Nature of Subdiffusion Crossover in Molecular and Polymeric Glassformers.

A crossover from a non-Gaussian to Gaussian subdiffusion has been observed ubiquitously in various polymeric and molecular glassformers. We have developed a framework that generalizes the fractional Brownian motion model to incorporate non-Gaussian features by introducing a jump kernel. We illustrate that the non-Gaussian fractional Brownian motion model accurately characterizes the subdiffusion crossover. From the solutions of the non-Gaussian fractional Brownian motion model, we gain insights into the nature of van Hove self-correlation in non-Gaussian subdiffusive regime, which is found to exhibit exponential tails, providing first such experimental evidence in molecular glassformers. The validity of the model is supported by comparison with incoherent quasielastic neutron scattering data obtained from several molecular and polymeric glassformers.

Links across disabilities: unveiling associations between functional domains.

BACKGROUND: Persons with disabilities experience higher risks of mortality as well as poorer health as compared to the general population. The aim of this study is to estimate the correlations between functional difficulties across several domains in six countries. METHODS: National census data with questions on disability from six countries (Mauritius, Morocco, Senegal, Myanmar, Vietnam, and Uruguay) was used in this study. We performed logistic regressions to assess the extent to which having a functional difficulty in one domain is correlated with having a functional difficulty in each of the other domains and report weighted odds ratios (ORs) overall and within age-groups ('18-44' years and '45+' years). Models adjust for age, sex, and location (rural or urban). Sensitivity analyses around different choices of predictors and response variables were conducted. FINDINGS: For all countries, reporting a functional difficulty in one domain was consistently and significantly positively correlated with reporting a functional difficulty in other domains (overall) and for each of the two age-groups considered - '18-44' years and '45+' years. All ORs were greater than one. Cognition, mobility, and hearing were the domains that were the most correlated ones with other domains. The highest pairwise correlations were for i/ hearing and cognition; ii/ mobility and cognition. Results were robust to changing the severity thresholds for functional difficulties. Across countries, Uruguay, the only high-income country among the six countries under study, had the lowest correlations between functional domains. CONCLUSIONS: There are consistent positive associations in the experience of functional difficulties in various domains in the six countries under study. Such correlations may reflect barriers to social services including healthcare services and resources (e.g. assistive devices) that may lead to an avoidable deterioration of functioning across domains. Further research is needed on the trajectories of functional difficulties and on structural barriers that people with functional difficulties may experience in their communities and in healthcare settings in particular. This is important as some functional difficulties may be preventable.

Neonatal Brain Temperature Monitoring Based on Broadband Near-Infrared Spectroscopy.

We present here the initial development of a novel algorithm based on broadband near-infrared spectroscopy (bNIRS) data to estimate the changes in brain temperature (BT) in neonates. We first explored the validity of the methodology on a simple numerical phantom and reported good agreements between the theoretical and retrieved values of BT and hemodynamic parameters changes, which are the parameters usually targeted by bNIRS. However, we noted an underestimation of the absolute values of temperature and haemoglobins' concentration changes when large variations of tissue saturation were induced, probably due to a crosstalk between the species in this specific case. We then tested this methodology on data acquired on 2 piglets during a protocol that induces seizures. We showed that despite a decrease in rectal temperature (RT) over time (-0.1048 °C 1.5 h after seizure induction, 95% CI: -0.1035 to -0.1061 °C), BT was raising (0.3122 °C 1.5 h after seizure induction, 95% CI: 0.3207 to 0.3237 °C). We also noted that the piglet displaying the largest decrease in RT also displays the highest increase in BT, which could be a marker of the severity of the seizure induced brain injury. These initial results are encouraging and show that having access to the changes in BT non-invasively could help to better understand the impact of BT on injury severity and to improve the current cooling methodologies in the neonatal neurocritical care following neonatal encephalopathy.

Noncanonical Relationship between Heterogeneity and the Stokes-Einstein Breakdown in Deep Eutectic Solvents.

