Tumour spheroids are widely used as an in vitro assay for characterising the dynamics and response to treatment of different cancer cell lines. Their popularity is largely due to the reproducible ...manner in which spheroids grow: the diffusion of nutrients and oxygen from the surrounding culture medium, and their consumption by tumour cells, causes proliferation to be localised at the spheroid boundary. As the spheroid grows, cells at the spheroid centre may become hypoxic and die, forming a necrotic core. The pressure created by the localisation of tumour cell proliferation and death generates an cellular flow of tumour cells from the spheroid rim towards its core. Experiments by Dorie et al. showed that this flow causes inert microspheres to infiltrate into tumour spheroids via advection from the spheroid surface, by adding microbeads to the surface of tumour spheroids and observing the distribution over time. We use an off-lattice hybrid agent-based model to re-assess these experiments and establish the extent to which the spatio-temporal data generated by microspheres can be used to infer kinetic parameters associated with the tumour spheroids that they infiltrate. Variation in these parameters, such as the rate of tumour cell proliferation or sensitivity to hypoxia, can produce spheroids with similar bulk growth dynamics but differing internal compositions (the proportion of the tumour which is proliferating, hypoxic/quiescent and necrotic/nutrient-deficient). We use this model to show that the types of experiment conducted by Dorie et al. could be used to infer spheroid composition and parameters associated with tumour cell lines such as their sensitivity to hypoxia or average rate of proliferation, and note that these observations cannot be conducted within previous continuum models of microbead infiltration into tumour spheroids as they rely on resolving the trajectories of individual microbeads.
In this study we propose a novel phase-field theory based on non-equilibrium thermodynamics that resolves both the macroscopic deformations and the internal structure of a polyelectrolyte gel ...immersed in an ionic solution. The governing equations for the gel account for its electro-chemical response, the nonlinear elasticity of its polyelectrolyte network, multi-component Stefan–Maxwell diffusion and the energy cost of internal interfaces that form upon phase separation. These equations are coupled to a hydrodynamic model for the surrounding ionic solution. The full time-dependent model describes the evolution of the gel-solution system across multiple time and spatial scales revealing the mechano-electro-chemical mechanisms that regulate phase separation of the gel, which results in the emergence of complex spatial patterns. The rich dynamics of this system are investigated for a constrained gel undergoing uni-axial deformations. We find that the regulation of phase separation in the gel-bath system is dependent on the competition between two physical length scales: the Debye and Kuhn lengths which characterise the thickness of electric double layers and diffuse interfaces, respectively. When the Kuhn length is much larger than the Debye length, the standard electroneutral assumption can be invoked. In this case, we show that large-scale solvent flux can result in the phase separation of the gel. Depending on the concentration of ions in the surrounding bath, swelling/deswelling of the gel occurs either via propagation of a front from the gel-bath interface or via front propagation combined with spinodal decomposition. In the limit where the Kuhn and Debye length are commensurate, our model predicts a novel mode of phase separation which results in the gel bulk organising into spatially localised stable charged domains that emanate from the Debye layer and propagate through the whole gel.
•Derive a phase-field model of a polyelectrolyte gel in ionic solution.•Self-organisation of the gel is dictated by interplay of Kuhn and Debye lengths.•Multiple routes to gel collapse involving spinodal decomposition.•The electric double layer can play an active role in phase separation.•New mode of localised patterning leads to breakdown of electroneutrality.
Clovis, with its distinctive biface, blade and osseous technologies, is the oldest widespread archaeological complex defined in North America, dating from 11,100 to 10,700 (14)C years before present ...(bp) (13,000 to 12,600 calendar years bp). Nearly 50 years of archaeological research point to the Clovis complex as having developed south of the North American ice sheets from an ancestral technology. However, both the origins and the genetic legacy of the people who manufactured Clovis tools remain under debate. It is generally believed that these people ultimately derived from Asia and were directly related to contemporary Native Americans. An alternative, Solutrean, hypothesis posits that the Clovis predecessors emigrated from southwestern Europe during the Last Glacial Maximum. Here we report the genome sequence of a male infant (Anzick-1) recovered from the Anzick burial site in western Montana. The human bones date to 10,705 ± 35 (14)C years bp (approximately 12,707-12,556 calendar years bp) and were directly associated with Clovis tools. We sequenced the genome to an average depth of 14.4× and show that the gene flow from the Siberian Upper Palaeolithic Mal'ta population into Native American ancestors is also shared by the Anzick-1 individual and thus happened before 12,600 years bp. We also show that the Anzick-1 individual is more closely related to all indigenous American populations than to any other group. Our data are compatible with the hypothesis that Anzick-1 belonged to a population directly ancestral to many contemporary Native Americans. Finally, we find evidence of a deep divergence in Native American populations that predates the Anzick-1 individual.
