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Dietary methyl-group donor intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)
No full text1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism;
(2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort;
(3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake;
(4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association
Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response
No full textADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Recessive ADPRHL2/ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2. We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control
A multi-country study using MALDI-TOF mass spectrometry for rapid identification of Burkholderia pseudomallei
No full textBackground
Burkholderia pseudomallei is the bacterial causative agent of melioidosis, a difficult disease to diagnose clinically with high mortality if not appropriately treated. Definitive diagnosis requires isolation and identification of the organism. With the increased adoption of MALDI-TOF MS for the identification of bacteria, we established a method for rapid identification of B. pseudomallei using the Vitek MS, a system that does not currently have B. pseudomallei in its in-vitro diagnostic database.
Results
A routine direct spotting method was employed to create spectra and SuperSpectra. An initial B. pseudomallei SuperSpectrum was created at Shoklo Malaria Research Unit (SMRU) from 17 reference isolates (46 spectra). When tested, this initial SMRU SuperSpectrum was able to identify 98.2 % (54/55) of Asian isolates, but just 46.7 % (35/75) of Australian isolates. Using spectra (430) from different reference and clinical isolates, two additional SMRU SuperSpectra were created. Using the combination of all SMRU SuperSpectra with seven existing SuperSpectra from Townsville, Australia 119 (100 %) Asian isolates and 31 (100 %) Australian isolates were correctly identified. In addition, no misidentifications were obtained when using these 11 SuperSpectra when tested with 34 isolates of other bacteria including the closely related species Burkholderia thailandensis and Burkholderia cepacia.
Conclusions
This study has established a method for identification of B. pseudomallei using Vitek MS, and highlights the impact of geographical differences between strains for identification using this technique
Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells
No full textProstate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response
Ribosome occupancy profiles are conserved between structurally and evolutionarily related yeast domains
No full textMotivation: Protein synthesis is a non-equilibrium process, meaning that the speed of translation can
influence the ability of proteins to fold and function. Assuming that structurally similar proteins fold by
similar pathways, the profile of translation speed along an mRNA should be evolutionarily conserved
between related proteins to direct correct folding and downstream function. The only evidence to date
for such conservation of translation speed between homologous proteins has used codon rarity as a
proxy for translation speed. There are, however, many other factors including mRNA structure and the
chemistry of the amino acids in the A- and P-sites of the ribosome that influence the speed of amino
acid addition.
Results: Ribosome profiling experiments provide a signal directly proportional to the underlying translation times at the level of individual codons. We compared ribosome occupancy profiles (extracted
from five different large-scale yeast ribosome profiling studies) between related protein domains to more directly test if their translation schedule was conserved. Our analysis reveals that the ribosome occupancy profiles of paralogous domains tend to be significantly more similar to one another than to
profiles of non-paralogous domains. This trend does not depend on domain length, structural classes, amino acid composition, or sequence similarity. Our results indicate that entire ribosome occupancy profiles and not just rare codon locations are conserved between even distantly related domains in
yeast, providing support for the hypothesis that translation schedule is conserved between structurally related domains to retain folding pathways and facilitate efficient folding
Upadacitinib response rates in patients with psoriatic arthritis enrolled in the SELECT-PsA-1 and SELECT-PsA-2 trials assessed according to modified PsARC
No full textPatent landscape of not-in-kind active cooling technologies between 1998 and 2017
No full textThe rise in global cooling demand will have significant impacts on our efforts to limit climate change and foster sustainable development. Minimising these impacts requires further development of active cooling technologies, starting with an examination of existing technologies and their characteristics. This paper provides an overview of active cooling technologies using a patent landscape based on patent application data over the past 20 years. In developing the patent landscape, we searched the Derwent Innovation patent database, which contains more than 90 million patent documents, using technology-specific keywords and patent classification codes. A careful assessment of the resulting patent dataset shows a range of important trends about the evolution of cooling in the last two decades. Specifically, we discuss annual cooling technology patent application trends, countries of application, and patent assignees. The results show that patenting activity in the field of active cooling has increased significantly since 2010, mainly driven by the rapid patenting trend in China. Patents of the incumbent technology have been dominated by established manufacturers from Japan and the United States. Not-in-kind cooling technologies with a high number of patent applications include thermoelectric, magnetocaloric, evaporative, pulse-tube, absorption, and adsorption cooling. The results from examining this global patent help in understanding and shaping the global development of active cooling technology by providing new information on the major supplier countries, the key manufacturers, and maturity levels of alternative cooling technologies
