Toward a mechanical control of drug delivery. On the relationship between Lipinski’s 2nd rule and cytosolic pH changes in doxorubicin resistance levels in cancer cells: a comparison to published data

Based on molecular and physiological resemblance, the mechanism that controls drug bioavailability and toxicity also shares strong similarities to the one that controls drug resistance. In both cases, this mechanism relies on the expression of drug transporters and the physico-chemical properties of drugs, which together alter the intracellular accumulation of chemicals in cells or tissues. However, a parameter that is central and has received great attention in the field of bioavailability, but almost none in the field of drug resistance, is the molecular weight of drugs. In the former area, it is well known that to achieve a reasonable bioavailability, drugs must have—among other properties—a molecular weight less than 500, known as Lipinski’s 2nd rule. Accordingly, it is worth questioning whether a similar rule exists in the field of drug resistance and what subsequent mechanism would control the membrane permeability to drugs as a function of their molecular weight. I demonstrate here that cytosolic pH fixes the molecular weight of drugs entering cells, by altering the cell membrane mechanical properties and that, both cytosolic pH and membrane mechanical properties are needed and sufficient to explain doxorubicin resistance levels in different cancerous cell lines. Finally, I discuss the efficiency of a drug handling activity by transporters in MDR and suggest ways to control drug delivery mechanically. In addition, and for the first time, the literal expression of a Law similar to Lipinski’s 2nd rule will be described as a function of cytosolic pH and lipid number asymmetry.

A symbiotic relationship of energy metabolism between a ‘non-glycolytic’ mammalian red cell and the liver

The red cell of newborn pig loses the ability to carry out glycolysis within a month after birth. The metabolic energy source for this ‘non-glycolytic’ mammalian red cell is unknown. Hepatectomy of an adult pig results in the loss of red cell ATP with a characteristic half-time of 7–8 h which is identical to the rate with which ATP disappears in the pig cells under in vitro substrate-free incubation. Exposure of pig red cells with either normal or depleted levels of ATP to isolated hepatocytes causes a net synthesis of red cell ATP during a 12 h incubation. These findings suggest that a symbiotic relationship of energy metabolism may exist between the red cell and the liver of the pig.     

Electrooptical properties of the microbial suspensions during a cell’s interaction with the antibodies of a different specificity

The electrooptical abilities of the microbial suspensions during a cells interaction with antibodies (ABs) of a different specificity have been studied on the example of the Azospirillum brasilense Sp245 cells and their interaction with the polyclonal monospecific and polyspecific antibodies. Measuring of the orientational spectra of the cells has been performed using the ELUS electrooptical analyzer. A discrete frequency set of an orienting electric field (740, 1000, 1450, 2000, and 2800 kHz) was used. It has been shown that an interaction of the polyspecific AB with the investigated cells redoubles the value of an electrooptical signal of the cells’ suspension as compared with the monospecific antibodies. These findings can be used for a development a new method of microorganism detection.     

Okasha’s evolution and the levels of selection: toward a broader conception of theoretical biology

The debate about the levels of selection has been one of the most controversial both in evolutionary biology and in philosophy of science. Okasha’s book makes the sort of contribution that simply will not be able to be ignored by anyone interested in this field for many years to come. However, my interest here is in highlighting some examples of how Okasha goes about discussing his material to suggest that his book is part of an increasingly interesting trend that sees scientists and philosophers coming together to build a broadened concept of “theory” through a combination of standard mathematical treatments and conceptual analyses. Given the often contentious history of the relationship between philosophy and science, such trend cannot but be welcome.     

Conservative treatment in Scheuermann’s kyphosis: comparison between lateral curve and variation of the vertebral geometry

Background

Conservative treatment in the Scheuermann’s kyphosis obtain, during skeletal growth, remodelling of the deformed vertebras. In a previous paper on Scheuermann’s kyphosis, we have studied the geometry variations of all vertebrae included in the curve, before and after the treatment.

The purpose of this study was to confirm the effectiveness of conservative treatment in Scheuermann’s kyphosis and was to evaluate and compare the variation of the vertebral geometry with the curve trend in Cobb degrees, before and after conservative treatment.

Methods

From a consecutive series of patients, we selected 90 patients with thoracic Scheuermann’s kyphosis, treated using anti-gravity brace: 59 male, 31 female. The mean age at the beginning of the treatment was 14 years.

