Multi-omic analysis of bat versus human fibroblasts reveals altered central metabolism.

Bats have unique characteristics compared to other mammals, including increased longevity and higher resistance to cancer and infectious disease. While previous studies have analyzed the metabolic requirements for flight, it is still unclear how bat metabolism supports these unique features, and no study has integrated metabolomics, transcriptomics, and proteomics to characterize bat metabolism. In this work, we performed a multi-omics data analysis using a computational model of metabolic fluxes to identify fundamental differences in central metabolism between primary lung fibroblast cell lines from the black flying fox fruit bat (Pteropus alecto) and human. Bat cells showed higher expression levels of Complex I components of electron transport chain (ETC), but, remarkably, a lower rate of oxygen consumption. Computational modeling interpreted these results as indicating that Complex II activity may be low or reversed, similar to an ischemic state. An ischemic-like state of bats was also supported by decreased levels of central metabolites and increased ratios of succinate to fumarate in bat cells. Ischemic states tend to produce reactive oxygen species (ROS), which would be incompatible with the longevity of bats. However, bat cells had higher antioxidant reservoirs (higher total glutathione and higher ratio of NADPH to NADP) despite higher mitochondrial ROS levels. In addition, bat cells were more resistant to glucose deprivation and had increased resistance to ferroptosis, one of the characteristics of which is oxidative stress. Thus, our studies revealed distinct differences in the ETC regulation and metabolic stress responses between human and bat cells.

A high-density microfluidic bioreactor for the automated manufacturing of CAR T cells.

The manufacturing of autologous chimaeric antigen receptor (CAR) T cells largely relies either on fed-batch and manual processes that often lack environmental monitoring and control or on bioreactors that cannot be easily scaled out to meet patient demands. Here we show that human primary T cells can be activated, transduced and expanded to high densities in a 2 ml automated closed-system microfluidic bioreactor to produce viable anti-CD19 CAR T cells (specifically, more than 60 million CAR T cells from donor cells derived from patients with lymphoma and more than 200 million CAR T cells from healthy donors). The in vitro secretion of cytokines, the short-term cytotoxic activity and the long-term persistence and proliferation of the cell products, as well as their in vivo anti-leukaemic activity, were comparable to those of T cells produced in a gas-permeable well. The manufacturing-process intensification enabled by the miniaturized perfusable bioreactor may facilitate the analysis of the growth and metabolic states of CAR T cells during ex vivo culture, the high-throughput optimization of cell-manufacturing processes and the scale out of cell-therapy manufacturing.

Computational modeling of light processing in the habenula and dorsal raphe based on laser ablation of functionally-defined cells.

BACKGROUND: The habenula is a major regulator of serotonergic neurons in the dorsal raphe, and thus of brain state. The functional connectivity between these regions is incompletely characterized. Here, we use the ability of changes in irradiance to trigger reproducible changes in activity in the habenula and dorsal raphe of zebrafish larvae, combined with two-photon laser ablation of specific neurons, to establish causal relationships. RESULTS: Neurons in the habenula can show an excitatory response to the onset or offset of light, while neurons in the anterior dorsal raphe display an inhibitory response to light, as assessed by calcium imaging. The raphe response changed in a complex way following ablations in the dorsal habenula (dHb) and ventral habenula (vHb). After ablation of the ON cells in the vHb (V-ON), the raphe displayed no response to light. After ablation of the OFF cells in the vHb (V-OFF), the raphe displayed an excitatory response to darkness. After ablation of the ON cells in the dHb (D-ON), the raphe displayed an excitatory response to light. We sought to develop in silico models that could recapitulate the response of raphe neurons as a function of the ON and OFF cells of the habenula. Early attempts at mechanistic modeling using ordinary differential equation (ODE) failed to capture observed raphe responses accurately. However, a simple two-layer fully connected neural network (NN) model was successful at recapitulating the diversity of observed phenotypes with root-mean-squared error values ranging from 0.012 to 0.043. The NN model also estimated the raphe response to ablation of D-off cells, which can be verified via future experiments. CONCLUSION: Lesioning specific cells in different regions of habenula led to qualitatively different responses to light in the dorsal raphe. A simple neural network is capable of mimicking experimental observations. This work illustrates the ability of computational modeling to integrate complex observations into a simple compact formalism for generating testable hypotheses, and for guiding the design of biological experiments.

