Differential effects of lobe A and lobe B of the Conserved Oligomeric Golgi complex on the stability of β1,4-galactosyltransferase 1 and α2,6-sialyltransferase 1

Initially described by Jaeken et al. in 1980, congenital disorders of glycosylation (CDG) is a rapidly expanding group of human multisystemic disorders. To date, many CDG patients have been identified with deficiencies in the conserved oligomeric Golgi (COG) complex which is a complex involved in the vesicular intra-Golgi retrograde trafficking. Composed of eight subunits that are organized in two lobes, COG subunit deficiencies have been associated with Golgi glycosylation abnormalities. Analysis of the total serum N-glycans of COG-deficient CDG patients demonstrated an overall decrease in terminal sialylation and galactosylation. According to the mutated COG subunits, differences in late Golgi glycosylation were observed and led us to address the question of an independent role and requirement for each of the two lobes of the COG complex in the stability and localization of late terminal Golgi glycosylation enzymes. For this, we used a small-interfering RNAs strategy in HeLa cells stably expressing green fluorescent protein (GFP)-tagged β1,4-galactosyltransferase 1 (B4GALT1) and α2,6-sialyltransferase 1 (ST6GAL1), two major Golgi glycosyltransferases involved in late Golgi N-glycosylation. Using fluorescent lectins and flow cytometry analysis, we clearly demonstrated that depletion of both lobes was associated with deficiencies in terminal Golgi N-glycosylation. Lobe A depletion resulted in dramatic changes in the Golgi structure, whereas lobe B depletion severely altered the stability of B4GALT1 and ST6GAL1. Only MG132 was able to rescue their steady-state levels, suggesting that B4GALT1- and ST6GAL1-induced degradation are likely the consequence of an accumulation in the endoplasmic reticulum (ER), followed by a retrotranslocation into the cytosol and proteasomal degradation. All together, our results suggest differential effects of lobe A and lobe B for the localization/stability of B4GALT1 and ST6GAL1. Lobe B would be crucial in preventing these two Golgi glycosyltransferases from inappropriate retrograde trafficking to the ER, whereas lobe A appears to be essential for maintaining the overall Golgi structur

Differential effects of lobe A and lobe B of the conserved oligomeric golgi complex on the stability of β1,4-galactosyltransferase 1 and α2,6-sialyltransferase 1

Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch)Initially described by Jaeken et al. in 1980, congenital disorders of glycosylation (CDG) is a rapidly expanding group of human multisystemic disorders. To date, many CDG patients have been identified with deficiencies in the conserved oligomeric Golgi (COG) complex which is a complex involved in the vesicular intra-Golgi retrograde trafficking. Composed of eight subunits that are organized in two lobes, COG subunit deficiencies have been associated with Golgi glycosylation abnormalities. Analysis of the total serum N-glycans of COG-deficient CDG patients demonstrated an overall decrease in terminal sialylation and galactosylation. According to the mutated COG subunits, differences in late Golgi glycosylation were observed and led us to address the question of an independent role and requirement for each of the two lobes of the COG complex in the stability and localization of late terminal Golgi glycosylation enzymes. For this, we used a small-interfering RNAs strategy in HeLa cells stably expressing green fluorescent protein (GFP)-tagged β1,4-galactosyltransferase 1 (B4GALT1) and α2,6-sialyltransferase 1 (ST6GAL1), two major Golgi glycosyltransferases involved in late Golgi N-glycosylation. Using fluorescent lectins and flow cytometry analysis, we clearly demonstrated that depletion of both lobes was associated with deficiencies in terminal Golgi N-glycosylation. Lobe A depletion resulted in dramatic changes in the Golgi structure, whereas lobe B depletion severely altered the stability of B4GALT1 and ST6GAL1. Only MG132 was able to rescue their steady-state levels, suggesting that B4GALT1- and ST6GAL1-induced degradation are likely the consequence of an accumulation in the endoplasmic reticulum (ER), followed by a retrotranslocation into the cytosol and proteasomal degradation. All together, our results suggest differential effects of lobe A and lobe B for the localization/stability of B4GALT1 and ST6GAL1. Lobe B would be crucial in preventing these two Golgi glycosyltransferases from inappropriate retrograde trafficking to the ER, whereas lobe A appears to be essential for maintaining the overall Golgi structure

