Effects of High-Mobility Group Box-1 on Mucosal Immunity and Epithelial Differentiation in Colitic Carcinoma.

Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.

Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage.

Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion. These results suggest that in cancer sarcopenia, mitochondrial oxidative stress caused by inflammatory cytokines leads to mitochondrial DNA damage, which in turn leads to decreased OXPHOS and the promotion of aging.

Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires.

Background: Cancer-targeted T-cell receptor T (TCR-T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain cancer-reactive TCR-T cells have been unsuccessful. Methods: Here, we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints. Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells, and then the expanded cells were applied to establish humanized mice. The human immune system was evaluated according to the kinetics of dendritic cells, monocytes, T-cell subsets, and cytokines. To fully stimulate the immune response and to obtain B-cell precursor NAML-6- and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells, we used the inactivated cells above to treat humanized mice twice a day every 7 days. Then, human T cells were processed for TCR ß-chain (TRB) sequencing analysis. After the repertoires had been constructed, features such as the fraction, diversity, and immune signature were investigated. Results: The results demonstrated an increase in diversity and clonality of T cells after treatment. The preferential usage and features of TRBV, TRBJ, and the V-J combination were also changed. The stress also induced highly clonal expansion. Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice. Conclusions: We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools. Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells. It therefore has the potential to greatly benefit cancer treatment.

A multi-source heterogeneous medical data enhancement framework based on lakehouse.

Obtaining high-quality data sets from raw data is a key step before data exploration and analysis. Nowadays, in the medical domain, a large amount of data is in need of quality improvement before being used to analyze the health condition of patients. There have been many researches in data extraction, data cleaning and data imputation, respectively. However, there are seldom frameworks integrating with these three techniques, making the dataset suffer in accuracy, consistency and integrity. In this paper, a multi-source heterogeneous data enhancement framework based on a lakehouse MHDP is proposed, which includes three steps of data extraction, data cleaning and data imputation. In the data extraction step, a data fusion technique is offered to handle multi-modal and multi-source heterogeneous data. In the data cleaning step, we propose HoloCleanX, which provides a convenient interactive procedure. In the data imputation step, multiple imputation (MI) and the SOTA algorithm SAITS, are applied for different situations. We evaluate our framework via three tasks: clustering, classification and strategy prediction. The experimental results prove the effectiveness of our data enhancement framework.

Particle-ozone complex pollution under diverse synoptic weather patterns in the Yangtze River Delta region: Synergistic relationships and the effects of meteorology and chemical compositions.

There is considerable academic interest in the particle-ozone synergistic relationship (PO) between fine particulate matter (PM2.5) and ozone (O3). Using various synoptic weather patterns (SWPs), we quantitatively assessed the variations in the PO, which is relevant to formulating policies aimed at controlling complex pollution in the air. First, based on one-year sampling data from March 2018 to February 2019, the SWPs classification of the Yangtze River Delta (YRD) was conducted using the sum-of-squares technique (SS). Five dominant SWPs can be found in the YRD region, including the Aleutian low under SWP1 (occurring 45 % of the year), a tropical cyclone under SWP2 (21 %), the tropical cyclone and western Pacific Subtropical High (WPSH) under SWP3 (15.4 %), the WPSH under SWP4 (6.9 %), and a continental high pressure under SWP5 (3.1 %). The phenomenon of a "seesaw" between PM2.5 and O3 concentrations exhibited significant spatial heterogeneity, which was influenced by meteorological mechanisms. Second, the multi-linear regression (MLR) model and the partial correlation (PCOR) analysis were employed to quantify the effects of dominant components and meteorological factors on the PO. Meteorological variables could collectively explain only 33.0 % of the PM2.5 variations, but 58.0 % for O3. O3 promoted each other with low concentrations of PM2.5 but was inhibited by high concentrations of PM2.5. High relative humidity (RH) was conducive to the generation of PM2.5 secondary components and enhanced the radiative effects of aerosols and the negative correlation of PO. In addition, attention should be paid to assessing the combined effects of precursor levels, weather, and chemical reactions on the particle-ozone complex pollution. The control of O3 pollutants should be intensified in summer, while the focus should be on reducing PM2.5 pollutants in winter. Prevention and control measures need to reflect the differences in weather conditions and pollution characteristics, with a focus on RH and secondary components of PM2.5.

