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- Kennedy, S. A., et al.
(author)
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Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D
- 2020
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
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- Teo, Kevin, et al.
(author)
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rs641738C>T near MBOAT7 is associated with liver fat, ALT, and fibrosis in NAFLD: a meta-analysis.
- 2021
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In: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 74:1, s. 20-30
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Journal article (peer-reviewed)abstract
- A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis.We performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models.Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05], pz=4.8x10-5) and diagnosis of NAFLD (OR 1.17 [95% CI 1.05 - 1.3], pz=0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI: 1.03 - 1.45], pz=0.021) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz=0.002) and lower serum triglycerides (pz=1.5x10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.
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- Gross, Sean M., et al.
(author)
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A multi-omic analysis of MCF10A cells provides a resource for integrative assessment of ligand-mediated molecular and phenotypic responses
- 2022
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In: Communications Biology. - : Springer Nature. - 2399-3642. ; 5:1
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Journal article (peer-reviewed)abstract
- The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, and extracellular matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic and molecular states associated with diverse diseases. To develop a detailed understanding of the linkage between molecular and phenotypic changes, we generated a comprehensive dataset that catalogs the transcriptional, proteomic, epigenomic and phenotypic responses of MCF10A mammary epithelial cells after exposure to the ligands EGF, HGF, OSM, IFNG, TGFB and BMP2. Systematic assessment of the molecular and cellular phenotypes induced by these ligands comprise the LINCS Microenvironment (ME) perturbation dataset, which has been curated and made publicly available for community-wide analysis and development of novel computational methods ( synapse.org/LINCS_MCF10A ). In illustrative analyses, we demonstrate how this dataset can be used to discover functionally related molecular features linked to specific cellular phenotypes. Beyond these analyses, this dataset will serve as a resource for the broader scientific community to mine for biological insights, to compare signals carried across distinct molecular modalities, and to develop new computational methods for integrative data analysis.
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- Chettiyam Thodi, Muhamed Fasil, et al.
(author)
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Using RS and GIS Techniques to Assess and Monitor Coastal Changes of Coastal Islands in the Marine Environment of a Humid Tropical Region
- 2023
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In: Water. - : MDPI. - 2073-4441. ; 15:21
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Journal article (peer-reviewed)abstract
- Vypin, Vallarpadam, and Bolgatty are significant tropical coastal islands situated in the humid tropical Kerala region of India, notable for their environmental sensitivity. This study conducted a comprehensive assessment of shoreline alterations on these islands by integrating Remote Sensing (RS) and Geographic Information Systems (GIS) techniques. Utilizing satellite imagery from the LANDSAT series with a spatial resolution of 30 m, the analysis spanned the years from 1973 to 2019. The Digital Shoreline Analysis System (DSAS) tool, integrated into the ArcGIS software, was employed to monitor and analyze shoreline shifts, encompassing erosion and accretion. Various statistical parameters, including Net Shoreline Movement (NSM), End Point Rate (EPR), and Linear Regression Rate (LRR), were utilized to evaluate these changes. Additionally, the study aimed to discern the root causes of shoreline modifications in the study area, encompassing disturbances and the construction of new structures on these islands. The results conclusively demonstrated the substantial impact endured by these coastal islands, with accretion on both sides leading to the creation of new landmasses. This manuscript effectively illustrates that these islands have experienced marine transgression, notably evidenced by accretion. Anthropogenic activities were identified as the primary drivers behind the observed shoreline changes, underscoring the need for careful management and sustainable practices in these fragile coastal ecosystems.
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| 9. |
- Fijoł, Natalia, et al.
(author)
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3D-printed monolithic biofilters based on a polylactic acid (PLA) - hydroxyapatite (HAp) composite for heavy metal removal from an aqueous medium
- 2021
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In: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 11:51, s. 32408-32418
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Journal article (peer-reviewed)abstract
- High flux, monolithic water purification filters based on polylactic acid (PLA) functionalised with fish scale extracted hydroxyapatite (HAp) were prepared by solvent-assisted blending and thermally induced phase separation (TIPS), followed by twin-screw extrusion into filaments and processed via three-dimensional (3D) printing. The printed filters with consistent pore geometry and channel interconnectivity as well as homogenous distribution of HAp in the PLA matrix showed adsorption capabilities towards heavy metals i.e. cadmium (Cd) and lead (Pb) with maximum adsorption capacity of 112.1 mg gHAp−1 and 360.5 mg gHAp−1 for the metal salt of Pb and Cd, respectively. The adsorption was found to be driven by a combination of ion exchange, dissolution and precipitation on HAp and surface complexation.
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- Frosi, Y, et al.
