Biology subjects

Ray, S.

Publications and source records attributed to Ray, S..

142 records · Page 8Linked to original sources

bioRxiv2019

Trophoblast paracrine signaling regulates placental hematoendothelial niche

The placenta acts as a major organ for hematopoiesis. It is believed that placental hematopoietic stem and progenitor cells (HSPCs) migrate to the fetal liver to ensure optimum hematopoiesis in the developing embryo. The labyrinth vasculature in a mid-gestation mouse placenta provides a niche for the definitive hematopoietic stem cell (HSC) generation and expansion. It has been proposed that these processes are regulated by a host of paracrine factors secreted by trophoblast giant cells (TGCs) at the maternal-fetal interface. However, the molecular mechanism by which the TGCs regulate the hematoendothelial niche in a developing placenta is yet to be defined. Using a TGC-specific Gata2 and Gata3 double knockout mouse model, we show that the loss of GATA2 and GATA3 at the TGC layer leads to fetal growth retardation and embryonic death due to disruptions in the delicate hematopoietic-angiogenic balance in the developing placenta. Using single-cell RNA-Seq analyses, we also show that the loss of GATA factors in the TGCs results in the loss of HSC population within the placental labyrinth and is associated with defective placental angiogenesis. Interestingly, we also found that this TGC-specific GATA factor-loss leads to impaired differentiation and distribution of trophoblast progenitor cells. Our study helps to define the GATA-dependent non-autonomous signaling mechanisms of the primary parietal trophoblast giant cells by which it regulates the delicate hematopoietic-angiogenic balance in the developing placenta.

developmental biology↗

bioRxiv2019

Comparison of tuning properties of gamma and high-gamma power in local field potential (LFP) versus electrocorticogram (ECoG) in visual cortex

Electrocorticogram (ECoG), obtained from macroelectrodes placed on the cortex, is typically used in drug-resistant epilepsy patients, and is increasingly being used to study cognition in humans. These studies often use power in gamma (30-70 Hz) or high-gamma (>80 Hz) ranges to make inferences about neural processing. However, while the stimulus tuning properties of gamma/high-gamma power have been well characterized in local field potential (LFP; obtained from microelectrodes), analogous characterization has not been done for ECoG. Using a hybrid array containing both micro and ECoG electrodes implanted in the primary visual cortex of two female macaques, we compared the stimulus tuning preferences of gamma/high-gamma power in LFP versus ECoG and found them to be surprisingly similar. High-gamma power, thought to index the average firing rate around the electrode, was highest for the smallest stimulus (0.3{degrees} radius), and decreased with increasing size in both LFP and ECoG, suggesting local origins of both signals. Further, gamma oscillations were similarly tuned in LFP and ECoG to stimulus orientation, contrast and spatial frequency. This tuning was significantly weaker in electroencephalogram (EEG), suggesting that ECoG is more like LFP than EEG. Overall, our results validate the use of ECoG in clinical and basic cognitive research.

neuroscience↗

bioRxiv2019

CODC: A copula based model to identify differential coexpression.

Differential coexpression has recently emerged as a new way to establish a fundamental difference in expression pattern among a group of genes between two populations. Earlier methods used some scoring techniques to detect changes in correlation patterns of a gene pair in two conditions. However, modeling differential coexpression by mean of finding differences in the dependence structure of the gene pair has hitherto not been carried out. We exploit a copula-based framework to model differential coexpression between gene pair in two different conditions. The Copula is used to model the dependency between expression profiles of a gene pair. For a gene pair, the distance between two joint distributions produced by copula is served as differential coexpression. We used five pan-cancer TCGA RNA-Seq data to evaluate the model which outperforms the existing state-of-the-art. Moreover, the proposed model can detect a mild change in the coexpression pattern across two conditions. For noisy expression data, the proposed method performs well because of the popular scale-invariant property of copula. Additionally, we have identified differentially coexpressed modules by applying hierarchical clustering on the distance matrix. The identified modules are analyzed through Gene Ontology terms and KEGG pathway enrichment analysis.

