Biology subjects

Viswanathan, M.

Publications and source records attributed to Viswanathan, M..

5 recordsLinked to original sources

bioRxiv2024

A Denoising Convolutional Autoencoder for SNR Enhancement in Chemical Exchange Saturation Transfer imaging: (DCAE-CEST)

PurposeTo develop a SNR enhancement method for chemical exchange saturation transfer (CEST) imaging using a denoising convolutional autoencoder (DCAE), and compare its performance with state-of-the-art denoising methods. MethodThe DCAE-CEST model encompasses an encoder and a decoder network. The encoder learns features from the input CEST Z-spectrum via a series of 1D convolutions, nonlinearity applications and pooling. Subsequently, the decoder reconstructs an output denoised Z-spectrum using a series of up-sampling and convolution layers. The DCAE-CEST model underwent multistage training in an environment constrained by Kullback-Leibler divergence, while ensuring data adaptability through context learning using Principal Component Analysis processed Z-spectrum as a reference. The model was trained using simulated Z-spectra, and its performance was evaluated using both simulated data and in-vivo data from an animal tumor model. Maps of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects were quantified using the multiple-pool Lorentzian fit, along with an apparent exchange-dependent relaxation metric. ResultsIn digital phantom experiments, the DCAE-CEST method exhibited superior performance, surpassing existing denoising techniques, as indicated by the peak SNR and Structural Similarity Index. Additionally, in vivo data further confirms the effectiveness of the DCAE-CEST in denoising the APT and NOE maps when compared to other methods. While no significant difference was observed in APT between tumors and normal tissues, there was a significant difference in NOE, consistent with previous findings. ConclusionThe DCAE-CEST can learn the most important features of the CEST Z-spectrum and provide the most effective denoising solution compared to other methods.

bioengineering↗

bioRxiv2022

Common and distinct genetic architecture of age at diagnosis of diabetes in South Indian and European populations

South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesised that studying the genomics of age of onset in these populations may give insight into earlier age at onset of T2D among individuals of South Asian descent. We conducted a meta-analysis of GWAS of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and Asian Indians. We identified two signals near the TCF7L2 and CDKAL1 associated with age at onset of T2D. The strongest genome-wide significant variants at chromosome 10q25.3 in TCF7L2 (lead SNP rs7903146; p = 2.4 x10-12; p-het =0.01; Beta = -0.436; SE = 0.02) and chromosome 6 p22.3 in CDKAL1 (rs9368219; p = 2.29 x10-8; p-het =0.007; Beta = -0.053; SE=0.01) were directionally consistent across ethnic groups and present at similar frequencies, however both loci harboured additional independent signals that were only present in the South Asian cohorts. A genome wide signal was also obtained at chromosome 10q26.12 in WDR11 (rs3011366; p = 2.4 x10-8; p-het =0.25; Beta = 1.44; SE=0.25) specifically in the South Asian Indian cohorts. Our study estimated 17% of heritability (h2) for age onset of T2D among South Indians; higher than the 5% heritability we observed in Europeans suggesting different genetic architectures between these populations. We further estimated the Asian Indian genome-wide polygenic risk score for T2D risk and identified that the variance explained by the Indian specific polygenic risk score (PRS) for age at onset of T2D is substantially higher (2%) in an independent cohort of Asian Indians compared to that seen in White Europeans (<0.1%). This reveals that although variants do exist that are shared between the two population there are also genetic disparities of age onset of T2D between the ethnicities. Author SummaryRecent large multi-ancestry genome-wide meta-analyses have identified over 277 genetic loci associated with type 2 diabetes (T2D). Most association studies for T2D have focused on populations of European ancestry, and the specific genetic architecture of T2D in the South Asian population has not been extensively investigated. Increasing evidence indicates that the prevalence of T2D is higher in South Asians with a strikingly earlier age at diagnosis when compared to Europeans. Genome-wide association studies (GWAS) on age at age at diagnosis of T2D are limited and can help elucidate underlying mechanisms. We conducted the largest meta-analysis to date of genome-wide association studies of age at diagnosis as a surrogate for age of onset of T2D in South Indians and Europeans. Our trans-ancestry meta-analysis identified genetic loci near TCF7L2 and CDKAL1 with substantial ethnic heterogeneity in both allele frequencies and effect sizes in early diagnosis with T2D. Two novel variants near TCF7L2 (rs570193324) and CDKAL1 (rs143316471) were associated with age of diagnosis of T2D only in South Indians and were present at much lower frequency in the European populations. Heritability estimates for age of onset were much stronger in Asian Indians compared to Europeans and a polygenic risk score was constructed using a South Indians, which explained about 2% trait variance compared to European ancestry (<0.1%). Our novel findings provide a better understanding of ethnic differences in the age at onset of T2D and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.

