Protein Chimerization: A New Frontier for Engineering Protein Therapeutics with Improved Pharmacokinetics.

With the advancement of medicine, the utility of protein therapeutics is increasing exponentially. However, a significant number of protein therapeutics suffer from grave limitations, which include their subpar pharmacokinetics. In this study, we have reviewed the emerging field of protein chimerization for improving the short circulatory half-life of protein therapeutics. We have discussed various aspects of protein therapeutics aiming at their mechanism of clearance and various approaches used to increase their short circulatory half-life with principal focus on the concept of chimerization. Furthermore, we have comprehensively reviewed various components of chimera, such as half-life extension partners and linkers, their shortcomings, and prospective work to be undertaken for developing effective chimeric protein therapeutics.

Detection of self-organized criticality behavior in an electronic circuit designed to solve a third order non-linear ODE (NL-ODE) for a damped KdV equation.

In this work, we present an electronic implementation of a damped Korteweg-de Vries equation modeled as a third order nonlinear autonomous ordinary differential equation (jerk equation). The circuit has been realized using operational amplifiers, multipliers, and passive electronic components which provides the time series solution of the equation in agreement with the numerical simulation results. Using nonlinear time series analysis on the acquired waveform data, we have obtained different types of phase space portraits and further analysis reflected long range correlation in the chaotic time series. Important findings include hysteresis induced bifurcation and self-organized criticality behavior in the system which is mentioned in this work.

Direct observation of the external force mediated conformational dynamics of an IHF bound Holliday junction.

We have investigated the isomerization dynamics and plausible energy landscape of 4-way Holliday junctions (4WHJs) bound to integration host factor (IHF, a DNA binding protein), considering the effect of applied external force, by single-molecule FRET methods. A slowing down of the forward as well as the backward rates of the isomerization process of the protein bound 4WHJ has been observed under the influence of an external force, which indicates an imposed restriction on the conformational switching. This has also been reflected by an increase in rigidity, as observed from the increase in the single-molecule FRET (smFRET)-anisotropy values (0.270 ± 0.012 to 0.360 ± 0.008). The application of an external force has assisted the conformational transitions to share the unstacked open structure intermediate, with different rate-limiting steps and a huge induced variation in the energy landscape. Furthermore, the associated landscape of the 4WHJ is visualized in terms of rarely interconverting states embedded into the two isoforms by using nonlinear dynamics analysis, which shows that the chaoticity of the system increases at intermediate force (0.4 to 1.6 pN). The identification of chaos in our investigation provides useful information for a comprehensive explanation of the origin of the complex behavior of the system, which effectively helps us to perceive the dynamics of IHF bound 4WHJs under the influence of external force, and also demonstrates the applicability of nonlinear dynamics analysis in the field of biology.

Network geometry of evidence from randomised controlled trials addressing donor selection and source of haematopoietic progenitor cells used in allogeneic transplantation: a systematic scoping review.

BACKGROUND AND METHODS: A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of donor for allogeneic haematopoietic cell transplantation (HCT) was performed to create a network of best evidence that allows us to identify new potential indirect comparisons for the strategic development of future studies that connect to the existing evidence network. RESULTS: A total of 19 eligible RCTs (2589 total patients) were identified. Nine studies (1566 patients) compared clinical outcomes following the use of peripheral blood progenitor cells (PBPCs) with bone marrow (BM) from matched related donors (eight studies) or matched unrelated donors (one study). The remaining studies compared BM or PBPCs with various methods of BM stimulation or manipulation (six studies), compared different methods of surface molecule-based selection and/or depletion of grafts (two studies) or compared the optimal number of units for paediatric cord blood transplantation (two studies). No published RCTs compared different types of donors. The geometry of the evidence network was analysed to identify opportunities for potential novel indirect comparisons and to identify opportunities to expand the network. Few indirect comparisons are currently feasible due to small sample size and heterogeneity in patient diagnoses and demographics between treatment nodes in the network. CONCLUSION: More RCTs that enrol greater numbers of similar patients are needed to leverage the current evidence network concerning donor choice and source of cells used in allogeneic HCT.

Frequency and wavelet based analyses of partial and complete measure synchronization in a system of three nonlinearly coupled oscillators.

