Bistability versus Bimodal Distributions in Gene Regulatory Processes from Population Balance

In recent times, stochastic treatments of gene regulatory processes have appeared in the literature in which a cell exposed to a signaling molecule in its environment triggers the synthesis of a specific protein through a network of intracellular reactions. The stochastic nature of this process leads to a distribution of protein levels in a population of cells as determined by a Fokker-Planck equation. Often instability occurs as a consequence of two (stable) steady state protein levels, one at the low end representing the “off” state, and the other at the high end representing the “on” state for a given concentration of the signaling molecule within a suitable range. A consequence of such bistability has been the appearance of bimodal distributions indicating two different populations, one in the “off” state and the other in the “on” state. The bimodal distribution can come about from stochastic analysis of a single cell. However, the concerted action of the population altering the extracellular concentration in the environment of individual cells and hence their behavior can only be accomplished by an appropriate population balance model which accounts for the reciprocal effects of interaction between the population and its environment. In this study, we show how to formulate a population balance model in which stochastic gene expression in individual cells is incorporated. Interestingly, the simulation of the model shows that bistability is neither sufficient nor necessary for bimodal distributions in a population. The original notion of linking bistability with bimodal distribution from single cell stochastic model is therefore only a special consequence of a population balance model

'I am on treatment since 5 months but I have not received any money': coverage, delays and implementation challenges of 'Direct Benefit Transfer' for tuberculosis patients - a mixed-methods study from South India.

Background: In March 2018, the Government of India launched a direct benefit transfer (DBT) scheme to provide nutritional support for all tuberculosis (TB) patients in line with END TB strategy. Here, the money (@INR 500 [~8 USD] per month) is deposited electronically into the bank accounts of beneficiaries. To avail the benefit, patients are to be notified in NIKSHAY (web-based notification portal of India's national TB programme) and provide bank account details. Once these details are entered into NIKSHAY, checked and approved by the TB programme officials, it is sent to the public financial management system (PFMS) portal for further processing and payment. Objectives: To assess the coverage and implementation barriers of DBT among TB patients notified during April-June 2018 and residing in Dakshina Kannada, a district in South India. Methods: This was a convergent mixed-methods study involving cohort analysis of patient data from NIKSHAY and thematic analysis of in-depth interviews of providers and patients. Results: Of 417 patients, 208 (49.9%) received approvals for payment by PFMS and 119 (28.7%) got paid by 1 December 2018 (censor date). Reasons for not receiving DBT included (i) not having a bank account especially among migrant labourers in urban areas, (ii) refusal to avail DBT by rich patients and those with confidentiality concerns, (iii) lack of knowledge and (iv) perception that money was too little to meet the needs. The median (IQR) delay from diagnosis to payment was 101 (67-173) days. Delays were related to the complexity of processes requiring multiple layers of approval and paper-based documentation which overburdened the staff, bulk processing once-a-month and technological challenges (poor connectivity and issues related to NIKSHAY and PFMS portals). Conclusion: DBT coverage was low and there were substantial delays. Implementation barriers need to be addressed urgently to improve uptake and efficiency. The TB programme has begun to take action

Effect of the chaperone-like alpha-crystallin on the refolding of lysozyme and ribonuclease A

Alpha-crystallin exhibits chaperone-like properties in preventing aggregation of proteins. We have studied the effect of alpha-crystallin on the refolding of denatured-disulfide intact and denatured-reduced lysozyme and RNase A. Alpha-crystallin does not have any effect on the refolding of both the denatured-disulfide intact enzymes. However, it inhibits the aggregation and oxidative renaturation of denatured-reduced lysozyme. Interestingly, it has no effect on the refolding of denatured-reduced RNase A. In order to probe the molecular basis of this differential behavior of alpha-crystallin towards lysozyme and RNase A, we have carried out circular dichroism and fluorescence studies on the refolding of denatured-reduced RNase A. It exhibits an extended conformation with little difference in the exposed hydrophobicity during the refolding process. We have earlier shown the presence of an aggregation-prone, refolding-competent, molten-globule-like intermediate on the refolding pathway of lysozyme. Alpha-crystallin binds to this intermediate, prevents its aggregation and inhibits its oxidative refolding. It was earlier believed that alpha-crystallin, unlike other chaperones, does not recognize intermediates on the refolding pathway but only recognizes intermediates on the unfolding pathway of proteins. Our present study clearly shows that it recognizes the refolding intermediates as well

Incidence of Dogbite in Dakshina Kannada, Karnataka: An Epidemiological assessment from 2009 to 2016

Background: Animal bites are the main cause of morbidity and death globally. Dog bite cases and rabies are under surveillance under Integrated Disease Surveillance Program in India. Efforts are taken to control dog population and prevent dog bites which are functioning effectively yet needs understanding of the burden of the problem and suitable measures to reduce the burden. Aims and Objective: To understand the incidence dog bite cases from 2009 to 2016 and suggest measures to control the problem. Methods: The cases of dog bite reported to Health facilities in the district were reported to District Surveillance Unit. These cases of dog bite from 2009 to 2016 were included and incidence analysis was done understand the Magnitude of dogbite cases in the District. Results: The article provides an overview of increasing incidence of dogbite cases in Dakshina Kannada from 2009 upto 2016. There is a need to increase effort to control dog population throughout the district and introduce cost-efficient vaccinations. Conclusion: Increasing number of dogs are posing a threat to the community. Majority of the dogs are not supervised, and several are left unvaccinated. The problem needs immediate attention and intersectoral coordination with public involvemen

Incidence of Dogbite in Dakshina Kannada, Karnataka: An Epidemiological assessment from 2009 to 2016

Background: Animal bites are the main cause of morbidity and death globally. Dog bite cases and rabies are under surveillance under Integrated Disease Surveillance Program in India. Efforts are taken to control dog population and prevent dog bites which are functioning effectively yet needs understanding of the burden of the problem and suitable measures to reduce the burden. Aims and Objective: To understand the incidence dog bite cases from 2009 to 2016 and suggest measures to control the problem. Methods: The cases of dog bite reported to Health facilities in the district were reported to District Surveillance Unit. These cases of dog bite from 2009 to 2016 were included and incidence analysis was done understand the Magnitude of dogbite cases in the District. Results: The article provides an overview of increasing incidence of dogbite cases in Dakshina Kannada from 2009 upto 2016. There is a need to increase effort to control dog population throughout the district and introduce cost-efficient vaccinations. Conclusion: Increasing number of dogs are posing a threat to the community. Majority of the dogs are not supervised, and several are left unvaccinated. The problem needs immediate attention and intersectoral coordination with public involvemen

Handling Biological Complexity Using Kron Reduction

We revisit a model reduction method for detailed-balanced chemical reaction networks based on Kron reduction on the graph of complexes. The resulting reduced model preserves a number of important properties of the original model, such as, the kinetics law and identity of the chemical species. For determining the set of chemical complexes for the deletion, we propose two alternative methods to the computation of error integral which requires numerical integration of the state equations. The first one is based on the spectral clustering method and the second one is based on the eigenvalue interlacing property of Kron reduction on the graph. The efficacy of the proposed methods is evaluated on two biological models