Proteasome-dependent protein quality control of the peroxisomal membrane protein Pxa1p

Peroxisomes are eukaryotic organelles that function in numerous metabolic pathways and defects in peroxisome function can cause serious developmental brain disorders such as adrenoleukodystrophy (ALD). Peroxisomal membrane proteins (PMPs) play a crucial role in regulating peroxisome function. Therefore, PMP homeostasis is vital for peroxisome function. Recently, we established that certain PMPs are degraded by the Ubiquitin Proteasome System yet little is known about how faulty/non-functional PMPs undergo quality control. Here we have investigated the degradation of Pxa1p, a fatty acid transporter in the yeast Saccharomyces cerevisiae. Pxa1p is a homologue of the human protein ALDP and mutations in ALDP result in the severe disorder ALD. By introducing two corresponding ALDP mutations into Pxa1p (Pxa1MUT), fused to mGFP, we show that Pxa1MUT-mGFP is rapidly degraded from peroxisomes in a proteasome-dependent manner, while wild type Pxa1-mGFP remains relatively stable. Furthermore, we identify a role for the ubiquitin ligase Ufd4p in Pxa1MUT-mGFP degradation. Finally, we establish that inhibiting Pxa1MUT-mGFP degradation results in a partial rescue of Pxa1p activity in cells. Together, our data demonstrate that faulty PMPs can undergo proteasome-dependent quality control. Furthermore, our observations may provide new insights into the role of ALDP degradation in ALD

Detection and characterisation of papillomavirus in skin lesions of giraffe and sable antelope in South Africa

Papillomavirus was detected electron microscopically in cutaneous fibropapillomas of a giraffe (Giraffa camelopardalis) and a sable antelope (Hippotragus niger). The virus particles measured 45 nm in diameter. Histopathologically, the lesions showed histopathological features similar to those of equine sarcoid as well as positive immunoperoxidase-staining of tissue sections for papillomavirus antigen. Polymerase chain reaction (PCR) detected bovine papillomavirus (BPV) DNA. Bovine papillomavirus-1 was characterised by real-time PCR in the sable and giraffe, and cloning and sequencing of the PCR product revealed a similarity to BPV-1. As in the 1st giraffe, the lesions from a 2nd giraffe revealed locally malignant pleomorphism, possibly indicating the lesional end-point of papilloma infection. Neither virus particles nor positively staining papillomavirus antigen could be demonstrated in the 2nd giraffe but papillomavirus DNA was detected by real-time PCR which corresponded with BPV-1 and BPV-2

Suitability of meteorological data for interpreting ammonia concentrations on Ballynahone Bog SAC.

Meteorology plays a key role in atmospheric nitrogen (N) input to designated sites, in terms of local ammonia (NH3) concentrations and N deposition originating from local, regional and transboundary sources. An earlier study by Williams et al. (2021) compared how local prevailing wind patterns could affect atmospheric nitrogen dispersion and thus the measured NH3 concentrations at Ballynahone Bog Special Area of Conservation (SAC). Other meteorological variables that influence local NH3 emissions and therefore N input to sensitive habitats, are temperature, precipitation and humidity. To determine how local weather patterns influence NH3 concentrations on the bog, we therefore need to investigate these other, potential confounding, meteorological parameters, in addition to wind direction and wind speed. The aim of this study was to investigate local meteorological patterns and their temporal variability using locally measured weather data for the period October 2020 to September 2021

The E5 oncoprotein of BPV-4 does not interfere with the biosynthetic pathway of non-classical MHC class I

The major histocompatibility complex (MHC) class I region in mammals contains both classical and non-classical MHC class I genes. Classical MHC class I molecules present antigenic peptides to cytotoxic T lymphocytes, whereas non-classical MHC class I molecules have a variety of functions. Both classical and non-classical MHC molecules interact with natural killer cell receptors and may under some circumstances prevent cell death by natural killer cytotoxicity. The E5 oncoprotein of BPV-4 down-regulates the expression of classical MHC class I on the cell surface and retains the complex in the Golgi apparatus. The inhibition of classical MHC class I to the cell surface results from both the impaired acidification of the Golgi, due to the interaction of E5 with subunit c of the H+ V-ATPase, and to the physical binding of E5 to the heavy chain of MHC class I. Despite the profound effect of E5 on classical MHC class I, E5 does not retain a non-classical MHC class I in the Golgi, does not inhibit its transport to the cell surface and does not bind its heavy chain. We conclude that, as is the case for HPV-16 E5, BPV-4 E5 does not down-regulate certain non-classical MHC class I, potentially providing a mechanism for the escape of the infected cell from attack by both cytotoxic T lymphocytes and NK cells

New insulating phases of two-dimensional electrons in high Landau levels: observation of sharp thresholds to conduction

The intriguing re-entrant integer quantized Hall states recently discovered in high Landau levels of high-mobility 2D electron systems are found to exhibit extremely non-linear transport. At small currents these states reflect insulating behavior of the electrons in the uppermost Landau level. At larger currents, however, a discontinuous and hysteretic transition to a conducting state is observed. These phenomena, found only in very narrow magnetic field ranges, are suggestive of the depinning of a charge density wave state, but other explanations can also be constructed.Comment: 5 pages, 5 figure

Magnetic ground state of the one-dimensional ferromagnetic chain compounds M(NCS)2(thiourea)2 (M=Ni,Co)