The relationship between Stokes-Einstein breakdown (SEB) and dynamical heterogeneity (DH) is of paramount importance in the physical chemistry of complex fluids. In this work, we employ neutron scattering to probe the DH and SEB in a series of deep eutectic solvents (DESs) composed of acetamide and lithium salts. Quasielastic neutron scattering experiments reveal SEB in the jump diffusion of acetamide, represented by a fractional Stokes-Einstein relationship. Among these DESs, lithium perchlorate exhibits the most pronounced SEB while lithium bromide displays the weakest. Concurrently, elastic incoherent neutron scans identify that bromide DES is the most heterogeneous and perchlorate is the least. For the first time, our study unveils a counterintuitive incommensurate relationship between DH and SEB. Further, it reveals the intricate contrasting nature of the SEB-DH relationship when investigated in proximity to the glass-transition temperature and further away from it.

A Practical Guide to 16S rRNA Microbiome Analysis in Musculoskeletal Disorders.

Microbial taxonomic assignment based on 16S marker gene amplification requires multiple data transformations, often encompassing the use of a variety of computational platforms. Bioinformatics analysis may represent a bottleneck for researchers as many tools require programmatic access in order to implement the software. Here we describe a step-by-step approach for taxonomic assignment using QIIME2 and highlight the utility of graphical-based microbiome tools for further analysis and identification of biological relevant taxa with reference to an outcome of interest.

Multi-Institutional Clinical Outcomes of Biopsy Gleason Grade Group 5 Prostate Cancers Treated With Contemporary High-Dose Radiation and Long-Term Androgen Deprivation Therapy.

AIMS: This multicentric retrospective study reports long-term clinical outcomes of non-metastatic grade group 5 prostate cancers treated with external beam radiotherapy (EBRT) alone with long-term androgen deprivation therapy (ADT). MATERIALS AND METHODS: Patients treated across 19 institutions were studied. The key endpoints that were evaluated were 5-year biochemical recurrence-free survival (bRFS), metastases-free survival (MFS), overall survival, together with EBRT-related acute and late toxicities. The impact of various prognostic factors on the studied endpoints was analysed using univariate and multivariate analyses. RESULTS: Among the 462 patients, 88% (405) had Gleason 9 disease and 31% (142) had primary Gleason pattern 5. A prostate-specific membrane antigen positron emission tomography-computed tomography scan was used for staging in 33% (153), 80% (371) were staged as T3/T4 and 30% (142) with pelvic nodal disease. The median ADT duration was 24 months; 66% received hypofractionated EBRT and 71.4% (330) received pelvic nodal irradiation. With a median follow-up of 56 months, the 5-year bRFS, MFS and overall survival were 73.1%, 77.4% and 90.5%, respectively. Primary Gleason pattern 5 was associated with worse bRFS, MFS and overall survival with hazard ratios of 0.51 (95% confidence interval 0.35 to 0.73, P < 0.001), 0.64 (95% confidence interval 0.43 to 0.96, P = 0.031) and 0.52 (95% confidence interval 0.28 to 0.97, P = 0.040), respectively, whereas pelvic nodal disease was associated with worse bRFS (hazard ratio 0.67, 95% confidence interval 0.46 to 0.98, P = 0.039) and MFS (hazard ratio 0.56, 95% confidence interval 0.37 to 0.85, P = 0.006). The acute and late radiation-related toxicities were low overall and pelvic nodal irradiation was associated with higher toxicities. CONCLUSION: Contemporary EBRT and long-term ADT led to excellent 5-year clinical outcomes and low rates of toxicity in this cohort of non-metastatic grade group 5 prostate cancers. Primary Gleason pattern 5 and pelvic node disease portends inferior clinical outcomes.

Variability in the diagnostic and management practices of post-hemorrhagic ventricular dilatation in very preterm infants across Canadian centers and comparison with European practices.

OBJECTIVES: To investigate the variability in diagnostic and therapeutic approaches to posthemorrhagic ventricular dilatation (PHVD) among Canadian neonatal centers, and secondary exploration of differences in approaches between Canadian and European practices. METHODS: We conducted a survey among Canadian tertiary neonatal centers on their local practices for managing very preterm infants with PHVD. The survey covered questions on the diagnostic criteria, timing and type of interventions and resources utilization (transfer to neurosurgical sites and neurodevelopmental follow-up). In a secondary exploration, Canadian responses were compared with responses to the same survey from European centers. RESULTS: 23/30 Canadian centers (77%) completed the survey. There was no consensus among Canadian centers on the criteria used for diagnosing PHVD or to initiate intervention. The therapeutic interventions also vary, both for temporizing procedures or permanent shunting. Compared to European practices, the Canadian approach relied less on the sole use of ultrasound criteria for diagnosing PHVD (43 vs 94%, p < 0.0001) or timing intervention (26 vs 63%, p = 0.007). Majority of European centers intervened early in the development of PHVD based on ultrasound parameters, whereas Canadian centers intervened based on clinical hydrocephalus, with fewer centers performing serial lumbar punctures prior to neurosurgical procedures (40 vs 81%, p = 0.003). CONCLUSION: Considerable variability exists in diagnosis and management of PHVD in preterm infants among Canadian tertiary centers and between Canadian and European practices. Given the potential implications of the inter-center practice variability on the short- and long-term outcomes of preterm infants with PHVD, efforts towards evidence-based Canada-wide practice standardization are underway.

