A practical study on the near-zero discharge of rainwater and the collaborative treatment and regeneration of rainwater and sewage.

Non-conventional water recovery, recycling, and reuse have been considered imperative approaches to addressing water scarcity in China. The objective of this study was to evaluate the technical and economic feasibility of Water Reclamation Plants (WRP) based on an anaerobic-anoxic-oxic membrane bioreactor (A2O-MBR) system for unconventional water resource treatment and reuse in towns (domestic sewage and rainwater). Rainwater is collected and stored in the rainwater reservoir through the rainwater pipe network, and then transported to the WRP for treatment and reuse through the rainwater reuse pumping station during the peak water demand period. During a year of operation and evaluation process, a total of 610,000 cubic meters of rainwater were reused, accounting for 10.4 % of the treated wastewater. In the A2O-MBR operation, the average effluent concentrations for COD (chemical oxygen demand), NH4+-N (ammonium), TN (total nitrogen), and TP (total phosphorus) were 14.23 ± 4.07 mg/L, 0.22 ± 0.26 mg/L, 11.97 ± 1.54 mg/L, and 0.13 ± 0.09 mg/L, respectively. The effluent quality met standards suitable for reuse in industrial cooling water or for direct discharge. The WRP demonstrates a positive financial outlook, with total capital and operating costs totaling 0.16 $/m3. A comprehensive cost-benefit analysis indicates a positive net present value for the WRP, and the estimated annualized net profit is 0.024 $/m3. This research has achieved near-zero discharge of wastewater and effective allocation of rainwater resources across time and space.

Emerging dimensions of autophagy in melanoma.

Macroautophagy/autophagy has previously been regarded as simply a way for cells to deal with nutrient emergency. But explosive work in the last 15 years has given increasingly new knowledge to our understanding of this process. Many of the functions of autophagy that are unveiled from recent studies, however, cannot be reconciled with this conventional view of cell survival but, instead, point to autophagy being integrally involved at a deeper level of cell biology, playing a critical role in maintaining homeostasis and promoting an integrated stress/immune response. The new appreciation of the role of autophagy in the evolutionary trajectory of cancer and cancer interaction with the immune system provides a mechanistic framework for understanding the clinical benefits of autophagy-based therapies. Here, we examine current knowledge of the mechanisms and functions of autophagy in highly plastic and aggressive melanoma as a model disease of human malignancy, while highlighting emerging dimensions indicating that autophagy is at play beyond its classical face.Abbreviation: AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; ATG: autophagy related; BRAF: B-Raf proto-oncogene, serine/threonine kinase; CAFs: cancer-associated fibroblasts; CCL5: C-C motif chemokine ligand 5; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTLA4: cytotoxic T-lymphocyte associated protein 4; CTL: cytotoxic T lymphocyte; DAMPs: danger/damage-associated molecular patterns; EGFR: epidermal growth factor receptor; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; FITM2: fat storage inducing transmembrane protein 2; HCQ: hydroxychloroquine; ICB: immune checkpoint blockade; ICD: immunogenic cell death; LDH: lactate dehydrogenase; MAPK: mitogen-activated protein kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NDP52: nuclear dot protein 52; NFKB/NF-κ B: nuclear factor kappa B; NBR1: the neighbor of BRCA1; NK: natural killer; NRF1: nuclear respiratory factor 1; NSCLC: non-small-cell lung cancer; OPTN: optineurin; PDAC: pancreatic ductal adenocarcinoma; PDCD1/PD-1: programmed cell death 1; PPT1: palmitoyl-protein thioesterase 1; PTEN: phosphatase and tensin homolog; PTK2/FAK1: protein tyrosine kinase 2; RAS: rat sarcoma; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TAX1BP1: Tax1 binding protein 1; TFEB: transcription factor EB; TGFB/TGF-ß: transforming growth factor beta; TMB: tumor mutational burden; TME: tumor microenvironment; TSC1: TSC complex subunit 1; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated.

Metagenomic characterization of the enhanced performance of multicomponent synergistic thermophilic anaerobic co-digestion of food waste utilizing kitchen waste or garden waste as co-substrate.

