A review: targeting UBR5 domains to mediate emerging roles and mechanisms: chance or necessity?

Ubiquitinases are known to catalyze ubiquitin chains on target proteins to regulate various physiological functions like cell proliferation, autophagy, apoptosis, and cell cycle progression. As a member of E3 ligase, ubiquitin protein ligase E3 component n-recognin 5 (UBR5) belongs to the HECT E3 ligase and has been reported to be correlated with various pathophysiological processes. In this review, we give a comprehensive insight into the structure and function of UBR5. We discuss the specific domains of UBR5 and explore their biological functions separately. Furthermore, we describe the involvement of UBR5 in different pathophysiological conditions, including immune response, virus infection, DNA damage response and protein quality control. Moreover, we provide a thorough summary of the important roles and regulatory mechanisms of UBR5 in cancers and other diseases. On the whole, investigating the domains and functions of UBR5, elucidating the underlying mechanisms of UBR5 with various substrates in detail may provide new theoretical basis for the treatment of diseases, including cancers, which could improve future studies to construct novel UBR5-targeted therapy strategies.

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade.

Here we report a concise and divergent synthesis of scabrolide A and havellockate, representative members of polycyclic marine natural product furano(nor)cembranoids. The synthesis features a highly efficient exo-exo-endo radical cascade. Through the generation of two rings, three C-C bonds, and three contiguous stereocenters in one step, this remarkable transformation not only assembles the bowl-shaped, common 6-5-5 fused ring system from simple building blocks but also precisely installs the functionalities at desired positions and sets the stage for further divergent preparation of both target molecules. Further studies reveal that the robust and unusual 6-endo radical addition in the cascade is likely facilitated by the rigidity of the substrate.

Shallow wet irrigation reduces nitrogen leaching loss rate in paddy fields by microbial regulation and lowers rate of downward migration of leaching water: a 15N-tracer study.

China consumes 35% of the world's fertilizer every year; however, most of the nitrogen fertilizers, which are essential for rice cultivation, are not used effectively. In this study, factors affecting the nitrogen leaching loss rate were studied in typical soil and rice varieties in South China. The effects of various irrigation measures on rice growth and nitrogen leaching loss were investigated by conducting experiments with eight groups. These groups included traditional irrigation (TI) and shallow wet irrigation (SWI). The TI is a common irrigation method for farmers in South China, maintaining a water layer of 5-8 cm depth. For SWI, after establishing a shallow water layer usually maintaining at 1-2 cm, paddy is irrigated when the field water level falls to a certain depth, then this process is then repeat as necessary. The nitrogen distribution characteristics were determined using 15N isotope tracing. In addition, the effects of nitrification, denitrification, and microbial composition on soil nitrogen transformation at different depths were studied by microbial functional gene quantification and high-throughput sequencing. The results revealed that in the SWI groups, the total nitrogen leaching loss rate reduced by 0.3-0.8% and the nitrogen use efficiency (NUE) increased by 2.18-4.43% compared with those in the TI groups. After the 15N-labeled nitrogen fertilizer was applied, the main pathways of nitrogen were found to be related to plant absorption and nitrogen residues. Furthermore, paddy soil ammonia-oxidizing archaea were more effective than ammonia-oxidizing bacteria for soil ammonia oxidation by SWI groups. The SWI measures increased the relative abundance of Firmicutes in paddy soil, enhancing the ability of rice to fix nitrogen to produce ammonium nitrogen, thus reducing the dependence of rice on chemical fertilizers. Moreover, SWI enhanced the relative abundance of nirS and nosZ genes within surface soil bacteria, thereby promoting denitrification in the surface soil of paddy fields. SWI also promoted ammonia oxidation and denitrification by increasing the abundance and activity of Proteobacteria, Nitrospirae, and Bacteroidetes. Collectively, SWI effectively reduced the nitrogen leaching loss rate and increase NUE.

On the role of asymmetric molecular geometry in high-performance organic solar cells.