The 5-year Spam: Tracking a Persistent Chinese Influence Operation

This report analyzes the behavior of a single, coordinated inauthentic information operator working within China and in the interests of the Chinese government. This operator has been called by different names by different analysts, including “Spamouflage Dragon“ (by the network analysis firm Graphika) and “Dragonbridge” (by the Google owned cybersecurity firm Mandiant) and has been operating continuously since, at least, April 2017. In this report we will refer to this actor as Dragonbridge. Section II of this report gives an update on several campaign this actor has engaged in recent months. Section III presents a synthetic overview of some of Dragonbridge’s past and ongoing tactics and targets. Section IV draws some more general lessons about how this actor operates

The N-terminal region of Jaw1 has a role to inhibit the formation of organized smooth endoplasmic reticulum as an intrinsically disordered region

Jaw1/LRMP is a type II integral membrane protein that is localized at the endoplasmic reticulum (ER) and outer nuclear membrane. We previously reported that a function of Jaw1 is to maintain the nuclear shape as a KASH protein via its carboxyl terminal region, a component of linker of nucleoskeleton and cytoskeleton complex in the oligomeric state. Although the oligomerization of some KASH proteins via the cytosolic regions serves to stabilize protein-protein interactions, the issue of how the oligomerization of Jaw1 is regulated is not completely understood. Therefore, we focused on three distinct regions on the cytosolic face of Jaw1: the N-terminal region, the coiled-coil domain and the stem region, in terms of oligomerization. A co-immunoprecipitation assay showed that its coiled-coil domain is a candidate for the oligomerization site. Furthermore, our data indicated that the N-terminal region prevents the aberrant oligomerization of Jaw1 as an intrinsically disordered region (IDR). Importantly, the ectopic expression of an N-terminal region deleted mutant caused the formation of organized smooth ER (OSER), structures such as nuclear karmellae and whorls, in B16F10 cells. Furthermore, this OSER interfered with the localization of the oligomer and interactors such as the type III inositol 1,4,5-triphosphate receptor (IP3R3) and SUN2. In summary, the N-terminal region of Jaw1 inhibits the formation of OSER as an IDR to maintain the homeostatic localization of interactors on the ER membrane

Crypto Bestiary: \u3ci\u3eA monstrous manual to the many fraudulent accounts involved in cryptocurrency scams and fraud.\u3c/i\u3e

Cryptocurrencies have fueled the growth of online fraud in various forms. They are poorly understood by many users, have value that shifts quickly and unexpectedly, and are easy to move in a digital world without borders. Cryptocurrency is seemingly purpose built as a tool for hucksters and scammers. The Federal Trade Commission claims that 46,000 people reported losing over a billion dollars in cryptocurrency to scammers in the first six months of 2021,1 a figure only including those potentially few people have been brave enough to share that they have been victims. The world of cryptocurrency can be scary for the uninitiated. One common way in which crypto-fraud is accomplished is through social media and the use of fake accounts. Some accounts purport to be crypto-fans, others make you belive they are experts in crypto-investment and are happy to help you uncover hidden riches. All of them, however, are seeking to take your money and leave you with nothing but fear and regret. This crypto-bestiary will present you, the neophyte, six of the most terrifying of crypto-creatures seeking to steal your treasure. Heed what we tell you as a lesson, be wary of where you venture and watch for the signs

Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics

A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level

Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function

Neurodegenerative disorders are associated with impaired cognitive function and worse physical health outcomes. This study aims to test whether polygenic risk for Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), or frontotemporal dementia (FTD) is associated with cognitive function and physical health in the UK Biobank, a cohort of healthy individuals. Group-based analyses were then performed to compare the top and bottom 10% for the three neurodegenerative polygenic risk scores; these groups were compared on the cognitive and physical health variables. Higher polygenic risk for AD, ALS, and FTD was associated with lower cognitive performance. Higher polygenic risk for FTD was also associated with increased forced expiratory volume in 1s and peak expiratory flow. A significant group difference was observed on the symbol digit substitution task between individuals with high polygenic risk for FTD and high polygenic risk for ALS. The results suggest some overlap between polygenic risk for neurodegenerative disorders, cognitive function and physical health

