PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication

DNA damage can stall the DNA replication machinery, leading to genomic instability. Thus, numerous mechanisms exist to complete genome duplication in the absence of a pristine DNA template, but identification of the enzymes involved remains incomplete. Here, we establish that Primase-Polymerase (PrimPol; CCDC111), an archaeal-eukaryotic primase (AEP) in eukaryotic cells, is involved in chromosomal DNA replication. PrimPol is required for replication fork progression on ultraviolet (UV) lightdamaged DNA templates, possibly mediated by its ability to catalyze translesion synthesis (TLS) of these lesions. This PrimPol UV lesion bypass pathway is not epistatic with the Pol h-dependent pathway and, as a consequence, protects xeroderma pigmentosum variant (XP-V) patient cells from UV-induced cytotoxicity. In addition, we establish that PrimPol is also required for efficient replication fork progression during an unperturbed S phase. These and other findings indicate that PrimPol is an important player in replication fork progression in eukaryotic cells

ACE and non-ACE pathways in the renal vascular response to RAS interruption in type 1 diabetes mellitus

ACE and non-ACE pathways in the renal vascular response to RAS interruption in type 1 diabetes mellitus.BackgroundThe enormous contribution of renin-angiotensin system (RAS) interruption with ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers (ARB) in the treatment of diabetic nephropathy has led to interest in the factors involved in angiotensin II (Ang II) generation. In normal subjects, RAS interruption using an ARB produced a 50% greater renal plasma flow (RPF) rise than with an ACE inhibitor, suggesting a substantial contribution of non-ACE pathways. Moreover, immunohistochemistry studies in kidneys of overtly proteinuric diabetic subjects showed up-regulation of chymase, an alternative Ang II-generating enzyme. Our aim was to determine the degree to which the non-ACE pathways contribute to RAS activation in type 1 diabetes mellitus (DM).MethodsType 1DM patients (N = 37, 14 M/23 F; age 31 ± 2 years; DM duration 16 ± 1.7 years; HbA1c 7.7.0 ± 0.3%) were studied on a high-salt diet. They received captopril 25mg po one day and candesartan 16mg po the next day. RPF and glomerular filtration rate (GFR) were measured before and up to 4 hours after drug administration.ResultsBoth captopril and candesartan induced a significant rise in RPF (baseline vs. peak <0.0001 for both), and the rise was concordant for the 2 drugs (r = 0.77,P < 0.001). However, the RPF responses were not significantly different between the 2 drugs (captopril 72 ± 11mL/min/1.73m2, candesartan 75 ± 12,P = 0.841).ConclusionIn predominantly normoalbuminuric, normotensive type 1 DM, activation of the intrarenal RAS reflects a mechanism involving primarily the classic ACE pathway

Effect of cold start on engine performance and emissions from diesel engines using IMO-Compliant distillate fuels

© 2019 Elsevier Ltd Emissions from ships at berth are small compared to the total ship emissions; however, they are one of the main contributors to pollutants in the air of densely-populated areas, consequently heavily affecting public health. This is due to auxiliary marine engines being used to generate electric power and steam for heating and providing services. The present study has been conducted on an engine representative of a marine auxiliary, which was a heavy duty, six-cylinder, turbocharged and after-cooled engine with a high pressure common rail injection system. Engine performance and emission characterisations during cold start are the focus of this paper, since cold start is significantly influential. Three tested fuels were used, including the reference diesel and two IMO (International Maritime Organization) compliant spiked fuels. The research engine was operated at a constant speed and 25% load condition after 12 h cooled soak. Results show that during cold start, significant heat generated from combustion is used to heat the engine block, coolant and lubricant. During the first minute, compared to the second minute, emissions of particle number (PN), carbon monoxide (CO), particulate matter (PM), and nitrogen oxides (NOx) were approximately 10, 4, 2 and 1.5 times higher, respectively. The engine control unit (ECU) plays a vital role in reducing engine emissions by changing the engine injection strategy based on the engine coolant temperature. IMO-compliant fuels, which were higher viscosity fuels associated with high sulphur content, resulted in an engine emission increase during cold start. It should be taken into account that auxiliary marine diesel engines, working at partial load conditions during cold start, contribute considerably to emissions in coastal areas. It demonstrates a need to implement practical measures, such as engine pre-heating, to obtain both environmental and public health advantages in coastal areas

