Effects of acidification on nitrification and associated nitrous oxide emission in estuarine and coastal waters

In the context of an increasing atmospheric carbon dioxide (CO2) level, acidification of estuarine and coastal waters is greatly exacerbated by land-derived nutrient inputs, coastal upwelling, and complex biogeochemical processes. A deeper understanding of how nitrifiers respond to intensifying acidification is thus crucial to predict the response of estuarine and coastal ecosystems and their contribution to global climate change. Here, we show that acidification can significantly decrease nitrification rate but stimulate generation of byproduct nitrous oxide (N2O) in estuarine and coastal waters. By varying CO2 concentration and pH independently, an expected beneficial effect of elevated CO2 on activity of nitrifiers (“CO2-fertilization” effect) is excluded under acidification. Metatranscriptome data further demonstrate that nitrifiers could significantly up-regulate gene expressions associated with intracellular pH homeostasis to cope with acidification stress. This study highlights the molecular underpinnings of acidification effects on nitrification and associated greenhouse gas N2O emission, and helps predict the response and evolution of estuarine and coastal ecosystems under climate change and human activities.publishedVersio

Postoperative serum squamous cell carcinoma antigen and carcinoembryonic antigen predict overall survival in surgical patients with esophageal squamous cell carcinoma

BackgroundTumor markers are routinely used in clinical practice. However, for resectable patients with esophageal squamous cell carcinoma (ESCC), they are applied infrequently as their prognostic significance is incompletely understood.MethodsThis historical cohort study included 2769 patients with resected ESCC from 2011 to 2018 in a high-risk area in northern China. Their clinical data were extracted from the Electronic Medical Record. Survival analysis of eight common tumor markers was performed with multivariable Cox proportional hazards regressions.ResultsWith a median follow-up of 39.5 months, 901 deaths occurred. Among the eight target markers, elevated postoperative serum SCC (Squamous cell carcinoma antigen) and CEA (Carcinoembryonic antigen) predicted poor overall survival (SCC HRadjusted: 2.67, 95% CI: 1.70-4.17; CEA HRadjusted: 2.36, 95% CI: 1.14-4.86). In contrast, preoperative levels were not significantly associated with survival. Stratified analysis also demonstrated poorer survival in seropositive groups of postoperative SCC and CEA within each TNM stage. The above associations were generally robust using different quantiles of concentrations above the upper limit of the clinical normal range as alternative cutoffs. Regarding temporal trends of serum levels, SCC and CEA were similar. Their concentrations fell rapidly after surgery and thereafter remained relatively stable.ConclusionPostoperative serum SCC and CEA levels predict the overall survival of ESCC surgical patients. More importance should be attached to the use of these markers in clinical applications

Spontaneous Abortion and Preterm Labor and Delivery in Nonhuman Primates: Evidence from a Captive Colony of Chimpanzees (Pan troglodytes)

Preterm birth is a leading cause of perinatal mortality, yet the evolutionary history of this obstetrical syndrome is largely unknown in nonhuman primate species.We examined the length of gestation during pregnancies that occurred in a captive chimpanzee colony by inspecting veterinary and behavioral records spanning a total of thirty years. Upon examination of these records we were able to confidently estimate gestation length for 93 of the 97 (96%) pregnancies recorded at the colony. In total, 78 singleton gestations resulted in live birth, and from these pregnancies we estimated the mean gestation length of normal chimpanzee pregnancies to be 228 days, a finding consistent with other published reports. We also calculated that the range of gestation in normal chimpanzee pregnancies is approximately forty days. Of the remaining fifteen pregnancies, only one of the offspring survived, suggesting viability for chimpanzees requires a gestation of approximately 200 days. These fifteen pregnancies constitute spontaneous abortions and preterm deliveries, for which the upper gestational age limit was defined as 2 SD from the mean length of gestation (208 days).The present study documents that preterm birth occurred within our study population of captive chimpanzees. As in humans, pregnancy loss is not uncommon in chimpanzees, In addition, our findings indicate that both humans and chimpanzees show a similar range of normal variation in gestation length, suggesting this was the case at the time of their last common ancestor (LCA). Nevertheless, our data suggest that whereas chimpanzees' normal gestation length is ∼20-30 days after reaching viability, humans' normal gestation length is approximately 50 days beyond the estimated date of viability without medical intervention. Future research using a comparative evolutionary framework should help to clarify the extent to which mechanisms at work in normal and preterm parturition are shared in these species