bioinformatics↗

bioRxiv2019

Fast gamma oscillations weaken with age in healthy elderly in human EEG

Gamma rhythms ([~]20-70 Hz) have been reported to be abnormal in mental disorders such as autism and schizophrenia in humans, and Alzheimers disease (AD) models in rodents. However, the effect of normal aging on these oscillations is not known, especially for elderly subjects (>49 years) for which AD is most prevalent. In a first large-scale (236 subjects; 104 females) electroencephalogram (EEG) study on gamma oscillations on elderly subjects (aged 50-88 years), we presented full-screen Cartesian gratings that induced two distinct gamma oscillations (slow: 20-34 Hz and fast: 36-66 Hz). Power and centre frequency significantly decreased with age for both slow and fast gamma, but not alpha (8-12 Hz). Reduction was more salient for fast gamma than slow. These results were independent of microsaccades and pupillary reactivity to stimulus, as well as variations in power spectral density with age. Steady-state visual evoked potentials (SSVEPs) also reduced with age. These results are crucial first steps towards using gamma/SSVEPs as biomarkers of cognitive decline in elderly.\n\nSignificance statementNo study in humans has examined visual narrow-band gamma oscillations with healthy aging in elderly subjects. In a first large-scale (236 subjects) EEG study on stimulus-induced narrow band gamma in cognitively normal elderly (>49 years) humans, we show that both power and centre frequency of slow and fast gamma (20-34 Hz and 36-66 Hz respectively) decrease with age, but alpha power does not. Steady-state visual evoked potential (SSVEPs) in gamma range also decrease with age. Any EEG-based biomarker is accessible and affordable to patients of a wide socio-economic spectrum. Our results are important steps for developing such screening/diagnostic tests for aging-related diseases, like Alzheimers disease.

neuroscience↗

bioRxiv2019

A bacterial resolvase first exploits, then constrains intrinsic dynamics of the Holliday junction to direct recombination

Homologous recombination forms and resolves an entangled DNA Holliday Junction (HJ) critical for achieving genome repair. We use single-molecule observation and cluster analysis to probe how prototypic bacterial resolvase RuvC selects two of four possible HJ strands for cleavage. RuvC first exploits, then constrains intrinsic HJ isomer exchange and branch migration dynamics to direct cleavage toward only a desired, catalytically competent HJ conformation, thus controlling recombination products.

biophysics↗

bioRxiv2019

Feedback inhibition and its control in an insect olfactory circuit

Inhibitory neurons play critical roles in regulating and shaping olfactory responses in vertebrates and invertebrates. In insects, these roles are performed by relatively few neurons, which can be interrogated efficiently, revealing fundamental principles of olfactory coding. Here, with electrophysiological recordings from the locust and a large-scale biophysical model, we analyzed the properties and functions of GGN, a unique giant GABAergic neuron that plays a central role in structuring olfactory codes in the locust mushroom body. Analysis of our in vivo recordings and simulations of our model of the olfactory network suggests that GGN extends the dynamic range of KCs, and leads us to predict the existence of a yet undiscovered olfactory pathway. Our analysis of GGNs intrinsic properties, inputs, and outputs, in vivo and in silico, reveals basic new features of this critical neuron and the olfactory network that surrounds it.

neuroscience↗

bioRxiv2019

Liquid-liquid phase separation and liquid-to-solid transition mediate α-synuclein amyloid fibril containing hydrogel formation

-Synuclein (-Syn) aggregation and amyloid formation is directly linked with Parkinsons disease (PD) pathogenesis. However, the early events involved in this process remain unclear. Here, using in vitro reconstitution and cellular model, we show that liquid-liquid phase separation (LLPS) of -Syn precedes its aggregation. In particular, in vitro generated -Syn liquid-like droplets eventually undergo a liquid-to-solid transition and form amyloid-hydrogel containing oligomers and fibrillar species. Factors known to aggravate -Syn aggregation such as low pH, phosphomimic substitution, and familial PD mutation also promote -Syn LLPS and its subsequent maturation. We further demonstrate -Syn liquid droplet formation in cells, under oxidative stress. These cellular -Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. The present work provides detailed insights into the phase separation behavior of natively unstructured -Syn and its conversion to a disease-associated aggregated state, which is highly relevant in PD pathogenesis.

neuroscience↗

bioRxiv2018

Arterial carboxyhaemoglobin levels in children admitted to PICU: a retrospective observational study