Neurochemical correlates of cognitive functions in euthymic patients with bipolar disorder: 1H-MRS study.

OBJECTIVES: We assessed and correlated neurochemical levels and cognitive functions in left dorsolateral prefrontal cortex (DLPFC) and left hippocampus in euthymic patients with bipolar disorder and compared these with healthy controls METHODOLOGY: Twenty-five right-handed euthymic patients (HAM-D score < 7, and YMRS score < 7) with bipolar disorder and 20 age and gender matched controls were compared for neurometabolites (n-acetylaspartate - tNAA, choline - Cho, creatinine - Cr, myoinositol - Ins, and glutamine/glutamate - Glu/Gln) measured in left DLPFC and left hippocampus using single voxel magnetic resonance spectroscopy (MRS) and cognitive functions assessed using trail making test (TMT - A and B), wisconsin card sorting test (WCST), and wechsler memory scale (WMS-III Indian adaptation). RESULTS: The two groups were comparable on socio-demographic variables. tNAA levels in DLPFC and hippocampus, and glutamate levels in hippocampus were found to be significantly lower and Inositol and glutamine levels in hippocampus were found to be significantly higher in patients as compared to controls. Patients performed significantly poorly as compared to controls on TMT A & B, all subscales of WMS - III, 5 subscales of WCST, including perseverative responses and errors. The tNAA and glutamate levels in left DLPFC in patients correlated with scores on TMT A & B, and several subscales of WCST and WMS-III. tNAA concentration in left hippocampus in patients correlated with scores on subscales of WMS-III. CONCLUSION: Neurochemical dysfunction in select brain areas directly correlates with impairment in cognitive functions seen in patients with bipolar disorder in euthymic phase.

Auditory perception of ambiguous and non-ambiguous sound in early and late blind children: A functional connectivity study.

INTRODUCTION: Auditory perception and associated cognition involve visual and auditory cortical areas for inference of meaningful soundscape. OBJECTIVE: To investigate auditory perception of ambiguous and non-ambiguous stimulation in auditory and visual cortical networks for categorical discrimination. METHODOLOGY: Functional mapping was carried out in twenty early (EB), twenty late blind (LB) and fifteen healthy children, during auditory ambiguous and non-ambiguous stimulation task in a 3 T MR scanner to estimate hemodynamic signal alteration and its effect on functional connectivity. The degree of amplitude low-frequency fluctuation (ALFF), correlation analysis and multiple comparison was carried out to map the impact of duration of education and onset of blindness (EB and LB). RESULTS AND DISCUSSION: Increased functional connectivity (FC) and cross-modal reorganization was observed in auditory, visual and language networks in EB children. FC was increased in contralateral hemisphere in both the blind children (EB and LB) groups and was positively correlated with duration of education performance. Cognitive assessment scores correlated (p < 0.01) with cluster coefficient of FC and BOLD response. CONCLUSION: FC alterations depend on onset age and audio-haptic training in children associated with increased auditory language and memory perception.

Complications associated with paediatric airway management during the COVID-19 pandemic: an international, multicentre, observational study.