Measure Synchronization (MS) is the generalization of synchrony to Hamiltonian Systems. Partial measure synchronization (PMS) and complete measure synchronization in a system of three nonlinearly coupled one-dimensional oscillators have been investigated for different initial conditions on the basis of numerical computation. The system is governed by the classical SU(2) Yang-Mills-Higgs (YMH) Hamiltonian with three degrees of freedom. Various transitions in the quasiperiodic (QP) region, namely, QP unsynchronized to PMS, PMS to PMS, and PMS to chaos are identified through the average bare energies and interaction energies route maps as the coupling strength is varied. The transition from quasiperiodicity to chaos is seen to be associated with a gradual transition to complete chaotic measure synchronization (CMS) which is followed by chaotic unsynchronized states, the most stable state in this case. The analyses illustrate the dependence on initial conditions. The explanation of the behavior in the QP regime is sought from the power spectral analysis. The existence of PMS is confirmed using the order parameter M (here M α ß for different combination pairs of oscillators), best suited to identify MS in coupled two-oscillator systems, and this definition is extended to obtain a new order parameter, M 3 , aiding to distinguish complete MS of three oscillators from other forms of motion. The study of wavelet coefficient spectra sheds new light on the relative phase information of the oscillators in the QP PMS regions, also highlighting the intertwined role played by the various frequency components and their amplitudes as they vary temporally. Furthermore, this technique helps to draw a sharp distinction between CMS and chaotic unsynchronized states. Based on the Continuous Wavelet Transform coefficients of the three oscillators, an order parameter M w a v is defined to indicate the extent of synchronization of the various scales (frequencies) for different coupling strengths in the chaotic regime.

Exploring the route to measure synchronization in non-linearly coupled Hamiltonian systems.

Measure Synchronization is a general term used for weak synchronization in Hamiltonian systems. Route to measure synchronization in a system of two non-linearly coupled one-dimensional oscillators, the potential of which is represented by the Pullen-Edmonds Potential is investigated on the basis of numerical computation. Transitions to measure synchronization and unsynchronization, both quasiperiodic and chaotic, are investigated and distinguished on the basis of the variation of average bare energies, average interaction energy, root-mean-square value of oscillations, phase difference, and frequencies with the coupling strength. A suitable order parameter to identify and characterize both quasiperiodic and chaotic measure synchronous states is sought, and drawbacks of the various order parameters, suggested previously, are discussed.

Are low birth weight neonates at risk for suboptimal renal growth and function during infancy?

BACKGROUND: To assess the renal growth and function of neonates during infancy in relation to birth weight and gestational age. METHODS: A longitudinal study was conducted at a tertiary hospital in South India from June 2010 to August 2014. Low birth weight neonates (LBW) were further sub-classified based on gestational age and compared with normal birth weight (NBW) full term neonates at birth, 6 months and 18-24months of age. The renal volume was measured by ultrasound and renal function by Cystatin C- derived glomerular filtration rate (CysGFR) at the three time points during the dynamic phase of renal maturation in infancy. RESULTS: We recruited 100 LBW and 66 NBW term neonates. Thirty five percent of the LBW neonates were SGA. Among the AGA neonates, 39 % were LBW neonates. The mean height and weight of the LBW neonates were significantly lower compared to NBW neonates throughout infancy. The increment in kidney volume was in accordance with the change in body size, being lower in LBW compared to NBW infants. The combined kidney volume was significantly lower in LBW and SGA neonates across all three time points (p < 0.001). CysGFR in the LBW and SGA infants, despite having low kidney volumes, were comparable to the GFRs of NBW and AGA neonates at the end of infancy. CONCLUSION: This study highlights the fact that both birth weight and gestational age influence kidney growth and function in infancy. At the end of infancy, despite a significant difference in kidney volumes and age at last follow up, the glomerular filtration rate was comparable between LBW and NBW infants. Though not statistically significant, there was a trend towards higher urine microalbumin in LBW compared to NBW in infancy.

Improving storage stability of recombinant organophosphorus hydrolase.

Organophosphorus hydrolase (OPH) is a ∼38kDa enzyme encoded by opd gene of Flavobacterium sp. The enzyme can hydrolyze and inactivate variety of organophosphate (OP)-compounds, including chemical warfare nerve agents. Thus, OPH is a strong candidate for the development of therapeutic intervention against OP-poisoning in humans and other animals. It is also a promising bio-decontaminating agent for clean-up of OP-contaminated objects and areas. For successful commercial application, long-term storage stability of purified OPH enzyme is important. In this study we have cloned and expressed recombinant OPH (r-OPH) in Escherichia coli and the effect of different excipients on the long-term storage stability of purified enzyme was analyzed. The enzyme was stored in either aqueous solution or in lyophilized form at 25°C for 60days in the presence or absence of different excipients and the stability of the enzyme was determined by monitoring the paraoxon-hydrolyzing activity. Our results suggest that, (a) maltose, trehalose, arginine and proline were most effective in stabilizing the enzyme when stored in aqueous buffer at 25°C, and (b) maltose, trehalose, and mannose exerted maximum stabilization effect when the enzyme was stored in lyophilized form at 25°C for 60days. The study shows that common excipients can be used to stabilize purified OPH enzyme in order to store it for long period of time under different storage conditions. The results of this study can be used to develop formulation(s) of OPH enzyme for commercial use.