Food waste (FW) single-substrate anaerobic digestion usually suffers from rapid acidification and inhibition of oil and salt. To overcome these problems and improve the process efficiency, supplementing other substrates has been used in FW anaerobic digestion. This study investigated the biogas production potential through co-digestion of FW with kitchen waste (KW) or garden waste (GW) in different ratios under thermophilic conditions. The results showed that the optimal ratios were FW:KW=60:40 and FW:GW=80:20 which biogas production improved 73.33% and 68.45% compared with single FW digestion, respectively. The organic matter removal rate of co-digestion was 84.46% for FW+KW group (RFK) and 65.64% for FW+GW group (RFG). Co-digestion increased the abundance of the dominant hydrolytic bacteria Defluviitoga and Hydrogenispora and hydrogenotrophic methanogen Methanoculleus. Furthermore, glycoside hydrolases (GHs), vital carbohydrate-active enzymes (CAZymes), were improved by co-digestion. Co-digestion could also effectively promote the function of cellulase and hemicellulose. This strategy for utilizing different organic wastes together as co-substrate provides a new avenue for bioenergy production.

Autophagy Paradox: Strategizing Treatment Modality in Melanoma.

OPINION STATEMENT: The primordial autophagy process, originally identified as a starvation response in baker's yeast, has since been shown to have a wide spectrum of functions other than survival. In many cases, it is accepted that autophagy operates as a key tumor suppressor mechanism that protects cells from adverse environmental cues by enforcing homeostasis and maintaining the functional and structural integrity of organelles. Paradoxically, heightened states of autophagy are also seen in some cancers, leading to the prevailing view that the pro-survival aspect of autophagy might be hijacked by some tumors to promote their fitness and pathogenesis. Notably, recent studies have revealed a broad range of cell-autonomous autophagy in reshaping tumor microenvironment and maintaining lineage integrity and immune homeostasis, calling for a renewed understanding of autophagy beyond its classical roles in cell survival. Here, we evaluate the increasing body of literature that argues the "double-edged" consequences of autophagy manipulation in cancer therapy, with a particular focus on highly plastic and mutagenic melanoma. We also discuss the caveats that must be considered when evaluating whether autophagy blockade is the effector mechanism of some anti-cancer therapy particularly associated with lysosomotropic agents. If autophagy proteins are to be properly exploited as targets for anticancer drugs, their diverse and complex roles should also be considered.

Charge Transport and Photoconductivity in a Hybrid Uranium(IV) Halide Perovskite.

Hybrid metal halide perovskites are extensively synthesized using p- and d-elements. However, the properties of hybrid halide perovskites involving 5f-elements are still elusive. Herein, we first report the semiconductive property of a uranium-bearing hybrid halide perovskite, [N(C2H5)4]2UCl6 (EAUCl). Single crystal X-ray crystallography demonstrates that EAUCl adopts a zero-dimensional molecular structure consisting of isolated [UCl6]2- anions and organic cations. The intrinsically semiconductive property endows EAUCl with obvious charge transport and photoconductivity, with a high carrier mobility lifetime (µτ) product of 9.91 × 10-4 cm2/V and a photocurrent on-off ratio of 380 under X-ray excitation. Theoretical calculations corroborate that the U 5f orbitals are involved in electron transitions and the formation of band structure.

Multivariate insights into enhanced biogas production in thermophilic dry anaerobic co-digestion of food waste with kitchen waste or garden waste: Process properties, microbial communities and metagenomic analyses.

Multisubstrate synergetic anaerobic co-digestion can effectively overcome low efficiency of food waste (FW) mono-digestion. This study investigated the effect of supplementing FW with kitchen waste (KW) or garden waste (GW) on thermophilic dry anaerobic co-digestion. FW-KW and FW-GW co-digestion enhanced biogas production by 24.69 % and 44.96 % at organic loading rate (OLR) of 3 g VS L-1 d-1, and increased OLR tolerance from 3 to 4 g VS L-1 d-1 through mitigating ammonia nitrogen inhibition and volatile fatty acids accumulation. Co-digestion enriched the dominant hydrolytic bacteria Defluviitoga, resulting in an acceleration of substrate hydrolysis. FW-KW co-digestion improved biogas production by increasing gene abundance related to key enzymes in methanogenesis pathways and promoting the conversion of intermediate products into methane. FW-GW co-digestion enhanced biogas production by enriching ABC transporters-associated genes, leading to efficient substrate utilization. This study provides a promising approach for FW treatment with multivariate insights into thermophilic dry anaerobic co-digestion.

Boosting the Optoelectronic Performance by Regulating Exciton Behaviors in a Porous Semiconductive Metal-Organic Framework.