While carbon monoxide (CO) is considered toxic, low levels of endogenously produced CO are protective against cellular injury induced by oxidative stress. Carboxyhaemoglobin (COHb) levels have been associated with outcomes in critically ill adults. We aimed to describe the distribution of carboxyhaemoglobin in critically ill children and the relationship of these levels with clinical outcomes. This retrospective observational study was conducted at a large tertiary paediatric intensive care unit (PICU). We included all children admitted to the PICU over a two-year period who underwent arterial blood gas analysis. We measured the following: Population and age-related differences in COHb distribution; (ii) Change in COHb over the first week of admission using a multi-level linear regression analysis; (ii) Uni- and multivariable relationships between COHb and length of ventilation and PICU survival. Arterial COHb levels were available for 559/2029 admissions. The median COHb level was 1.20% (IQR 1.00-1.60%). Younger children had significantly higher COHb levels (p-value <2 x 10-16). Maximum Carboxyhaemoglobin was associated with survival 1.67 (95% CI 1.01-2.57, p-value=0.02) and length of ventilation (odds ratio 5.20, 95% CI 3.07-7.30, p-value 1.8 x 10-6) following multi-variable analysis. First measured and minimum COHb values were weakly associated with length of ventilation, but not survival. In conclusion, children have increased COHb levels in critical illness, which are greater in younger children. Higher COHb levels are associated with longer length of ventilation and death in PICU. This is likely to reflect increased oxidative stress.

physiology↗

bioRxiv2018

millepattes micropeptides are an ancient developmental switch required for embryonic patterning

Small open reading frames (smORFs) that code for \"micropeptides\" (10-100 amino acids) exhibit remarkable evolutionary complexity. Conserved micropeptides encoded by the millepattes (mlpt) gene are essential in Tribolium for embryogenesis but in Drosophila, function only in leg and cuticle differentiation. We find that a module identified in Drosophila trichome patterning, comprising Mlpt, UBR3, and Shaven-baby (Svb), coordinates early embryo patterning in several insect orders. Intriguingly, Mlpt segmentation function can be re-awakened in the Drosophila blastoderm, demonstrating the potency of an ancestral developmental switch retained despite evolving embryonic patterning modes. smORFs like millepattes thus illustrate plasticity of micropeptide functions despite constraints of essential genetic networks.\n\nOne sentence summaryA module comprising the small ORFs mlpt/pri/tal, the transcription factor Svb, and the ubiquitin ligase UBR3, possesses an ancestral function in insect embryo patterning which is lost in flies but reactivated when Svb expression is restored.

developmental biology↗

bioRxiv2017

Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations

The therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free-energy calculations to predict how kinase mutations modulate inhibitor affinities to Abl, a major target in chronic myelogenous leukemia (CML). We find these calculations can achieve useful accuracy in predicting resistance for a set of eight FDA-approved kinase inhibitors across 144 clinically-identified point mutations, achieving a root mean square error in binding free energy changes of [Formula] kcal/mol (95% confidence interval) and correctly classifying mutations as resistant or susceptible with [Formula] accuracy. Since these calculations are fast on modern GPUs, this benchmark establishes the potential for physical modeling to collaboratively support the rapid assessment and anticipation of the potential for patient mutations to affect drug potency in clinical applications.

cancer biology↗

bioRxiv2017

Cross talk between photo-pigments and graphene electron cloud - Designing a biodiode

We report emergence of a new electrical material by growing photosynthetic biofilm on a Dirac material, graphene. The material showed new conducting as well as semiconducting properties. Frequency dependent capacitive spectra further indicated presence of electrical isosbestic points(at 0.8 and 9MHz), implying two state dieletric transitions at critical frequencies. A notable reult was a Schottky diode like behavior in the IV curve. Voltage dependent conductance with conductance peaks near the Schottky diode threshold was observed. We obtained facilitated growth of photosynthetic biofilm in presence of graphene. Lastly higher bacterial metabolism was seen in graphene incorporated biofilm. For this zero band gap Dirac material this can only be interpreted as coupling of the electron transport chain of the bacterial biofilm and the graphene electron cloud.

biophysics↗

bioRxiv2017

Non-canonical circadian oscillations in Drosophila S2 cells drive gene-expression cycles coupled to metabolic oscillations

Circadian rhythms are cell-autonomous biological oscillations with a period of about 24 hours. Current models propose that transcriptional feedback loops are the principal mechanism for the generation of circadian oscillations. In these models, Drosophila S2 cells are generally regarded as non-rhythmic cells, as they do not express several canonical circadian components. Using an unbiased multi-omics approach, we made the surprising discovery that Drosophila S2 cells do in fact display widespread daily rhythms. Transcriptomics and proteomics analyses revealed that hundreds of genes and their products are rhythmically expressed in a 24-hour cycle. Metabolomics analyses extended these findings and illustrated that central carbon metabolism and amino acid metabolism are the main pathways regulated in a rhythmic fashion. We thus demonstrate that daily genome-wide oscillations, coupled to metabolic cycles, take place in eukaryotic cells without the contribution of known circadian regulators.