A 500 kV, 10 kA, 40 ns coaxial Marx generator pulser for cable fed flash x-ray system.

Flash x-ray (FXR) systems are used for dynamic radiography. Depending on the speed of the object, these systems typically require a very short pulse duration (∼25 ns) for image acquisition without motion blur. The conventional Marx generators with zigzag discharge paths result in higher inductance; hence, they do not meet the requirement of shorter pulse duration (30-40 ns) and low impedance (40-60 Ω) simultaneously. A coaxial Marx generator has been designed and developed, which is capable of generating 500 kV peak voltages and 10 kA peak current within a 40 ns pulse duration. The CST simulation of the coaxial Marx generator has been carried out to validate the design parameters. The FXR electron beam diode is powered by this Marx generator. Experiments were carried out to measure the x-ray parameters like pulse width, source size, x-ray energy spectrum, penetration depth, and cone angle. The maximum measured x-ray dose was 62 mR at 1 m distance from the source window. The x-ray radiograph demonstrates a penetration depth of 32 mm in steel kept at 2.5 m distance from the source for 500 kV diode voltages.

Modulation of Diffusion Mechanism and Its Correlation with Complexation in Aqueous Deep Eutectic Solvents.

Aqueous mixtures of deep eutectic solvents (DESs) have gained traction recently as an effective template to tailor their physicochemical properties. But detailed microscopic insights into the effects of water on the molecular relaxation phenomenon in DESs are not entirely understood. DESs are strong network-forming liquids due to the extensive hydrogen bonding and complex formation between their species, and therefore, water can behave as a controlled disruptor altering the microscopic structure and dynamics in DESs. In this study, the role of water in the diffusion mechanism of acetamide in the aqueous mixtures of DESs synthesized using acetamide and lithium perchlorate is investigated using molecular dynamics (MD) simulation and quasielastic neutron scattering (QENS). The acetamide dynamics comprises localized diffusion within transient cages and a jump diffusion process across cages. The jump diffusion process is observed to be strongly enhanced by about a factor of 10 as the water content in the system is increased. Meanwhile, the geometry of the localized dynamics is unaltered by addition of water, but the localized diffusion becomes significantly faster and more heterogeneous with increasing water concentration. The accelerating effects of water on localized diffusion are also substantiated by QENS experiments. The water concentration in the DES is observed to control the solvation structure of lithium ions, with the ions becoming significantly hydrated at 20 wt % water. The formation of interwater and water-acetamide hydrogen bonds is observed. The increase in water concentration is found to increase the number of H-bonds; however, their lifetimes are found to decrease substantially. Similarly, the lifetimes of acetamide-lithium complexes are also found to be diminished by increasing water concentration. A power-law scaling relationship between lifetimes and diffusion constants is established, elucidating the extent of coupling between diffusive processes and hydrogen bonding and microscopic complexation. This study demonstrates the ability to use water as an agent to probe the role of structural relaxation and complex lifetimes of diffusive processes at different time and length scales.

Stress-Induced Haematohidrosis: a Case Report.

We describe a case of stress-induced haematohidrosis in a 14-year-old boy who responded well to stress management together with sertraline medication.

CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk.

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, mutually exclusive of STAT3 mutations and associated with gene expression programs that resembled normal CD16dim/CD56bright NK cells. Mechanistically, the mutations resulted in ligand-biased chemokine receptor signaling, with decreased internalization of the G-protein-coupled receptor (GPCR) for CCL22, CCR4, via impaired ß-arrestin recruitment. This resulted in increased cell chemotaxis in vitro, bidirectional crosstalk with the hematopoietic microenvironment and enhanced NK cell proliferation in vivo in transgenic human IL-15 mice. Somatic CCL22 mutations illustrate a unique mechanism of tumor formation in which gain-of-function chemokine mutations promote tumorigenesis by biased GPCR signaling and dysregulation of microenvironmental crosstalk.

