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Abstract Traumatic brain injury (TBI) is associated with poor clinical outcomes; autopsy studies of TBI victims demonstrate significant oligodendrocyte progenitor cell (OPC) death post TBI; an observation, which may explain the lack of meaningful repair of injured axons. Whilst high-mobility group box-1 (HMGB1) and its key receptors TLR2/4 are identified as key initiators of neuroinflammation post-TBI, they have been identified as attractive targets for development of novel therapeutic approaches to improve post-TBI clinical outcomes. In this report we establish unequivocal evidence that HMGB1 released in vitro impairs OPC response to mechanical injury; an effect that is pharmacologically reversible. We show that needle scratch injury hyper-acutely induced microglial HMGB1 nucleus-to-cytoplasm translocation and subsequent release into culture medium. Application of injury-conditioned media resulted in significant decreases in OPC number through anti-proliferative effects. This effect was reversed by co-treatment with the TLR2/4 receptor antagonist BoxA. Furthermore, whilst injury conditioned medium drove OPCs towards an activated reactive morphology, this was also abolished after BoxA co-treatment. We conclude that HMGB1, through TLR2/4 dependant mechanisms, may be detrimental to OPC proliferation following injury in vitro, negatively affecting the potential for restoring a mature oligodendrocyte population, and subsequent axonal remyelination. Further study is required to assess how HMGB1-TLR signalling influences OPC maturation and myelination capacity.

Objective: Pulmonary arterioplasty (PA plasty) at bidirectional cavopulmonary anastomosis (BDCA) is associated with increased morbidity, but outcomes to final stage palliation are unknown. We sought to determine the influence of PA plasty on pulmonary artery growth and hemodyamics at Fontan. Methods: We retrospectively reviewed clinical data and outcomes for BDCA patients from 2006 to 2018. PA plasty was categorized by extent (type 1-4), as previously described. Outcomes included pulmonary artery reintervention and mortality before final palliation. Results: Five hundred eighty-eight patients underwent BDCA. One hundred seventy-nine patients (30.0%) underwent concomitant PA plasty. Five hundred seventy (97%) patients (169 [94%] PA plasty) survived to BDCA discharge. One hundred forty out of 570 survivors (25%) required PA/Glenn reintervention before final stage palliation (59 out of 169 [35%]) PA plasty; 81 out of 401 (20%) non-PA plasty; P

Abstract Anthropogenic factors have impacted the diversity and evolutionary trajectory of various species. This can be through factors such as pressure on population size or range, habitat fragmentation, or extensive manipulation and translocation. Here we use time-calibrated data to better understand the pattern and processes of evolution in the heavily manipulated European fallow deer (Dama dama). During the Pleistocene, fallow deer had a broad distribution across Europe and were found as far north as Britain during the Eemian interglacial. The last glacial period saw fallow deer retreat to southern refugia and they did not disperse north afterwards. Their recolonisation was mediated by people and, from northern Europe and the British Isles, fallow deer were transported around the world. We use ancient and modern mitochondrial DNA (mtDNA) and mitogenomic data from Eemian Britain to assess the pattern of change in distribution and lineage structure across Europe over time. We find founder effects and mixed lineages in the northern populations, and stability over time for populations in southern Europe. The Eemian sample was most similar to a lineage currently in Italy, suggesting an early establishment of the relevant refuge. We consider the implications for the integration of anthropogenic and natural processes towards a better understanding of the evolution of fallow deer in Europe.

How was testing—and not testing—for coronavirus articulated as a testing situation on social media in the Spring of 2020? Our study examines everyday situations of Covid-19 testing by analyzing a large corpus of Twitter data collected during the first 2 months of the pandemic. Adopting a sociological definition of testing situations, as moments in which it is no longer possible to go on in the usual way, we show how social media analysis can be used to surface a range of such situations across scales, from the individual to the societal. Practicing a form of large-scale data exploration we call “interpretative querying” within the framework of situational analysis, we delineated two types of coronavirus testing situations: those involving locations of testing and those involving relations. Using lexicon analysis and composite image analysis, we then determined what composes the two types of testing situations on Twitter during the relevant period. Our analysis shows that contrary to the focus on individual responsibility in UK government discourse on Covid-19 testing, English-language Twitter reporting on coronavirus testing at the time thematized collective relations. By a variety of means, including in-memoriam portraits and infographics, this discourse rendered explicit challenges to societal relations and arrangements arising from situations of testing and not testing for Covid-19 and highlighted the multifaceted ways in which situations of corona testing amplified asymmetrical distributions of harms and benefits between different social groupings, and between citizens and state, during the first months of the pandemic.