Intrinsic noise induced coherence resonance in a glow discharge plasma.

Experimental evidence of intrinsic noise induced coherence resonance in a glow discharge plasma is being reported. Initially the system is started at a discharge voltage (DV) where it exhibited fixed point dynamics, and then with the subsequent increase in the DV spikes were excited which were few in number and with further increase of DV the number of spikes as well as their regularity increased. The regularity in the interspike interval of the spikes is estimated using normalized variance. Coherence resonance was determined using normalized variance curve and also corroborated by Hurst exponent and power spectrum plots. We show that the regularity of the excitable spikes in the floating potential fluctuation increases with the increase in the DV, up to a particular value of DV. Using a Wiener filter, we separated the noise component which was observed to increase with DV and hence conjectured that noise can play an important role in the generation of the coherence resonance. From an anharmonic oscillator equation describing ion acoustic oscillations, we have been able to obtain a FitzHugh-Nagumo like model which has been used to understand the excitable dynamics of glow discharge plasma in the presence of noise. The numerical results agree quite well with the experimental results.

The Australia and New Zealand Fontan Registry: description and initial results from the first population-based Fontan registry.

BACKGROUND: The Fontan procedure is the final in a series of staged palliations for single-ventricle congenital heart disease, which encompasses rare and heterogeneous cardiac lesions. It represents an unusual and novel physiological state characterised by absence of a subpulmonary ventricle. AIMS: The population is growing steadily, prompting creation of this registry to study their epidemiology, demographic trends, treatment and outcomes. METHODS: This multicentre, binational, prospective and retrospective, web-based registry involving all congenital cardiac centres in the region has identified nearly all Fontan patients in Australia and New Zealand. Patients identified retrospectively were approached for recruitment. New recipients are automatically enrolled prospectively unless they choose to opt-out. Follow-up data are collected yearly. RESULTS: Baseline data were obtained in 1072 patients as at 1 January 2011. Ninety-nine patients died; 64 were lost to follow up. Forty-four per cent of patients lost were between 20 and 30 years of age. The size of the Fontan population is increasing steadily. Among 973 living patients, 541 (56%) gave consent for prospective collection of follow up. Between 1 January 2011 and 1 January 2013, an additional 47 subjects were enrolled prospectively. The current proportion of patients operated with hypoplastic left heart syndrome is currently 29% and is growing rapidly. CONCLUSION: The population surviving after the Fontan procedure has been growing in recent decades, especially since survival with hypoplastic left heart syndrome has improved. The Australia and New Zealand Fontan Registry provides population-based data, and only large databases like this will give opportunities for understanding the population and performing prospective trials.

Non-stationary dynamics in the bouncing ball: a wavelet perspective.

The non-stationary dynamics of a bouncing ball, comprising both periodic as well as chaotic behavior, is studied through wavelet transform. The multi-scale characterization of the time series displays clear signatures of self-similarity, complex scaling behavior, and periodicity. Self-similar behavior is quantified by the generalized Hurst exponent, obtained through both wavelet based multi-fractal detrended fluctuation analysis and Fourier methods. The scale dependent variable window size of the wavelets aptly captures both the transients and non-stationary periodic behavior, including the phase synchronization of different modes. The optimal time-frequency localization of the continuous Morlet wavelet is found to delineate the scales corresponding to neutral turbulence, viscous dissipation regions, and different time varying periodic modulations.

Multi-scale dynamics of glow discharge plasma through wavelets: self-similar behavior to neutral turbulence and dissipation.

The multiscale dynamics of glow discharge plasma is analysed through wavelet transform, whose scale dependent variable window size aptly captures both transients and non-stationary periodic behavior. The optimal time-frequency localization ability of the continuous Morlet wavelet is found to identify the scale dependent periodic modulations efficiently, as also the emergence of neutral turbulence and dissipation, whereas the discrete Daubechies basis set has been used for detrending the temporal behavior to reveal the multi-fractality of the underlying dynamics. The scaling exponents and the Hurst exponent have been estimated through wavelet based detrended fluctuation analysis, and also Fourier methods and rescale range analysis.

