OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis

Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease with a complex pathology including oxidative stress. Oxidative stress triggers oxidative DNA lesions such as formation of 7,8-dihydro-8-oxo-2′-oxoguanine (8-oxoG) and also causes DNA strand breaks. DNA breaks can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) which contributes to AP pathology. 8-oxoG is recognized by 8-oxoG glycosylase 1 (OGG1) resulting in the removal of 8-oxoG from DNA as an initial step of base excision repair. Since OGG1 also possesses a DNA nicking activity, OGG1 activation may also trigger PARP1 activation. In the present study we investigated the role played by OGG1 in AP. We found that the OGG1 inhibitor compound TH5487 reduced edema formation, inflammatory cell migration and necrosis in a cerulein-induced AP model in mice. Moreover, TH5487 caused 8-oxoG accumulation and reduced tissue poly(ADP-ribose) levels. Consistent with the indirect PARP inhibitory effect, TH5487 shifted necrotic cell death (LDH release and Sytox green uptake) towards apoptosis (caspase activity) in isolated pancreatic acinar cells. In the in vivo AP model, TH5487 treatment suppressed the expression of various cytokine and chemokine mRNAs such as those of TNF, IL-1β, IL1ra, IL6, IL16, IL23, CSF, CCL2, CCL4, CCL12, IL10 and TREM as measured with a cytokine array and verified by RT-qPCR. As a potential mechanism underlying the transcriptional inhibitory effect of the OGG1 inhibitor we showed that while 8-oxoG accumulation in the DNA facilitates NF-κB binding to its consensus sequence, when OGG1 is inhibited, target site occupancy of NF-κB is impaired. In summary, OGG1 inhibition provides protection from tissue injury in AP and these effects are likely due to interference with the PARP1 and NF-κB activation pathways

Middle Bronze Age humidity and temperature variations, and societal changes in East-Central Europe

Archaeological evidence points to substantial changes in Bronze Age societies in the European-Mediterranean region. Isotope geochemical proxies have been compiled to provide independent ancillary data to improve the paleoenvironmental history for the period of interest and support the interpretation of the archaeological observations. In addition to published compositions, in this study we gathered new H isotope data from fluid inclusion hosted water from a stalagmite of the Trió Cave, Southern Hungary, and compared the H isotope data with existing stable isotope and trace element compositions reported for the stalagmite. Additionally, animal bones and freshwater bivalve shells (Unio sp.) were collected from Bronze Age archaeological excavations around Lake Balaton and their stable C and O isotope compositions were measured in order to investigate climate changes and lake evolution processes during this period. The data indicate warm and humid conditions with elevated summer precipitation around 3.7 cal ka BP (Before Present, where present is 1950 CE), followed by a short-term deterioration in environmental conditions at about 3.5 cal ka BP. The environment became humid and cold with winter precipitation dominance around 3.5 to 3.4 cal ka BP, then gradually changed to drier conditions at ∼3.2 cal ka BP. Significant cultural changes have been inferred for this period on the basis of observations during archaeological excavations. The most straightforward consequences of environmental variations have been found in changes of settlement structure. The paleoclimatological picture is well in line with other East-Central European climate records, indicating that the climate fluctuations took place on a regional scale

SISALv2: A comprehensive speleothem isotope database with multiple age-depth models

Characterizing the temporal uncertainty in palaeoclimate records is crucial for analysing past climate change, correlating climate events between records, assessing climate periodicities, identifying potential triggers and evaluating climate model simulations. The first global compilation of speleothem isotope records by the SISAL (Speleothem Isotope Synthesis and Analysis) working group showed that age model uncertainties are not systematically reported in the published literature, and these are only available for a limited number of records (ca. 15 %, n = 107=691). To improve the usefulness of the SISAL database, we have (i) improved the database's spatiooral coverage and (ii) created new chronologies using seven different approaches for age depth modelling. We have applied these alternative chronologies to the records from the first version of the SISAL database (SISALv1) and to new records compiled since the release of SISALv1. This paper documents the necessary changes in the structure of the SISAL database to accommodate the inclusion of the new age models and their uncertainties as well as the expansion of the database to include new records and the qualitycontrol measures applied. This paper also documents the age depth model approaches used to calculate the new chronologies. The updated version of the SISAL database (SISALv2) contains isotopic data from 691 speleothem records from 294 cave sites and new age depth models, including age depth temporal uncertainties for 512 speleothems. SISALv2 is available at https://doi.org/10.17864/1947.256 (Comas-Bru et al., 2020a). © 2020 Author(s)

Identification of a Small TAF Complex and Its Role in the Assembly of TAF-Containing Complexes