Impact of blade structural and aerodynamic uncertainties on wind turbine loads

Offshore wind power has been in the spotlight among renewable energy sources. The current trends of increased power ratings and longer blades come together with the aim to reduce energy costs by design optimisation. The standard approach to deal with uncertainties in wind-turbine design has been by the use of characteristic values and safety factors. This paper focusses on modelling the effect of structural and aerodynamic uncertainties in blades. First, the uncertainties in laminate properties are characterised and propagated in a blade structural model by means of a Monte Carlo simulation. Wind tunnel measurement data are then used to define the variability in lift and drag coefficients for both clean and rough aerofoil behaviour, which is then used to extrapolate rough behaviours throughout the blade. A stochastic spatial interpolation parameter is used to define the evolution of the degradation level. The combined effect and the variance contribution of these two uncertainty sources in turbine loads is finally defined by aeroelastic turbine simulation. This research aims to provide a framework to deal with uncertainties in wind-turbine blade design and understand their effects in turbine behaviour

Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy

Prognosis for patients suffering from malignant glioma has not substantially improved. Specific immunotherapy as a novel treatment concept critically depends on target antigens, which are highly overexpressed in the majority of gliomas, but the number of such antigens is still very limited. SOX2 was identified by screening an expression database for transcripts that are overexpressed in malignant glioma, but display minimal expression in normal tissues. Expression of SOX2 mRNA was further investigated in tumour and normal tissues by real-time PCR. Compared to cDNA from pooled normal brain, SOX2 was overexpressed in almost all (9 out of 10) malignant glioma samples, whereas expression in other, non-malignant tissues was almost negligible. SOX2 protein expression in glioma cell lines and tumour tissues was verified by Western blot and immunofluorescence. Immunohistochemistry demonstrated SOX2 protein expression in all malignant glioma tissues investigated ranging from 6 to 66% stained tumour cells. Human leucocyte antigen-A*0201-restricted SOX2-derived peptides were tested for the activation of glioma-reactive CD8+ cytotoxic T lymphocytes (CTLs). Specific CTLs were raised against the peptide TLMKKDKYTL and were capable of lysing glioma cells. The abundant and glioma-restricted overexpression of SOX2 and the generation of SOX2-specific and tumour-reactive CTLs may recommend this antigen as target for T-cell-based immunotherapy of glioma

The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010–08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes

Developing integrated care pathways for atopic dermatitis—challenges and unmet needs

BACKGROUND: GA2 LEN-ADCARE is a branch of the largest multidisciplinary network of research centres and clinical care in allergy and asthma, GA2 LEN, focussing on the field of atopic dermatitis (AD). AD is a chronic inflammatory skin disease with high burden and many comorbidities requiring different levels of treatment. The need for aligned information from all involved healthcare providers led to the discussion of an integrated care pathway (ICP) plan for AD patient care involving all stakeholders and considering the complexity and variability of the disease, with a particular focus placed on the large number of patients with milder forms of AD. METHODS: The GA2 LEN ADCARE network and all stakeholders, abbreviated the AD-ICPs working group, were involved in the discussion and preparation of the AD-ICPs during a series of subgroup workshops and meetings in years 2020 and 2021. RESULTS: Here we discuss the unmet needs in AD, the methodology for devising an AD-ICP and the ICP action plan. CONCLUSION: The GA2 LEN ADCARE network has outlined the unmet needs in AD and provided an action plan for devising AD-ICPs, considering the complexity and variability of the disease