A 3D-printable robotic gripper based on thick panel origami
No full textOrigami has been a source of inspiration for the design of robots because it can be easily produced using 2D materials and its motions can be well quantified. However, most applications to date have utilised origami patterns for thin sheet materials with a negligible thickness. If the thickness of the material cannot be neglected, commonly known as the thick panel origami, the creases need to be redesigned. One approach is to place creases either on top or bottom surfaces of a sheet of finite thickness. As a result, spherical linkages in the zero-thickness origami are replaced by spatial linkages in the thick panel one, leading to a reduction in the overall degrees of freedom (DOFs). For instance, a waterbomb pattern for a zero-thickness sheet shows multiple DOFs while its thick panel counterpart has only one DOF, which significantly reduces the complexity of motion control. In this article, we present a robotic gripper derived from a unit that is based on the thick panel six-crease waterbomb origami. Four such units complete the gripper. Kinematically, each unit is a plane-symmetric Bricard linkage, and the gripper can be modelled as an assembly of Bricard linkages, giving it single mobility. A gripper prototype was made using 3D printing technology, and its motion was controlled by a set of tendons tied to a single motor. Detailed kinematic modelling was done, and experiments were carried out to characterise the gripper's behaviours. The positions of the tips on the gripper, the actuation force on tendons, and the grasping force generated on objects were analysed and measured. The experimental results matched well with the analytical ones, and the repeated tests demonstrate that the concept is viable. Furthermore, we observed that the gripper was also capable of grasping non-symmetrical objects, and such performance is discussed in detail in the paper
Analyzing failed institutional change attempts
No full textTheoretical advances in the study of institutional change center around a productive
paradox. While change agents can take strategic action to change institutions, institutions
display a remarkable level of formal stability. From this paradox, we expect that attempts
to change institutions are an empirical regularity and that many formal change attempts
will fail. This article contributes to historical institutionalism by analyzing the political
effects of failed formal institutional change attempts on institutional sequences. Failed
institutional change attempts could be mere blips, having little effect on subsequent
institutional trajectories, or even inoculate against future attempts. Failed attempts could
also lay the ideational groundwork, aid in coalition building, and garner concessions for
subsequent institutional change, or convince change agents to alter their strategy. The
article suggests analytical strategies to assess the effects of failed institutional change
attempts, drawing on examples from comparative politics and two extended case
illustrations from Italian party politics and the Affordable Care Act in the US
Plastic Drawdown: A rapid assessment tool for developing national responses to plastic pollution when data availability is limited, as demonstrated in the Maldives
No full textGovernments are increasingly supporting initiatives to address plastic pollution, but efforts are largely opportunistic or driven by national socio-political priorities. There is an urgent need to move away from piecemeal single product instruments (e.g. single use plastic bag taxes or plastic straw bans) to deliver system-wide strategies that minimise the most pervasive sources of plastic pollution. Developing a common understanding of a jurisdiction’s plastic waste stream and the solutions available to decision-makers is vital to build consensus across stakeholders and to align on an evidence-based portfolio of priority instruments.
This paper presents the Plastic Drawdown framework as a boundary-spanning tool to quickly create a coherent, relevant, and credible analysis and visualisation for stakeholders of plastic waste, leakage hotspots and minimisation opportunities. Using a new plastic waste modelling framework with a consultative structure, Plastic Drawdown explores plastic waste and leakage over a ten-year period and assesses impacts of policy instruments on this projection. Plastic Drawdown is adaptable to the data poor environment typical of many countries and designed as a rapid assessment tool to support the decision making of governments operating in a highly resource-constrained context.
The Maldives is used as a case study to show the utility of the tool, where it highlighted strategies with the potential to reduce leakage of plastic waste into the marine environment by up to 85% by 2030. Plastic Drawdown built the case for phasing out single-use plastic waste across the Maldives and supported the Government’s decision to set ambitious targets, as announced at the United Nations General Assembly in 2019