systems biology↗

bioRxiv2017

Switchable amplification of fluoresence from a photosynthetic microbe

One known attribute of the photosynthetic apparatus is photon capture and generation of metabolic energy. The thermodynamic implications of fluorescence, invariably associated with the photosynthetic components is however poorly understood. In this paper we report a density dependent amplification of such fluorescence which can be interpreted as a thermodynamic strategy of controlled energy release by the cell. We show in support of this hypothesis that prolonged photo-exitation of cell free extract of Rhodobacter capsulatus SB1003 at 395 nm, induces fluorescence emission amplifying with time as long as the fluorophore density is above a critical level. The fact that the amplification disappears at low temperature and at dilute condition, is in accordance with the thermodynamic interpretation that energy is released as per requirement. Live cell imaging is also validation of the phenomenon even at the cellular level. Single cells of Rhodobacter capsulatus SB1003 shows time dependent loss of fluorescence, the process being reversed for cellular clusters. To explain the mechanism of this bistable fluorescence (F) amplification, variation of the scale free kinetic constant k=1/F (dF/dt) is studied at varying temperatures in presence and absence of static magnetic field. The sign of k shifts from positive to negative if T is lowered or if the system is diluted. But at low T, k again switches from negative to positive value, if static magnetic field is applied. The chain of events can be explained by a simple model assuming excretion of a porphyrin by the microbe and possible photon dependent aggregation behavior of such porphyrin complex, differential temperature and magnetic field sensitivity of the monomeric or aggregated forms of porphyrin being reported earlier.

biophysics↗

bioRxiv2017

Light Amplification By Biofilm And Its Polarization Dependence

We report amplified, transmitted light intensity, compared to input, when photosynthetic biofilms were placed in the path of Rayleigh scattered, monochromatic light. Enhancement spectrum shows peak at around 505 nm, which corresponds to the pore wall thickness in biofilm ultra-structure, suggesting role of resonant Mie scattering. Enhancement factors differed when biofilms from different stages of growth were used. Enhancement factors were found to depend on the nature of Rayleigh scattering liquid. Polarizing Rayleigh scattered light by the use of polarizers affected the percentage of enhancement. Amplified output is achievable with constructive interference arising out of coherent forward light scattering, a theoretically predicted outcome of Anderson localization of photons. Possible uses of photosynthetic biofilms in organic material based photonic devices have been discussed.

bioengineering↗

bioRxiv2017

Bistability In Fluorescence From A Purple Non-Sulfur Bacteria

Bistable optical emission has been observed for photosynthetic purple non-sulfur bacteria Rhodobacter capsulatus SB1003. The microbes respond to UV excitation (at 395nm) in a bifurcating way one branch corresponding to increase and the other corresponding to diminishing fluorescent emission in the range 590-685nm.The switching between such bifurcating branches can be observed when parameters like concentration, temperature are varied or static magnetic field is applied. Thus switching from amplification to reduction occurs if fluorophore concentration lowered. Again if temperature is lowered a steady quenching (instead of amplification) of fluorescence is observed. However presence of magnetic field of the order of 0.5 T reverts this and once again the systems resumes its fluoresence amplifying state. We propose that aggregation of bacterial porphyrin and regulation of such aggregation by photon excitation may explain this bistablity. Possible ecological implication of the photosynthetic bistability is suggested.

systems biology↗

bioRxiv2017

Emerging Electrical Properties of Graphene incorporated Photosynthetic Biofilms

We report emergence of a new electrical material by growing photosynthetic biofilm on a Dirac material, graphene. The material showed new conducting as well as semiconducting properties. Frequency dependent capacitive spectra further indicated presence of electrical isosbestic points(at 0.8 and 9MHz), implying two state dieletric transitions at critical frequencies. A notable reult was a Schottky diode like behavior in the IV curve. Voltage dependent conductance with conductance peaks near the Schottky diode threshold was observed. We obtained facilitated growth of photosynthetic biofilm in presence of graphene. Lastly higher bacterial metabolism i was seen in the biofilm in contact with graphene as compared to its normal growth condition. For this zero band gap Dirac material this can only be interpreted as coupling of the electron transport chain of the bacterial biofilm and the graphene electron cloud.

biophysics↗