Stabilization of TGF-ß Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-ß Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.

Dysregulation of the transforming growth factor-ß (TGF-ß) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-ß receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-ß-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-ß receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-ß signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-ß signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-ß signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-ß signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-ß signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

Genomic characterization and risk stratification of esophageal squamous dysplasia.

Objectives: The majority of esophageal squamous dysplasia (ESD) patients progress slowly, while a subset of patients can undergo recurrence rapidly or progress to invasive cancer even after proper treatment. However, the molecular mechanisms underlying these clinical observations are still largely unknown. Methods: By sequencing the genomic data of 160 clinical samples from 49 tumor-free ESD patients and 88 esophageal squamous cell carcinoma (ESCC) patients, we demonstrated lower somatic mutation and copy number alteration (CNA) burden in ESD compared with ESCC. Results: Cross-species screening and functional assays identified ACSM5 as a novel driver gene for ESD progression. Furthermore, we revealed that miR-4292 promoted ESD progression and could serve as a non-invasive diagnostic marker for ESD. Conclusions: These findings largely expanded our understanding of ESD genetics and tumorigenesis, which possessed promising significance for improving early diagnosis, reducing overtreatment, and identifying high-risk ESD patients.

Anaerobic biodegradation enables zero liquid discharge of two-stage nanofiltration system for microelectronic wastewater treatment.

Nanofiltration (NF) is a promising technology in the treatment of microelectronic wastewater. However, the treatment of concentrate derived from NF system remains a substantial technical challenge, impeding the achievement of the zero liquid discharge (ZLD) goal in microelectronic wastewater industries. Herein, a ZLD system, coupling a two-stage NF technology with anaerobic biotechnology was proposed for the treatment of tetramethylammonium hydroxide (TMAH)-contained microelectronic wastewater. The two-stage NF system exhibited favorable efficacy in the removal of conductivity (96 %), total organic carbon (TOC, 90 %), and TMAH (96 %) from microelectronic wastewater. The membrane fouling of this system was dominated by organic fouling, with the second stage NF membrane experiencing a more serious fouling compared to the first stage membrane. The anaerobic biotechnology achieved a near-complete removal of TMAH and an 80 % reduction in TOC for the first stage NF concentrate. Methyloversatilis was the key genus involved in the anaerobic treatment of the microelectronic wastewater concentrate. Specific genes, including dmd-tmd, mtbA, mttB and mttC were identified as significant players in mediating the dehydrogenase and methyl transfer pathways during the process of TMAH biodegradation. This study highlights the potential of anaerobic biodegradation to achieve ZLD in the treatment of TMAH-contained microelectronic wastewater by NF system.

Assessing the impact of circulating inflammatory cytokines and proteins as drivers and therapeutic targets in epilepsy: A Mendelian randomization study.

BACKGROUND: Previous research has demonstrated that neuroinflammation is a key element in the progress of epilepsy. Nevertheless, it is currently unidentified which inflammatory factors and proteins increase or decrease the risk of epilepsy. METHODS: We adopted Mendelian randomization techniques to explore the causal relationship between circulating inflammatory factors and proteins and various epilepsy. Our principal approach was inverse variance weighting, supplemented by several sensitivity analyses to guarantee the robustness of our findings. RESULTS: Studies have identified associations between epilepsy and specific inflammatory factors and proteins: three inflammatory factors and six proteins are linked to epilepsy in general; one inflammatory factor and four proteins are associated with focal epilepsy with no documented lesions; two inflammatory factors and three proteins are related to focal epilepsy, excluding cases with hippocampal sclerosis; two inflammatory factors and two proteins are connected to juvenile myoclonic epilepsy; two inflammatory factors and five proteins are linked to juvenile absence epilepsy; four inflammatory proteins are associated with childhood absence epilepsy; two inflammatory factors are related to focal epilepsy overall; two inflammatory factors and two proteins are connected to generalized epilepsy; and two inflammatory proteins are linked to generalized epilepsy with tonic-clonic seizures. Additionally, six inflammatory factors may play a downstream role in focal epilepsy. CONCLUSION: Our study uncovers various inflammatory factors and proteins that influence the risk of epilepsy, offering instructive insights to the diagnosis and therapy of the condition.