Potential of a suite of robot/computer-assisted motivating systems for personalized, home-based, stroke rehabilitation

BACKGROUND: There is a need to improve semi-autonomous stroke therapy in home environments often characterized by low supervision of clinical experts and low extrinsic motivation. Our distributed device approach to this problem consists of an integrated suite of low-cost robotic/computer-assistive technologies driven by a novel universal access software framework called UniTherapy. Our design strategy for personalizing the therapy, providing extrinsic motivation and outcome assessment is presented and evaluated. METHODS: Three studies were conducted to evaluate the potential of the suite. A conventional force-reflecting joystick, a modified joystick therapy platform (TheraJoy), and a steering wheel platform (TheraDrive) were tested separately with the UniTherapy software. Stroke subjects with hemiparesis and able-bodied subjects completed tracking activities with the devices in different positions. We quantify motor performance across subject groups and across device platforms and muscle activation across devices at two positions in the arm workspace. RESULTS: Trends in the assessment metrics were consistent across devices with able-bodied and high functioning strokes subjects being significantly more accurate and quicker in their motor performance than low functioning subjects. Muscle activation patterns were different for shoulder and elbow across different devices and locations. CONCLUSION: The Robot/CAMR suite has potential for stroke rehabilitation. By manipulating hardware and software variables, we can create personalized therapy environments that engage patients, address their therapy need, and track their progress. A larger longitudinal study is still needed to evaluate these systems in under-supervised environments such as the home

A multi-technique approach to study the microstructural properties of tin-based transparent conductive oxides

Transparent conductive oxides (TCOs) are semiconductor-like materials that exhibit high electrical conductivity and high optical transparency combined. They are adopted in various applications ranging from gas sensors, to electrochromic windows, to photovoltaic cells. Indium-based TCOs represent the industry standard. Nevertheless, indium is among the less abundant elements in the earth crust and forecasts based on its current consumption envisage an urgent need to replace it. Tin-based TCOs are a promising alternative, since their opto- electronic characteristics mimic the ones of indium-based materials. This thesis aims to investigate the link between optoelectronic and microstructural properties of tin dioxide and zinc tin oxide (ZTO) with a composition Zn0.05Sn0.30O0.65 and their stability when submitted to thermal treatments. Indeed, lots of practi- cal applications require the TCO to operate in high temperature conditions. To conduct this study, a combination of analytical techniques, such as transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDX), X- ray diffraction (XRD), electron paramagnetic resonance (EPR) and differential scanning calorimetry (DSC) was employed. Amorphous SnO2 and ZTO were deposited by RF sputtering and annealed up to 1050°C in different atmospheres. The influence of annealing temperature and atmosphere were decoupled and led us to an in-depth comprehension of the mechanisms governing the optoelectronic properties of both materials. When annealed in air, between room temperature and 300°C, ZTO exhibits increased mobility and carrier concentration with respect to the as-deposited state. This increase, investigated with DSC, was ascribed to a structural relaxation that allows point defects to release electrons in conduction band. Between 300°C and 500°C atmospheric oxygen passivates oxygen vacancies, drastically decreasing the carrier concentration and therefore causing a large drop of the conductivity. EPR experiments allowed to ascribe the drop in conductivity to the decrease of carrier concentration, which occurs slightly before the phase change. At 570°C (and 930°C for the case of vacuum annealing) the phase change occurs and the ZTO crystallizes in the rutile form of SnO2. The material becomes completely insulating. When the temperature is increased to 1050°C, evaporation of zinc is observed. In order to improve the electrical conductivity of ZTO at high temperature, a doping strategy was implemented starting from DFT calculations conducted by a partner group, who screened among the entire periodic table, which elements are the best candidates to act as n-dopants for ZTO. Bromine and iodine were retained, since they were found to be the most energetically favorable to become substitutional defects for a tin site. An exploratory doping route is therefore presented and the treated samples analyzed with TEM, EDX and UV-VIS-IR spectroscopy. Finally, the structural properties of an indium-based TCO (zirconium-doped indium oxide) were investigated and used as a benchmark to propose a crystallization model for the tin-based, as well as the indium-based materials. The influence of pa- rameters such as the material thickness, annealing atmosphere and temperature and deposition pressure are discussed for both materials