Although asymmetric molecular design has been widely demonstrated effective for organic photovoltaics (OPVs), the correlation between asymmetric molecular geometry and their optoelectronic properties is still unclear. To access this issue, we have designed and synthesized several symmetric-asymmetric non-fullerene acceptors (NFAs) pairs with identical physical and optoelectronic properties. Interestingly, we found that the asymmetric NFAs universally exhibited increased open-circuit voltage compared to their symmetric counterparts, due to the reduced non-radiative charge recombination. From our molecular-dynamic simulations, the asymmetric NFA naturally exhibits more diverse molecular interaction patterns at the donor (D):acceptor (A) interface as compared to the symmetric ones, as well as higher D:A interfacial charge-transfer state energy. Moreover, it is observed that the asymmetric structure can effectively suppress triplet state formation. These advantages enable a best efficiency of 18.80%, which is one of the champion results among binary OPVs. Therefore, this work unambiguously demonstrates the unique advantage of asymmetric molecular geometry, unveils the underlying mechanism, and highlights the manipulation of D:A interface as an important consideration for future molecular design.

Kidney function decline mediates the adverse effects of per- and poly-fluoroalkyl substances (PFAS) on uric acid levels and hyperuricemia risk.

Previous studies indicated per- and poly-fluoroalkyl substances (PFAS) were related to uric acid and hyperuricemia risk, but evidence for the exposure-response (E-R) curves and combined effect of PFAS mixture is limited. Moreover, the potential mediation effect of kidney function was not assessed. Hence, we conducted a national cross-sectional study involving 13,979 US adults in NHANES 2003-2018 to examine the associations of serum PFAS with uric acid and hyperuricemia risk, and the mediation effects of kidney function. Generalized linear models and E-R curves showed positive associations of individual PFAS with uric acid and hyperuricemia risk, and nearly linear E-R curves indicated no safe threshold for PFAS. Weighted quantile sum regression found positive associations of PFAS mixture with uric acid and hyperuricemia risk, and PFOA was the dominant contributor to the adverse effect of PFAS on uric acid and hyperuricemia risk. Causal mediation analysis indicated significant mediation effects of kidney function decline in the associations of PFAS with uric acid and hyperuricemia risk, with the mediated proportion ranging from 19 % to 57 %. Our findings suggested that PFAS, especially PFOA, may cause increased uric acid and hyperuricemia risk increase even at low levels, and kidney function decline plays a crucial mediation effect.

Uncertainty Quantification and Interpretability for Clinical Trial Approval Prediction.

Background: Clinical trial is a crucial step in the development of a new therapy (e.g., medication) and is remarkably expensive and time-consuming. Forecasting the approval of clinical trials accurately would enable us to circumvent trials destined to fail, thereby allowing us to allocate more resources to therapies with better chances. However, existing approval prediction algorithms did not quantify the uncertainty and provide interpretability, limiting their usage in real-world clinical trial management. Methods: This paper quantifies uncertainty and improves interpretability in clinical trial approval predictions. We devised a selective classification approach and integrated it with the Hierarchical Interaction Network, the state-of-the-art clinical trial prediction model. Selective classification, encompassing a spectrum of methods for uncertainty quantification, empowers the model to withhold decision-making in the face of samples marked by ambiguity or low confidence. This approach not only amplifies the accuracy of predictions for the instances it chooses to classify but also notably enhances the model's interpretability. Results: Comprehensive experiments demonstrate that incorporating uncertainty markedly enhances the model's performance. Specifically, the proposed method achieved 32.37%, 21.43%, and 13.27% relative improvement on area under the precision-recall curve over the base model (Hierarchical Interaction Network) in phase I, II, and III trial approval predictions, respectively. For phase III trials, our method reaches 0.9022 area under the precision-recall curve scores. In addition, we show a case study of interpretability that helps domain experts to understand model's outcome. The code is publicly available at https://github.com/Vincent-1125/Uncertainty-Quantification-on-Clinical-Trial-Outcome-Prediction. Conclusion: Our approach not only measures model uncertainty but also greatly improves interpretability and performance for clinical trial approval prediction.

Semaphorins in tumor microenvironment: Biological mechanisms and therapeutic progress.

Hallmark features of the tumor microenvironment include immune cells, stromal cells, blood vessels, and extracellular matrix (ECM), providing a conducive environment for the growth and survival of tumors. Recent advances in the understanding of cancer biology have highlighted the functional role of semaphorins (SEMAs). SEMAs are a large and diverse family of widely expressed secreted and membrane-binding proteins, which were initially implicated in axon guidance and neural development. However, it is now clear that they are widely expressed beyond the nervous system and participate in regulating immune responses and cancer progression. In fact, accumulating evidence disclosed that different SEMAs can either stimulate or restrict tumor progression, some of which act as important regulators of tumor angiogenesis. Conversely, limited information is known about the functional relevance of SEMA signals in TME. In this setting, we systematically elaborate the role SEMAs and their major receptors played in characterized components of TME. Furthermore, we provide a convergent view of current SEMAs pharmacological progress in clinical treatment and also put forward their potential application value and clinical prospects in the future.