The disulphide cleavage derivative (C42-4) of 11′-deoxyverticillin A (C42) fails to induce apoptosis and genomic instability in HeLa cells

ABSTRACTOur previous study revealed 11’-deoxyverticillin A (C42), a natural product isolated from the Ophiocordyceps-associated fungus Clonostachys rogersoniana and a member of the epipolythiodioxopiperazines (ETPs), induced both apoptosis and autophagy in HCT116 cells; however, the role of disulphide/polysulphide bridges of C42 in the regulation of autophagy remains unexplored. Here, we revealed that C42 activated both caspase-dependent apoptosis and autophagy in HeLa cells, whereas its disulphide cleavage derivative C42-4 failed to induce the cleavage of both caspase-3 and PARP-1. In contrast, both C42 and C42-4 increased the formation of autophagosomes, punctate staining of LC3, and the ratio of LC3-II to actin, suggesting that disulphide/polysulphide bridges are dispensable for the induction of the autophagic process. Moreover, we found that C42 but not C42-4 led to nuclear instability by increasing the formation of micronuclei and expression of phosphorylated histone H2AX (γ-H2AX), a widely used marker for DNA double strand breaks (DSBs), while Rad51, a protein pivotal for DNA repair, was decreased upon challenge with C42. These results demonstrate that the disulphide bonds in ETPs play an essential role in the induction of caspase-dependent apoptosis and nuclear stability

HER3 targeting augments the efficacy of panobinostat in claudin-low triple-negative breast cancer cells

Abstract Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine the mechanisms of action of panobinostat, a pan-inhibitor of histone deacetylase (HDAC) and FDA-approved medication for multiple myeloma, in TNBC and to provide a rationale for effective drug combinations against this aggressive disease. RNA sequencing analyses of the claudin-low (CL) TNBC (MDA-MB-231) cells untreated or treated with panobinostat were performed to identify the differentially expressed genes. Adaptive alterations in gene expression were analyzed and validated in additional CL TNBC cells. Tumor xenograft models were used to test the in vivo antitumor activity of panobinostat alone or its combinations with gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). Panobinostat potently inhibited proliferation and induced apoptosis in all TNBC cells tested. However, in CL TNBC cells, this HDAC inhibitor markedly enhanced expression of HER3, which interacted with EGFR to activate both receptors and Akt signaling pathways. Combinations of panobinostat and gefitinib synergistically suppressed CL TNBC cell proliferation and promoted apoptosis in vitro and in vivo. Upregulation of HER3 compromises the efficacy of panobinostat in CL TNBC. Inactivation of HER3 combined with panobinostat represents a practical approach to combat CL TNBC

Grb2 interacts with necrosome components and is involved in rasfonin-induced necroptosis

Abstract The underlying mechanism by which growth factor receptor-bound protein 2 (Grb2) regulates necroptosis remains unexplored. In the present study, we found that rasfonin, a fungal natural product and an activator of necroptosis, enhanced Grb2 binding to receptor-interacting serine/threonine kinase 1 (RIP1), which plays a critical role in regulating programmed necrosis. Moreover, we observed that SQSTM/p62 (p62), a protein that can form necrosomes with RIP1, increased its interaction with Grb2 upon rasfonin challenge. Although it has been used as an activator of autophagy in our previous study, here we found that a high dose of rasfonin was able to inhibit autophagic process. Inhibition of RIP1 either chemically or genetically reversed the inhibition of rasfonin on autophagy, whereas knockdown of Grb2 markedly reduced rasfonin-induced necrosis. Additionally, we found that the compound failed to upregulate the expression of RIP1 in Grb2-deprived cells. In summary, our data revealed that Grb2 actively participated in rasfonin-induced necroptosis by interacting with the components of necrosome and mediating their expression