Exciton behaviors including exciton formation and dissociation dynamics play an essential role in the optoelectronic performance of semiconductive materials but remain unexplored in semiconductive metal-organic frameworks (MOFs). Herein, we reveal that the exciton behaviors in semiconductive MOFs can be regulated by framework-guest interactions, a feature often not achievable in traditional inorganic or organic semiconductors. Incorporation of the electron-deficient molecule within the pores of a terbium-based semiconductive MOF (Tb2L2·4H2O·6DMF, L = TATAB3-, 4,4',4″-s-triazine-1,3,5-triyltri-p-aminobenzoate, DMF = N,N-dimethylformamide) results in efficient energy transfer from the MOF skeleton to molecular acceptors, with a yield of up to 77.4%. This interaction facilitates distinctive exciton type conversion, giving rise to modified conductivity and photoelectric performance. We further fabricated a MOF-based X-ray detection device to demonstrate how the new architecture bolsters the optoelectronic efficiency, which outperforms the properties of parent semiconductive MOFs, with more than 60 times and 40 times enhancement of the photocurrent on-off ratio and detection sensitivity, respectively. With judiciously optimized exciton behaviors, the detection device exhibits a high sensitivity of 51.9 µC Gyair-1 cm-2 and records a charge carrier mobility-lifetime product of 1.12 × 10-3 cm2 V-1 among MOF-based X-ray detectors, which are competitive with values for commercially available detectors. These findings demonstrate a rational synthetic approach to designing exciton arrangements to improve the optoelectronic efficiency of semiconductive MOFs.

Fates of intracellular and extracellular antibiotic resistance genes during the cattle farm wastewater treatment process.

Cattle farm wastewater, as a significant reservoir for antibiotic resistance genes (ARGs), has received wide attention. Intracellular and extracellular ARGs (iARGs and eARGs) were detected during wastewater treatment, including solid-liquid separation, anaerobic regulation, upflow anaerobic sludge blanket (UASB) digestion, an anoxic-oxic-anoxic-oxic (A2O2) process, a membrane bioreactor (MBR), and ozone disinfection. Ten abundant ARGs were chosen as the target ARGs according to metagenomic sequencing. The concentrations of the total target iARGs and eARGs were 6.12 × 107 and 3.24 × 106 copy numbers/mL in raw wastewater, and then 3.79 × 103 and 3.95 × 105 copy numbers/mL in final effluent, because UASB, A2O2, MBR and ozone disinfection can gradually reduce the concentrations of most ARGs. The concentrations of ARGs were positively correlated with almost all wastewater quality indicators. Positive correlation was also observed between iARGs and Bacteroidetes, Firmicutes and Spirochaetes, indicating that the bacteria in these three phyla might be the main hosts of ARGs. Wastewater quality indicators and bacterial community composition affected the distribution and removal of ARGs during cattle wastewater treatment.

Comparison of Prior Bridging Intravenous Thrombolysis With Direct Endovascular Thrombectomy for Anterior Circulation Large Vessel Occlusion: Systematic Review and Meta-Analysis.

Background: Whether bridging treatment combining intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) is superior to direct EVT alone for emergent large vessel occlusion (LVO) in the anterior circulation is unknown. A systematic review and a meta-analysis were performed to investigate and assess the effect and safety of bridging treatment vs. direct EVT in patients with LVO in the anterior circulation. Methods: PubMed, EMBASE, and the Cochrane library were searched to assess the effect and safety of bridging treatment and direct EVT in LVO. Functional independence, mortality, asymptomatic and symptomatic intracranial hemorrhage (aICH and sICH, respectively), and successful recanalization were evaluated. The risk ratio and the 95% CI were analyzed. Results: Among the eight studies included, there was no significant difference in the long-term functional independence (OR = 1.008, 95% CI = 0.845-1.204, P = 0.926), mortality (OR = 1.060, 95% CI = 0.840-1.336, P = 0.624), recanalization rate (OR = 1.015, 95% CI = 0.793-1.300, P = 0.905), and the incidence of sICH (OR = 1.320, 95% CI = 0.931-1.870, P = 0.119) between bridging therapy and direct EVT. After adjusting for confounding factors, bridging therapy showed a lower recanalization rate (effect size or ES = -0.377, 95% CI = -0.684 to -0.070, P = 0.016), but there was no significant difference in the long-term functional independence (ES = 0.057, 95% CI = -0.177 to 0.291, P = 0.634), mortality (ES = 0.693, 95% CI = -0.133 to 1.519, P = 0.100), and incidence of sICH (ES = -0.051, 95% CI = -0.687 to 0.585, P = 0.875) compared with direct EVT. Meanwhile, in the subgroup analysis of RCT, no significant difference was found in the long-term functional independence (OR = 0.927, 95% CI = 0.727-1.182, P = 0.539), recanalization rate (OR = 1.331, 95% CI = 0.948-1.867, P = 0.099), mortality (OR = 1.072, 95% CI = 0.776-1.481, P = 0.673), and sICH incidence (OR = 1.383, 95% CI = 0.806-2.374, P = 0.977) between patients receiving bridging therapy and those receiving direct DVT. Conclusion: For stroke patients with acute anterior circulation occlusion and who are eligible for intravenous thrombolysis, there is no significant difference in the clinical effect between direct EVT and bridging therapy, which needs to be verified by more randomized controlled trials.