Respiratory adverse events in adults with COVID-19 undergoing general anaesthesia can be life-threatening. However, there remains a knowledge gap about respiratory adverse events in children with COVID-19. We created an international observational registry to collect airway management outcomes in children with COVID-19 who were having a general anaesthetic. We hypothesised that children with confirmed or suspected COVID-19 would experience more hypoxaemia and complications than those without. Between 3 April 2020 and 1 November 2020, 78 international centres participated. In phase 1, centres collected outcomes on all children (age ≤ 18 y) having a general anaesthetic for 2 consecutive weeks. In phase 2, centres recorded outcomes for children with test-confirmed or suspected COVID-19 (based on symptoms) having a general anaesthetic. We did not study children whose tracheas were already intubated. The primary outcome was the incidence of hypoxaemia during airway management. Secondary outcomes included: incidence of other complications; and first-pass success rate for tracheal intubation. In total, 7896 children were analysed (7567 COVID-19 negative and 329 confirmed or presumed COVID-19 positive). The incidence of hypoxaemia during airway management was greater in children who were COVID-19 positive (24 out of 329 (7%) vs. 214 out of 7567 (3%); OR 2.70 (95%CI 1.70-4.10)). Children who had symptoms of COVID-19 had a higher incidence of hypoxaemia compared with those who were asymptomatic (9 out of 51 (19%) vs. 14 out of 258 (5%), respectively; OR 3.7 (95%CI 1.5-9.1)). Children with confirmed or presumed COVID-19 have an increased risk of hypoxaemia during airway management in conjunction with general anaesthesia.

Change in cardiometabolic risk factors among Asian Indian adults recruited in a mHealth-based diabetes prevention trial.

OBJECTIVE: India is experiencing an increasing prevalence of type 2 diabetes and cardiovascular diseases. Mobile health technology may be a strategy to reduce the risk of cardiometabolic disorders. This paper reports on the effect of a mobile health intervention on cardiometabolic risk factors. METHODS: The mobile health and diabetes intervention was a 12-week reality television-based mobile health program application delivered via videos, short message service and infographics through a smartphone application followed-up weekly by health coach calls. mobile health and diabetes was conducted in a randomized control trial mode randomized controlled trial methodology in three Indian cities (Chennai, Bengaluru and New Delhi) with participants recruited via community screening events. This paper looks at the pre-post changes in cardiometabolic risks among the participants and the place of demography in influencing these. RESULTS: The mobile health and diabetes intervention group experienced a small reduction in waist circumference (1.8 cm) compared to the control group (0.5 cm, p < 0.05) and a greater decrease in systolic blood pressure (2.7 mmHg) compared to the control group (p < 0.05). The improvements in cardiometabolic risk factors were more pronounced in individuals with obesity, although overall effects were very modest. CONCLUSIONS: Cardiometabolic risk factors can be reduced with a mobile health application using human coaching, especially in obese individuals, but the improvements are small. To be more effective and clinically meaningful, intensive engagement with the participants is probably required.

Structural and white matter changes associated with duration of Braille education in early and late blind children.

In early (EB) and late blind (LB) children, vision deprivation produces cross-modal plasticity in the visual cortex. The progression of structural- and tract-based spatial statistics changes in the visual cortex in EB and LB, as well as their impact on global cognition, have yet to be investigated. The purpose of this study was to determine the cortical thickness (CT), gyrification index (GI), and white matter (WM) integrity in EB and LB children, as well as their association to the duration of blindness and education. Structural and diffusion tensor imaging data were acquired in a 3T magnetic resonance imaging in EB and LB children (n = 40 each) and 30 sighted controls (SCs) and processed using CAT12 toolbox and FSL software. Two sample t-test was used for group analyses with P < 0.05 (false discovery rate-corrected). Increased CT in visual, sensory-motor, and auditory areas, and GI in bilateral visual cortex was observed in EB children. In LB children, the right visual cortex, anterior-cingulate, sensorimotor, and auditory areas showed increased GI. Structural- and tract-based spatial statistics changes were observed in anterior visual pathway, thalamo-cortical, and corticospinal tracts, and were correlated with education onset and global cognition in EB children. Reduced impairment in WM, increased CT and GI and its correlation with global cognitive functions in visually impaired children suggests cross-modal plasticity due to adaptive compensatory mechanism (as compared to SCs). Reduced CT and increased FA in thalamo-cortical areas in EB suggest synaptic pruning and alteration in WM integrity. In the visual cortical pathway, higher education and the development of blindness modify the morphology of brain areas and influence the probabilistic tractography in EB rather than LB.