TFIID plays a role in nucleating RNA polymerase II preinitiation complex assembly on protein-coding genes. TFIID is a multisubunit complex comprised of the TATA box binding protein (TBP) and 14 TBP-associated factors (TAFs). Another class of multiprotein transcriptional regulatory complexes having histone acetyl transferase (HAT) activity, and containing TAFs, includes TFTC, STAGA and the PCAF/GCN5 complex. Looking for as yet undiscovered subunits by a proteomic approach, we had identified TAF8 and SPT7L in human TFTC preparations. Subsequently, however, we demonstrated that TAF8 was not a stable component of TFTC, but that it is present in a small TAF complex (SMAT), containing TAF8, TAF10 and SPT7L, that co-purified with TFTC. Thus, TAF8 is a subunit of both TFIID and SMAT. The latter has to be involved in a pathway of complex formation distinct from the other known TAF complexes, since these three histone fold (HF)-containing proteins (TAF8, TAF10 and SPT7L) can never be found together either in TFIID or in STAGA/TFTC HAT complexes. Here we show that TAF8 is absolutely necessary for the integration of TAF10 in a higher order TFIID core complex containing seven TAFs. TAF8 forms a heterodimer with TAF10 through its HF and proline rich domains, and also interacts with SPT7L through its C-terminal region, and the three proteins form a complex in vitro and in vivo. Thus, the TAF8-TAF10 and TAF10-SPT7L HF pairs, and also the SMAT complex, seem to be important regulators of the composition of different TFIID and/or STAGA/TFTC complexes in the nucleus and consequently may play a role in gene regulation

The mineralogical composition of calcium and calcium-magnesium carbonate pedofeatures of calcareous soils in the European prairie ecodivision in Hungary

Abstract There is little data on the mineralogy of carbonate pedofeatures in the calcareous soils in Hungary which belong to the European prairie ecodivision. The aim of the present study is to enrich these data. The mineralogical composition of the carbonate pedofeatures from characteristic profiles of the calcareous soils in Hungary was studied by X-ray diffractometry, thermal analysis, SEM combined with microanalysis, and stable isotope determination. Regarding carbonate minerals only aragonite, calcite (+ magnesian calcite) and dolomite (+proto-dolomite) were identified in carbonate grains, skeletons and pedofeatures. The values relating, respectively, to stable isotope compositions (C13, O18) of carbonates in chernozems and in salt-affected soils were in the same range as those for recent soils (latter data reported earlier). There were no considerable differences between the values for the carbonate nodules and tubules from the same horizons, nor were there significant variations between the values of the same pedofeatures from different horizons (BC-C) of the same profile. Thus it can be assumed that there were no considerable changes in conditions of formation. Tendencies were recognized in the changes of (i) carbonate mineral associations, (ii) the MgCO3 content of calcites, (iii) the corrected decomposition temperatures, and (iv) the activation energies of carbonate thermal decompositions among the various substance-regimes of soils. Differences were found in substance-regimes types of soils rather than in soil types

Moving from contractor to owner operator: Impact on safety culture; a case study

Purpose – The purpose of this paper is to investigate whether a change in staffing contractual arrangements, specific training in hazard identification, mentoring of supervisors and the introduction of a robust safety system could improve an organisation\u27s safety culture. How safety conditions change under contracted out labour compared to direct labour and the influence that contracting out has on organisational safety culture is explored. Design/methodology/approach – The study used a case study methodology to detail how the change occurred over a six month period in 2011. As part of the analysis a model of the change process and push-pull factors is offered. Findings – As a result of the change, all areas saw some improvement. Work-related injury statistics dropped significantly, supervisors were clear of their roles, actively monitoring their crews to ensure they worked in a safer manner than before, and staff were actively addressing work-place hazards. With the safety system in place the organisation should be deemed compliant and diligent by the state auditing authorities. This study has also shown that using contractor workers together with in-house workers that are managed under different safety regimes is problematic. The problems don’t occur due to the contractor\u27s safety systems being less robust than the parent company\u27s or that contract workers are themselves less safe; it is the added complexity of managing multiple safety regimes and the lack of trust of the robustness of each system that create conflict. Research limitations/implications – The paper reports on the change process of one mining organisation in Western Australia as a case study from a managerial sample and is thereby limited. Practical implications – This study demonstrates the difficulties in changing safety culture in an underground mining organisation. The paper argues the need for specialised training in identifying hazards by the staff, the mentoring of supervisory staff and the adoption of a robust safety system to support improved safety culture. Originality/value – There is little research conducted in the resources sector researching changes in human resource supply and OHS management, in particular moving from contracted labour to hiring in-house. This case provides an insight into how a change in staffing hiring arrangements, together with specific safety initiatives, has a positive impact on safety performance