Association of Parkinson's Disease With Microbes and Microbiological Therapy.

Parkinson's disease (PD) is the most common movement disorder in the world, affecting 1-2 per 1,000 of the population. The main pathological changes of PD are damage of dopaminergic neurons in substantia nigra of the central nervous system and formation of Lewy bodies. These pathological changes also occur in the intestinal tract and are strongly associated with changes in intestinal flora. By reviewing the research progress in PD and its association with intestinal flora in recent years, this review expounded the mechanism of action between intestinal flora and PD as well as the transmission mode of α - synuclein in neurons. In clinical studies, ß diversity of intestinal flora in PD patients was found to change significantly, with Lactobacillusaceae and Verrucomicrobiaceae being significantly increased and Lachnospiraceae and Prevotellaceae being significantly decreased. In addition, a longer PD course was associated with fewer bacteria and probiotics producing short chain fatty acids, but more pathogenic bacteria. Moreover, the motor symptoms of PD patients may be related to Enterobacteriaceae and bacteria. Most importantly, catechol-O-methyltransferase inhibitors and anticholinergic drugs could change the intestinal flora of PD patients and increase the harmful flora, whereas other anti-PD drugs such as levodopa, dopamine agonist, monoamine oxidase inhibitors, and amantadine did not have these effects. Probiotics, prebiotics, and synbiotics treatment had some potential values in improving the constipation of PD patients, promoting the growth of probiotics, and improving the level of intestinal inflammation. At present, there were only a few case studies and small sample studies which have found certain clinical efficacy of fecal microbiome transplants. Further studies are necessary to elaborate the relationship of PD with microbes.

Bacterial community compositions and nitrogen metabolism function in a cattle farm wastewater treatment plant revealed by Illumina high-throughput sequencing.

Bacteria play an important role in pollutant transformation in activated sludge-based wastewater treatment plants (WWTPs). Exploring the microbial community structure and diversity is essential to improving the performance of wastewater treatment processes. This study employed Illumina MiSeq high-throughput sequencing to investigate the microbial community composition and diversity in a cattle farm wastewater treatment plant (Cf-WWTP). The results showed that the dominant phyla in the whole process were Proteobacteria, Bacteroidetes, and Firmicutes. The principal coordinate analysis (PCoA) indicated that the different stages had a significant impact on the microbial community structure; Bacteroidetes was the dominant phylum in the anearobic stage and Proteobacteria was the dominant phylum in the anoxic-oxic stage. Redundancy analysis (RDA) revealed that total phosphorus (TP) was the most significant factor that regulated the microbial community composition, followed by chemical oxygen demand (COD), total nitrogen (TN), and pH. Proteobacteria, Patescibacteria, and Chloroflexi were simultaneously negatively correlated with TN, COD, and TP. Nitrogen metabolic pathway and transformation mechanism was elucidated by a complete denitrification function predicted with phylogenetic investigation of communities with reconstruction of unobserved states (PICRUSt), as well as detection of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB). These results provide new insights into our understanding of microbial community and metabolic functions of Cf-WWTP.

Intrinsic Semiconducting Behavior in a Large Mixed-Valent Uranium(V/VI) Cluster.