Response of changes in lake area to drought and land use change.

The lake area is a crucial parameter that characterizes the state of a lake. Under the dual pressures of climate change and human activity, the magnitude and frequency of changes in lake areas become more pronounced. This process poses a serious threat to the local ecological environment. In this study, we constructed a lake water extraction model (LakeNet) based on a fully convolutional neural network. We extracted and analyzed the spatiotemporal characteristics of the area of nine major lakes from 1987 to 2022, as well as the driving factors behind these changes. Our results indicate that: 1) LakeNet exhibits high extraction accuracy and can remove some clouds. 2) The area of the nine major lakes shows a fluctuating downward trend (-8.11km2/10a), with drought and land use changes identified as significant driving forces behind the changes in lake boundaries, drought events caused the lake area to decrease, and the expansion of cropland further reduced the lake area. 3) Due to variations in lake area, the impact of drought on the area of the nine major lakes exhibits a lag effect, smaller lakes are likely to respond more quickly to drought.

A near-infrared hepatocyte-targeting probe based on Tricyanofuran to detect cysteine in vivo: Design, synthesis and evaluation.

In this work, a near-infrared hepatocyte-targeting fluorescence probe TCF-Gal-Cys was developed. The TCF-Gal-Cys exhibited a low detection limit, good sensitivity and selectivity toward Cys. The responsive mechanism of TCF-Gal-Cys was proposed that the acrylate of TCF-Gal-Cys was subsequently attacked by the thiol group and the amino group of Cys, releasing a strong near-infrared fluorescent group. TCF-Gal-Cys displayed a good hepatocyte-targeting capacity and could specifically distinguish hepatocytes from A549, Hela, SGC-7901 cells because the galactose group of TCF-Gal-Cys can be recognized by HepG2 cells overexpressing ASGPR. The TCF-Gal-Cys has achieved excellently imaging performance to Cys in the zebrafish, so TCF-Gal-Cys has potential to be an effective tool to in real time monitor Cys-related diseases in vitro and in vivo.

Rapid discrimination of African swine fever virus nucleic acid and virions using BenzoNuclease.

African swine fever (ASF) is an acute and severe infectious disease caused by the African Swine Fever Virus (ASFV). ASFV exhibits significant resistance and stability in the environment, which, coupled with its double-stranded DNA and large genome, predisposes it to contaminate laboratory samples. This characteristic can lead to false-positive results in swine farm settings even days after disinfection, as detectable through polymerase chain reaction (PCR) or real-time fluorescent quantitative PCR (qPCR) assays. To meet the demand for efficient clinical methods capable of discriminating between ASFV nucleic acid and ASFV virions, this study aims to ascertain the efficacy of the nuclease "BenzoNuclease" in distinguishing ASFV nucleic acid (ASFV-DNA) from ASFV virions. BenzoNuclease is a versatile nucleic acid enzyme with the capacity to degrade nearly all forms of DNA and RNA. Initially, this research established a highly sensitive general PCR detection method for ASFV. Subsequently, a positive control was constructed using the M13 bacteriophage to substitute for active ASFV, facilitating the development of an improved qPCR method. It is important to note that common disinfectants have the potential to deactivate BenzoNuclease. However, in an environment simulating actual production applications, residual disinfectants do not interfere with the enzymatic efficacy of BenzoNuclease, thus not affecting the detection capabilities of this method. Positive clinical samples from pig farms, upon testing with the improved method, revealed that three samples were positive, indicating the presence of viral particles, while the remaining samples were negative, indicating the presence of nucleic acids. This provides an additional new option for sample testing in pig farms.

Optimizing storage on fog computing edge servers: A recent algorithm design with minimal interference.

