| 1. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 2. |
- Elsik, Christine G., et al.
(författare)
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The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
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Tidskriftsartikel (refereegranskat)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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| 3. |
- Park, Tae-Eun, et al.
(författare)
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Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies
- 2019
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.
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| 4. |
- Sobolev, Egor, et al.
(författare)
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Megahertz single-particle imaging at the European XFEL
- 2020
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Ingår i: Communications Physics. - : Springer Science and Business Media LLC. - 2399-3650. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- The emergence of high repetition-rate X-ray free-electron lasers (XFELs) powered by superconducting accelerator technology enables the measurement of significantly more experimental data per day than was previously possible. The European XFEL is expected to provide 27,000 pulses per second, over two orders of magnitude more than any other XFEL. The increased pulse rate is a key enabling factor for single-particle X-ray diffractive imaging, which relies on averaging the weak diffraction signal from single biological particles. Taking full advantage of this new capability requires that all experimental steps, from sample preparation and delivery to the acquisition of diffraction patterns, are compatible with the increased pulse repetition rate. Here, we show that single-particle imaging can be performed using X-ray pulses at megahertz repetition rates. The results obtained pave the way towards exploiting high repetition-rate X-ray free-electron lasers for single-particle imaging at their full repetition rate.
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| 5. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 6. |
- Baronio, Cesare M., et al.
(författare)
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The amide I spectrum of parallel β-sheet proteins
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The amide I absorption of the polypeptide backbone has long been used to analyze the secondary structure of proteins. This approach has gained additional attention in the context of amyloid diseases where a particular focus is on the distinction between parallel and antiparallel β-sheets because these structures often discriminate between pre-fibrillar structures and fibrils. Some earlier infrared spectra with typical features of antiparallel β-sheets were interpreted as arising from the parallel β-sheets of fibrils. Therefore, the ability of infrared spectroscopy to distinguish between both types of β-sheets is debated. While it is established that regular, antiparallel β-sheets give rise to a high wavenumber band near 1690 cm-1, it is less clear whether or not this band may also occur for parallel β-sheets. Here we present and analyze the amide I spectra of two β-helix proteins, SV2 and Pent. The overall shape of the proteins is that of a cuboid which has parallel β-sheets on its four sides, which are connected by bends. The main features of their amide I spectrum are a band at 1665, and two bands between 1645 and 1628 cm-1. Both proteins exhibit also a weak component band near 1690 cm-1. Calculations of the amide I spectrum indicate that the absorption at high wavenumbers is not caused by the parallel β-sheets but by the bends between the β-strands. We therefore suggest to modify the interpretation of the amide I spectrum as follows: a high wavenumber band near 1690 cm-1 may be caused by other structures than antiparallel β-sheets. However, when the spectrum consists of only two distinct bands, one near 1690 cm-1 and one near 1630 cm-1, then an assignment to antiparallel β-sheets is consistent with the literature.
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| 7. |
- Gaziano, Liam, et al.
(författare)
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Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
- 2022
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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| 8. |
- Huang, Ting Ting, et al.
(författare)
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No symphony without bassoon and piccolo : Changes in synaptic active zone proteins in Huntington's disease
- 2020
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown. We studied the gene expression levels and patterns of a number of proteins forming the cytoskeletal matrix of the presynaptic active zones in HD transgenic mice (R6/1), in hippocampal neuronal cultures overexpressing mutant huntingtin and in postmortem brain tissues of HD patients. To investigate the interactions between huntingtin and active proteins, we performed confocal microscopic imaging and immunoprecipitation in mouse and HEK 293 cell line models. The mRNA and protein levels of Bassoon were reduced in mouse and cell culture models of HD and in brain tissues of patients with HD. Moreover, a striking re-distribution of a complex of proteins including Bassoon, Piccolo and Munc 13-1 from the cytoplasm and synapses into intranuclear huntingtin aggregates with loss of active zone proteins and dendritic spines. This re-localization was age-dependent and coincided with the formation of huntingtin aggregates. Using co-immunoprecipitation, we demonstrated that huntingtin interacts with Bassoon, and that this interaction is likely mediated by a third linking protein. Three structural proteins involved in neurotransmitter release in the presynaptic active zones of neurons are altered in expression and that the proteins are redistributed from their normal functional site into mutant huntingtin aggregates.
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| 9. |
- Ikuta, K. S., et al.