New Alkalescent Electrolyte Chemistry for Zinc-Ferricyanide Flow Battery.

Alkaline zinc-ferricyanide flow batteries are efficiency and economical as energy storage solutions. However, they suffer from low energy density and short calendar life. The strongly alkaline conditions (3 mol L-1 OH-) reduce the solubility of ferri/ferro-cyanide (normally only 0.4 mol L-1 at 25 °C) and induce the formation of zinc dendrites at the anode. Here, we report a new zinc-ferricyanide flow battery based on a mild alkalescent (pH 12) electrolyte. Using a chelating agent to rearrange ferri/ferro-cyanide ion-solvent interactions and improve salt dissociation, we increased the solubility of ferri/ferro-cyanide to 1.7 mol L-1 and prevented zinc dendrites. Our battery has an energy density of ~74 Wh L-1 catholyte at 60 °C and remains stable for 1800 cycles (1800 hours) at 0 °C and for >1400 cycles (2300 hours) at 25 °C. An alkalescent zinc-ferricyanide cell stack built using this alkalescent electrolyte stably delivers 608 W of power for ~40 days.

Carbon Nanotube Network Induces Porous Deposited MnO2 for High-Areal Capacity Zn/Mn Batteries.

Mn2+/MnO2 aqueous battery is a promising candidate for large-scale energy storage owing to its feature of low-cost and abundant crustal reserves. However, the inherent MnO2 shedding issue results in a limited areal capacity and poor cycling life, which prohibits its further commercialization. In this manuscript, it is revealed that the cause of shedding is the cracking of MnO2 layer due to stress. To circumvent this challenge, carbon nanotubes framework is introduced on pristine carbon felt, which provides more deposition sites and induces the formation of a porous deposition layer. Compared to the dense deposition layer on pristine carbon felt, the porous structure can effectively avoid cracking and subsequent shedding issue. Moreover, the porous deposited layer is conducive to proton diffusion and rich in defects, which facilitates the subsequent dissolution reaction. As results, the assembled Zn/Mn battery demonstrates more than 200 cycles with the areal capacity of 15 mAh cm-2 at 40 mA cm-2. Even with a high areal capacity of 40 mAh cm-2, it can still run for more than 60 cycles. This breakthrough paves a way toward practical manganese-based batteries, bringing us closer to achieve cost-effective batteries.

Electrolyte Design with Dual -C≡N Groups Containing Additives to Enable High-Voltage Na3V2(PO4)2F3-Based Sodium-Ion Batteries.

Na3V2(PO4)2F3 is recognized as a promising cathode for high energy density sodium-ion batteries due to its high average potential of ∼3.95 V (vs Na/Na+). A high-voltage-resistant electrolyte is of high importance due to the long duration of 4.2 V (vs Na/Na+) when improving cyclability. Herein, a targeted electrolyte containing additives with two -C≡N groups like succinonitrile has been designed. In this design, one -C≡N group is accessible to the solvation sheath and enables the other -C≡N in dinitrile being exposed and subsequently squeezed into the electric double layer. Then, the squeezed -C≡N group is prone to a preferential adsorption on the electrode surface prior to the exposed -CH2/-CH3 in Na+-solvent and oxidized to construct a stable and electrically insulating interface enriched CN-/NCO-/Na3N. The Na3V2(PO4)2F3-based sodium-ion batteries within a high-voltage of 2-4.3 V (vs Na/Na+) can accordingly achieve an excellent cycling stability (e.g., 95.07% reversible capacity at 1 C for 1,5-dicyanopentane and 98.4% at 2 C and 93.0% reversible capacity at 5 C for succinonitrile after 1000 cycles). This work proposes a new way to design high-voltage electrolytes for high energy density sodium-ion batteries.

Exploring 0D lead-free metal halide with highly efficient blue light emission and high-sensitivity photodetection.