The burgeoning field of fog computing introduces a transformative computing paradigm with extensive applications across diverse sectors. At the heart of this paradigm lies the pivotal role of edge servers, which are entrusted with critical computing and storage functions. The optimization of these servers' storage capacities emerges as a crucial factor in augmenting the efficacy of fog computing infrastructures. This paper presents a novel storage optimization algorithm, dubbed LIRU (Low Interference Recently Used), which synthesizes the strengths of the LIRS (Low Interference Recency Set) and LRU (Least Recently Used) replacement algorithms. Set against the backdrop of constrained storage resources, this research endeavours to formulate an algorithm that optimizes storage space utilization, elevates data access efficiency, and diminishes access latencies. The investigation initiates a comprehensive analysis of the storage resources available on edge servers, pinpointing the essential considerations for optimization algorithms: storage resource utilization and data access frequency. The study then constructs an optimization model that harmonizes data frequency with cache capacity, employing optimization theory to discern the optimal solution for storage maximization. Subsequent experimental validations of the LIRU algorithm underscore its superiority over conventional replacement algorithms, showcasing significant improvements in storage utilization, data access efficiency, and reduced access delays. Notably, the LIRU algorithm registers a 5% increment in one-hop hit ratio relative to the LFU algorithm, a 66% enhancement over the LRU algorithm, and a 14% elevation in system hit ratio against the LRU algorithm. Moreover, it curtails the average system response time by 2.4% and 16.5% compared to the LRU and LFU algorithms, respectively, particularly in scenarios involving large cache sizes. This research not only sheds light on the intricacies of edge server storage optimization but also significantly propels the performance and efficiency of the broader fog computing ecosystem. Through these insights, the study contributes a valuable framework for enhancing data management strategies within fog computing architectures, marking a noteworthy advancement in the field.

Comparative analysis of genetic risk scores for predicting biochemical recurrence in prostate cancer patients after radical prostatectomy.

BACKGROUND: In recent years, Genome-Wide Association Studies (GWAS) has identified risk variants related to complex diseases, but most genetic variants have less impact on phenotypes. To solve the above problems, methods that can use variants with low genetic effects, such as genetic risk score (GRS), have been developed to predict disease risk. METHODS: As the GRS model with the most incredible prediction power for complex diseases has not been determined, our study used simulation data and prostate cancer data to explore the disease prediction power of three GRS models, including the simple count genetic risk score (SC-GRS), the direct logistic regression genetic risk score (DL-GRS), and the explained variance weighted GRS based on directed logistic regression (EVDL-GRS). RESULTS AND CONCLUSIONS: We used 26 SNPs to establish GRS models to predict the risk of biochemical recurrence (BCR) after radical prostatectomy. Combining clinical variables such as age at diagnosis, body mass index, prostate-specific antigen, Gleason score, pathologic T stage, and surgical margin and GRS models has better predictive power for BCR. The results of simulation data (statistical power = 0.707) and prostate cancer data (area under curve = 0.8462) show that DL-GRS has the best prediction performance. The rs455192 was the most relevant locus for BCR (p = 2.496 × 10-6) in our study.

Intermittent Fasting Targets Osteocyte Neuropeptide Y to Relieve Osteoarthritis.

Osteoarthritis is a highly prevalent progressive joint disease that still requires an optimal therapeutic approach. Intermittent fasting is an attractive dieting strategy for improving health. Here this study shows that intermittent fasting potently relieves medial meniscus (DMM)- or natural aging-induced osteoarthritic phenotypes. Osteocytes, the most abundant bone cells, secrete excess neuropeptide Y (NPY) during osteoarthritis, and this alteration can be altered by intermittent fasting. Both NPY and the NPY-abundant culture medium of osteocytes (OCY-CM) from osteoarthritic mice possess pro-inflammatory, pro-osteoclastic, and pro-neurite outgrowth effects, while OCY-CM from the intermittent fasting-treated osteoarthritic mice fails to induce significant stimulatory effects on inflammation, osteoclast formation, and neurite outgrowth. Depletion of osteocyte NPY significantly attenuates DMM-induced osteoarthritis and abolishes the benefits of intermittent fasting on osteoarthritis. This study suggests that osteocyte NPY is a key contributing factor in the pathogenesis of osteoarthritis and intermittent fasting represents a promising nonpharmacological antiosteoarthritis method by targeting osteocyte NPY.

Systemic Administration of Neurotransmitter-Derived Lipidoids-PROTACs-DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) poses a significant burden on the economy and healthcare systems worldwide. Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis-targeting chimera (PROTAC), a novel protein-degradation technique that mediates degradation of target proteins via the ubiquitin-proteasome system, and a neurotransmitter-derived lipidoid (NT-lipidoid) nanoparticle delivery system with high blood-brain barrier-penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau-targeting PROTAC is loaded onto the positively charged nanoparticles using DNA-intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood-brain barrier-penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which in turn enhances cognition.