The magnetic properties of the two isostructural molecule-based magnets—Ni(NCS)2(thiourea)2, S = 1 [thiourea = SC(NH2 )2] and Co(NCS)2 (thiourea)2, S = 3/2—are characterized using several techniques in order to rationalize their relationship with structural parameters and to ascertain magnetic changes caused by substitution of the spin. Zero-field heat capacity and muon-spin relaxation measurements reveal low-temperature long-range ordering in both compounds, in addition to Ising-like (D < 0) single-ion anisotropy (DCo ∼ −100 K, DNi ∼ −10 K). Crystal and electronic structure, combined with dc-field magnetometry, affirm highly quasi-onedimensional behavior, with ferromagnetic intrachain exchange interactions JCo ≈ +4 K and JNi ∼ +100 K and weak antiferromagnetic interchain exchange, on the order of J ∼ −0.1 K. Electron charge- and spin-density mapping reveals through-space exchange as a mechanism to explain the large discrepancy in J-values despite, from a structural perspective, the highly similar exchange pathways in both materials. Both species can be compared to the similar compounds MCl2(thiourea)4, M = Ni(II) (DTN) and Co(II) (DTC), where DTN is known to harbor two magnetic-field-induced quantum critical points. Direct comparison of DTN and DTC with the compounds studied here shows that substituting the halide Cl− ion for the NCS− ion results in a dramatic change in both the structural and magnetic properties

Rearrangement-free hydroxylation of methylcubanes by a cytochrome P450: the case for dynamical coupling of C-H abstraction and rebound

The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported k = 2.9 × 1010 s-1 at 25 °C) through scission of two bonds of the cube. The rearrangement has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C-H oxidations. This paper reports the discovery of highly selective cytochrome P450-catalyzed methylcubane oxidations which notionally proceed via cubylmethyl radical intermediates yet are remarkably free of rearrangement. The bacterial cytochrome P450 CYP101B1 from Novosphingobium aromaticivorans DSM 12444 is found to hydroxylate the methyl group of a range of methylcubane substrates containing a regio-directing carbonyl functionality at C-4. Unlike other reported P450-catalyzed methylcubane oxidations, the designed methylcubanes are hydroxylated with high efficiency and selectivity, giving cubylmethanols in yields of up to 93%. The lack of cubane core ring-opening implies that the cubylmethyl radicals formed during these CYP101B1-catalyzed hydroxylations must have very short lifetimes, of just a few picoseconds, which are too short for them to manifest the side reactivity characteristic of a fully equilibrated P450 intermediate. We propose that the apparent ultrafast radical rebound can be explained by a mechanism in which C-H abstraction and C-O bond formation are merged into a dynamically coupled process, effectively bypassing a discrete radical intermediate. Related dynamical phenomena can be proposed to predict how P450s may achieve various other modes of reactivity by controlling the formation and fate of radical intermediates. In principle, dynamical ideas and two-state reactivity are each individually able to explain apparent ultrashort radical lifetimes in P450 catalysis, but they are best considered together.Md. Raihan Sarkar, Sevan D. Houston, G. Paul Savage, Craig M. Williams, Elizabeth H. Krenske, Stephen G. Bell and James J. De Vos

Risk factors for Luminal A ductal carcinoma in situ (DCIS) and invasive breast cancer in the Carolina Breast Cancer Study

Purpose Invasive breast cancers are thought to arise from in situ lesions, but some ductal carcinoma in situ (DCIS) are indolent with low likelihood of progressing to invasive carcinoma. Comparison of risk factor associations between DCIS and invasive disease may elucidate which factors influence early versus late stages of carcinogenesis. Therefore, we determined whether there were differences in risk factor profiles for screen-detected DCIS and invasive breast cancer among Luminal A lesions. Methods We conducted a case-control analysis using data from the Carolina Breast Cancer Study (1993-2001). Analyses were restricted to Luminal A tumors and screen-detected tumors among mammography-eligible women, to limit confounding by mode of detection (N = 108 DCIS; N = 203 invasive). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between risk factors and lesion type. Results In stratified analyses, we observed qualitative differences in the direction of association for ever smoking, obese BMI, high waist-To-hip-ratio (WHR), and ?10 years of oral contraceptive use between DCIS and invasive disease. Breastfeeding was inversely associated with invasive disease and was not associated with DCIS. Interaction tests for risk factor associations between Luminal A DCIS and invasive breast cancer were not statistically significant (p>0.05). Conclusions Among Luminal A tumors, established breast cancer risk factors may exert stronger effects on progression of early lesions to invasive disease, with lesser effects on risk of DCIS

A review of the Dividend Discount Model: from deterministic to stochastic models

This chapter presents a review of the dividend discount models starting from the basic models (Williams 1938, Gordon and Shapiro 1956) to more recent and complex models (Ghezzi and Piccardi 2003, Barbu et al. 2017, D'Amico and De Blasis 2018) with a focus on the modelling of the dividend process rather than the discounting factor, that is assumed constant in most of the models. The Chapter starts with an introduction of the basic valuation model with some general aspects to consider when performing the computation. Then, Section 1.3 presents the Gordon growth model (Gordon 1962) with some of its extensions (Malkiel 1963, Fuller and Hsia 1984, Molodovsky et al. 1965, Brooks and Helms 1990, Barsky and De Long 1993), and reports some empirical evidence. Extended reviews of the Gordon stock valuation model and its extensions can be found in Kamstra (2003) and Damodaran (2012). In Section 1.4, the focus is directed to more recent advancements which make us of the Markov chain to model the dividend process (Hurley and Johnson 1994, Yao 1997, Hurley and Johnson 1998, Ghezzi and Piccardi 2003, Barbu et al. 2017, D'Amico and De Blasis 2018). The advantage of these models is the possibility to obtain a different valuation that depends on the state of the dividend series, allowing the model to be closer to reality. In addition, these models permit to obtain a measure of the risk of the single stock or a portfolio of stocks