(författare)
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Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019
- 2022
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Ingår i: Lancet. - : Elsevier BV. - 0140-6736. ; 400:10369, s. 2221-2248
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Tidskriftsartikel (refereegranskat)abstract
- Background Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes. Methods We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2.5th and 97.5th percentiles across 1000 posterior draws for each quantity of interest. Findings From an estimated 13.7 million (95% UI 10.9-17.1) infection-related deaths in 2019, there were 7.7 million deaths (5.7-10.2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13.6% (10.2-18.1) of all global deaths and 56.2% (52.1-60.1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54.9% (52.9-56.9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52.2 deaths (37.4-71.5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths. Interpretation The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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| 10. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 11. |
- Lokachari, Nitin, et al.
(författare)
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A comprehensive experimental and kinetic modeling study of di-isobutylene isomers : Part 1
- 2023
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Ingår i: Combustion and Flame. - : Elsevier BV. - 0010-2180. ; 251
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Tidskriftsartikel (refereegranskat)abstract
- Di-isobutylene has received significant attention as a promising fuel blendstock, as it can be synthesized via biological routes and is a short-listed molecule from the Co-Optima initiative. Di-isobutylene is also popularly used as an alkene representative in multi-component surrogate models for engine studies of gasoline fuels. However, there is limited experimental data available in the literature for neat di-isobutylene under engine-like conditions. Hence, most existing di-isobutylene models have not been extensively validated, particularly at lower temperatures (< 1000 K). Most gasoline surrogate models include the di-isobutylene sub-mechanism published by Metcalfe et al. [1] with little or no modification. The current study is undertaken to develop a detailed kinetic model for di-isobutylene and validate the model using a wide range of relevant experimental data. Part 1 of this study exclusively focuses on the low- to intermediate temperature kinetics of di-isobutylene. An upcoming part 2 discusses the high-temperature model development and validation of the relevant experimental targets. Ignition delay time measurements for the di-isobutylene isomers were performed at pressures ranging from 15 – 30 bar at equivalence ratios of 0.5, 1.0, and 2.0 diluted in air and in the temperature range 650 – 900 K using two independent rapid compression machine facilities. In addition, measurements of species identified during the oxidation of these isomers were performed in a jet-stirred reactor and in a rapid compression machine. A detailed kinetic model for the di-isobutylene isomers is developed to capture the wide range of new experimental targets. For the first time, a comprehensive low-temperature chemistry submodel is included. The differences in the important reaction pathways for the accurate prediction of the oxidation of the two DIB isomers are compared using reaction path analysis. The most sensitive reactions controlling the ignition delay times of the DIB isomers under the pressure and temperature conditions necessary for autoignition in engines are identified.
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| 12. |
- Lokachari, Nitin, et al.
(författare)
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A comprehensive experimental and kinetic modeling study of di-isobutylene isomers : Part 2
- 2023
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Ingår i: Combustion and Flame. - : Elsevier BV. - 0010-2180. ; 251
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Tidskriftsartikel (refereegranskat)abstract
- A wide variety of high temperature experimental data obtained in this study complement the data on the oxidation of the two di-isobutylene isomers presented in Part I and offers a basis for an extensive validation of the kinetic model developed in this study. Due to the increasing importance of unimolecular decomposition reactions in high-temperature combustion, we have investigated the di-isobutylene isomers in high dilution utilizing a pyrolysis microflow reactor and detected radical intermediates and stable products using vacuum ultraviolet (VUV) synchrotron radiation and photoelectron photoion coincidence (PEPICO) spectroscopy. Additional speciation data at oxidative conditions were also recorded utilizing a plug flow reactor at atmospheric pressure in the temperature range 725–1150 K at equivalence ratios of 1.0 and 3.0 and at residence times of 0.35 s and 0.22 s, respectively. Combustion products were analyzed using gas chromatography (GC) and mass spectrometry (MS). Ignition delay time measurements for di-isobutylene were performed at pressures of 15 and 30 bar at equivalence ratios of 0.5, 1.0, and 2.0 diluted in ‘air’ in the temperature range 900–1400 K using a high-pressure shock-tube facility. New measurements of the laminar burning velocities of di-isobutylene/air flames are also presented. The experiments were performed using the heat flux method at atmospheric pressure and initial temperatures of 298–358 K. Moreover, data consistency was assessed with the help of analysis of the temperature and pressure dependencies of laminar burning velocity measurements, which was interpreted using an empirical power-law expression. Electronic structure calculations were performed to compute the energy barriers to the formation of many of the product species formed. The predictions of the present mechanism were found to be in adequate agreement with the wide variety of experimental measurements performed.
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| 13. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 14. |
- Majounie, Elisa, et al.
(författare)
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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
- 2012
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Ingår i: Lancet Neurology. - 1474-4465. ; 11:4, s. 323-330
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Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9472 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
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| 15. |
- Munke, Anna, et al.