Visualization and standardized quantification of surface charge density for triboelectric materials.

Triboelectric nanogenerator (TENG) operates on the principle of utilizing contact electrification and electrostatic induction. However, visualization and standardized quantification of surface charges for triboelectric materials remain challenging. Here, we report a surface charge visualization and standardized quantification method using electrostatic surface potential measured by Kevin probe and the iterative regularization strategy. Moreover, a tuning strategy on surface charge is demonstrated based on the corona discharge with a three-electrode design. The long-term stability and dissipation mechanisms of the injected negative or positive charges demonstrate high dependence on deep carrier traps in triboelectric materials. Typically, we achieved a 70-fold enhancement on the output voltage (~135.7 V) for the identical polytetrafluoroethylene (PTFE) based TENG (neg-PTFE/PTFE or posi-PTFE/PTFE triboelectric pair) with stable surface charge density (5% decay after 140 days). The charged PTFE was demonstrated as a robot e-skins for non-contact perception of object geometrics. This work provides valuable tools for surface charge visualization and quantification, giving a new strategy for a deeper understanding of contact electrification.

Hepatitis B infection is associated with periodontitis: the national health and nutrition examination survey (2009-2014).

BACKGROUND: Current research has been inconclusive regarding whether hepatitis B infection is associated with an increased risk of periodontitis. This study aims to test the null hypothesis that no association exists between hepatitis B infection and an increased risk of periodontitis using the National Health and Nutrition Examination Survey (2009-2014). METHODS: We performed a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database (2009-2014) to assess the rate of the prevalence of periodontitis in patients with and without hepatitis B infection. Participants who had tested for hepatitis B and periodontitis were included. The included participants were divided into no/mild periodontitis and moderate/severe periodontitis groups according to their periodontal status. The association between hepatitis B infection and chronic periodontitis was evaluated by multivariable regression analyses adjusting for age, gender, race/ethnicity, education level, income-to-poverty ratio, smoking, alcohol, BMI, ALT, AST, creatinine, hypertension, and diabetes. RESULTS: A total of 5957 participants were included and divided into two groups: inactive periodontitis group (n = 3444) and active periodontitis group (n = 2513). The results showed that participants with hepatitis B had a higher risk of periodontitis. After adjusting for covariables, adults with hepatitis B infection were 38% more likely to have periodontitis compared to those without hepatitis B infection (95% Confidence Interval [CI]:1.085-1.754). CONCLUSIONS: In general, the results suggest that CHB is positively associated with the more severe periodontitis. These results suggest that people with hepatitis B infection should take good periodontal care measures to avoid the occurrence and development of periodontitis.

Impact of additional cytogenetic aberrations at diagnosis on prognosis of adults patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation: a retrospective analysis.

Additional chromosomal abnormalities(ACAs) at diagnosis are associated with inferior prognosis in chronic myeloid leukemia. However, the prognostic significance of ACAs in adult patients with Philadelphia Chromosome Positive acute lymphoblastic leukemia (Ph + ALL) receiving TKI-targeted drugs and allogeneic hematopoietic stem cell transplantation(HSCT) is unknown. One hundred thirty-six adult patients with Ph + ALL were included in the study and retrospectively analysed, evaluating the effect of ACAs on outcomes of transplantation. ACAs are observed in 60 cases (44%). ACAs detected in more than 5% of cases were defined as major-route and encompass: +der(22), +der(9), + 8, -7 and complex karyotype. The median follow-up was 26.4 months. In the subgroup analyses of major route ACAs, three-year cumulative incidence of relapse (CIR) and progression-free survival(PFS) are statistically significant in + 8[66.7% vs.23.7%, P = 0.024; 77.8% vs. 23.7%, P = 0.0087], -7[53.8% vs. 23.7%, P = 0.035%; 61.5% vs. 32.9%, P = 0.033], and complex karyotypes[42.9% vs. 23.7%, P = 0.027; 47.6% vs. 23.7%] compared with t(9;22) sole. Additionally, the 3-year CIR for Ph + ALL with + der(22) is 44% vs. 23.7% for t(9;22) sole(P = 0.045). The 3-year overall survival (OS) in the - 7 group is 46.5%, which is statistically significant compared with the other groups(P = 0.001). In multivariate analyses, three years CIR and PFS are statistically significant in + der(22), + 8, -7 and complex karyotype compared with t(9;22) sole(P < 0.05). More importantly, Ph + ALL with - 7 was negatively associated with the rate of 3-year OS(P = 0.012). Thus, ACAs at diagnosis appear to have a significant prognostic impact on transplantation outcomes in patients with Ph + ALL.