•We homogenize transport equation in multiscale porous media and multiphase systems.•We compare the multiscale asymptotic and the volume averaging theories.•This paper is also intended as a ...pedagogical guide and may be viewed as a tutorial for graduate students.
A wide variety of techniques have been developed to homogenize transport equations in multiscale and multiphase systems. This has yielded a rich and diverse field, but has also resulted in the emergence of isolated scientific communities and disconnected bodies of literature. Here, our goal is to bridge the gap between formal multiscale asymptotics and the volume averaging theory. We illustrate the methodologies via a simple example application describing a parabolic transport problem and, in so doing, compare their respective advantages/disadvantages from a practical point of view. This paper is also intended as a pedagogical guide and may be viewed as a tutorial for graduate students as we provide historical context, detail subtle points with great care, and reference many fundamental works.
Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI ...regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy.
Retrospective single-centre cohort.
Adults who switched to RAL or DTG before or between January 2015 and October 2017 were identified. Virologically suppressed, treatment-experienced (≥2 years) individuals, at least 6 months on INSTI, with weight measurements 2 years or less pre and postswitch were included. Our analysis used a random effects model with linear slope pre and post-INSTI with adjustment for age, sex, ethnicity, preswitch-regimen (protease inhibitor vs. nonprotease inhibitor), and RAL vs. DTG use.
A total of 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and BMI at switch of 76.6 kg and 25.3 kg/m, respectively, were included. Weight increased by an average of 0.63 kg/year (95% confidence interval 0.17-1.09) preswitch with no overall change in rate of weight gain postswitch +0.05 kg/year (-0.61-0.71, P = 0.88). In our adjusted model, a transition from minimal weight change to weight gain postswitch was isolated to older individuals though this lacked statistical significance e.g., +1.59 kg/year (-0.26-3.45) if aged 65 years. Our findings did not differ by sex, ethnicity, preswitch regimen, or RAL vs. DTG. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone.
We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically suppressed individuals.
•The immunology underlying autoimmune myocarditis is captured in a mathematical model.•Disease outcomes can be represented by multiple non-negative steady states.•Immune checkpoint inhibitors lower ...the threshold for disease development.•Different patients and their risk of disease can be explored using the model.
Autoimmune myocarditis is a rare, but frequently fatal, side effect of immune checkpoint inhibitors (ICIs), a class of cancer therapies. Despite extensive experimental work on the causes, development and progression of this disease, much still remains unknown about the importance of the different immunological pathways involved. We present a mathematical model of autoimmune myocarditis and the effects of ICIs on its development and progression to either resolution or chronic inflammation. From this, we gain a better understanding of the role of immune cells, cytokines and other components of the immune system in driving the cardiotoxicity of ICIs. We parameterise the model using existing data from the literature, and show that qualitative model behaviour is consistent with disease characteristics seen in patients in an ICI-free context. The bifurcation structures of the model show how the presence of ICIs increases the risk of developing autoimmune myocarditis. This predictive modelling approach is a first step towards determining treatment regimens that balance the benefits of treating cancer with the risk of developing autoimmune myocarditis.
Knowledge of protein dynamics is fundamental to the understanding of biological processes, with NMR and 2D-IR spectroscopy being two of the principal methods for studying protein dynamics. Here, we ...combine these two methods to gain a new understanding of the complex mechanism of a cytokine:receptor interaction. The dynamic nature of many cytokines is now being recognised as a key property in the signalling mechanism. Interleukin-17s (IL-17) are proinflammatory cytokines which, if unregulated, are associated with serious autoimmune diseases such as psoriasis, and although there are several therapeutics on the market for these conditions, small molecule therapeutics remain elusive. Previous studies, exploiting crystallographic methods alone, have been unable to explain the dramatic differences in affinity observed between IL-17 dimers and their receptors, suggesting there are factors that cannot be fully explained by the analysis of static structures alone. Here, we show that the IL-17 family of cytokines have varying degrees of flexibility which directly correlates to their receptor affinities. Small molecule inhibitors of the cytokine:receptor interaction are usually thought to function by either causing steric clashes or structural changes. However, our results, supported by other biophysical methods, provide evidence for an alternate mechanism of inhibition, in which the small molecule rigidifies the protein, causing a reduction in receptor affinity. The results presented here indicate an induced fit model of cytokine:receptor binding, with the more flexible cytokines having a higher affinity. Our approach could be applied to other systems where the inhibition of a protein-protein interaction has proved intractable, for example due to the flat, featureless nature of the interface. Targeting allosteric sites which modulate protein dynamics, opens up new avenues for novel therapeutic development.