Warfare Nerve Agents and Paraoxonase-1 as a Potential Prophylactic Therapy against Intoxication.

Nerve agents are a class of lethal neurotoxic chemicals used in chemical warfare. In this review, we have briefly discussed a brief history of chemical warfare, followed by an exploration of the historical context surrounding nerve agents. The article explores the classification of these agents, their contemporary uses, their toxicity mechanisms, and the disadvantages of the current treatment options for nerve agent poisoning. It then discusses the possible application of enzymes as prophylactics against nerve agent poisoning, outlining the benefits and drawbacks of paraoxonase-1. Finally, the current studies on paraoxonase-1 are reviewed, highlighting that several challenges need to be addressed in the use of paraoxonase-1 in the actual field and that its potential as a prophylactic antidote against nerve agent poisoning needs to be evaluated. The literature used in this manuscript was searched using various electronic databases, such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent, and books using the keywords chemical warfare agent, Butyrylcholinesterase, enzyme, nerve agent, prophylactic, and paraoxonase- 1, with the time scale for the analysis of articles between 1960 to 2023, respectively. The study has suggested that concerted efforts by researchers and agencies must be made to develop effective countermeasures against NA poisoning and that PON1 has suitable properties for the development of efficient prophylaxis against NA poisoning.

Acute kidney injury in sick neonates: a comparative study of diagnostic criteria, assessment of risk factors and outcomes.

INTRODUCTION: Neonatal acute kidney injury (nAKI) poses unique challenges with diagnostic criteria specific to neonates evolving over time. Urine output (UOP) criterion has a special place in the diagnosis of nAKI although significant clarity on the ideal diagnostic threshold for UOP is not established. Risk factors peculiar to the tropical region for acute kidney injury (AKI) in neonates needs attention. It would be interesting to assess for kidney function in neonates who survived AKI during the dynamic phase of infancy. OBJECTIVES: To compare criteria of modified kidney disease improving global outcome (mKDIGO) and neonatal risk, injury, failure, loss, and end-stage criteria (nRIFLE) in diagnosing AKI in sick neonates; to study the risk factors for AKI and clinical outcomes at the end of neonatal ICU stay and during infancy. METHODS: This prospective study was conducted at a tertiary neonatal ICU that screened and staged sick neonates by applying mKDIGO and nRIFLE criteria. Risk factors were assessed and glomerular filtration rate was calculated by cystatin C in survivors of nAKI for 12 months post conception age. RESULTS: nAKI was observed in 30% (49/163) of sick neonates. The mKDIGO (94%) detected a higher number of neonates with AKI compared to nRIFLE (49%). Based on only UOP, nRIFLE diagnosed a higher proportion of neonates with mild AKI compared to mKDIGO (29% versus 16%), respectively. Besides known risk factors, hypernatremic dehydration (18%) was an important risk factor for AKI. With 20% mortality, the risk of developing AKI was comparable using either mKDIGO or nRIFLE diagnostic criteria. At the end of infancy, mean cystatin C eGFR of neonates was 101.3 ± 29.2 ml/1.73 m2/min. CONCLUSION: In sick neonates, mKDIGO criteria performed better than nRIFLE in detecting AKI. However, the risk of mortality was comparable using either diagnostic criterion. Hypernatremic dehydration was an important risk factor for AKI and renal function of neonates following complete recovery of AKI was normal at the end of infancy.

Evolutionary history and identification of conservation units in the giant otter, Pteronura brasiliensis.

The giant otter, Pteronura brasiliensis, occupies a range including the major drainage basins of South America, yet the degree of structure that exists within and among populations inhabiting these drainages is unknown. We sequenced portions of the mitochondrial DNA (mtDNA) cytochrome b (612bp) and control region (383 bp) genes in order to determine patterns of genetic variation within the species. We found high levels of mtDNA haplotype diversity (h = 0.93 overall) and support for subdivision into four distinct groups of populations, representing important centers of genetic diversity and useful units for prioritizing conservation within the giant otter. We tested these results against the predictions of three hypotheses of Amazonian diversification (Pleistocene Refugia, Paleogeography, and Hydrogeology). While the phylogeographic pattern conformed to the predictions of the Refugia Hypothesis, molecular dating using a relaxed clock revealed the phylogroups diverged from one another between 1.69 and 0.84 Ma, ruling out the influence of Late Pleistocene glacial refugia. However, the role of Plio-Pleistocene climate change could not be rejected. While the molecular dating also makes the influence of geological arches according to the Paleogeography Hypothesis extremely unlikely, the recent Pliocene formation of the Fitzcarrald Arch and its effect of subsequently altering drainage pattern could not be rejected. The data presented here support the interactions of both climatic and hydrological changes resulting from geological activity in the Plio-Pleistocene, in shaping the phylogeographic structure of the giant otter.

