| 1. |
- Al-Amin, Rasel A., Researcher, 1983-, et al.
(författare)
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Monitoring drug–target interactions through target engagement-mediated amplification on arrays and in situ
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 50:22, s. e129-e129
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Tidskriftsartikel (refereegranskat)abstract
- Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug–target interactions at spatial resolution in protein arrays, cells and in tissues.
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| 2. |
- Ali, Muhammad, et al.
(författare)
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Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:5
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Tidskriftsartikel (refereegranskat)abstract
- Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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| 3. |
- Andric, Stefan, et al.
(författare)
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Performance, Analysis, and Modeling of III-V Vertical Nanowire MOSFETs on Si at Higher Voltages
- 2022
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Ingår i: IEEE Transactions on Electron Devices. - 0018-9383. ; 69:6, s. 3055-3055
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Tidskriftsartikel (refereegranskat)abstract
- Heterostructure engineering in III-V vertical nanowire (VNW) MOSFETs enables tuning of transconductance and breakdown voltage. In this work, an InxGa 1−x As channel with a Ga-composition grading ( x= 1–0.4) in the channel and drain region, combined with field plate engineering, enables breakdown voltage above 2.5 V, while maintaining transconductance of about 1 mS/ μm , in VNW MOSFETs. The field plate consists of a vertically integrated SiO2 layer and a gate contact, which screens the electric field in the drain region, extending the device operating voltage. By scaling the field plate, a transconductance of 2 mS/ μm , alongside the breakdown voltage of 1.5 V, is obtained, demonstrating the benefit of field engineering in the drain. The scalability of the field plate and the gate is measured, showing an ON-resistance increase by 23 Ω⋅μm , and transconductance decrease by 5 μS/μm , per nm field plate length. This behavior is captured in a new and modified virtual source model, where device transmission and drain resistance are altered to capture the field plate scaling effect. The modeling is applied to nanowire (NW) devices with field plate lengths ranging from 5 to 115 nm, capturing accurately essential device performance parameters. Finally, a modified band-to-band (BTB) tunneling approach is used to accurately describe the device behavior above 1.5 V.
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| 4. |
- Arnelo, Urban, et al.
(författare)
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Intraoperative pancreatoscopy can improve the detection of skip lesions during surgery for intraductal papillary mucinous neoplasia : a pilot study
- 2023
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Ingår i: Pancreatology (Print). - : Elsevier. - 1424-3903 .- 1424-3911. ; 23:6, s. 704-711
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Intraoperative pancreatoscopy is a promising procedure that might guide surgical resection for suspected main duct (MD) and mixed type (MT) intraductal papillary mucinous neoplasms (IPMNs). The aim of the present study was to assess the diagnostic yield and clinical impact of intraoperative pancreatoscopy in patients operated on for MD and MT-IPMNs.Methods: This is a retrospective cohort study. Patients undergoing surgery for suspected MD or MT-IPMN underwent intraoperative pancreatoscopy and frozen section analysis. In all patients who required extended resection due to pancreatoscopic findings, we compared the final histology with the results of the intraoperative frozen section analysis.Results: In total, 46 patients, 48% females, mean age (range) 67 years (45–82 years) underwent intraoperative pancreatoscopy. No mortality or procedure related complications were observed. Pancreatoscopy changed the operative course in 30 patients (65%), leading to extended resections in 20 patients (43%) and to parenchyma sparing procedures in 10 patients (22%). Analyzing the group of patients who underwent extended resections, 7 (35%) displayed lesions that needed further surgical treatment (six high grade dysplasia and one with G1 pancreatic neuroendocrine tumor) and among those 7, just 1 (14%) would have been detected exclusively with histological frozen section analysis of the transection margin. The combination of both pancreatoscopy and frozen section analysis lead to 86% sensitivity and 92% specificity for the detection of pathological tissue in the remnant pancreas.Conclusion: Intraoperative pancreatoscopy is a safe and feasible procedure and might allow the detection of skip lesions during surgery for suspect MD-involving IPMNs.
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| 5. |
- Bañuls, Mari Carmen, et al.
(författare)
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Quantum information perspective on meson melting
- 2023
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Ingår i: Physical Review D. - 2470-0010. ; 108:7
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Tidskriftsartikel (refereegranskat)abstract
- We propose to use quantum information notions to characterize thermally induced melting of nonperturbative bound states at high temperatures. We apply tensor networks to investigate this idea in static and dynamical settings within the Ising quantum field theory, where bound states are confined fermion pairs - mesons. An equilibrium signature of meson melting is identified in the temperature dependence of the thermal-state second Rényi entropy, which varies from exponential to power-law scaling. Out of equilibrium, we identify as the relevant signature the transition from an oscillatory to a linear growing behavior of reflected entropy after a thermal quench. These analyses apply more broadly, which brings new ways of describing in-medium meson phenomena in quantum many-body and high-energy physics.
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| 6. |
- Bataille, Christopher, et al.
