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This is the first study to comprehensively analyze the toxicity of Al coagulants, which are widely present in the effluent of water treatment plants and in natural water in the form of polynuclear Al (e.g., nano-Al13) and mononuclear Al (Alm), on the siphoning efficiency, antioxidant defense system and histological alterations of Corbicula fluminea. The results showed that Almhad a stronger inhibitory effect on siphoning than the nano-Al13coagulant. For all the selected enzyme indexes, induction by nano-Al13was more intense in the digestive gland, while that by Almwas more obvious in the gills. Either Almor nano-Al13can enlarge the tubule lumen and reduce the thickness of the epithelia of digestive tubules, but nano-Al13caused more severe damage to the cellular membrane. Inferred from the bright clusters observed by microscopy, granular nano-Al13enters the digestive gland mainly viaswallowing, while gill filtration is another method by which the ionic Almcan enter the clam body. The presence of nano-Al13and inhibition of enzymes associated with GSH, such as GST and GR, led to the damage of cell membranes. For both Al coagulants, the influence of higher concentrations is more negative. As an effective coagulant, the toxicity of PACl cannot be ignored.

Nano-Al13clusters have the potential to form and remain in a coagulation process, but cannot be directly traced by traditional instrumental techniques in real time since there is only a trace concentration after being dosed. In this study, an optimized electrospray ionization mass spectrometry (ESI-MS) method was introduced for the first time to determine the coagulation pathways when using AlCl3(monomeric Al, i.e., Alm) and polymeric aluminum chloride (PACl) as coagulants. The transformation mechanisms of Al clusters, including Alm, oligomeric Al (Alo), Al13and transient Al (Alts), were clearly elucidated using statistical analysis and a real-time tracking experiment. The nano-Al13clusters could be detected in the coagulation batch experiment conducted using AlCl3as the coagulant. Moreover, using a statistical method, the Al13clusters in the PACl coagulant and the Al13clusters formed by AlCl3coagulation were confirmed to be an efficient coagulant species. In the real-time tracking experiments, the reversible transformations among Alm, Alo, Al13and Altsclusters were instantly observed after the addition of the coagulant (i.e., during the coagulation process). In the subsequent process (i.e., the flocculation process), only floc aggregation occurred, and no obvious transformations among the four types of Al clusters were observed. The continuous aggregation and increase in floc were mainly attributed to particle coalescence with the Al clusters. The mineral–water interface was inferred to favor the transformation of Almand Aloaggregates into Al13as well as the reverse reaction (e.g., the degradation of Al13).

Background We aimed to investigate the determinant factors of anti-PD-1 therapy outcome in nasopharyngeal carcinoma (NPC).Methods In this retrospective study, we included 64 patients with recurrent/metastatic NPC. The association of patients’ characteristics, C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and lactate dehydrogenase (LDH) with survival benefit of anti-PD-1 therapy were analyzed using Cox regression models and Kaplan-Meier analyses. Patients were divided based on the median value of CRP, NLR or LDH into different subgroups.Results At a median follow-up time of 11.4 months (range: 1-28 months), median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% CI, .18-3.6) and 15 months (95% CI, 10.9-19.1) months, respectively. Pretreatment metastases numbers was significant predictor of PFS (HR = 1.99; 95% CI 1.10-3.63; P= .024) and OS (HR = 2.77; 95% CI 1.36-5.61; P= .005). Baseline LDH level was independent predictor of OS (HR = 7.01; 95% CI 3.09-15.88; P< .001). Patients with LDH level >435 U/L at the baseline had significantly shorter PFS and OS compared to patients with LDH level ≤435 U/L (median PFS: 1.7 vs 3.5 months, P= .040; median OS: 3.7 vs 18.5 months, P< .001). Patients with non-durable clinical benefit (NDB) had significantly higher LDH level at the baseline compared to patients who achieved durable clinical benefit (DCB) (P= .025). Post-treatment levels of CRP, LDH, and NLR were decreased compared to baseline in patients with DCB (P= .030, P= .088, and P= .066, respectively), whereas, there was a significant increase in post-treatment level of LDH compared with baseline in patients with NDB (P= .024).Conclusions LDH level at the baseline was an independent predictor of OS and pretreatment metastases numbers was a significant predictor of PFS and OS.

ABSTRACTStressed replication forks can be conservatively repaired and restarted using homologous recombination (HR), initiated by nuclease cleavage of branched structures at stalled forks. We previously reported that the 5′ nuclease EEPD1 is recruited to stressed replication forks, where it plays critical early roles in HR initiation by promoting fork cleavage and end resection. HR repair of stressed replication forks prevents their repair by non-homologous end-joining (NHEJ), which would cause genome instability. Rapid cell division during vertebrate embryonic development generates enormous pressure to maintain replication speed and accuracy. To determine the role of EEPD1 in maintaining replication fork integrity and genome stability during rapid cell division in embryonic development, we assessed the role of EEPD1 during zebrafish embryogenesis. We show here that when EEPD1 is depleted, zebrafish embryos fail to develop normally and have a marked increase in death rate. Zebrafish embryos depleted of EEPD1 are far more sensitive to replication stress caused by nucleotide depletion. We hypothesized that the HR defect with EEPD1 depletion would shift repair of stressed replication forks to unopposed NHEJ, causing chromosome abnormalities. Consistent with this, EEPD1 depletion results in nuclear defects including anaphase bridges and micronuclei in stressed zebrafish embryos, similar to BRCA1 deficiency. These results demonstrate that the newly characterized HR protein EEPD1 maintains genome stability during embryonic replication stress. These data also imply that the rapid cell cycle transit seen during embryonic development produces replication stress that requires HR to resolve.