We disclose the intrinsic semiconducting properties of one of the largest mixed-valent uranium clusters, [H3 O+ ][UV (UVI O2 )8 (µ3 -O)6 (PhCOO)2 (Py(CH2 O)2 )4 (DMF)4 ] (Ph=phenyl, Py=pyridyl, DMF=N,N-dimethylformamide) (1). Single-crystal X-ray crystallography demonstrates that UV center is stabilized within a tetraoxo core surrounded by eight uranyl(VI) pentagonal bipyramidal centers. The oxidation states of uranium are substantiated by spectroscopic data and magnetic susceptibility measurement. Electronic spectroscopy and theory corroborate that UV species serve as electron donors and thus facilitate 1 being a n-type semiconductor. With the largest effective atomic number among all reported radiation-detection semiconductor materials, charge transport properties and photoconductivity were investigated under X-ray excitation for 1: a large on-off ratio of 500 and considerable charge mobility lifetime product of 2.3×10-4  cm2 V-1 , as well as a high detection sensitivity of 23.4 µC Gyair -1 cm-2 .

Removal of antibiotic resistance genes from swine wastewater by membrane filtration treatment.

Antibiotic resistance genes (ARGs) have attracted extensive attention as an emerging environmental contaminant potentially threatening humans. One of the main emission sources of ARGs is swine wastewater. In this study, integrated membrane filtration including ultrafiltration and two-stage reverse osmosis was conducted for swine wastewater treatment. The abundances of 16 target ARGs, which accounted for 72.64% of the total ARGs in swine wastewater according to metagenomic sequencing, were quantified by quantitative real-time PCR (qPCR) during each stage of the membrane filtration process. The results showed that integrated membrane filtration could reduce more than 99.0% of conventional pollutants and 99.79% of ARGs (from 3.02 × 108 copy numbers/mL to 6.45 × 105 copy numbers/mL). Principal component analysis (PCA) indicated that the removal efficiency of ARGs subtype by membrane filtration did not depend on ARGs type. However, strong correlations were found between ARGs and the wastewater quality indicators TP, SS and EC according to Cooccurrence patterns, indicating that ARG removal was closely associated with insoluble solid particles and soluble ions in swine wastewater. These results showed that membrane filtration could not only remove conventional pollutants such as nitrogen and phosphorus but also reduce the emerging pollutant of ARGs and decrease the risk of ARGs flowing into natural water.

HIV-1 Nef counteracts autophagy restriction by enhancing the association between BECN1 and its inhibitor BCL2 in a PRKN-dependent manner.

Macroautophagy/autophagy is an auto-digestive pro-survival pathway activated in response to stress to target cargo for lysosomal degradation. In recent years, autophagy has become prominent as an innate antiviral defense mechanism through multiple processes, such as targeting virions and viral components for elimination. These exciting findings have encouraged studies on the ability of autophagy to restrict HIV. However, the role of autophagy in HIV infection remains unclear. Whereas some reports indicate that autophagy is detrimental for HIV, others have claimed that HIV deliberately activates this pathway to increase its infectivity. Moreover, these contrasting findings seem to depend on the cell type investigated. Here, we show that autophagy poses a hurdle for HIV replication, significantly reducing virion production. However, HIV-1 uses its accessory protein Nef to counteract this restriction. Previous studies have indicated that Nef affects autophagy maturation by preventing the fusion between autophagosomes and lysosomes. Here, we uncover that Nef additionally blocks autophagy initiation by enhancing the association between BECN1 and its inhibitor BCL2, and this activity depends on the cellular E3 ligase PRKN. Remarkably, the ability of Nef to counteract the autophagy block is more frequently observed in pandemic HIV-1 and its simian precursor SIVcpz infecting chimpanzees than in HIV-2 and its precursor SIVsmm infecting sooty mangabeys. In summary, our findings demonstrate that HIV-1 is susceptible to autophagy restriction and define Nef as the primary autophagy antagonist of this antiviral process.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin, beta; ATG16L1: autophagy related 16 like 1; BCL2: bcl2 apoptosis regulator; BECN1: beclin 1; cDNA: complementary DNA; EGFP: enhanced green fluorescence protein; ER: endoplasmic reticulum; Gag/p55: group-specific antigen; GFP: green fluorescence protein; GST: glutathione S transferase; HA: hemagglutinin; HIV: human immunodeficiency virus; IP: immunoprecipitation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nef: negative factor; PRKN: parkin RBR E3 ubiquitin ligase; PtdIns3K: phosphatidylinositol 3 kinase; PtdIns3P: phosphatidylinositol 3 phosphate; PTM: post-translational modification; RT-qPCR: reverse transcription followed by quantitative PCR; RUBCN: rubicon autophagy regulator; SEM: standard error of the mean; SERINC3: serine incorporator 3; SERINC5: serine incorporator 5; SIV: simian immunodeficiency virus; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; UVRAG: UV radiation resistance associated gene; VSV: vesicular stomatitis virus; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

Three-Dimensional Polycatenation of a Uranium-Based Metal-Organic Cage: Structural Complexity and Radiation Detection.