Association of cognitive impairment with sleep quality, depression and cardiometabolic risk factors in individuals with type 2 diabetes mellitus: A cross sectional study.

AIM: The aim of this study was to evaluate the association of cognitive impairment with sleep quality, depression, and cardiometabolic risk factors among participants with type 2 diabetes mellitus. METHODS: Subjects underwent clinical interview to capture socio-demographic details, medical history, sleep quality, presence of depression, along with anthropometric and biochemical measurements. A detailed neuropsychological assessment [Montreal cognitive assessment scale (MoCA), Trail making A and B, Digit span, Spatial span, Letter Number Sequencing] was done. Cognitive impairment was defined as MoCA score of <23. RESULTS: Participants (n=250, 50% women, 63.6% middle-age) had a mean (±SD) age of 53.6 (±9.1) years and HbA1c of 55.1±6.8mmol/mol (7.2±0.6%). Cognitive impairment was present in 57 (22.8%) participants. In the middle-age subgroup, cognitive impairment was higher (23.9%) than those in the fourth decade (6.3%), but comparable (24.0%) to the older age (60-70years) individuals. Diabetes-related vascular complications [Odds ratio (95% CI) 2.03 (1.05, 3.94)]; hypertension [2.00 (1.04, 3.84)], depression [2.37 (1.24, 4.55)] and lower education [2.73 (1.42, 5.23)] had a significant association with cognitive impairment on multivariate logistic regression analysis. CONCLUSION: The high burden of cognitive impairment calls for an urgent need to establish longitudinal cohorts in midlife to understand this population's cognitive trajectories and see the influence of various bio-psychosocial variables.

Computational modeling suggests binding-induced expansion of Epsin disordered regions upon association with AP2.

Intrinsically disordered regions (IDRs) are prevalent in the eukaryotic proteome. Common functional roles of IDRs include forming flexible linkers or undergoing allosteric folding-upon-binding. Recent studies have suggested an additional functional role for IDRs: generating steric pressure on the plasma membrane during endocytosis, via molecular crowding. However, in order to accomplish useful functions, such crowding needs to be regulated in space (e.g., endocytic hotspots) and time (e.g., during vesicle formation). In this work, we explore binding-induced regulation of IDR steric volume. We simulate the IDRs of two proteins from Clathrin-mediated endocytosis (CME) to see if their conformational spaces are regulated via binding-induced expansion. Using Monte-Carlo computational modeling of excluded volumes, we generate large conformational ensembles (3 million) for the IDRs of Epsin and Eps15 and dock the conformers to the alpha subunit of Adaptor Protein 2 (AP2α), their CME binding partner. Our results show that as more molecules of AP2α are bound, the Epsin-derived ensemble shows a significant increase in global dimensions, measured as the radius of Gyration (RG) and the end-to-end distance (EED). Unlike Epsin, Eps15-derived conformers that permit AP2α binding at one motif were found to be more likely to accommodate binding of AP2α at other motifs, suggesting a tendency toward co-accessibility of binding motifs. Co-accessibility was not observed for any pair of binding motifs in Epsin. Thus, we speculate that the disordered regions of Epsin and Eps15 perform different roles during CME, with accessibility in Eps15 allowing it to act as a recruiter of AP2α molecules, while binding-induced expansion of the Epsin disordered region could impose steric pressure and remodel the plasma membrane during vesicle formation.

Pan-cancer analysis of transcripts encoding novel open-reading frames (nORFs) and their potential biological functions.