Environmentally friendly and highly efficient blue luminescent materials are an unremitting pursuit in the optoelectronic field. Herein, we assembled a new 0D lead-free metal halide of (F-PPA)ZnBr4, which exhibits narrow blue light emission with a remarkable PLQY of 50.15%, high stability and high detection sensitivity toward UV light. These results indicate the potential for the application of low-dimensional zinc-based halides in multiple optoelectronic devices.

Unexpected Cyclization Product Discovery from the Photoinduced Bioconjugation Chemistry between Tetrazole and Amine.

Bioconjugation chemistry has emerged as a powerful tool for the modification of diverse biomolecules under mild conditions. Tetrazole, initially proposed as a bioorthogonal photoclick handle for 1,3-dipolar cyclization with alkenes, was later demonstrated to possess broader photoreactivity with carboxylic acids, serving as a versatile bioconjugation and photoaffinity labeling probe. In this study, we unexpectedly discovered and validated the photoreactivity between tetrazole and primary amine to afford a new 1,2,4-triazole cyclization product. Given the significance of functionalized N-heterocycles in medicinal chemistry, we successfully harnessed the serendipitously discovered reaction to synthesize both pharmacologically relevant DNA-encoded chemical libraries (DELs) and small molecule compounds bearing 1,2,4-triazole scaffolds. Furthermore, the mild reaction conditions and stable 1,2,4-triazole linkage found broad application in photoinduced bioconjugation scenarios, spanning from intramolecular peptide macrocyclization and templated DNA reaction cross-linking to intermolecular photoaffinity labeling of proteins. Triazole cross-linking products on lysine side chains were identified in tetrazole-labeled proteins, refining the comprehensive understanding of the photo-cross-linking profiles of tetrazole-based probes. Altogether, this tetrazole-amine bioconjugation expands the current bioconjugation toolbox and creates new possibilities at the interface of medicinal chemistry and chemical biology.

Analysis of correlative risk factors for radiation-induced hypothyroidism in head and neck tumors.

OBJECTIVE: The aim of the study is to identify clinical and dosimetric factors that could predict the risk of radiation-induced hypothyroidism(RIHT) in head and neck cancer(HNC) patients following intensity-modulated radiotherapy(IMRT). METHODS: A total of 103 HNC patients were included in our study. General clinical characteristic and dosimetric data of all recruited patients were analyzed, respectively. The univariate and multivariate logistic regression anlalysis were successively conducted to identify optimal predictors, which aim to construct the nomogram. And the joint prediction was performed. RESULTS: The incidence of patients with HNC was 36.9% (38/103). Among the clinical factors, gender, N stage, chemotherapy, frequency of chemotherapy and surgery involving the thyroid were related to RIHT. Logistic regression analysis showed that thyroid volume, Dmean, VS45, VS50, VS60 and V30,60 were independent predictors of RIHT, which were also incorporated in the nomogram. An AUC of 0.937 (95%CI, 0.888-0.958) also was showed outstanding resolving ability of the nomogram. When the volume of the thyroid was greater than 10.6 cm3, the incidence of RIHT was 14.8%, and when the volume of the thyroid was equal to or smaller than 10.6 cm3, the incidence was 72.5%. The incidence rates of RIHT in the group with VS60≦8.4cm3 and VS60 > 8.4cm3 were 61.4% and 19.3%, respectively. CONCLUSIONS: Thyroid volume and thyroid VS60 are independent predictors of RIHT in patients with HNC. Moreover, more attention should be paid to patients with thyroid volume ≤ 10.6cm3. Thyroid VS60 > 8.4cm3 may be a useful threshold for predicting the development of RIHT. The nomogram conducted by the research may become a potential and valuable tool that could individually predict the risk of RIHT for HNC patients.

Application of LRG mechanism in normal pressure hydrocephalus.