Kinetics of chlorine and chloramine reactions in reverse osmosis permeate and their impact on radical formation during UV/chlorine advanced oxidation for potable reuse.

Knowledge of the speciation of chlorine and chloramines in reverse osmosis (RO) permeate is needed to estimate the performance (i.e., pollutant log reduction) of subsequent UV/chlorine advanced oxidation processes (AOPs). To accurately predict the speciation, a previously reported breakpoint chlorination kinetic model was experimentally validated for pH 5.5 and reaction times < 3 min and used to predict the kinetics of breakpoint chlorination in RO permeate. The predictions showed that eliminating chloramines by adding chlorine at a dose beyond the chlorine-to-nitrogen (Cl/N) breakpoint ratio is not practical due to the high breakpoint Cl/N ratio for RO permeate (∼3.0 molar ratio) and an estimated > 40 min reaction time. The conversion from monochloramine (NH2Cl) to dichloramine (NHCl2) is the major process involved, and either or both free chlorine and chloramines may be the major species present, depending on the Cl/N ratio. Model simulations showed that increasing the oxidant dose may not always enhance the performance of UV/chlor(am)ine in RO permeate, due to the need for a low free chlorine dose for optimal •OH exposure in RO permeate. Further UV/AOPs modelling showed that it is important to control the NH2Cl concentration to improve the UV/AOP performance in RO permeate, which may be achieved by extending the reaction time after chlorine is added or increasing the applied Cl/N ratio (e.g., increasing chlorine dose). However, these measures only enhance the pollutant percentage removal by about 5 % under the conditions modelled. A simulation tool was developed and is provided to predict the speciation of chlor(am)ine in RO permeate.

Quantitative evaluation of urban green exposure and its impact on human health: A case study on the 3-30-300 green space rule.

BACKGROUND AND AIMS: Urban green spaces offer various health benefits, yet the impact of comprehensive green exposure criteria on multidimensional health remains unclear. The 3-30-300 green space rule represents the green exposure indicators with specific thresholds. This study aims to quantitatively evaluate urban green exposure in cities and can support investigation of its relationship with human health. METHODS: We conducted a cross-sectional study based on 902 investigated individuals in 261 residential locations aged 11-95 years from Xiamen City, China. 3-30-300 green exposure was calculated using field surveys, GIS, and Baidu Maps Application Programming Interface (API). Physical health data was based on Occupational Stress Indicator (OSI)-2. Mental health was from the 12-item General Health Questionnaire (GHQ-12). Social health was from a self-constructed evaluation questionnaire. Statistical analyses were conducted using Geographically Weighted Regression and Geographically Weighted Logistic Regression for global and local effects on green exposure and multidimensional health. RESULT: Among the investigated individuals, only 3.55 % (32/902) fully meet the 3-30-300 rule in Xiamen. Global results show that individuals achieved at least 30 % vegetation coverage (Yes) is associated with better physical (ß: 0.76, p < 0.01) and social (ß: 0.5, p < 0.01) health. GWLR global results indicate that individuals can "see at least 3 trees from home" meeting one (OR = 0.46, 95%CI: 0.25-0.86, p < 0.05) or two (OR = 0.41, 95%CI: 0.22,0.78, p < 0.01; OR = 0.24, 95%CI: 0.07-0.77, p < 0.05) 3-30-300 rule components are significantly associated with reduced medical visits and hospitalizations refer to not met these criterias. In the GWR local analysis, achieved 30 % vegetation cover is significantly related to improved social health at all locations. Meeting any two indicators also contribute to improved social health (n = 511, ß: 0.46-0.51, P < 0.05). CONCLUSION: Green exposure indicators based on the 3-30-300 rule guiding healthy urban green space development. We observed multidimensional health benefits when 1/3 or 2/3 of the indicators were met.

Interactive design generation and optimization from generative adversarial networks in spatial computing.