Uncharacterized and unannotated open-reading frames, which we refer to as novel open reading frames (nORFs), may sometimes encode peptides that remain unexplored for novel therapeutic opportunities. To our knowledge, no systematic identification and characterization of transcripts encoding nORFs or their translation products in cancer, or in any other physiological process has been performed. We use our curated nORFs database (nORFs.org), together with RNA-Seq data from The Cancer Genome Atlas (TCGA) and Genotype-Expression (GTEx) consortiums, to identify transcripts containing nORFs that are expressed frequently in cancer or matched normal tissue across 22 cancer types. We show nORFs are subject to extensive dysregulation at the transcript level in cancer tissue and that a small subset of nORFs are associated with overall patient survival, suggesting that nORFs may have prognostic value. We also show that nORF products can form protein-like structures with post-translational modifications. Finally, we perform in silico screening for inhibitors against nORF-encoded proteins that are disrupted in stomach and esophageal cancer, showing that they can potentially be targeted by inhibitors. We hope this work will guide and motivate future studies that perform in-depth characterization of nORF functions in cancer and other diseases.

Cognitive Performance and Neuro-Metabolites in HIV Using 3T Magnetic Resonance Spectroscopy: A Cross-Sectional Study from India.

BACKGROUND: Cognitive impairment in patients with human immunodeficiency virus (HIV) is associated with higher morbidity. The prevalence of the metabolite changes in the brain associated with cognitive impairment in anti-retroviral therapy naïve patients with HIV is unknown. OBJECTIVE: To estimate the prevalence of the neurometabolites associated with cognitive impairment in antiretroviral therapy (ART) naïve patients with HIV. METHODS: We conducted a cross-sectional study among ART naïve patients with HIV aged 18-50 years in a tertiary care center in India. Cognition was tested using the Post Graduate Institute battery of brain dysfunction across five domains; memory, attention-information processing, abstraction executive, complex perceptual, and simple motor skills. We assessed the total N-acetyl aspartyl (tNAA), creatine (tCr) and glutamate + glutamine (Glx) using 3T magnetic resonance spectroscopy. Cognitive impairment was defined as an impairment in ≥2 domains. RESULTS: Among 43 patients eligible for this study, the median age was 32 years (IQR 29, 40) and 30% were women. Median CD4 count and viral load were 317 cells/µL (IQR 157, 456) and 9.3 copies/ µL (IQR 1.4, 38), respectively. Impairment in at least one cognitive domain was present in 32 patients (74.4%). Impairment in simple motor skills and memory was present in 46.5% and 44% of patients, respectively. Cognitive impairment, defined by impairment in ≥2 domains, was found in 22 (51.2%) patients. There was a trend towards higher concentration of tNAA (7.3 vs. 7.0 mmol/kg), tGlx (9.1 vs. 8.2 mmol/kg), and tCr (5.5 vs. 5.2 mmol/kg) in the frontal lobe of patients with cognitive impairment vs. without cognitive impairment but it did not reach statistical significance (p>0.05 for all). There was no difference in the concentration of these metabolites in the two groups in the basal ganglia. CONCLUSION: There is a high prevalence of cognitive impairment in ART naïve patients with HIV. There is no difference in metabolites in patients with or without cognitive impairment. Further studies, with longitudinal follow-up are required to understand the underlying pathophysiological mechanisms.

Cortical thickness and gyrification index measuring cognition in Parkinson's disease.