(författare)
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Net-zero deep decarbonization pathways in Latin America : Challenges and opportunities
- 2020
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Ingår i: Energy Strategy Reviews. - : Elsevier BV. - 2211-467X .- 2211-4688. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- This synthesis paper presents the objectives, approach and cross-cutting results of the Latin American Deep Decarbonization Pathways project (DDP-LAC). It synthesizes and compares detailed national and sectoral deep decarbonization pathways (DDPs) to 2050 compatible with the Paris Agreement objectives and domestic development priorities in Argentina, Colombia, Costa Rica, Ecuador, Mexico and Peru. The first five countries analysed in detail the energy system and agriculture, forestry and land use (AFOLU) at a high level, while Peru focussed on a detailed analysis of AFOLU given its predominance in its GHG emissions. While economy-wide results were produced, this paper focuses on the electricity, passenger transport, and AFOLU results because of their current emissions, potential to grow, and identification of successful strategies for decarbonization (e.g. switching to clean electricity and other net-zero emissions fuels across the economy; urban planning, mode shifting, and electrification in passenger transport; and intensive sustainable agriculture, assignment of land use rights and their enforcement and afforestation in AFOLU). It also highlights where significant emissions remain in 2050, notably in industry, AFOLU, freight, and oil and gas production, all areas for future research. It derives insights for the design of domestic policy packages and identifies priorities for international cooperation. This analysis provides critical information for Long-Term Strategies, Nationally Determined Contributions and Global Stocktaking in the context of the Paris Agreement.
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| 7. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 8. |
- Dzhigaev, Dmitry, et al.
(författare)
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Strain mapping inside an individual processed vertical nanowire transistor using scanning X-ray nanodiffraction
- 2020
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Ingår i: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3372 .- 2040-3364. ; 12:27, s. 14487-14493
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Tidskriftsartikel (refereegranskat)abstract
- Semiconductor nanowires in wrapped, gate-all-around transistor geometry are highly favorable for future electronics. The advanced nanodevice processing results in strain due to the deposited dielectric and metal layers surrounding the nanowires, significantly affecting their performance. Therefore, non-destructive nanoscale characterization of complete devices is of utmost importance due to the small feature sizes and three-dimensional buried structure. Direct strain mapping inside heterostructured GaSb-InAs nanowire tunnel field-effect transistor embedded in dielectric HfO2, W metal gate layers, and an organic spacer is performed using fast scanning X-ray nanodiffraction. The effect of 10 nm W gate on a single embedded nanowire with segment diameters down to 40 nm is retrieved. The tensile strain values reach 0.26% in the p-type GaSb segment of the transistor. Supported by the finite element method simulation, we establish a connection between the Ar pressure used during the W layer deposition and the nanowire strain state. Thus, we can benchmark our models for further improvements in device engineering. Our study indicates, how the significant increase in X-ray brightness at 4th generation synchrotron, makes high-throughput measurements on realistic nanoelectronic devices viable.
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| 9. |
- Fukumasu, Jumpei, et al.
(författare)
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Oxalate-extractable aluminum alongside carbon inputs may be a major determinant for organic carbon content in agricultural topsoils in humid continental climate
- 2021
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Ingår i: Geoderma. - : Elsevier BV. - 0016-7061 .- 1872-6259. ; 402
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Tidskriftsartikel (refereegranskat)abstract
- The relative importance of various soil mineral constituents (e.g. clay-sized particles, aluminum- and iron-bearing mineral reactive phases) in protecting soil organic carbon (SOC) from decomposition is not yet fully understood in arable soils formed from quaternary deposits in humid continental climates. In this study, we investigated the relationships between soil physico-chemical properties (i.e. contents of oxalate-extractable aluminum (Alox) and iron (Feox) and clay size particle < 2 mu m), grain yield (as a proxy for carbon input) and total SOC as well as SOC in different soil fractions for samples taken from the topsoil of an arable field at Bjertorp in south-west Sweden. We found a positive correlation between Alox and total SOC content, where Alox explained ca. 48% of the spatial variation in SOC. We also found that ca. 80% of SOC was stored in silt- and claysized (SC) fractions, where Al-bearing reactive mineral phases (estimated by Alox) may be important for organicmineral associations and clay aggregation. Our results were supported by data collated from the literature for arable topsoil in similar climates, which also showed positive correlations between SOC and Alox contents (R-2 = 23.1 - 74.5%). Multiple linear regression showed that including spatially-variable crop yields as a proxy for carbon inputs improved the prediction of SOC variation across the Bjertorp field. Other unquantified soil properties such as exchangeable calcium may account for the remaining unexplained variation in topsoil SOC. We conclude that Al-bearing reactive mineral phases are more important than clay content and Fe-bearing reactive mineral phases for SOC stabilization in arable topsoil in humid continental climates.
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| 10. |
- Johansson, Naimi, 1988-, et al.
(författare)
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Reductions in out-of-pocket prices and forward-looking moral hazard in health care demand
- 2023
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Ingår i: Journal of Health Economics. - : Elsevier. - 0167-6296 .- 1879-1646. ; 87
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about how patients dynamically respond to a forthcoming reduction in health care out-of-pocket prices. Using a kinked Donut Regression Discontinuity design with kinks entering and exiting the donut, we evaluate a Swedish cost-sharing policy, where primary care out-of-pocket prices were eliminated at age 85. We find evidence of forward-looking moral hazard with older adults delaying primary care visits up to four months before the out-of-pocket elimination and shifting these visits until shortly after. These health care delays are driven by non-urgent care: non-physician visits, planned visits and follow up visits. We find no evidence of severe negative health effects in the short-term as a result of the delay. Contrary to our finding of forward-looking behavior with respect to out-of-pocket prices, we do not find evidence of typical moral hazard, as we do not find a persistent increase in primary health care use after the copayment elimination.
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