Identification of Clostridium innocuum hypothetical protein that is cross-reactive with C. difficile anti-toxin antibodies.

OBJECTIVES: Previously considered solely an opportunistic pathogen, Clostridium innocuum (CI) was recently reported in Taiwan to be an emerging cause of antibiotic-associated diarrhea and clinically indistinguishable from Clostridioides difficile (CD) infection. We previously identified CI culture supernatant being cross-reactive with commercial CD toxin enzyme immunoassays. We aimed to identify and characterize the cross-reacting protein and determine whether it functioned as a human toxin. METHODS: We performed western blots using CI culture supernatants and CD anti-toxin antibodies and identified interacting bands. We identified protein(s) using tandem mass spectrometry and evaluated them by cytotoxicity assays. RESULTS: CI, but not CD, was isolated from stool of 12 children and adults with diarrhea. Culture supernatant from 6/12 CI isolates, and an ATCC reference strain, tested positive for CD toxins (total 7/13 isolates) by commercial EIA. Using two of these isolates, we identified two ∼40 kDa hypothetical proteins, CI_01447 and CI_01448, and confirmed cross-reactivity with CD anti-toxin antibodies by enzyme immunoassay and Western blot. Whole-genome sequencing confirmed all 13 isolates contained both genes, which were highly conserved. We observed no cytopathic or cytotoxic effects to HeLa cells when treated with these proteins. We identified amino acid sequence similarity to the NlpC/P60 family of proteins. CONCLUSIONS: Our findings do not suggest CI proteins CI_01448 and CI_01447, which cross-react with antibodies against CD toxins A and B, are toxic to HeLa cells. Further studies are needed to determine the function of these cross-reacting proteins and the potential virulence factors that could be responsible for CI diarrheal disease.

Bivalent recognition of fatty acyl-CoA by a human integral membrane palmitoyltransferase.

S-acylation, also known as palmitoylation, is the most abundant form of protein lipidation in humans. This reversible posttranslational modification, which targets thousands of proteins, is catalyzed by 23 members of the DHHC family of integral membrane enzymes. DHHC enzymes use fatty acyl-CoA as the ubiquitous fatty acyl donor and become autoacylated at a catalytic cysteine; this intermediate subsequently transfers the fatty acyl group to a cysteine in the target protein. Protein S-acylation intersects with almost all areas of human physiology, and several DHHC enzymes are considered as possible therapeutic targets against diseases such as cancer. These efforts would greatly benefit from a detailed understanding of the molecular basis for this crucial enzymatic reaction. Here, we combine X-ray crystallography with all-atom molecular dynamics simulations to elucidate the structure of the precatalytic complex of human DHHC20 in complex with palmitoyl CoA. The resulting structure reveals that the fatty acyl chain inserts into a hydrophobic pocket within the transmembrane spanning region of the protein, whereas the CoA headgroup is recognized by the cytosolic domain through polar and ionic interactions. Biochemical experiments corroborate the predictions from our structural model. We show, using both computational and experimental analyses, that palmitoyl CoA acts as a bivalent ligand where the interaction of the DHHC enzyme with both the fatty acyl chain and the CoA headgroup is important for catalytic chemistry to proceed. This bivalency explains how, in the presence of high concentrations of free CoA under physiological conditions, DHHC enzymes can efficiently use palmitoyl CoA as a substrate for autoacylation.

A high-resolution computed tomography based scoring system to predict ease of electrode insertion in cochlear implantation.

OBJECTIVE: This study aimed to formulate a scoring system based on high-resolution computed tomography scans to predict ease of electrode insertion during cochlear implantation via posterior tympanotomy in paediatric patients. METHOD: A scoring system Cochlear Implantation Radiological Assessment Score (CIRAS) was formulated based on six parameters. This score was correlated with intra-operative findings, and receiver operating characteristic analysis was performed to determine the optimal cut-off score to predict difficulty of surgery and to establish the inherent validity of the scoring system by area under curve. RESULTS: Receiver operating characteristic analysis showed that optimal cut-off score was 8 (93.1 per cent specificity and 56.52 per cent sensitivity), and area under the curve was 0.828. Patients with CIRAS of more than 8 had significantly higher time for surgery (p < 0.05). CONCLUSION: CIRAS is an easy to administer tool by utilising classical axial and coronal sections, without any numerical measures. Pre-operative assessment by this score gives a good idea of intra-operative challenges.