genetics↗

bioRxiv2022

Bayesian multi-level calibration of a process-based maize phenology model

Plant phenology models are important components in process-based crop models, which are used to assess the impact of climate change on food production. For reliable model predictions, parameters in phenology models have to be accurately known. They are usually estimated by calibrating the model to observations. However, at regional scales in which different cultivars of a crop species may be grown, not accounting for inherent differences in phenological development between cultivars in the model and the presence of model deficits lead to inaccurate parameter estimates. To account for inherent differences between cultivars and to identify model deficits, we used a Bayesian multi-level approach to calibrate a phenology model (SPASS) to observations of silage maize grown across Germany between 2009 and 2017. We evaluated four multi-level models of increasing complexity, where we accounted for different combinations of ecological, weather, and year effects, as well as the hierarchical classification of cultivars nested within ripening groups of the maize species. We compared the calibration quality from this approach to the commonly used pooled approach in which none of these factors are considered. Our approach proved successful in improving calibration quality by incorporating the hierarchical classification of cultivars within ripening groups of maize. Our findings have implications for regional model calibration and data-gathering studies, since it emphasizes that ripening group and cultivar information is essential. Furthermore, we found that if this information is not available, at least weather, ecological regions and year effects should be taken into account. Our results can facilitate model improvement studies since we identified possible model limitations related to temperature effects in the reproductive (post-flowering) phase and to soil-moisture. We demonstrate that Bayesian multi-level calibration of a phenology model facilitates the incorporation of hierarchical dependencies and the identification of model limitations. Our approach can be extended to full crop models at different spatial scales.

plant biology↗

bioRxiv2022

Neuronopathic GBA1 L444P mutation accelerates glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

The most common genetic risk factor for Parkinsons disease (PD) is heterozygous mutations in the GBA1 gene which encodes for the lysosomal enzyme, glucocerebrosidase (GCase). GCase impairments are associated with an accumulation of abnormal -synuclein (-syn) called Lewy pathology, which characterizes PD. PD patients heterozygous for the GBA1 L444P mutation (GBA1+/L444P) have a 5.6-fold increased risk of cognitive impairments. In this study, we used GBA1+/L444P mice to determine the effects of this severe GBA1 mutation on lipid metabolism, expression of synaptic proteins, behavior, and -syn inclusion formation. GBA1+/L444P mice showed reduced GCase activity in limbic brain regions and expressed lower levels of hippocampal vGLUT1 compared to wildtype (GBA1+/+) mice. GBA+/L444P mice also demonstrated impaired fear conditioning, but no motor deficits. We show, using mass spectrometry, that mutant GCase and age increased levels of glucosylsphingosine (GlcSph), but not glucosylceramide (GlcCer), in the brains and serum of GBA1+/L444P mice. Aged GBA1+/+ mice also showed increased levels of GlcSph, and decreased GlcCer. To model disease pathology, templated -syn pathology was used. -Syn inclusions were increased in the hippocampus of GBA1+/L444P mice compared to GBA1+/+ mice, but not in the cortex, or substantia nigra pars compacta (SNc). Pathologic -syn did not cause a loss of dopamine neurons in the SNc. Treatment with a GlcCer synthase inhibitor prevented loss of cortical -syn inclusions, but not loss of dopamine neurons. Overall, these data suggest the critical importance to evaluate the contribution of hippocampal pathologic -syn and brain and serum glucosylsphingosine in synucleinopathies. SIGNIFICANCE STATEMENTSynucleinopathies, such as Parkinsons disease (PD) and Dementia with Lewy bodies (DLB), are both pathologically characterized by abnormal -synuclein (-syn). Mutant GBA1 is a risk factor for both PD and DLB where a reduction of glucocerebrosidase (GCase) activity is seen. Collectively, this indicates the significance of evaluating mutant GCase in synucleinopathies. Our data suggest the critical importance to evaluate the contribution of hippocampal pathologic -syn and brain and serum glucosylsphingosine (GlcSph) accumulation in synucleinopathies. Moreover, these pathologic outcomes may contribute to the nonmotor symptoms clinically observed in PD and DLB. Our findings highlight the importance of GlcSph as a relevant biomarker for future therapeutics.

neuroscience↗

bioRxiv2020

Circulating adiponectin mediates the association between omentin gene polymorphism and cardiometabolic health in Asian Indians

BackgroundPlasma omentin levels have been shown to be associated with circulating adiponectin concentrations and cardiometabolic disease-related outcomes. However, the findings have been inconsistent due to high level of confounding. In this study, we aim to examine the association of omentin gene polymorphism with plasma adiponectin levels and cardiometabolic health status using a genetic approach, which is less prone to confounding, and investigate whether these associations are modified by lifestyle factors such as diet and physical activity. MethodsThe study included 945 normal glucose tolerant and 941 unrelated individuals with type 2 diabetes randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Study participants were further classified into cardiometabolically healthy and unhealthy, where cardiometabolically healthy were those without hypertension, diabetes, and dyslipidemia. Fasting serum adiponectin levels were measured by radioimmunoassay. The A326T (rs2274907) single nucleotide polymorphism (SNP) in the exon 4 of the omentin gene was screened by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. ResultsThe A allele of the omentin SNP was significantly associated with lower adiponectin concentrations after adjusting for age, sex, body mass index (BMI), waist circumference (WC) and cardiometabolic health status (p=1.90 x 10-47). There was also a significant association between circulating adiponectin concentrations and cardiometabolic health status after adjusting for age, sex, BMI, WC and Omentin SNP (p=7.47x10-10). However, after adjusting for age, sex, BMI, WC and adiponectin levels, the association of A allele with cardiometabolic health status disappeared (p=0.79) suggesting that adiponectin serves as a mediator of the association between omentin SNP and cardiometabolic health status. There were no significant interactions between the SNP and dietary factors on adiponectin levels and cardiometabolic health status (p>0.25, for all comparisons). ConclusionsOur findings show that adiponectin might function as a mechanistic link between omentin SNP and increased risk of cardiometabolic diseases independent of common and central obesity in this Asian Indian population. Further studies are required to confirm the molecular mechanisms involved in this triangular relationship between omentin gene, adiponectin and cardiometabolic diseases.

genetics↗