, functional, and dynamic properties of the protein interaction networks rewired by benzo(a)pyrene.

Benzo(a)pyrene is a common environmental and foodborne pollutant that has been identified as a human carcinogen. Although the carcinogenicity of benzo(a)pyrene has been extensively reported, its precise molecular mechanisms and the influence on system-level protein networks are not well understood. To investigate the system-level influence of benzo(a)pyrene on protein interactions and regulatory networks, a benzo(a)pyrene-rewired protein interaction network was constructed based on 769 key proteins derived from more than 500 literature reports. The protein interaction network rewired by benzo(a)pyrene was a scale-free, highly-connected biological system. Ten modules were identified, and 25 signaling pathways were enriched, most of which belong to the human diseases category, especially cancer and infectious disease. In addition, two lung-specific and two liver-specific pathways were identified. Three pathways were specific in short and medium-term networks (<48h), and five pathways were enriched only in the medium-term network (6h-48h). Finally, the expression of linker genes in the network was validated by Western blotting. These findings establish the overall, tissue- and time-specific benzo(a)pyrene-rewired protein interaction networks and provide insights into the biological effects and molecular mechanisms of action of benzo(a)pyrene.

A Privacy Preservation Model for Health-Related Social Networking Sites.

The increasing use of social networking sites (SNS) in health care has resulted in a growing number of individuals posting personal health information online. These sites may disclose users' health information to many different individuals and organizations and mine it for a variety of commercial and research purposes, yet the revelation of personal health information to unauthorized individuals or entities brings a concomitant concern of greater risk for loss of privacy among users. Many users join multiple social networks for different purposes and enter personal and other specific information covering social, professional, and health domains into other websites. Integration of multiple online and real social networks makes the users vulnerable to unintentional and intentional security threats and misuse. This paper analyzes the privacy and security characteristics of leading health-related SNS. It presents a threat model and identifies the most important threats to users and SNS providers. Building on threat analysis and modeling, this paper presents a privacy preservation model that incorporates individual self-protection and privacy-by-design approaches and uses the model to develop principles and countermeasures to protect user privacy. This study paves the way for analysis and design of privacy-preserving mechanisms on health-related SNS.

Targeting KDM4 family epigenetically triggers antitumour immunity via enhancing tumour-intrinsic innate sensing and immunogenicity.

Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detection, thereby highlighting the potential for pharmacologically targeting epigenetic regulators to restore the impaired immunosurveillance and re-sensitise tumours to immunotherapy. Herein, we demonstrated that KDM4-targeting chemotherapeutic drug JIB-04, epigenetically triggered the tumour-intrinsic innate immune responses and immunogenic cell death (ICD), resulting in impressive antitumour effects. Specifically, JIB-04 induced H3K9 hypermethylation through specific inhibition of the KDM4 family (KDM4A-D), leading to impaired DNA repair signalling and subsequent DNA damage. As a result, JIB-04 not only activated the tumour-intrinsic cyclic GMP-AMP synthase (cGAS)-STING pathway via DNA-damage-induced cytosolic DNA accumulation, but also promoted ICD, releasing numerous damage-associated molecular patterns. Furthermore, JIB-04 induced adaptive resistance through the upregulation of programmed death-ligand 1 (PD-L1), which could be overcome with additional PD-L1 blockade. In human tumours, KDM4B expression was negatively correlated with clinical outcomes, type I interferon signatures, and responses to immunotherapy. In conclusion, our results demonstrate that targeting KDM4 family can activate tumour-intrinsic innate sensing and immunogenicity, and synergise with immunotherapy to improve antitumour outcomes.

Novel gene clusters and metabolic pathway involved in 3,5,6-trichloro-2-pyridinol degradation by Ralstonia sp. strain T6.

3,5,6-Trichloro-2-pyridinol (TCP) is a widespread pollutant. Some bacteria and fungi have been reported to degrade TCP, but the gene clusters responsible for TCP biodegradation have not been characterized. In this study, a fragment of the reduced flavin adenine dinucleotide (FADH2)-dependent monooxygenase gene tcpA was amplified from the genomic DNA of Ralstonia sp. strain T6 with degenerate primers. The tcpA disruption mutant strain T6-ΔtcpA could not degrade TCP but could degrade the green intermediate metabolite 3,6-dihydroxypyridine-2,5-dione (DHPD), which was generated during TCP biodegradation by strain T6. The flanking sequences of tcpA were obtained by self-formed adaptor PCR. tcpRXA genes constitute a gene cluster. TcpR and TcpX are closely related to the LysR family transcriptional regulator and flavin reductase, respectively. T6-ΔtcpA-com, the complementation strain for the mutant strain T6-ΔtcpA, recovered the ability to degrade TCP, and the strain Escherichia coli DH10B-tcpRXA, which expressed the tcpRXA gene cluster, had the ability to transform TCP to DHPD, indicating that tcpA is a key gene in the initial step of TCP degradation and that TcpA dechlorinates TCP to DHPD. A library of DHPD degradation-deficient mutants of strain T6 was obtained by random transposon mutagenesis. The fragments flanking the Mariner transposon were amplified and sequenced, and the dhpRIJK gene cluster was cloned. DhpJ could transform DHPD to yield an intermediate product, 5-amino-2,4,5-trioxopentanoic acid (ATOPA), which was further degraded by DhpI. DhpR and DhpK are closely related to the AraC family transcriptional regulator and the MFS family transporter, respectively.