Light-Activated In Situ Vaccine with Enhanced Cytotoxic T Lymphocyte Infiltration and Function for Potent Cancer Immunotherapy.

In situ cancer vaccination is an attractive strategy that stimulates protective antitumor immunity. Cytotoxic T lymphocytes (CTLs) are major mediators of the adaptive immune defenses, with critical roles in antitumor immune response and establishing immune memory, and are consequently extremely important for in situ vaccines to generate systemic and lasting antitumor efficacy. However, the dense extracellular matrix and hypoxia in solid tumors severely impede the infiltration and function of CTLs, ultimately compromising the efficacy of in situ cancer vaccines. To address this issue, a robust in situ cancer vaccine, Au@MnO2 nanoparticles (AMOPs), based on a gold nanoparticle core coated with a manganese dioxide shell is developed. The AMOPs modulated the unfavorable tumor microenvironment (TME) to restore CTLs infiltration and function and efficiently induced immunogenic cell death. The Mn2+-mediated stimulator of the interferon genes pathway can be activated to further augment the therapeutic efficacy of the AMOPs. Thus, the AMOPs vaccine successfully elicited long-lasting antitumor immunity to considerably inhibit primary, recurrent, and metastatic tumors. This study not only highlights the importance of revitalizing CTLs efficacy against solid tumors but also makes progress toward overcoming TME barriers for sustained antitumor immunity.

Enhanced Thermoelectric Performance in Flexible Sulfur-Alloyed Ag2Se Thin Films.

Flexible thermoelectric generators can directly convert thermal energy harvested from the human body into electricity. The Ag2Se flexible film, a promising material for wearable thermoelectric generators, normally demonstrates an inferior electrical transport property due to its weakened in-plane mobility. In this study, the in-plane electrical transport properties of flexible Ag2Se films were optimized by alloying with additional sulfur. This optimization is achieved by leveraging the differences in elemental electronegativity and the preferred orientation of the Ag2Se films. The sulfur-alloyed Ag2Se thin film, with a nominal ratio of 3 atom %, can reach a maximum mobility of 1150 cm-2 V-1 s-1 at 300 K. So, the optimized room-temperature power factor increases to 1935 µW m-1 K-2. Furthermore, the Ag2Se film alloyed with 3 atom % sulfur exhibits excellent flexibility even after 1000 bending cycles with a radius of 5 mm, characterized by a relative resistance increment of less than 3%. In addition, the corresponding π-type flexible thermoelectric generator possesses a maximum power density of 51 W m-2 at a temperature difference of 50 K.

Ultrafast evanescently coupled waveguide MUTC-PDs with high responsivity.

Novel evanescently coupled waveguide modified uni-traveling carrier photodiodes (MUTC-PDs) employing a thick multi-layer coupling waveguide are reported. To improve the optical-to-electrical (O/E) conversion efficiency, a thick multi-layer coupling waveguide with a gradually increased refractive index from the bottom layer to the absorption layer is utilized. The refractive index profile facilitates the upward transmission of incident light into the absorption region, thereby enhancing the evanescent coupling efficiency. Meanwhile, the coupling waveguide, with a total thickness of 1.75 µm, expands the mode field diameter, thereby reducing the input coupling loss. Additionally, the top layer of the coupling waveguide also serves as the drift layer. This configuration facilitates efficient light absorption within a short PD length, thus ensuring ultrawide bandwidth and high O/E conversion efficiency simultaneously. Without an additional spot size coupler or anti-reflection coating, the measured responsivity is as high as 0.38 A/W for the PD with an active area of 5 × 6 µm2. Meanwhile, an ultrawide 3-dB bandwidth of 153 GHz has been demonstrated.