Lafora disease: Current biology and therapeutic approaches.

The ubiquitin system impacts most cellular processes and is altered in numerous neurodegenerative diseases. However, little is known about its role in neurodegenerative diseases due to disturbances of glycogen metabolism such as Lafora disease (LD). In LD, insufficiently branched and long-chained glycogen forms and precipitates into insoluble polyglucosan bodies (Lafora bodies), which drive neuroinflammation, neurodegeneration and epilepsy. LD is caused by mutations in the gene encoding the glycogen phosphatase laforin or the gene coding for the laforin interacting partner ubiquitin E3 ligase malin. The role of the malin-laforin complex in regulating glycogen structure remains with full of gaps. In this review we bring together the disparate body of data on these two proteins and propose a mechanistic hypothesis of the disease in which malin-laforin's role to monitor and prevent over-elongation of glycogen branch chains, which drive glycogen molecules to precipitate and accumulate into Lafora bodies. We also review proposed connections between Lafora bodies and the ensuing neuroinflammation, neurodegeneration and intractable epilepsy. Finally, we review the exciting activities in developing therapies for Lafora disease based on replacing the missing genes, slowing the enzyme - glycogen synthase - that over-elongates glycogen branches, and introducing enzymes that can digest Lafora bodies. Much more work is needed to fill the gaps in glycogen metabolism in which laforin and malin operate. However, knowledge appears already adequate to advance disease course altering therapies for this catastrophic fatal disease.

Comparative pathology, molecular pathogenicity, immunological features, and genetic characterization of three highly pathogenic human coronaviruses (MERS-CoV, SARS-CoV, and SARS-CoV-2).

The last two decades have witnessed the emergence of three deadly coronaviruses (CoVs) in humans: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are still no reliable and efficient therapeutics to manage the devastating consequences of these CoVs. Of these, SARS-CoV-2, the cause of the currently ongoing coronavirus disease 2019 (COVID-19) pandemic, has posed great global health concerns. The COVID-19 pandemic has resulted in an unprecedented crisis with devastating socio-economic and health impacts worldwide. This highlights the fact that CoVs continue to evolve and have the genetic flexibility to become highly pathogenic in humans and other mammals. SARS-CoV-2 carries a high genetic homology to the previously identified CoV (SARS-CoV), and the immunological and pathogenic characteristics of SARS-CoV-2, SARS-CoV, and MERS contain key similarities and differences that can guide therapy and management. This review presents salient and updated information on comparative pathology, molecular pathogenicity, immunological features, and genetic characterization of SARS-CoV, MERS-CoV, and SARS-CoV-2; this can help in the design of more effective vaccines and therapeutics for countering these pathogenic CoVs.

Modulation of host epigenome by coronavirus infections and developing treatment modalities for COVID-19 beyond genetics.

The recent Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) outbreak has resulted in coronavirus disease 2019 (COVID-19) pandemic worldwide, affecting millions of lives. Although vaccines are presently made available, and vaccination drive is in progress to immunize a larger population; still the risk of SARS-CoV-2 infection and related mortality is persistent amid threats of the third wave of the ongoing pandemic. In the scenario of unavailability of robust and efficient treatment modalities, it becomes essential to understand the mechanism of action of the virus and deeply study the molecular mechanisms (both at the virus level and the host level) underlying the infection processes. Recent studies have shown that coronaviruses (CoVs) cause-specific epigenetic changes in the host cells to create a conducive microenvironment for replicating, assembling, and spreading. Epigenetic mechanisms can contribute to various aspects of the SARS-CoV-2 multiplication cycle, like expressing cytokine genes, viral receptor ACE2, and implicating different histone modifications. For SARS-CoV-2 infection, viral proteins are physically associated with various host proteins resulting in numerous interactions between epigenetic enzymes (i.e., histone deacetylases, bromodomain-containing proteins). The involvement of epigenetic mechanisms in the virus life cycle and the host immune responses to control infection result in epigenetic factors recognized as emerging prognostic COVID-19 biomarkers and epigenetic modulators as robust therapeutic targets to curb COVID-19. Therefore, this narrative review aimed to summarize and discuss the various epigenetic mechanisms that control gene expression and how these mechanisms are altered in the host cells during coronavirus infection. We also discuss the opportunities to exploit these epigenetic changes as therapeutic targets for SARS-CoV-2 infection. Epigenetic alterations and regulation play a pivotal role at various levels of coronavirus infection: entry, replication/transcription, and the process of maturation of viral proteins. Coronaviruses modulate the host epigenome to escape the host immune mechanisms. Therefore, host epigenetic alterations induced by CoVs can be considered to develop targeted therapies for COVID-19.

