Dietary bioaccumulation potential of silver nanomaterials compared to silver nitrate in wistar rats using an ex vivo gut sac technique

Chronic dietary bioaccumulation tests with rodents are required for new substances, including engineered nanomaterials (ENMs), in order to provide information on the potential hazards to human health. However, screening tools are needed to manage the diversity of ENMs and alternative methods are desirable with respect to animal welfare. Here, an ex vivo gut sac method was used to estimate the dietary bioaccumulation potential of silver nanomaterials. The entire gastrointestinal tract (except the caecum) was removed and filled with a gut saline containing 1 mg L-1 of Ag as either AgNO3, silver nanoparticles (Ag NPs) or silver sulphide nanoparticles (Ag2S NPs), and compared to controls with no added Ag. The gut sacs were incubated for 4 h, rinsed to remove excess media, and the total Ag determined in the mucosa and muscularis. There was no detected Ag in the control treatments. Within the Ag treatments, 1.4-22% of the exposure dose was associated with the tissues and serosal saline. Within the mucosa of the AgNO3 treatment, the highest Ag concentration was associated with the intestinal regions (3639-7087 ng g-1) compared to the stomach (639 ± 128 ng g-1). This pattern was also observed in the Ag NP and Ag2S NP treatments, but there was no significant differences between any Ag treatments for the mucosa. However, differences between treatments were observed in the muscularis concentration. For example, both the Ag NP (907 ± 284 ng g -1) and Ag2S NP (1482 ± 668 ng g-1) treatments were significantly lower compared to the AgNO3 treatment (2514 ± 267 ng g-1). The duodenum demonstrated serosal accumulation in both the AgNO3 (~10 ng mL-1) and Ag NP (~3 ng mL-1) treatments. The duodenum showed some of the highest Ag accumulation with 41, 61 and 57% of the total Ag in the mucosa compared to the muscularis for the AgNO3, Ag NP and Ag2S NP treatments, respectively. In conclusion, the ex vivo gut sac method demonstrates the uptake of Ag in all Ag treatments, with the duodenum the site of highest accumulation. Based on the serosal saline accumulation, the ranked order of accumulation is AgNO3 > Ag NPs > Ag2S NPs

Evolution of an ancient protein function involved in organized multicellularity in animals.

To form and maintain organized tissues, multicellular organisms orient their mitotic spindles relative to neighboring cells. A molecular complex scaffolded by the GK protein-interaction domain (GKPID) mediates spindle orientation in diverse animal taxa by linking microtubule motor proteins to a marker protein on the cell cortex localized by external cues. Here we illuminate how this complex evolved and commandeered control of spindle orientation from a more ancient mechanism. The complex was assembled through a series of molecular exploitation events, one of which - the evolution of GKPID's capacity to bind the cortical marker protein - can be recapitulated by reintroducing a single historical substitution into the reconstructed ancestral GKPID. This change revealed and repurposed an ancient molecular surface that previously had a radically different function. We show how the physical simplicity of this binding interface enabled the evolution of a new protein function now essential to the biological complexity of many animals

Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma.

Schwannoma tumours typically arise on the 8th cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the 8th or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a pre-clinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth

Discovery of SQSTM1/p62-dependent P-bodies that regulate the NLRP3 inflammasome

Autophagy and ribonucleoprotein granules, such as P-bodies (PBs) and stress granules, represent vital stress responses to maintain cellular homeostasis. SQSTM1/p62 phase-separated droplets are known to play critical roles in selective autophagy; however, it is unknown whether p62 can exist as another form in addition to its autophagic droplets. Here, we found that, under stress conditions, including proteotoxicity, endotoxicity, and oxidation, autophagic p62 droplets are transformed to a type of enlarged PBs, termed p62-dependent P-bodies (pd-PBs). p62 phase separation is essential for the nucleation of pd-PBs. Mechanistically, pd-PBs are triggered by enhanced p62 droplet formation upon stress stimulation through the interactions between p62 and DDX6, a DEAD-box ATPase. Functionally, pd-PBs recruit the NLRP3 inflammasome adaptor ASC to assemble the NLRP3 inflammasome and induce inflammation-associated cytotoxicity. Our study shows that p62 droplet-to-PB transformation acts as a stress response to activate the NLRP3 inflammasome process, suggesting that persistent pd-PBs lead to NLRP3-dependent inflammation toxicity

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS

BACKGROUND: Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site “COGS-2” study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. METHODS: Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. RESULTS: 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis × test site interaction. HCS > schizophrenia PPI differences were greatest among patients not taking 2(nd) generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. DISCUSSION: The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia “endophenotype” of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses

Influence de la variété et des zones de pression d'infection virale sur le taux de tubercules atteints par les virus et sur le rendement en culture de plant de pommes de terre en Pologne

International audienc

Wpływ sposobu stosowania herbicydów na zachwaszczenie i plony ziarna pszenicy ozimej

W badaniach polowych przeprowadzonych w latach 1999-2001 określono skuteczność chwastobójczą herbicydu Treflan 480 EC (trifluralina) stosowanego bezpośrednio po zasiewie pszenicy ozimej do zwalczania miotły zbożowej (Apera spica-venti) w mieszaninach z herbicydami zwalczającymi chwasty jedno- i/lub dwuliścienne: Afalon Dyspersyjny 450 SC (linuron), Glean 75 DF (chlorosulfuron) i Stomp 330 EC (pendimetalina). Mieszaniny tych herbicydów porównywano z zalecanym dwukrotnym sposobem stosowania herbicydów – Treflan 480 EC (jesienią po zasiewie pszenicy) + Mustang 306 SE (2,4-D + florasulam) w okresie wiosennym – w celu zwalczenia chwastów dwuliściennych. Najwyższą skuteczność zwalczania miotły zbożowej i chwastów dwuliściennych zapewniła mieszanina herbicydów Treflan 480 EC (1,25 dm3·ha-1) + Glean 75 DF (15 g·ha-1) stosowana jesienią bezpośrednio po zasiewie pszenicy. Łączne stosowanie tych herbicydów w terminie jesiennym zapewniło jednocześnie najwyższy przyrost plonów ziarna i największą opłacalność odchwaszczania pszenicy ozimej.Three-year field experiment (1999-2001) was conducted to determine the effectiveness of Treflan 480 EC herbicide (trifluraline) for common windgrass (Apera spica-venti) control applied directly after winter wheat sowing in mixtures with herbicides for grass and/or dicotyledonous weed control: Afalon Dyspersyjny 450 EC (linuron), Glean 75 DF (chlorsulfuron) and Stomp 330 EC (pendimethaline). Treflan 480 EC applied directly after winter wheat sowing followed by Mustang 306 SE (2,4-D + florasulam) applied in spring at wheat tillering period constituted the control. The best common windgrass and dicotyledonous weed control, yield increase and net profit were recorded for the mixture of Treflan 480 EC (1,25 dm3·ha-1) with Glean 75 DF (15 g·ha-1) applied in autumn, directly after winter wheat sowing