OBJECTIVE: Cortical dynamics is driven by cortico-cortical connectivity and it characterizes cortical morphological features. These brain surface features complement volumetric changes and may offer improved understanding of disease pathophysiology. Hence, present study aims to investigate surface features; cortical thickness (CT) and gyrification index (GI) in Parkinson's disease (PD) patients of normal cognition (PD-CN), cognitively impaired patients with PD (PD-CI) in comparison with cognitively normal healthy controls (HC) to better elucidate cognition linked features in PD. METHOD: Anatomical MRI (3DT1) was carried out in 30 HC (56.53 ± 8.42 years), 30 PD-CN (58.8 ± 6.07 years), and 30 PD-CI (60.3 ± 6.43 years) subjects. Whole brain ROI based parcellation using Desikan-Killiany (DK-40) atlas followed by regional CT and GI differentiation [with 'age' and 'total intracranial volume' (TIV) correction], multiple linear regression (with 'age', 'TIV', and 'education' correction) with clinical variables, ROC analysis, and CT-GI correlation across the groups was used for data analysis. RESULTS: Widespread cortical thinning with regional GI reduction was evident in PD-CI with respect to other two groups (HC and PD-CN), and with absence of such alterations in PD-CN compared to HC. Frontal, parietal, and temporal CT/GI significantly correlated with cognition and presented classification abilities for cognitive state in PD. Mean regional CT and GI were found negatively correlated across groups with heterogeneous regions. CONCLUSION: Fronto-parietal and temporal regions suffer cognition associated cortical thinning and GI reduction. CT may serve better discriminator properties and may be more consistent than GI in studying cognition in PD. Heterogeneous surface dynamics across the groups may signify neuro-developmental alterations in PD.

Frontal lobe metabolic alterations characterizing Parkinson's disease cognitive impairment.

BACKGROUND AND PURPOSE: Diagnosis of Parkinson's disease (PD) cognitive impairment at early stages is challenging compared to the stage of PD dementia where functional impairment is apparent and easily diagnosed. Hence, to evaluate potential early stage cognitive biomarkers, we assessed frontal lobe metabolic alterations using in vivo multi-voxel proton magnetic resonance spectroscopic imaging (1H-MRSI). METHOD: Frontal metabolism was studied in patients with PD with normal cognition (PD-CN) (n = 26), with cognitive impairment (PD-CI) (n = 27), and healthy controls (HC) (n = 30) using a single slice (two-dimensional) 1H-MRSI at 3 T. The acquired spectra were post-processed distinctly for voxels corresponding to the bilateral middle/superior frontal gray matter (GM) and frontal white matter (WM) regions (delineated employing neuromorphometrics atlas) using the LC-Model software. RESULT: Significant (post hoc p < 0.016) reduction in the concentration of N-acetyl aspartate (NAA) in the middle and superior frontal GMs and total choline (tCho) and total creatine (tCr) in the frontal WM was observed in PD-CI compared to PD-CN and HC, while that in HC and PD-CN groups were comparable. The NAA and tCr/tCho metabolite concentrations showed significant (p < 0.05) positive correlations with cognitive test scores in the frontal GM and WM, respectively. The receiver operating curve (ROC) analysis revealed significant (p < 0.05) "area under curve" for NAA/tNAA in the frontal GM and tCho in the frontal WM. CONCLUSION: The frontal metabolic profile is altered in cognitively impaired PD compared with cognitively normal PD. Neuronal function loss (NAA), altered energy metabolism (Cr), and cholinergic (Cho) neural transmission are implicated in PD cognitive pathology. Frontal neuro-metabolism may promisingly serve as PD cognitive biomarker.

Identification of potential urine biomarkers in idiopathic parkinson's disease using NMR.