(författare)
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Data Descriptor : Coherent diffraction of single Rice Dwarf virus particles using hard X-rays at the Linac Coherent Light Source
- 2016
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Ingår i: Scientific Data. - : Nature Publishing Group. - 2052-4463. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Single particle diffractive imaging data from Rice Dwarf Virus (RDV) were recorded using the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS). RDV was chosen as it is a wellcharacterized model system, useful for proof-of-principle experiments, system optimization and algorithm development. RDV, an icosahedral virus of about 70 nm in diameter, was aerosolized and injected into the approximately 0.1 mu m diameter focused hard X-ray beam at the CXI instrument of LCLS. Diffraction patterns from RDV with signal to 5.9 angstrom ngstrom were recorded. The diffraction data are available through the Coherent X-ray Imaging Data Bank (CXIDB) as a resource for algorithm development, the contents of which are described here.
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| 16. |
- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 17. |
- Prudencio, Mercedes, et al.
(författare)
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Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
- 2020
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:566
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Tidskriftsartikel (refereegranskat)abstract
- Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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| 18. |
- Reddy, Hemanth K. N., et al.
(författare)
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Coherent soft X-ray diffraction imaging of coliphage PR772 at the Linac coherent light source
- 2017
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Ingår i: Scientia Danica. Series H. Humanistica 4. - : Nature Publishing Group. - 1904-5506 .- 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Single-particle diffraction from X-ray Free Electron Lasers offers the potential for molecular structure determination without the need for crystallization. In an effort to further develop the technique, we present a dataset of coherent soft X-ray diffraction images of Coliphage PR772 virus, collected at the Atomic Molecular Optics (AMO) beamline with pnCCD detectors in the LAMP instrument at the Linac Coherent Light Source. The diameter of PR772 ranges from 65-70 nm, which is considerably smaller than the previously reported similar to 600 nm diameter Mimivirus. This reflects continued progress in XFEL-based single-particle imaging towards the single molecular imaging regime. The data set contains significantly more single particle hits than collected in previous experiments, enabling the development of improved statistical analysis, reconstruction algorithms, and quantitative metrics to determine resolution and self-consistency.
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| 19. |
- Richards, Stephen, et al.
(författare)
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The genome of the model beetle and pest Tribolium castaneum.
- 2008
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Ingår i: Nature. - 1476-4687. ; 452:7190, s. 949-55
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Tidskriftsartikel (refereegranskat)abstract
- Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
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| 20. |
- Semakula, Henry Musoke, et al.
(författare)
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Prediction of future malaria hotspots under climate change in sub-Saharan Africa
- 2017
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Ingår i: Climatic Change. - : Springer Science and Business Media LLC. - 0165-0009 .- 1573-1480. ; 143:3-4, s. 415-428
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Tidskriftsartikel (refereegranskat)abstract
- Malaria is a climate sensitive disease that is causing rampant deaths in sub-Saharan Africa (SSA) and its impact is expected to worsen under climate change. Thus, pre-emptive policies for future malaria control require projections based on integrated models that can accommodate complex interactions of both climatic and non-climatic factors that define malaria landscape. In this paper, we combined Geographical Information System (GIS) and Bayesian belief networks (BBN) to generate GIS-BBN models that predicted malaria hotspots in 2030, 2050 and 2100 under representative concentration pathways (RCPs) 4.5 and 8.5. We used malaria data of children of SSA, gridded environmental and social-economic data together with projected climate data from the 21 Coupled Model Inter-comparison Project Phase 5 models to compile the GIS-BBN models. Our model on which projections were made has an accuracy of 80.65% to predict the high, medium, low and no malaria prevalence categories correctly. The non-spatial BBN model projection shows a moderate variation in malaria reduction for the high prevalence category among RCPs. Under the low prevalence category, an increase in malaria is seen but with little variation ranging between 4.6 and 5.6 percentage points. Spatially, under RCP 4.5, most parts of SSA will have medium malaria prevalence in 2030, while under RCP 8.5, most parts will have no malaria except in the highlands. Our BBN-GIS models show an overall shift of malaria hotspots from West Africa to the eastern and southern parts of Africa especially under RCP 8.5. RCP 8.5 will not expand the high and medium malaria prevalence categories in all the projection years. The generated probabilistic maps highlight future malaria hotspots under climate change on which pre-emptive policies can be based.
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| 21. |
- Sheena, B. S., et al.