The varying dynamic nature of IL-17 dimers correlates to their affinity for IL-17 receptor A. An inhibitor of IL-17:receptor A binding was shown to rigidify IL-17A revealing an important new regulatory mechanism.
Found in 1968, the archaeological site of Anzick, Montana, contains the only known Clovis burial. Here, the partial remains of a male infant, Anzick-1, were found in association with a Clovis ...assemblage of over 100 lithic and osseous artifacts—all red-stained with ochre. The incomplete, unstained cranium of an unassociated, geologically younger individual, Anzick-2, was also recovered. Previous chronometric work has shown an age difference between Anzick-1 and the Clovis assemblage (represented by dates from two antler rod samples). This discrepancy has led to much speculation, with some discounting Anzick-1 as Clovis. To resolve this issue, we present the results of a comprehensive radiocarbon dating program that utilized different pretreatment methods on osseous material from the site. Through this comparative approach, we obtained a robust chronometric dataset that suggests that Anzick-1 is temporally coeval with the dated antler rods. This implies that the individual is indeed temporally associated with the Clovis assemblage.
Three dimensions of thermolabile sex determination Waters, Paul D.; Graves, Jennifer A. Marshall; Whiteley, Sarah L. ...
BioEssays,
February 2023, 2023-02-00, 20230201, Letnik:
45, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The molecular mechanism of temperature‐dependent sex determination (TSD) is a long‐standing mystery. How is the thermal signal sensed, captured and transduced to regulate key sex genes? Although ...there is compelling evidence for pathways via which cells capture the temperature signal, there is no known mechanism by which cells transduce those thermal signals to affect gene expression. Here we propose a novel hypothesis we call 3D‐TSD (the three dimensions of thermolabile sex determination). We postulate that the genome has capacity to remodel in response to temperature by changing 3D chromatin conformation, perhaps via temperature‐sensitive transcriptional condensates. This could rewire enhancer–promoter interactions to alter the expression of key sex‐determining genes. This hypothesis can accommodate monogenic or multigenic thermolabile sex‐determining systems, and could be combined with upstream thermal sensing and transduction to the epigenome to commit gonadal fate.
Our 3D‐TSD hypothesis (three dimensions of thermolabile sex determination) proposes that temperature can directly induce spatial reorganization of chromatin within transcriptional condensates (pink circle). This would affect expression of sex‐determining genes by rewiring enhancer ‐ promoter (yellow and red bars) interactions that commit to ovary (pink) or testis (blue) developmental pathways.
Objectives
Integrase strand transfer inhibitors (INSTIs) are commonplace in modern antiretroviral therapy (ART). Increased weight gain with their use is increasingly scrutinized. We evaluated weight ...changes in treatment‐naïve adults with HIV‐1 attending a UK centre who started regimens including raltegravir or dolutegravir.
Methods
A retrospective cohort study of adults prescribed an INSTI between January 2015 and March 2020 were categorized as having started an ART regimen containing raltegravir, dolutegravir, a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Individuals with one or more weight measurement ≤ 5 years both pre‐ and post‐ART initiation, who started a three‐drug regimen with ≥ 6 months duration and achieved virological suppression (< 50 copies/mL) within 6 months were included. A random effects model with linear slope pre‐ and post‐ART was used, adjusting for age, gender, ethnicity, ART regimen, backbone and year of initiation.
Results
The cohort included 390 adults; 88.7% were male, 66.4% were of white ethnicity, their median age was 40 years, there was a median of six weight measurements, 2.2 years from diagnosis to ART initiation, 2.9 years from ART to the last weight measurement, and weight and body mass index at initiation were 75 kg and 24.1 kg/m2 respectively. Of these, 254 (65%) started an INSTI. The average pre‐ART rate of weight gain was 0.44 kg/year 95% confidence interval (CI): 0.19–0.70, increasing to 0.88 kg/year (0.63–1.10, p = 0.04) after ART initiation. Our adjusted model found no evidence of an association between ART regimen and rate of weight gain.
Conclusions
Weight increased in the cohort both pre‐ and post‐ART. We found no evidence of a higher rate of weight gain following ART initiation with an INSTI compared with other regimens.
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