The potential applications of metal-organic cages (MOCs) are mostly achieved through specific host-guest interactions within their cavities. Electronic applications would require an effective electron transport pathway, which has been extensively studied in hybrid organic-inorganic materials with extended structures. These properties have not been considered for MOCs because cage-to-cage interactions in these materials have rarely been examined and are challenging to functionalize. We report here a previously unobserved actinide-based MOC assembled from four hexagonal-bipyramidal-coordinated uranyl ions and six bidentate flexible ligands. Remarkably, each isolated cage is further interlocked with six adjacent ones through mechanical bonds, resulting in the first case of a 0D → 3D f-element polycatenated metal-organic cage, SCU-14. Long-range π-π stacking extending throughout the structure is built via polycatenation, providing a visible carrier transmission path. SCU-14 is also an extremely rare case of an intrinsically semiconductive MOC with a wide band gap of 2.61 eV. Combined with the high X-ray attenuation efficiency, SCU-14 can effectively convert X-ray photons to electrical current signals and presents a promising sensitivity of 54.93 µC Gy-1 cm-2.

A Photoconductive X-ray Detector with a High Figure of Merit Based on an Open-Framework Chalcogenide Semiconductor.

A wide range of tunability in the physical parameters of a semiconductor used for X-ray detection is desirable to achieve targeted performance optimization. However, in a dense-phase semiconductor, fine-tuning one parameter often leads to unwanted changes in other parameters. Herein, the intrinsic openness in an open-framework semiconductor has been confirmed, for the first time, to be a key structural factor that weakens the mutual exclusivity of the adjustable physical parameters owing to a non-linear control mechanism. The controllable doping of S in a zeolitic In-Se host results in an optimal balance between resistivity, band gap, and carrier mobility, which finally results in an excellent X-ray detector with a high figure of merit for the mobility-lifetime product (7.12×10-4  cm2 V-1 ); this value is superior to that of a commercial α-Se detector. The current strategy of choosing open-framework semiconductor materials opens a new window for targeting high-performance X-ray detection.

p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs.

Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.

Thermoplastic Membranes Incorporating Semiconductive Metal-Organic Frameworks: An Advance on Flexible X-ray Detectors.

Semiconductive metal-organic frameworks (MOFs) have emerged in applications such as chemical sensors, electrocatalysts, energy storage materials, and electronic devices. However, examples of semiconductive MOFs within flexible electronics have not been reported. We present flexible X-ray detectors prepared by thermoplastic dispersal of a semiconductive MOF (SCU-13) through a commercially available polymer, poly(vinylidene fluoride). The flexible detectors exhibit efficient X-ray-to-electric current conversion with enhanced charge-carrier mobility and low trap density compared to pelleted devices. A high X-ray detection sensitivity of 65.86 µCGyair -1 cm-2 was achieved, which outperforms other pelleted devices and commercial flexible X-ray detectors. We demonstrate that the MOF-based flexible detectors can be operated at multiple bending angles without a deterioration in detection performance. As a proof-of-concept, an X-ray phase contrast under bending conditions was constructed using a 5×5 pixelated MOF-based imager.

How autophagy is tied to inflammation and cancer.

It is not completely understood how autophagy is tied to inflammation and age-related cancer predisposition. Here, we used a mouse model with inducible expression of a cancer-derived frameshift mutation in UV radiation resistance associated (UVRAG) to demonstrate that intervention with autophagy suppressor could exacerbate inflammation and promote age-related spontaneous cancers.

UVRAG in autophagy, inflammation, and cancer.

Macroautophagy/autophagy deregulation has been observed in perpetuated inflammation and the proliferation of tumor cells. However, the mechanisms underlying these changes have yet to be well-identified. UVRAG is one of the key players of autophagy, but its role in vivo remained puzzling. Our recent study utilized a mouse model with inducible expression of a cancer-derived frameshift (FS) mutation in UVRAG that dominant-negatively inhibits wild-type UVRAG, resulting in impaired stimulus-induced autophagy. The systemically compromised autophagy, particularly mitophagy, notably increases inflammation and associated pathologies. Furthermore, our discovery indicates that time-dependent autophagy suppression and ensuing CTNNB1/ß-catenin activation may serve as one tumor-promoting mechanism underpinning age-related cancer susceptibility.