Networks have risen to prominence as intellectual technologies and graphical representations, not only in science, but also in journalism, activism, policy, and online visual cultures. Inspired by approaches taking trouble as occasion to (re)consider and reflect on otherwise implicit knowledge practices, in this article we explore how problems with network practices can be taken as invitations to attend to the diverse settings and situations in which network graphs and maps are created and used in society. In doing so, we draw on cases from our research, engagement and teaching activities involving making networks, making sense of networks, making networks public, and making network tools. As a contribution to “critical data practice,” we conclude with some approaches for slowing down and caring for network practices and their associated troubles to elicit a richer picture of what is involved in making networks work as well as reconsidering their role in collective forms of inquiry.

The lubricant inlet meniscus in a rolling element bearing acts as a reservoir that feeds the elastohydrodynamic contact, resulting in a sufficiently thick film to avoid wear. A shortening and/or thinning of the inlet meniscus towards the contact centre is an indicator of bearing starvation and impaired lubricant performance. This work introduces an ultrasonic method to measure meniscus dimensions. Using in situ ultrasonic sensors on a full-scale cylindrical roller bearing test rig, we show that ultrasonic waves can cause oil films to resonate, and that the resonant frequency is directly related to the film thickness. Using a benchtop rig we validate the relationship between resonant frequency and film thickness. This allows for the measurement of meniscus thickness and length in situ during bearing operation. Menisci were measured at both the inlet and outlet of rolling bearing line contacts while lubricated with different viscosity oils and grease. All lubricants used showed they could be monitored using this approach. The implication of this paper is that it is possible to measure a critically important lubrication mechanism during operation without major component modifications.

Optimal human islet isolation requires the delivery of bacterial collagenase to the pancreatic islet–exocrine interface. However, we have previously demonstrated the presence of collagenase within human islets immediately following intraductal collagenase administration. This potentially has significant implications for patient safety. The present study aimed to determine if collagenase becomes internalized into islets during the isolation procedure and if it remains within the islet postisolation. Islet samples were taken at various stages throughout 14 clinical human islet isolations: during digest collection, following University of Wisconsin solution incubation, immediately postisolation, and after 24 h of culture. Samples were embedded in agar, cryosectioned, and then assessed by immunolabeling for collagenase and insulin. Immunoreactivity for collagenase was not observed in isolated islets in any preparation. Collagenase labeling was detected in one sample taken at the digest collection phase in one islet preparation only. No collagenase-specific labeling was seen in islets sampled at any of the other time points in any of the 14 islet preparations. Collagenase that enters islets during intraductal administration is washed out of the islets during the collection phase of the isolation process and thus does not remain in islets after isolation. This observation alleviates some of the important safety concerns that collagenase remains within islet grafts.

There is a concerted global effort to digitize biodiversity occurrence data from herbarium and museum collections that together offer an unparalleled archive of life on Earth over the past few centuries. The Global Biodiversity Information Facility provides the largest single gateway to these data. Since 2004 it has provided a single point of access to specimen data from databases of biological surveys and collections. Biologists now have rapid access to more than 120 million observations, for use in many biological analyses. We investigate the quality and coverage of data digitally available, from the perspective of a biologist seeking distribution data for spatial analysis on a global scale. We present an example of automatic verification of geographic data using distributions from the International Legume Database and Information Service to test empirically, issues of geographic coverage and accuracy. There are over 1/2 million records covering 31% of all Legume species, and 84% of these records pass geographic validation. These data are not yet a global biodiversity resource for all species, or all countries. A user will encounter many biases and gaps in these data which should be understood before data are used or analyzed. The data are notably deficient in many of the world's biodiversity hotspots. The deficiencies in data coverage can be resolved by an increased application of resources to digitize and publish data throughout these most diverse regions. But in the push to provide ever more data online, we should not forget that consistent data quality is of paramount importance if the data are to be useful in capturing a meaningful picture of life on Earth.

The formal Laplace-Borel transform of an analytic integral operator, known as a Fliess operator, is defined and developed. Then, in conjunction with the composition product over formal power series, the formal Laplace-Borel transform is shown to provide an isomorphism between the semigroup of all Fliess operators under operator composition and the semigroup of all locally convergent formal power series under the composition product. Finally, the formal Laplace-Borel transform is applied in a systems theory setting to explicitly derive the relationship between the formal Laplace transform of the input and output functions of a Fliess operator. This gives a compact interpretation of the operational calculus of Fliess for computing the output response of an analytic nonlinear system.