A facile method had been applied to introduce hydrophobic properties to cellulose materials by incorporation of polyurethane acrylate (PUA) prepolymers into the porous structured cellulose matrix through dip-coating; then, PUA prepolymers were cured around interconnected cellulose fibers under UV light, encapsulating a cellulose matrix with a hydrophobic polymer shell. The characterization of the composite films confirmed the success of the heterogeneous modification, and the chemical structure of the cellulose matrix was preserved. The composite films integrated the merits of cellulose and PUA resin, but the highly hydrophilic behavior of cellulose has been reduced. Contact angle measurements with water demonstrated that the composite films had obvious hydrophobic properties and an obvious reduction in the water uptake and the permeability toward water vapor gas at different relative humidity was also observed. The transmittance of the composite films at 550 nm was about 85%. The thermal and mechanical properties of the composite films were improved when compared with that of PUA resin. The obtained composite based on cellulose and UV curing technology was a good choice for the development of biomass materials with modified surface properties.

Chromosomal translocations are common contributors to malignancy, yet little is known about the precise molecular mechanisms by which they are generated. Sequencing translocation junctions in acute leukemias revealed that the translocations were likely mediated by a DNA double-strand break repair pathway termed nonhomologous end-joining (NHEJ). There are major 2 types of NHEJ: (1) the classical pathway initiated by the Ku complex, and (2) the alternative pathway initiated by poly ADP-ribose polymerase 1 (PARP1). Recent reports suggest that classical NHEJ repair components repress translocations, whereas alternative NHEJ components were required for translocations. The rate-limiting step for initiation of alternative NHEJ is the displacement of the Ku complex by PARP1. Therefore, we asked whether PARP1 inhibition could prevent chromosomal translocations in 3 translocation reporter systems. We found that 2 PARP1 inhibitors or repression of PARP1 protein expression strongly repressed chromosomal translocations, implying that PARP1 is essential for this process. Finally, PARP1 inhibition also reduced both ionizing radiation–generated and VP16-generated translocations in 2 cell lines. These data define PARP1 as a critical mediator of chromosomal translocations and raise the possibility that oncogenic translocations occurring after high-dose chemotherapy or radiation could be prevented by treatment with a clinically available PARP1 inhibitor.

Chromosomal translocations are common contributors to malignancy, yet little is known about the precise molecular mechanisms by which they are generated. Sequencing translocation junctions in acute leukemias revealed that the translocations were likely mediated by a DNA double-strand break repair pathway termed nonhomologous end-joining (NHEJ). There are major 2 types of NHEJ: (1) the classical pathway initiated by the Ku complex, and (2) the alternative pathway initiated by poly ADP-ribose polymerase 1 (PARP1). Recent reports suggest that classical NHEJ repair components repress translocations, whereas alternative NHEJ components were required for translocations. The rate-limiting step for initiation of alternative NHEJ is the displacement of the Ku complex by PARP1. Therefore, we asked whether PARP1 inhibition could prevent chromosomal translocations in 3 translocation reporter systems. We found that 2 PARP1 inhibitors or repression of PARP1 protein expression strongly repressed chromosomal translocations, implying that PARP1 is essential for this process. Finally, PARP1 inhibition also reduced both ionizing radiation–generated and VP16-generated translocations in 2 cell lines. These data define PARP1 as a critical mediator of chromosomal translocations and raise the possibility that oncogenic translocations occurring after high-dose chemotherapy or radiation could be prevented by treatment with a clinically available PARP1 inhibitor.

MicroRNAs (miRNAs) are a class of naturally occurring, small, non-coding RNAs that control gene expression during development, normal cell function, and disease. Although there is emerging evidence that some miRNAs can function as oncogenes or tumor suppressors, there is limited understanding of the role of miRNAs in cancer. In this study, we observed that the expression of miR-125a was inversely correlated with HuR expression in several different breast carcinoma cell lines. HuR is a stress-induced RNA binding protein whose expression is elevated or localization perturbed in several different cancers. Increased cytoplasmic localization of HuR is a prognostic marker in breast cancer. Real time PCR and gene reporter assays indicated that HuR was translationally repressed by miR-125a. Re-establishing miR-125a expression in breast cancer cells decreased HuR protein level and inhibited cell growth. Using MCF-7 breast cancer cells, we further clarified that miR-125a inhibited cell growth via a dramatic suppression of cell proliferation and promotion of apoptosis. In addition, cell migration was also inhibited by miR-125a overexpression. Importantly, the repression of cell proliferation and migration engendered by miR-125a was partly rescued by HuR re-expression. Our results suggest that miR-125a may function as a tumor suppressor for breast cancer, with HuR as a direct and functional target.

Traditional fresh produce washing systems mainly rely on mechanical forces and usage of chlorine bleach solutions to aid in removal and sanitization of microorganisms attached on surfaces of fresh produce during washing processes. Frequent outbreaks of foodborne diseases from ready-to-eat produce indicate insufficient sanitization of the washing processes. Herein, we present a scalable methodology for creating antimicrobial and chlorine rechargeable hydrogel beads using an in situformed network of polyacrylamide and natural polysaccharide alginate through an emulsion polymerization. The resulting hydrogel beads exhibited robust mechanical strength, rechargeable chlorination capability, rapid up to 99.99% bacterial killing efficiency, and high produce sanitizaiton efficiency, enabling the hydrogel beads as a promising additive in chlorine sanitization to effectively sanitize the produce and automatically being recharged and reused.