Normal pressure hydrocephalus (NPH) is a prevalent type of hydrocephalus, including secondary normal pressure hydrocephalus (SNPH) and idiopathic normal pressure hydrocephalus (INPH). However, its clinical diagnosis and pathological mechanism are still unclear. Leucine-rich α-2 glycoprotein (LRG) is involved in various human diseases, including cancer, diabetes, cardiovascular disease, and nervous system diseases. Now the physiological mechanism of LRG is still being explored. According to the current research results on LRG, we found that the agency of LRG has much to do with the known pathological process of NPH. This review focuses on analyzing the LRG signaling pathways and the pathological mechanism of NPH. According to the collected literature evidence, we speculated that LRG probably be involved in the pathological process of NPH. Finally, based on the mechanism of LRG and NPH, we also summarized the evidence of molecular targeted therapies for future research and clinical application.

Long-term exposure to PM1 is associated with increased prevalence of metabolic diseases: evidence from a nationwide study in 123 Chinese cities.

Exposure to particulate matter (PM) has been linked to metabolic diseases. However, the effects of PM with an aerodynamic diameter ≤ 1.0 µm (PM1) on metabolic diseases remain unclear. This study is aimed at assessing the associations of PM1 with metabolic disease risk and quantifying the concentration-response (C-R) relationship of PM1 with metabolic disease risk. A national cross-sectional study was conducted, including 12,495 middle-aged and older adults in 123 Chinese cities. The two-year average concentration of PM1 was evaluated using satellite-based spatiotemporal models. Metabolic diseases, including abdominal obesity, diabetes, hypertension, dyslipidemia, and metabolic syndrome, were identified based on physical examination, blood standard biochemistry examination, and self-reported disease histories. Generalized linear models and C-R curves were used to evaluate the associations of PM1 with metabolic diseases. A total of 12,495 participants were included in this study, with a prevalence of 45.73% for abdominal obesity, 20.22% for diabetes, 42.46% for hypertension, 41.01% for dyslipidemia, and 33.78% for metabolic syndrome. The mean ± standard deviation age of participants was 58.79 ± 13.14 years. In addition to dyslipidemia, exposure to PM1 was associated with increased risks of abdominal obesity, diabetes, hypertension, and metabolic syndrome. Each 10 µg/m3 increase in PM1 concentrations was associated with 39% (odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.33, 1.46) increase in abdominal obesity, 18% (OR = 1.18, 95%CI 1.12, 1.25) increase in diabetes, 11% (OR = 1.11, 95%CI 1.06, 1.16) increase in hypertension, and 25% (OR = 1.25, 95%CI 1.19, 1.31) in metabolic syndrome, respectively. C-R curves showed that the OR values of abdominal obesity, diabetes, hypertension, and metabolic syndrome were increased gradually with the increase of PM1 concentrations. Subgroup analysis indicated that exposure to PM1 was associated with increased metabolic disease risks among participants with different lifestyles and found that solid fuel users were more susceptible to PM1 than clean fuel users. This national cross-sectional study indicated that exposure to higher PM1 might increase abdominal obesity, diabetes, hypertension, and metabolic syndrome risk, and solid fuel use might accelerate the adverse effects of PM1 on metabolic syndrome risk. Further longitudinal cohort studies are warranted to establish a causal inference between PM1 exposure and metabolic disease risk.

A Choline-Based Antifreezing Complexing Agent with Selective Compatibility for Zn-Br2 Flow Batteries.

The high freezing point of polybromides, charging products, is a significant obstacle to the rapid development of zinc-bromine flow batteries (Zn-Br2 FBs). Here, a choline-based complexing agent (CCA) is constructed to liquefy the polybromides at low temperatures. Depending on quaternary ammonium group, choline can effectively complex with polybromide anions and form dense oil-phase that has excellent antifreezing property. Benefiting from indispensable strong ion-ion interaction, the highly selectively compatible CCA, consisting of choline and N-methyl-N-ethyl-morpholinium salts (CCA-M), can be achieved to further enhance bromine fixing ability. Interestingly, the formed polybromides with CCA-M are able to keep liquid even at -40 °C. The CCA-M endows Zn-Br2 FBs at 40 mA cm-2 with unprecedented long cycle life (over 150 cycles) and high Coulombic efficiency (CE, average ≈98.8%) at -20 °C, but also at room temperature (over 1200 cycles, average CE: ≈94.7%). The CCA shows a promising prospect of application and should be extended to other antifreezing bromine-based energy storage systems.