Comparison of the buccal injection versus buccal and palatal injection for extraction of permanent maxillary posterior teeth using 4% articaine: a split mouth study.

In spite of the development of modern injection techniques, palatal injection is still a painful experience for patients. A plethora of techniques has been tested to reduce this. One such technique that has been claimed to work is administering articaine on the buccal side alone for the extraction of maxillary teeth due to its ability to diffuse through soft and hard tissues more reliably than other local anaesthetics. This split mouth study evaluated the efficacy of 4% articaine with 1:100000 adrenaline to avoid the painful palatal injection for bilateral permanent maxillary tooth extraction in 50 patients. The 100mm 10 point Visual Analog Scale/Wong Baker Facial Pain Scale was used to rate the amount of pain felt on injection, on probing the tissues prior to, or during, extraction, and one hour postoperatively. Although the buccal injection alone resulted in lower pain while injecting the anaesthetic, it did not result in the absence of pain before tooth extraction as has been suggested by various studies. A total of 74% patients required a palatal injection on the study side. We conclude that in most cases, when using a buccal injection alone, one cannot rely on the diffusion of articaine for effective palatal anaesthesia. Despite this, we suggest that as an initial option in young patients, the operator can consider avoiding the painful palatal injection by the use of articaine to prevent aversion to dental treatment. Postoperatively, the difference in pain levels was not statistically significant and no patient showed signs of lesions at the injection sites.

Coherence resonance in a unijunction transistor relaxation oscillator.

The phenomenon of coherence resonance is investigated in an unijunction transistor relaxation oscillator and quantified by estimating the normal variance (NV). Depending on the measuring points, two types of NV curves have been obtained. We have observed that the degradations in coherency at higher noise amplitudes in our system is probably the result of direct interference of coherent oscillations and the stochastic perturbation. Degradation of coherency may be minimal if this direct interference of noise and coherent oscillations is eliminated.

Is Human Paraoxonase 1 the Saviour Against the Persistent Threat of Organophosphorus Nerve Agents?

Nerve agents have been used extensively in chemical warfare in the past. However, recent use of Novichok agents have reignited the debate on the threat posed by Organophosphorus Nerve Agents (OPNAs). The currently available therapy for OPNA toxicity is only symptomatic and is potentially ineffective in neutralizing OPNAs. Hence, there is a dire need to develop a prophylactic therapy for counteracting OPNA toxicity. In this regard, human paraoxonase 1 has emerged as the enzyme of choice. In this review, we have focussed upon the recent and past events of OPNA use, their mechanism of action and toxicity. Further, we have emphasized upon the potential of enzyme based therapy and the various advances in the development of paraoxonase 1 as a countermeasure for OPNA poisoning. Finally, we have elaborated the shortcomings of paraoxonase 1 and the work that needs to be undertaken in order to develop human paraoxonase 1 as a prophylactic against OPNA poisoning.

Using wavelet analysis to investigate synchronization.

Wavelet analysis is shown to be a more robust technique than previously used methods in the investigation of synchronization. The highlight of the technique is that it encompasses most of the information obtained by conventional methods into a single picture, while giving a deeper insight into the dynamics of the system. Order parameters derived from continuous wavelet transform coefficients are proposed, which can be used in the quantification of measure synchronization in Hamiltonian systems and identical synchronization in dissipative systems, irrespective of the nature of coupling, the nature of synchronization (complete or partial, quasiperiodic or chaotic), and the number of coupled subsystems.

Noise-invoked resonances near a homoclinic bifurcation in the glow discharge plasma.

Stochastic resonance (SR) and coherence resonance (CR) have been studied experimentally in discharge plasmas close to a homoclinic bifurcation. For the SR phenomenon, it is observed that a superimposed subthreshold periodic signal can be recovered via stochastic modulations of the discharge voltage. Furthermore, it is realized that even in the absence of a subthreshold deterministic signal, the system dynamics can be recovered and optimized using noise. This effect is defined as CR in the literature. In the present experiments, induction of SR and CR is quantified using the absolute mean difference and normalized variance techniques, respectively.