Several mathematical formulations have analyzed the time-dependent behavior of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the thermodynamically constrained averaging theory. A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TCs), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HCs); and an interstitial fluid for the transport of nutrients. The equations are solved by a finite element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTSs) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behavior: initially, the rapidly growing TCs tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 μ m, surrounded by a shell of viable TCs whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case—mostly due to the relative adhesion of the TCs and HCs to the ECM, and the less favorable transport of nutrients. In particular, for HCs adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas TC infiltration is predicted for the opposite condition. Interestingly, the infiltration potential of the tumor mass is mostly driven by the relative cell adhesion to the ECM. In the third case, a tumor cord model is analyzed where the malignant cells grow around microvessels in a three-dimensional geometry. It is shown that TCs tend to migrate among adjacent vessels seeking new oxygen and nutrients. This model can predict and optimize the efficacy of anticancer therapeutic strategies. It can be further developed to answer questions on tumor biophysics, related to the effects of ECM stiffness and cell adhesion on TC proliferation.

As a tool for addressing problems of scale, we consider an evolving approach known as the thermodynamically constrained averaging theory (TCAT), which has broad applicability to hydrology. We consider the case of modeling of two-fluid-phase flow in porous media, and we focus on issues of scale as they relate to various measures of pressure, capillary pressure, and state equations needed to produce solvable models. We apply TCAT to perform physics-based data assimilation to understand how the internal behavior influences the macroscale state of two-fluid porous medium systems. A microfluidic experimental method and a lattice Boltzmann simulation method are used to examine a key deficiency associated with standard approaches. In a hydrologic process such as evaporation, the water content will ultimately be reduced below the irreducible wetting-phase saturation determined from experiments. This is problematic since the derived closure relationships cannot predict the associated capillary pressures for these states. We demonstrate that the irreducible wetting-phase saturation is an artifact of the experimental design, caused by the fact that the boundary pressure difference does not approximate the true capillary pressure. Using averaging methods, we compute the true capillary pressure for fluid configurations at and below the irreducible wetting-phase saturation. Results of our analysis include a state function for the capillary pressure expressed as a function of fluid saturation and interfacial area.

Culture of human pancreatic islets is now routinely carried out prior to clinical islet allotransplantation, using conditions that have been developed empirically. One of the major causes of early islet destruction after transplantation is the process termed instant blood-mediated inflammatory reaction (IBMIR). The aim of this study was to develop in vitro methods to investigate IBMIR and apply them to the culture conditions used routinely in our human islet isolation laboratory. Freshly isolated or precultured (24 h, 48 h) human islets were incubated in either ABO-compatible allogeneic human blood or Hank's buffered salt solution (HBSS) for 1 h at 37°C. Tissue factor (TF) expression and leukocyte migration were assessed by light microscopy. TF was also quantified by ELISA. To assess β-cell function, glucose-stimulated insulin secretion (GSIS) assay was carried out. The extent of islet β-cell damage was quantified using a proinsulin assay. Islets cultured for 24 h had higher GSIS when compared to freshly isolated or 48-h precultured islets. Freshly isolated islets had significantly higher TF content than 24-h and 48-h precultured islets. Incubation of freshly isolated human islets in allogeneic human blood released 6.5-fold higher level of proinsulin in comparison to freshly isolated human islets in HBSS. The high level of proinsulin released was significantly attenuated when precultured islets (24 h or 48 h) were exposed to fresh blood. Histological examination of fresh islets in blood clot showed that some islets were fragmented, showing signs of extraislet insulin leakage and extensive neutrophil infiltration and necrosis. These features were markedly reduced when the islets were cultured for 24 h. These results suggest that our standard 24-h islet culture is markedly beneficial in attenuating IBMIR, as evidenced by increased GSIS, lower content of TF, decrease islet fragmentation, and proinsulin release.

A method for isolating mouse islets which consistently gives a high yield with good purity is described. Using a bovine serum albumin gradient, the mean yield of islets per pancreas is 425 (SEM ± 15) with a consistent purity of over 90%. Single donor to single recipient of islets transplanted under the renal capsule restores normoglycemia in the diabetic recipients within 2 to 5 days of transplantation.