INTRODUCTION: Parkinson's disease (PD) is the most common neurodegenerative disease caused by the loss of dopamine chemicals resulting in urinary incontinence, gastrointestinal dysfunction, gait impairment and mitochondrial dysfunction. Study investigated urinary metabolic profiles of patients with idiopathic PD as compared to healthy controls (HC) to identify the potential biomarkers. METHODS: Urine samples were collected from 100 PD subjects and 50 HC using standard protocol. Metabolomic analyses were performed using high resolution nuclear magnetic resonance (NMR) spectroscopy. The integral values of 17 significant metabolites were estimated and concentration values were calculated, which were subjected to univariate and multivariate statistical analysis. RESULTS: We found significantly increased levels of ornithine, phenylalanine, isoleucine, ß-hydroxybutyrate, tyrosine and succinate in the urine of patients with PD in comparison with HC. These metabolites exhibited area under the curve greater than 0.60 on ROC curve analysis. We also observed a significant association between succinate concentration and UPDRS motor scores of PD. DISCUSSION: Metabolic pathway alterations were observed in aromatic amino acid metabolism, ketone bodies synthesis, branched chain amino acid metabolism and ornithine metabolism. Comprehensive metabolomic profiling revealed variations in urinary signatures associated with severity of idiopathic PD. This profiling relies on non-invasive sampling and is complementary to existing clinical modalities.

Reliability and Validity of a Physical Activity Questionnaire for Indian Children and Adolescents.

BACKGROUND: In low- and middle-income countries, sedentary behavior is widely prevalent in the young. Reliable and valid instruments are essential for evaluating sedentary behavior and physical activity in children and adolescents. OBJECTIVE: To evaluate the reliability and validity of an easy to use physical activity questionnaire for children and adolescents from India. STUDY DESIGN: Evaluation of a questionnaire tool. PARTICIPANTS: 104 children and adolescents belonging to the age group of 10-17 years were selected using a purposive sampling technique. METHODS: The Madras Diabetes Research Foundation - Physical Activity Questionnaire for Children and Adolescents [MPAQ(c)] was used to assess the various dimensions of physical activity. Physical activity was also objectively assessed using accelerometer worn around the waist for five complete days. The baseline administration of MPAQ(c) was done between November and December, 2017. Reliability of MPAQ was assessed by repeat administration after 2 weeks for upto a month later. Validity of MPAQ(c) was measured against accelerometer using Spearman's correlation and Bland and Altman agreements. RESULTS: Test-retest reliability of the questionnaire revealed good agreement (ICC: 0.77 min/wk). Correlation coefficients (95% CI) for sedentary behavior and moderate to vigorous physical activity for MPAQ(c) against accelerometer were 0.52 (0.36, 0.64) and 0.41 (0.23, 0.55), respectively indicating moderate correlation. Good agreement was present between MPAQ(c) and accelerometer for sedentary behavior [mean bias = -4.9 (±2SD -197.1 to 187.3) min/d]. CONCLUSIONS: MPAQ(c) is a valid and reliable instrument for evaluating physical activity in Indian children aged 10-17 years.

Quantitative metabolomics of saliva using proton NMR spectroscopy in patients with Parkinson's disease and healthy controls.

INTRODUCTION: Parkinson's disease (PD) is a multisystem disorder of unknown etiology, highlights a broad array of symptoms and pathological features influencing organs throughout the body. The metabolic profile of saliva in patients with PD may be influenced by malabsorption in the gastroenteric tract, neurodegeneration, and mitochondrial dysfunction. In the present study, we apply a powerful NMR metabolomics approach for biomarker identification in PD using saliva, a non-invasive bio-fluid. METHODS: Metabolic profiling of saliva were studied in patients with PD (n = 76) and healthy controls (HC, n = 37) were analyzed and differentiated PD from HC. A total of 40 metabolites including aromatic amino acids, short-chain fatty acids, branched chain amino acids, taurine, and N-acetylglutamate were identified. Spectral binned data and concentration of metabolites were estimated for analysis. RESULTS: Increased concentration of phenylalanine, tyrosine, histidine, glycine, acetoacetate, taurine, TMAO, GABA, N-acetylglutamate, acetoin, acetate, alanine, fucose, propionate, isoleucine, and valine were observed in PD as compared to HC. Further, subgroup analysis among early PD, advanced PD, and HC groups, revealed increased metabolite concentration in early PD group as compared to advanced PD and HC group. DISCUSSION: Analysis revealed potential biomarkers and their involvement in amino acid metabolism, energy metabolism, neurotransmitters metabolism, and microflora system. Patients with early PD exhibited higher metabolite concentration as compared to advanced PD group which might be associated with dopaminergic treatment. CONCLUSION: The results of our data indicate that patients with PD might be characterized by metabolic imbalances like gut microflora system, energy metabolites, and neurotransmitters which may contribute to the PD pathogenesis.