This paper focuses on exploring the application possibilities and optimization problems of Generative Adversarial Networks (GANs) in spatial computing to improve design efficiency and creativity and achieve a more intelligent design process. A method for icon generation is proposed, and a basic architecture for icon generation is constructed. A system with generation and optimization capabilities is constructed to meet various requirements in spatial design by introducing the concept of interactive design and the characteristics of requirement conditions. Next, the generated icons can effectively maintain diversity and innovation while meeting the conditional features by integrating multi-feature recognition modules into the discriminator and optimizing the structure of conditional features. The experiment uses publicly available icon datasets, including LLD-Icon and Icons-50. The icon shape generated by the model proposed here is more prominent, and the color of colored icons can be more finely controlled. The Inception Score (IS) values under different models are compared, and it is found that the IS value of the proposed model is 7.05, which is higher than that of other GAN models. The multi-feature icon generation model based on Auxiliary Classifier GANs performs well in presenting multiple feature representations of icons. After introducing multi-feature recognition modules into the network model, the peak error of the recognition network is only 2.000 in the initial stage, while the initial error of the ordinary GAN without multi-feature recognition modules is as high as 5.000. It indicates that the improved model effectively helps the discriminative network recognize the core information of icon images more quickly. The research results provide a reference basis for achieving more efficient and innovative interactive space design.

Bipolar membrane electrodialysis integrated with in-situ CO2 absorption for simulated seawater concentrate utilization, carbon storage and production of sodium carbonate.

In the context of carbon capture, utilization, and storage, the high-value utilization of carbon storage presents a significant challenge. To address this challenge, this study employed the bipolar membrane electrodialysis integrated with carbon utilization technology to prepare Na2CO3 products using simulated seawater concentrate, achieving simultaneous saline wastewater utilization, carbon storage and high-value production of Na2CO3. The effects of various factors, including concentration of simulated seawater concentrate, current density, CO2 aeration rate, and circulating flow rate of alkali chamber, on the quality of Na2CO3 product, carbon sequestration rate, and energy consumption were investigated. Under the optimal condition, the CO32- concentration in the alkaline chamber reached a maximum of 0.817 mol/L with 98 mol% purity. The resulting carbon fixation rate was 70.50%, with energy consumption for carbon sequestration and product production of 5.7 kWhr/m3 CO2 and 1237.8 kWhr/ton Na2CO3, respectively. This coupling design provides a triple-win outcome promoting waste reduction and efficient utilization of resources.

A mixed blessing of influent leachate microbes in downstream biotreatment systems of a full-scale landfill leachate treatment plant.

In landfill leachate treatment plants (LLTPs), the microbiome plays a pivotal role in the decomposition of organic compounds, reduction in nutrient levels, and elimination of toxins. However, the effects of microbes in landfill leachate influents on downstream treatment systems remain poorly understood. To address this knowledge gap, we collected 23 metagenomic and 12 metatranscriptomic samples from landfill leachate and activated sludge from various treatment units in a full-scale LLTP. We successfully recovered 1,152 non-redundant metagenome-assembled genomes (MAGs), encompassing a wide taxonomic range, including 48 phyla, 95 classes, 166 orders, 247 families, 238 genera, and 1,152 species. More diverse microbes were observed in the influent leachate than in the downstream biotreatment systems, among which, an unprecedented ∼30 % of microbes with transcriptional expression migrated from the influent to the biological treatment units. Network analysis revealed that 399 shared MAGs across the four units exhibited high node centrality and degree, thus supporting enhanced interactions and increased stability of microbial communities. Functional reconstruction and genome characterization of MAGs indicated that these shared MAGs possessed greater capabilities for carbon, nitrogen, sulfur, and arsenic metabolism compared to non-shared MAGs. We further identified a novel species of Zixibacteria in the leachate influent with discrete lineages from those in other environments that accounted for up to 17 % of the abundance of the shared microbial community and exhibited notable metabolic versatility. Meanwhile, we presented groundbreaking evidence of the involvement of Zixibacteria-encoded genes in the production of harmful gas emissions, such as N2O and H2S, at the transcriptional level, thus suggesting that influent microbes may pose safety risks to downstream treatment systems. In summary, this study revealed the complex impact of the influent microbiome on LLTP and emphasizes the need to consider these microbial characteristics when designing treatment technologies and strategies for landfill leachate management.

S100A6 drives lymphatic metastasis of liver cancer via activation of the RAGE/NF-kB/VEGF-D pathway.