Inundative practice for screening siRNA management candidates against a notorious predatory beetle using olfactory silencing.

Calosoma maximoviczi, a predatory pest beetle, poses a significant threat to wild silk farm production due to its predation on wild silkworms. Given the coexistence of this species with beneficial silkworms in the farm orchards, chemical pesticides are not an ideal solution for controlling its population. In this study, we employed a comprehensive multi-target RNA interference (RNAi) approach to disrupt the olfactory perception of C. maximoviczi through independently silencing 16 odorant receptors (ORs) in the respective genders. Specifically, gene-specific siRNAs were designed to target a panel of ORs, allowing us to investigate the specific interactions between odorant receptors and ligands within this species. Our investigation led to identifying four candidate siOR groups that effectively disrupted the beetle's olfactory tracking of various odorant ligands associated with different trophic levels. Furthermore, we observed sex-specific differences in innate RNAi responses reflected by subsequent gene expression, physiological and behavioral consequences, underscoring the complexity of olfactory signaling and emphasizing the significance of considering species/sex-specific traits when implementing pest control measures. These findings advance our understanding of olfactory coding patterns in C. maximoviczi beetles and establish a foundation for future research in the field of pest management strategies.

Enabling Long-Life Aqueous Organic Redox Flow Batteries with a Highly Stable, Low Redox Potential Phenazine Anolyte.

Aqueous organic redox flow batteries (AORFBs) are considered a promising energy storage technology due to the sustainability and designability of organic active molecules. Despite this, most of AORFBs suffer from limited stability and low voltage because of the chemical instability and high redox potential of organic molecules in anolyte. Herein, we propose a new phenazine derivative, 4,4'-(phenazine-2,3-diylbis(oxy))dibutyric acid (2,3-O-DBAP), as a water-soluble and chemically stable anodic active molecules. By combining calculations and experiments, we demonstrate that 2,3-O-DBAP exhibits a higher solubility, a lower redox potential (-0.699 V vs SHE), and greater chemical stability than other O-DBAP isomers. Then, we demonstrate a long-lasting flow cell with an average discharge voltage of 1.12 V, a low fade rate of 0.0127%, and a lifespan of 62 days at pH 14 using 2,3-O-DBAP paired with ferri/ferrocyanide. The negligible self-discharge behavior also verifies the high stability of 2,3-O-DBAP. These results highlight the importance of molecular engineering for AORFBs.

Research progress on the role of the Wnt signaling pathway in pituitary adenoma.

Pituitary adenoma (PA) is the third most common central nervous system tumor originating from the anterior pituitary, but its pathogenesis remains unclear. The Wnt signaling pathway is a conserved pathway involved in cell proliferation, Self-renewal of stem cells, and cell differentiation. It is related to the occurrence of various tumors, including PA. This article reviews the latest developments in Wnt pathway inhibitors and pathway-targeted drugs. It discusses the possibility of combining Wnt pathway inhibitors with immunotherapy to provide a theoretical basis for the combined treatment of PA.

A Ubiquitin-Dependent Switch on MEF2D Senses Pro-Metastatic Niche Signals to Facilitate Intrahepatic Metastasis of Liver Cancer.