(författare)
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Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019
- 2022
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Ingår i: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 7:9, s. 796-829
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Tidskriftsartikel (refereegranskat)abstract
- Background Combating viral hepatitis is part of the UN Sustainable Development Goals (SDGs), and WHO has put forth hepatitis B elimination targets in its Global Health Sector Strategy on Viral Hepatitis (WHO-GHSS) and Interim Guidance for Country Validation of Viral Hepatitis Elimination (WHO Interim Guidance). We estimated the global, regional, and national prevalence of hepatitis B virus (HBV), as well as mortality and disability-adjusted life-years (DALYs) due to HBV, as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. This included estimates for 194 WHO member states, for which we compared our estimates to WHO elimination targets. Methods The primary data sources were population-based serosurveys, claims and hospital discharges, cancer registries, vital registration systems, and published case series. We estimated chronic HBV infection and the burden of HBV-related diseases, defined as an aggregate of cirrhosis due to hepatitis B, liver cancer due to hepatitis B, and acute hepatitis B. We used DisMod-MR 2.1, a Bayesian mixed-effects meta-regression tool, to estimate the prevalence of chronic HBV infection, cirrhosis, and aetiological proportions of cirrhosis. We used mortality-to-incidence ratios modelled with spatiotemporal Gaussian process regression to estimate the incidence of liver cancer. We used the Cause of Death Ensemble modelling (CODEm) model, a tool that selects models and covariates on the basis of out-ofsample performance, to estimate mortality due to cirrhosis, liver cancer, and acute hepatitis B. Findings In 2019, the estimated global, all-age prevalence of chronic HBV infection was 4 center dot 1% (95% uncertainty interval [UI] 3 center dot 7 to 4 center dot 5), corresponding to 316 million (284 to 351) infected people. There was a 31 center dot 3% (29 center dot 0 to 33 center dot 9) decline in all-age prevalence between 1990 and 2019, with a more marked decline of 76 center dot 8% (76 center dot 2 to 77 center dot 5) in prevalence in children younger than 5 years. HBV-related diseases resulted in 555 000 global deaths (487 000 to 630 000) in 2019. The number of HBV-related deaths increased between 1990 and 2019 (by 5 center dot 9% [-5 center dot 6 to 19 center dot 2]) and between 2015 and 2019 (by 2 center dot 9% [-5 center dot 9 to 11 center dot 3]). By contrast, all-age and age-standardised death rates due to HBV-related diseases decreased during these periods. We compared estimates for 2019 in 194 WHO locations to WHO-GHSS 2020 targets, and found that four countries achieved a 10% reduction in deaths, 15 countries achieved a 30% reduction in new cases, and 147 countries achieved a 1% prevalence in children younger than 5 years. As of 2019, 68 of 194 countries had already achieved the 2030 target proposed in WHO Interim Guidance of an all-age HBV-related death rate of four per 100 000. Interpretation The prevalence of chronic HBV infection declined over time, particularly in children younger than 5 years, since the introduction of hepatitis B vaccination. HBV-related death rates also decreased, but HBV-related death counts increased as a result of population growth, ageing, and cohort effects. By 2019, many countries had met the interim seroprevalence target for children younger than 5 years, but few countries had met the WHO-GHSS interim targets for deaths and new cases. Progress according to all indicators must be accelerated to meet 2030 targets, and there are marked disparities in burden and progress across the world. HBV interventions, such as vaccination, testing, and treatment, must be strategically supported and scaled up to achieve elimination.
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| 22. |
- Zhu, Lijuan, et al.
(författare)
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Binding modes of cabazitaxel with the different human beta-tubulin isotypes : DFT and MD studies
- 2020
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Ingår i: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 26:6
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Tidskriftsartikel (refereegranskat)abstract
- Taxanes (paclitaxel, docetaxel, cabazitaxel) are anticancer drugs as microtubule inhibitors. Following our previous studies on paclitaxel and docetaxel, in this work, we examine cabazitaxel and compare these three taxenes. The binding interaction of three taxanes with various beta-tubulin isotypes is studied by homology modeling, molecular docking, and molecular dynamics simulations. The results show that the effects of docetaxel on beta I-tubulin (- 29.5 kcal/mol) and of paclitaxel on beta IIa-tubulin (- 25.5 kcal/mol) are much stronger than their effects on beta III-tubulin (- 17.8 kcal/mol and - 8.6 kcal/mol, respectively). However, the effect of cabazitaxel on beta III-tubulin (- 23.0 kcal/mol) is comparable with that on beta I-tubulin (- 24.0 kcal/mol) and beta IIa-tubulin (- 25.9 kcal/mol), consistent with the fact that overexpression of beta III-tubulin increases the drug resistance to paclitaxel and docetaxel, but has little influence for cabazitaxel. This theoretical research supports the use of cabazitaxel for patients who are resistant to the action of paclitaxel and docetaxel.
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| 23. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 24. |
- Aad, G., et al.
(författare)
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- 2012
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Tidskriftsartikel (refereegranskat)
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| 25. |
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- 2017
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Ingår i: Physical Review D. - 2470-0010 .- 2470-0029. ; 96:2
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Tidskriftsartikel (refereegranskat)
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