Patients diagnosed with lymph node (LN) metastatic liver cancer face an exceedingly grim prognosis. In-depth analysis of LN metastatic patients' characteristics and tumor cells' interactions with human lymphatic endothelial cells (HLECs), can provide important biological and therapeutic insights. Here we identify at the single-cell level that S100A6 expression differs between primary tumor and their LN metastasis. Of particular significance, we uncovered the disparity in S100A6 expression between tumors and normal tissues is greater in intrahepatic cholangiocarcinoma (ICC) patients, frequently accompanied by LN metastases, than that in hepatocellular carcinoma (HCC), with rare occurrence of LN metastasis. Furthermore, in the infrequent instances of LN metastasis in HCC, heightened S100A6 expression was observed, suggesting a critical role of S100A6 in the process of LN metastasis. Subsequent experiments further uncovered that S100A6 secreted from tumor cells promotes lymphangiogenesis by upregulating the expression and secretion of vascular endothelial growth factor-D (VEGF-D) in HLECs through the RAGE/NF-kB/VEGF-D pathway while overexpression of S100A6 in tumor cells also augmented their migration and invasion. Taken together, these data reveal the dual effects of S100A6 in promoting LN metastasis in liver cancer, thus highlighting its potential as a promising therapeutic target.

Urinary Microbiome Dysbiosis and Immune Dysregulations as Potential Diagnostic Indicators of Bladder Cancer.

There are a total of 82,290 new cases and 16,710 deaths estimated for bladder cancer in the United States in 2023. Currently, urine cytology tests are widely used for bladder cancer diagnosis, though they suffer from variable sensitivity, ranging from 45 to 97%. More recently, the microbiome has become increasingly recognized for its role in human diseases, including cancers. This study attempts to characterize urinary microbiome bladder cancer-specific dysbiosis to explore its diagnostic potential. RNA-sequencing data of urine samples from patients with bladder cancer (n = 18) and matched controls (n = 12) were mapped to bacterial sequences to yield species-level abundance approximations. Urine samples were analyzed at both the population and species level to reveal dysbiosis associated with bladder cancer. A panel of 35 differentially abundant species was discovered, which may be useful as urinary biomarkers for this disease. We further assessed whether these species were of similar significance in a validation dataset (n = 81), revealing that the genera Escherichia, Acinetobacter, and Enterobacter were consistently differentially abundant. We discovered distinct patterns of microbial-associated immune modulation in these samples. Several immune pathways were found to be significantly enriched with respect to the abundance of these species, including antigen processing and presentation, cytosolic DNA sensing, and leukocyte transendothelial migration. Differential cytokine activity was similarly observed, suggesting the urinary microbiome's correlation to immune modulation. The adherens junction and WNT signaling pathways, both implicated in the development and progression of bladder cancer, were also enriched with these species. Our findings indicate that the urinary microbiome may reflect both microbial and immune dysregulations of the tumor microenvironment in bladder cancer. Given the potential biomarker species identified, the urinary microbiome may provide a non-invasive, more sensitive, and more specific diagnostic tool, allowing for the earlier diagnosis of patients with bladder cancer.

Delayed Crystallization Kinetics Allowing High-Efficiency All-Polymer Photovoltaics with Superior Upscaled Manufacturing.

Though encouraging performance is achieved in small-area organic photovoltaics (OPVs), reducing efficiency loss when evoluted to large-area modules is an important but unsolved issue. Considering that polymer materials show benefits in film-forming processability and mechanical robustness, a high-efficiency all-polymer OPV module is demonstrated in this work. First, a ternary blend consisting of two polymer donors, PM6 and PBQx-TCl, and one polymer acceptor, PY-IT, is developed, with which triplet state recombination is suppressed for a reduced energy loss, thus allowing a higher voltage; and donor-acceptor miscibility is compromised for enhanced charge transport, thus resulting in improved photocurrent and fill factor; all these contribute to a champion efficiency of 19% for all-polymer OPVs. Second, the delayed crystallization kinetics from solution to film solidification is achieved that gives a longer operation time window for optimized blend morphology in large-area module, thus relieving the loss of fill factor and allowing a record efficiency of 16.26% on an upscaled module with an area of 19.3 cm2 . Besides, this all-polymer system also shows excellent mechanical stability. This work demonstrates that all-polymer ternary systems are capable of solving the upscaled manufacturing issue, thereby enabling high-efficiency OPV modules.

Risk factors for surgical site infection after percutaneous endoscopic lumbar discectomy.