Effective treatment for metastasis, a leading cause of cancer-associated death, is still lacking. To seed on a distal organ, disseminated cancer cells (DCCs) must adapt to the local tissue microenvironment. However, it remains elusive how DCCs respond the pro-metastatic niche signals. Here, systemic motif-enrichment identified myocyte enhancer factor 2D (MEF2D) as a critical sensor of niche signals to regulate DCCs adhesion and colonization, leading to intrahepatic metastasis and recurrence of liver cancer. In this context, MEF2D transactivates Itgb1 (coding ß1-integrin) and Itgb4 (coding ß4-integrin) to execute temporally unique functions, where ITGB1 recognizes extracellular matrix for early seeding, and ITGB4 acts as a novel sensor of neutrophil extracellular traps-DNA (NETs-DNA) for subsequent chemotaxis and colonization. In turn, an integrin-FAK circuit promotes a phosphorylation-dependent USP14-orchastrated deubiquitination switch to stabilize MEF2D via circumventing degradation by the E3-ubiquitin-ligase MDM2. Clinically, the USP14(pS432)-MEF2D-ITGB1/4 feedback loop is often hyper-active and indicative of inferior outcomes in human malignancies, while its blockade abrogated intrahepatic metastasis of DCCs. Together, DCCs exploit a deubiquitination-dependent switch on MEF2D to integrate niche signals in the liver mesenchyme, thereby amplifying the pro-metastatic integrin-FAK signaling. Disruption of this feedback loop is clinically applicable with fast-track potential to block microenvironmental cues driving metastasis.

Analysis of the Mediation Effects of Adverse Mental Health Outcomes in HIV-Infected Women of Childbearing Age from Multiple Perspectives Including Discrimination Perception.

Objective: To Analysis of the mediation effects of adverse mental health outcomes in HIV-infected women of childbearing age from multiple perspectives including discrimination perception, social capital, and other factors. Methods: A cross-sectional survey was conducted among 553 people in Xinjiang region of China using Survey scale. AMOS was used to identify factors that influenced the "discrimination perception/mental resilience/social capital-depression-poor mental health outcomes" pathway. Results: A total of 44.85% and 42.13% of the study participants had anxiety and depression symptoms, as perceived discrimination increased, the higher the level of depression in HIV-infected women of childbearing age. Correlation coefficient among depression with poor mental health outcomes was also significant. Psychological resilience, social capital and depression have mediating effects on perceived discrimination and poor mental health outcomes, discrimination perception had an indirect effect on depression through social capital and an indirect effect on adverse mental health outcomes through depression and psychological resilience. The modified model has a good fitting effect. Conclusion: Discrimination perception was shown to affect adverse mental health outcomes by impacting mental resilience, depression, and social capital. The findings suggest the need for measures to reduce adverse mental health outcomes by decreasing discrimination perception, increasing social capital, and enhancing psychological resilience.

Shikonin-Loaded Hollow Fe-MOF Nanoparticles for Enhanced Microwave Thermal Therapy.

Microwave (MW) thermal therapy has been widely used for the treatment of cancer in clinics, but it still shows limited efficacy and a high recurrence rate owing to non-selective heat delivery and thermo-resistance. Regulating glycolysis shows great promise to improve MW thermal therapy since glycolysis plays an important role in thermo-resistance, progression, metabolism, and recurrence. Herein, we developed a delivery nanosystem of shikonin (SK)-loaded and hyaluronic acid (HA)-modified hollow Fe-MOF (HFM), HFM@SK@HA, as an efficient glycolysis-meditated agent to improve the efficacy of MW thermal therapy. The HFM@SK@HA nanosystem shows a high SK loading capacity of 31.7 wt %. The loaded SK can be effectively released from the HFM@SK@HA under the stimulation of an acidic tumor microenvironment and MW irradiation, overcoming the intrinsically low solubility and severe toxicity of SK. We also find that the HFM@SK@HA can not only greatly improve the heating effect of MW in the tumor site but also mediate MW-enhancing dynamic therapy efficiency by catalyzing the endogenous H2O2 to generate reactive oxygen species (ROS). As such, the MW irradiation treatment in the presence of HFM@SK@HA in vitro enables a highly improved anti-tumor efficacy due to the combined effect of released SK and generated ROS on inhibiting glycolysis in cancer cells. Our in vivo experiments show that the tumor inhibition rate is up to 94.75% ± 3.63% with no obvious recurrence during the 2 weeks after treatment. This work provides a new strategy for improving the efficacy of MW thermal therapy.