| 1. |
- McWhinney, Sean R, et al.
(författare)
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Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity.
- 2024
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Ingår i: Human brain mapping. - 1097-0193 .- 1097-0193. ; 45:8
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Tidskriftsartikel (refereegranskat)abstract
- Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.
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| 2. |
- Kumar Maroju, Praveen, et al.
(författare)
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Attosecond pulse shaping using a seeded free-electron laser
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578, s. 386-391
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Tidskriftsartikel (refereegranskat)abstract
- Attosecond pulses are central to the investigation of valence- and core-electron dynamics on their natural timescales. The reproducible generation and characterization of attosecond waveforms has been demonstrated so far only through the process of high-order harmonic generation. Several methods for shaping attosecond waveforms have been proposed, including the use of metallic filters, multilayer mirrors and manipulation of the driving field. However, none of these approaches allows the flexible manipulation of the temporal characteristics of the attosecond waveforms, and they suffer from the low conversion efficiency of the high-order harmonic generation process. Free-electron lasers, by contrast, deliver femtosecond, extreme-ultraviolet and X-ray pulses with energies ranging from tens of microjoules to a few millijoules. Recent experiments have shown that they can generate subfemtosecond spikes, but with temporal characteristics that change shot-to-shot. Here we report reproducible generation of high-energy (microjoule level) attosecond waveforms using a seeded free-electron laser. We demonstrate amplitude and phase manipulation of the harmonic components of an attosecond pulse train in combination with an approach for its temporal reconstruction. The results presented here open the way to performing attosecond time-resolved experiments with free-electron lasers.
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| 3. |
- Maroju, Praveen K., et al.
(författare)
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A Novel Attosecond Timing Tool for Free-Electron Laser Experiment
- 2020
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Ingår i: High Intensity Lasers and High Field Phenomena 2020. - 9781943580736
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Konferensbidrag (refereegranskat)abstract
- We demonstrate a novel timing tool for Free-Electron Lasers to determine the delay between an attosecond pulse train and infrared pulse with sub-optical-cycle resolu-. tion.
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| 4. |
- Maroju, Praveen Kumar, et al.
(författare)
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Complex attosecond waveform synthesis at fel fermi
- 2021
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Ingår i: Applied Sciences (Switzerland). - : MDPI AG. - 2076-3417. ; 11:21
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Tidskriftsartikel (refereegranskat)abstract
- Free-electron lasers (FELs) can produce radiation in the short wavelength range extending from the extreme ultraviolet (XUV) to the X-rays with a few to a few tens of femtoseconds pulse duration. These facilities have enabled significant breakthroughs in the field of atomic, molecular, and optical physics, implementing different schemes based on two-color photoionization mechanisms. In this article, we present the generation of attosecond pulse trains (APTs) at the seeded FEL FERMI using the beating of multiple phase-locked harmonics. We demonstrate the complex attosecond waveform shaping of the generated APTs, exploiting the ability to manipulate independently the amplitudes and the phases of the harmonics. The described generalized attosecond waveform synthesis technique with an arbitrary number of phase-locked harmonics will allow the generation of sub-100 as pulses with programmable electric fields.
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| 5. |
- Mazza, Tiziano, et al.
(författare)
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Structural basis for the modulation of MRP2 activity by phosphorylation and drugs
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Multidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson syndrome or by off-target inhibition, for example by the uricosuric drug probenecid, elevates circulating bilirubin glucuronide and is a cause of jaundice. Here, we determine the cryo-EM structure of rat Mrp2 (rMrp2) in an autoinhibited state and in complex with probenecid. The autoinhibited state exhibits an unusual conformation for this class of transporter in which the regulatory domain is folded within the transmembrane domain cavity. In vitro phosphorylation, mass spectrometry and transport assays show that phosphorylation of the regulatory domain relieves this autoinhibition and enhances rMrp2 transport activity. The in vitro data is confirmed in human hepatocyte-like cells, in which inhibition of endogenous kinases also reduces human MRP2 transport activity. The drug-bound state reveals two probenecid binding sites that suggest a dynamic interplay with autoinhibition. Mapping of the Dubin-Johnson mutations onto the rodent structure indicates that many may interfere with the transition between conformational states. The ABC transporter MRP2/ABCC2 is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. Dysfunction leads to Dubin-Johnson syndrome. Here the authors provide structural and biochemical evidence on the modulation of MRP2 by intracellular kinases and inhibition by therapeutic drugs.
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| 6. |
- McWhinney, Sean R, et al.
(författare)
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Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals.
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:11, s. 6806-6819
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediatedby BMI (Z=2.73, p=0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.
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| 7. |
- McWhinney, Sean R, et al.
(författare)
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Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness-ENIGMA study in 2436 individuals.
- 2022
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Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 24:5, s. 509-520
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Tidskriftsartikel (refereegranskat)abstract
- Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry.We obtained body mass index (BMI) and magnetic resonance imaging-derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control individuals from 14sites within the ENIGMA-BD Working Group. We identified regionally specific profiles of cortical thickness using K-means clustering and studied clinical characteristics associated with individual cortical profiles.We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the sample) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD individuals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex.We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in individuals with higher BMI, which was additive and similar to the BD-associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD.
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| 8. |
- McWhinney, Sean R, et al.
(författare)
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Mega-analysis of association between obesity and cortical morphology in bipolar disorders: ENIGMA study in 2832 participants.
- 2023
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Ingår i: Psychological medicine. - 1469-8978. ; 53:14, s. 6743-6753
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI.We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.
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| 9. |
- Varvarezos, Lazaros, et al.
(författare)
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Near-threshold two-photon double ionization of Kr in the vacuum ultraviolet
- 2021
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Ingår i: Physical Review A. - 2469-9926. ; 103:2
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Tidskriftsartikel (refereegranskat)abstract
- We report angle-resolved measurements on photoelectrons emitted upon near-threshold two-photon double ionization (TPDI) of Kr irradiated by free-electron laser (FEL) pulses. These photoelectron angular distributions (PADs) are compared with the results of semirelativistic R-matrix calculations. As reported by Augustin et al. [Phys. Rev. A 98, 033408 (2018)10.1103/PhysRevA.98.033408], it is found that the presence of autoionizing resonances within the bandwidth of the exciting FEL pulse strongly influences the PADs. In contrast to measurements on lower-Z targets such as Ne and Ar, the larger spin-orbit interaction, inherent in 4p-subshell hole states of Kr, permits us to resolve and study PADs associated with some of the fine-structure components of the Kr+ and Kr2+ ions.
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