(author)
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Engineering an autonomous VH domain to modulate intracellular pathways and to interrogate the eIF4F complex
- 2022
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4854-
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Journal article (peer-reviewed)abstract
- An attractive approach to target intracellular macromolecular interfaces and to model putative drug interactions is to design small high-affinity proteins. Variable domains of the immunoglobulin heavy chain (VH domains) are ideal miniproteins, but their development has been restricted by poor intracellular stability and expression. Here we show that an autonomous and disufhide-free VH domain is suitable for intracellular studies and use it to construct a high-diversity phage display library. Using this library and affinity maturation techniques we identify VH domains with picomolar affinity against eIF4E, a protein commonly hyper-activated in cancer. We demonstrate that these molecules interact with eIF4E at the eIF4G binding site via a distinct structural pose. Intracellular overexpression of these miniproteins reduce cellular proliferation and expression of malignancy-related proteins in cancer cell lines. The linkage of high-diversity in vitro libraries with an intracellularly expressible miniprotein scaffold will facilitate the discovery of VH domains suitable for intracellular applications.
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| 11. |
- Jagadesh, M., et al.
(author)
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Altering Natural Ecosystems Causes Negative Consequences on the Soil Physical Qualities: An Evidence-Based Study from Nilgiri Hill Region of Western Ghats, India
- 2023
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In: Land. - : Multidisciplinary Digital Publishing Institute (MDPI). - 2073-445X. ; 12:10
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Journal article (peer-reviewed)abstract
- Land use change (LUC) has direct and indirect consequences on soil quality. To gain insight into how LUC influences the physical properties of soil, it can be advantageous to compare undisturbed ecosystems with those that have naturally evolved over time, as well as to use soil quality indices to pinpoint the sensitivity of each ecosystem and land use change (LUC). A soil survey was carried out in the six major ecosystems of the Nilgiri Hill Region: cropland (CL), deciduous forest (DF), evergreen forest (EF), forest plantation (FP), scrubland (SL), and tea plantation (TP), with those having an establishment for over 50 years being selected and analyzed for soil physical parameters. In addition, soil quality indices were also derived to pinpoint the vulnerability of each ecosystem to LUC. The results reveal that the changes in land use significantly altered the soil physical properties. The content of clay was higher in EF and DF and increased with the soil profile’s depth, whereas the sand content was higher in CL and TP and decreased with the depth increment. BD and PD were significantly lower in EF, DF, SL, and FP, whereas they were higher in CL and TP. PS and ASM followed a similar trend to BD and PD. Owing to undisturbed natural settings, an abundance of litter input, and higher carbon concentrations, the HC was higher in EF, DF, SL, and FP, whereas, in the case of anthropogenic-influenced ecosystems such as CL and TP, it was lower. We discovered that LUC has altered Ag S, WSA, and MWD. Due to tillage and other cultural practices, Ag S, WSA, and MWD were significantly lower in CL and TP. However, the results confirm that native ecosystems (EF and DF) with a higher carbon content prevent such degradation, thereby resulting in good Ag S, WSA, and MWD.
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| 12. |
- Kuemmerli, Christoph, et al.
(author)
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Impact of enhanced recovery protocols after pancreatoduodenectomy : meta-analysis
- 2022
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In: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 109:3, s. 256-266
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Journal article (peer-reviewed)abstract
- BACKGROUND: This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy. METHODS: The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission. RESULTS: Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate. CONCLUSION: ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged.
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| 13. |
- Pomara, N., et al.
(author)
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Plasma Amyloid-beta dynamics in late-life major depression: a longitudinal study
- 2022
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1
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Journal article (peer-reviewed)abstract
- Depressed individuals are twice as likely to develop Alzheimer's disease (AD) as compared to controls. Brain amyloid-beta (A beta) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of A beta dynamics and depression. The aim of this study was to test if plasma A beta levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-beta(1-40) (A beta 40) and amyloid-beta(1-42) (A beta 42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the A beta 42/A beta 40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, A beta 42/A beta 40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma A beta 42/A beta 40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low A beta 42/A beta 40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma A beta 42/A beta 40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.
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| 14. |
- Tang, Jiexiong, et al.
(author)
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Neural Outlier Rejection For Self-Supervised Keypoint Learning
- 2020
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In: <em>8th International Conference on Learning Representations, ICLR 2020</em>. - : International Conference on Learning Representations, ICLR.
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Conference paper (peer-reviewed)abstract
- Identifying salient points in images is a crucial component for visual odometry, Structure-from-Motion or SLAM algorithms. Recently, several learned keypoint methods have demonstrated compelling performance on challenging benchmarks. However, generating consistent and accurate training data for interest-point detection in natural images still remains challenging, especially for human annotators. We introduce IO-Net (i.e. InlierOutlierNet), a novel proxy task for the self-supervision of keypoint detection, description and matching. By making the sampling of inlier-outlier sets from point-pair correspondences fully differentiable within the keypoint learning framework, we show that are able to simultaneously self-supervise keypoint description and improve keypoint matching. Second, we introduce KeyPointNet, a keypoint-network architecture that is especially amenable to robust keypoint detection and description. We design the network to allow local keypoint aggregation to avoid artifacts due to spatial discretizations commonly used for this task, and we improve fine-grained keypoint descriptor performance by taking advantage of efficient sub-pixel convolutions to upsample the descriptor feature-maps to a higher operating resolution. Through extensive experiments and ablative analysis, we show that the proposed self-supervised keypoint learning method greatly improves the quality of feature matching and homography estimation on challenging benchmarks over the state-of-the-art.
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