Radiographical measurements were performed on radiographs from a lateral projection, at the beginning (t1) and at the end of the treatment (t5). Vertebral geometry modifications at t1 and t5 were analysed according to the following parameters and evaluated by three independent observers: Anterior wedging angle (ALFA) of the apex vertebra and Posterior wall inclination (APOS) of the limiting lower vertebra. The curve was measured in Cobb degrees.

Results

The results from our study showed that of the 90 patients with a thoracic curve mean value of Cobb degrees was 57.8 ± 6.0 SD at t1 and 41.3 ± 5.6 SD at t5. The differences between t1(angle at baseline) and t5 (end of treatment) were calculated for Cobb, ALFA and APOS angle and were respectively −16.4 ± 4.5, −6.4 ± 1.4 and −2.7 ± 1.2; tested with paired t-test were significative (p < 0.01). The results of the regression analysis to test the relationship between the three measures for the kyphosis (Cobb degree, ALFA and APOS) showed that the best association was between Cobb t5 and ALFA t5 (p < 0.01) and Cobb t1 and APOS t1 (p < 0.01). No significative association was found between the difference between ALFA and APOS.

Conclusion

We sustain that using new parameters to study vertebral remodelling allows us to reach a better comprehension of Scheuermann spine response to anti-gravity brace treatment. Furthermore, the evaluation of the ALFA angle of the apex vertebra confirms to be more reliable than Cobb’s angle because it cannot be affected by the radiological position.

     

Effect of variable periodontal ligament thickness and its non-linear material properties on the location of a tooth’s centre of resistance

In orthodontics, the 3D translational and rotational movement of a tooth is determined by the force–moment system applied and the location of the tooth’s centre of resistance (CR). Because of the practical constraints of in-vivo experiments, the finite element (FE) method is commonly used to determine the CR. The objective of this study was to investigate the geometric model details required for accurate CR determination, and the effect of material non-linearity of the periodontal ligament (PDL). A FE model of a human lower canine derived from a high-resolution µCT scan (voxel size: 50 µm) was investigated by applying four different modelling approaches to the PDL. These comprised linear and non-linear material models, each with uniform and realistic PDL thickness. The CR locations determined for the four model configurations were in the range 37.2–45.3% (alveolar margin: 0%; root apex: 100%). We observed that a non-linear material model introduces load-dependent results that are dominated by the PDL regions under tension. Load variation within the range used in clinical orthodontic practice resulted in CR variations below 0.3%. Furthermore, the individualized realistic PDL geometry shifted the CR towards the alveolar margin by 2.3% and 2.8% on average for the linear and non-linear material models, respectively. We concluded that for conventional clinical therapy and the generation of representative reference data, the least sophisticated modelling approach with linear material behaviour and uniform PDL thickness appears sufficiently accurate. Research applications that require more precise treatment monitoring and planning may, however, benefit from the more accurate results obtained from the non-linear constitutive law and individualized realistic PDL geometry.     

Cost of resistance: relationship between reduced fertility and increased resistance in a snail—schistosome host—parasite system

Natural host populations often exhibit genetic variability in resistance to parasitism. One possible mechanism for maintaining such diversity is a trade-off between fitness costs associated with resistance and fitness costs associated with parasitism. However, little is known about the nature or magnitude of these costs in animal populations. Using artificial selection experiments in a Biomphalaria glabrata–Schistosoma mansoni host–parasite system, we demonstrated that resistance and susceptibility to infection are heritable. We then investigated whether resistance had any associated costs in terms of snail reproductive success. Susceptible-selected snail lines showed significantly higher fertility (number of offspring produced) than resistant-selected or unselected control snail lines, irrespective of current infection status. There were no consistent differences between snail lines in fecundity, proportion of abnormal egg masses produced, or mean number of eggs per egg mass. Mortality rate was higher among infected than uninfected snails. These results are consistent with snails incurring costs of resistance to schistosome infection in the absence of the parasite.     

Democratic Hauntings: Michael Hanchard’s the Spectre of Race and the challenge of comparison

Michael Hanchard’s the Spectre of Race: How Discrimination Haunts Western Democracy is a sophisticated examination of the disciplinary absence and seething presence of race in the subfield and substance of comparative politics. Hanchard’s analysis reveals a genealogy of how certain concepts, such as political culture, came to be institutionalized in the discipline. Because disciplines discipline, the resultant marginalization of race in comparative politics is itself an act of power. Many of his insights are revelatory, though a more explicit excavation of racial transnationalism is warranted. Such an effort would: first, demonstrate that the transnational “entanglements” Hanchard details are even more knotted than originally presumed; second, challenge the conflation of racialization and colonialism; and third, question whether liberal democratic inclusion is possible or even worth the price of the ticket.     