Can the microscopic and macroscopic transport phenomena in deep eutectic solvents be reconciled?

Deep eutectic solvents (DESs) have become ubiquitous in a variety of industrial and pharmaceutical applications since their discovery. However, the fundamental understanding of their physicochemical properties and their emergence from the microscopic features is still being explored fervently. Particularly, the knowledge of transport mechanisms in DESs is essential to tune their properties, which shall aid in expanding the territory of their applications. This perspective presents the current state of understanding of the bulk/macroscopic transport properties and microscopic relaxation processes in DESs. The dependence of these properties on the components and composition of the DES is explored, highlighting the role of hydrogen bonding (H-bonding) interactions. Modulation of these interactions by water and other additives, and their subsequent effect on the transport mechanisms, is also discussed. Various models (e.g. hole theory, free volume theory, etc.) have been proposed to explain the macroscopic transport phenomena from a microscopic origin. But the formation of H-bond networks and clusters in the DES reveals the insufficiency of these models, and establishes an antecedent for dynamic heterogeneity. Even significantly above the glass transition, the microscopic relaxation processes in DESs are rife with temporal and spatial heterogeneity, which causes a substantial decoupling between the viscosity and microscopic diffusion processes. However, we propose that a thorough understanding of the structural relaxation associated to the H-bond dynamics in DESs will provide the necessary framework to interpret the emergence of bulk transport properties from their microscopic counterparts.

Water accelerates the hydrogen-bond dynamics and abates heterogeneity in deep eutectic solvent based on acetamide and lithium perchlorate.

Deep eutectic solvents (DESs) have become a prevalent and promising medium in various industrial applications. The addition of water to DESs has attracted a lot of attention as a scheme to modulate their functionalities and improve their physicochemical properties. In this work, we study the effects of water on an acetamide based DES by probing its microscopic structure and dynamics using classical molecular dynamics simulation. It is observed that, at low water content, acetamide still remains the dominant solvate in the first solvation shell of lithium ions, however, beyond 10 wt. %, it is replaced by water. The increase in the water content in the solvent accelerates the H-bond dynamics by drastically decreasing the lifetimes of acetamide-lithium H-bond complexes. Additionally, water-lithium H-bond complexes are also found to form, with systematically longer lifetimes in comparison to acetamide-lithium complexes. Consequently, the diffusivity and ionic conductivity of all the species in the DES are found to increase substantially. Non-Gaussianity parameters for translational motions of acetamide and water in the DES show a conspicuous decrease with addition of water in the system. The signature of jump-like reorientation of acetamide is observed in the DES by quantifying the deviation from rotational Brownian motion. However, a notable decrease in the deviation is observed with an increase in the water content in the DES. This study demonstrates the intricate connection between H-bond dynamics and various microscopic dynamical parameters in the DES, by investigating the modulation of the former with addition of water.

Systems Biology Model of Cerebral Oxygen Delivery and Metabolism During Therapeutic Hypothermia: Application to the Piglet Model.

Hypoxic ischaemic encephalopathy (HIE) is a significant cause of death and disability. Therapeutic hypothermia (TH) is the only available standard of treatment, but 45-55% of cases still result in death or neurodevelopmental disability following TH. This work has focussed on developing a new brain tissue physiology and biochemistry systems biology model that includes temperature effects, as well as a Bayesian framework for analysis of model parameter estimation. Through this, we can simulate the effects of temperature on brain tissue oxygen delivery and metabolism, as well as analyse clinical and experimental data to identify mechanisms to explain differing behaviour and outcome. Presented here is an application of the model to data from two piglets treated with TH following hypoxic-ischaemic injury showing different responses and outcome following treatment. We identify the main mechanism for this difference as the Q10 temperature coefficient for metabolic reactions, with the severely injured piglet having a median posterior value of 0.133 as opposed to the mild injury value of 5.48. This work demonstrates the use of systems biology models to investigate underlying mechanisms behind the varying response to hypothermic treatment.