The objective of this study was to investigate the risk factors associated with surgical site infection (SSI) after percutaneous endoscopic lumbar discectomy (PELD) in patients with lumbar disc herniation (LDH). A retrospective analysis was performed on a cohort of 335 patients who underwent PELD between January 2016 and January 2023. Data were derived from the Hospital Information System (HIS), and a comprehensive statistical assessment was performed using IBM SPSS Statistics version 25.0. Both univariate and multivariate logistic regression analyses assessed a range of risk determinants, such as age, body mass index (BMI), comorbidities, laboratory test parameters and surgery-related variables. The incidence of SSI after PELD was 2.7% (9/335). Univariate analysis highlighted BMI, diabetes mellitus, long-term corticosteroid consumption, surgical time and cerebrospinal fluid leakage as significant predictors of SSI. Multivariate logistic regression identified BMI, diabetes mellitus, long-term corticosteroid consumption, surgical time and cerebrospinal fluid leakage as significant risk factors for SSI after PELD. High BMI, diabetes mellitus, long-term corticosteroid consumption, long surgical time and postoperative cerebrospinal fluid leakage are predisposing factors for SSI in patients undergoing PELD. Precise interventions focused on such risk components, including careful preoperative assessment and strategic postoperative care, are essential to reduce the incidence of SSI and improve surgical efficacy.

Thorough Optimization for Intrinsically Stretchable Organic Photovoltaics.

The development of intrinsically stretchable organic photovoltaics (is-OPVs) with a high efficiency is of significance for practical application. However, their efficiencies lag far behind those of rigid or even flexible counterparts. To address this issue, an advanced top-illuminated OPV is designed and fabricated, which is intrinsically stretchable and has a high performance, through systematic optimizations from material to device. First, the stretchability of the active layer is largely increased by adding a low-elastic-modulus elastomer of styrene-ethylene-propylene-styrene tri-block copolymer (SEPS). Second, the stretchability and conductivity of the opaque electrode are enhanced by a conductive polymer/metal (denoted as M-PH1000@Ag) composite electrode strategy. Third, the optical and electrical properties of a sliver nanowire transparent electrode are improved by a solvent vapor annealing strategy. High-performance is-OPVs are successfully fabricated with a top-illuminated structure, which provides a record-high efficiency of 16.23%. Additionally, by incorporating 5-10% elastomer, a balance between the efficiency and stretchability of the is-OPVs is achieved. This study provides valuable insights into material and device optimizations for high-efficiency is-OPVs, with a low-cost production and excellent stretchability, which indicates a high potential for future applications of OPVs.

cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence.

Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.

Impact analysis of operating conditions on carbon dioxide reduction in microbial electrosynthesis: Insight into the substance utilization and microbial response.

Microbial electrosynthesis (MES) is facing a series of problems including low energy utilization and production efficiency of high value-added products, which seriously hinder its practical application. In this study, a more practical direct current power source was used and the anaerobic activated sludge from wastewater treatment plants was inoculated to construct the acetic acid-producing MES. The operating conditions of acetic acid production were further optimized and the specific mechanisms involving the substance utilization and microbial response were revealed. The optimum conditions were the potential of 3.0 V and pH 6.0. Under these conditions, highly electroactive biofilms formed and all kinds of substances were effectively utilized. In addition, dominant bacteria (Acetobacterium, Desulfovibrio, Sulfuricurvum, Sulfurospirillum, and Fusibacter) had high abundances. Under optimal conditions, acetic acid-forming characteristic genera (Acetobacterium) had the highest relative abundance (Biocathode-25.82 % and Suspension-17.24 %). This study provided references for the optimal operating conditions of MES and revealed the corresponding mechanisms.

PlzD modifies Vibrio vulnificus foraging behavior and virulence in response to elevated c-di-GMP.

IMPORTANCE: Many free-swimming bacteria propel themselves through liquid using rotary flagella, and mounting evidence suggests that the inhibition of flagellar rotation initiates biofilm formation, a sessile lifestyle that is a nearly universal surface colonization paradigm in bacteria. In general, motility and biofilm formation are inversely regulated by the intracellular second messenger bis-(3´-5´)-cyclic dimeric guanosine monophosphate (c-di-GMP). Here, we identify a protein, PlzD, bearing a conserved c-di-GMP binding PilZ domain that localizes to the flagellar pole in a c-di-GMP-dependent manner and alters the foraging behavior, biofilm, and virulence characteristics of the opportunistic human pathogen, Vibrio vulnificus. Our data suggest that PlzD interacts with components of the flagellar stator to decrease bacterial swimming speed and changes in swimming direction, and these activities are enhanced when cellular c-di-GMP levels are elevated. These results reveal a physical link between a second messenger (c-di-GMP) and an effector (PlzD) that promotes transition from a motile to a sessile state in V. vulnificus.