Transcompp: understanding phenotypic plasticity by estimating Markov transition rates for cell state transitions.

MOTIVATION: Gradual population-level changes in tissues can be driven by stochastic plasticity, meaning rare stochastic transitions of single-cell phenotype. Quantifying the rates of these stochastic transitions requires time-intensive experiments, and analysis is generally confounded by simultaneous bidirectional transitions and asymmetric proliferation kinetics. To quantify cellular plasticity, we developed Transcompp (Transition Rate ANalysis of Single Cells to Observe and Measure Phenotypic Plasticity), a Markov modeling algorithm that uses optimization and resampling to compute best-fit rates and statistical intervals for stochastic cell-state transitions. RESULTS: We applied Transcompp to time-series datasets in which purified subpopulations of stem-like or non-stem cancer cells were exposed to various cell culture environments, and allowed to re-equilibrate spontaneously over time. Results revealed that commonly used cell culture reagents hydrocortisone and cholera toxin shifted the cell population equilibrium toward stem-like or non-stem states, respectively, in the basal-like breast cancer cell line MCF10CA1a. In addition, applying Transcompp to patient-derived cells showed that transition rates computed from short-term experiments could predict long-term trajectories and equilibrium convergence of the cultured cell population. AVAILABILITY AND IMPLEMENTATION: Freely available for download at http://github.com/nsuhasj/Transcompp. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

De novo ensemble modeling suggests that AP2-binding to disordered regions can increase steric volume of Epsin but not Eps15.

Proteins with intrinsically disordered regions (IDRs) have large hydrodynamic radii, compared with globular proteins of equivalent weight. Recent experiments showed that IDRs with large radii can create steric pressure to drive membrane curvature during Clathrin-mediated endocytosis (CME). Epsin and Eps15 are two CME proteins with IDRs that contain multiple motifs for binding the adaptor protein AP2, but the impact of AP2-binding on these IDRs is unknown. Some IDRs acquire binding-induced function by forming a folded quaternary structure, but we hypothesize that the IDRs of Epsin and/or Eps15 acquire binding-induced function by increasing their steric volume. We explore this hypothesis in silico by generating conformational ensembles of the IDRs of Epsin (4 million structures) or Eps15 (3 million structures), then estimating the impact of AP2-binding on Radius of Gyration (RG). Results show that the ensemble of Epsin IDR conformations that accommodate AP2 binding has a right-shifted distribution of RG (larger radii) than the unbound Epsin ensemble. In contrast, the ensemble of Eps15 IDR conformations has comparable RG distribution between AP2-bound and unbound. We speculate that AP2 triggers the Epsin IDR to function through binding-induced-expansion, which could increase steric pressure and membrane bending during CME.

Effect of Doxorubicin on Squamous Cell Carcinoma of Skin: Assessment by MRI Relaxometry at 4.7T.

Squamous cell carcinoma (SCC) of skin has no standard treatment regimen, resulting in recurrences/metastasis. Although, doxorubicin (Dox), an anthracycline antibiotic has demonstrated some degree of efficacy. Molecular imaging can help in assessment of treatment response and prognosis of SCCs. MRI data showed that spin-spin relaxation (T2) time was longer (138 ± 2 msec) in Dox treated Test-II and there is no significant difference in spin-lattice relaxation (T1) time with respective controls. These findings further corroborated with the histology, proliferation index, apoptotic index, and HMGA1 protein expression. Thus, MRI may be a useful tool for monitoring treatment response noninvasively for skin tumor prognosis.