Can long range mechanical interaction between drugs and membrane proteins define the notion of molecular promiscuity? Application to P-glycoprotein-mediated multidrug resistance (MDR)

Background

Failure of treatment in over 90% of patients with metastatic cancer is due to acquired MDR. P-glycoprotein (Pgp) remains the archetypal drug membrane transporter expressed in many MDR cancer cells. Albeit the ATPase activity of Pgp is triggered by the presence of drug in the membrane, it is commonly assumed that when two drug molecules meet the same Pgp the protein cannot handle them efficiently due to steric effects and as a result the ATPase activity drops. However it is also possible that drug accumulating in the lipid-phase may affect the membrane in such a way that it imposes the mechanical closure of transporters by opposing the force mediated by ATP consumption. In this context, long range interactions between drug and membrane proteins could exist.

Methods

Recent data concerning Pgp structure have allowed us to formalize this hypothesis and we present a physico-mathematical model that is not based on predictive QSAR or other empirical methods applied to experimental data.

Results

Long range mechanical interactions between Pgp and drugs are predicted to occur at an external concentration of drug ~ 10–100 μM as previously determined experimentally at which concentration ~ 50% of transporters should be rendered inactive.

Conclusion

Distance interaction(s) between Pgp and drugs exist explaining an ill-defined effect concerning the ability of any drug to inhibit Pgp once a threshold concentration in the membrane has been reached.

General significance

Potential application of the theory in the field of pharmacology concentrating on the notion of molecular promiscuity and toxicity in drug discovery prediction is discussed.     

Functional and metabolic assessment of the blood cell’s response to exposure to local vibration

Physiological characteristics of blood cells in workers exposed to long-term local vibration were studied. The total cell peroxidase activity, the level of the phagocytic response, neutrophil alkaline phosphatase and acid phosphatase activity levels, and glycogen content in neutrophils and lymphocytes were measured. Changes associated with a decrease in the functional metabolic parameters, depending on the duration of contact with vibrating tools and the severity of clinical symptoms, were detected. The detected differences in changes in cell response may reflect the specific features of the mechanisms of adaptive regulation.     

Mitochondrial dynamics,cell death and the pathogenesis of Parkinson’s disease

The structure and function of the mitochondrial network is regulated by mitochondrial biogenesis, fission, fusion, transport and degradation. A well-maintained balance of these processes (mitochondrial dynamics) is essential for neuronal signaling, plasticity and transmitter release. Core proteins of the mitochondrial dynamics machinery play important roles in the regulation of apoptosis, and mutations or abnormal expression of these factors are associated with inherited and age-dependent neurodegenerative disorders. In Parkinson’s disease (PD), oxidative stress and mitochondrial dysfunction underlie the development of neuropathology. The recessive Parkinsonism-linked genes PTEN-induced kinase 1 (PINK1) and Parkin maintain mitochondrial integrity by regulating diverse aspects of mitochondrial function, including membrane potential, calcium homeostasis, cristae structure, respiratory activity, and mtDNA integrity. In addition, Parkin is crucial for autophagy-dependent clearance of dysfunctional mitochondria. In the absence of PINK1 or Parkin, cells often develop fragmented mitochondria. Whereas excessive fission may cause apoptosis, coordinated induction of fission and autophagy is believed to facilitate the removal of damaged mitochondria through mitophagy, and has been observed in some types of cells. Compensatory mechanisms may also occur in mice lacking PINK1 that, in contrast to cells and Drosophila, have only mild mitochondrial dysfunction and lack dopaminergic neuron loss. A better understanding of the relationship between the specific changes in mitochondrial dynamics/turnover and cell death will be instrumental to identify potentially neuroprotective pathways steering PINK1-deficient cells towards survival. Such pathways may be manipulated in the future by specific drugs to treat PD and perhaps other neurodegenerative disorders characterized by abnormal mitochondrial function and dynamics.     

Dependence of red blood cell dynamics in microvessel bifurcations on the endothelial surface layer’s resistance to flow and compression

Red blood cells (RBCs) make up 40–45% of blood and play an important role in oxygen transport. That transport depends on the RBC distribution throughout the body, which is highly heterogeneous. That distribution, in turn, depends on how RBCs are distributed or partitioned at diverging vessel bifurcations where blood flows from one vessel into two. Several studies have used mathematical modeling to consider RBC partitioning at such bifurcations in order to produce useful insights. These studies, however, assume that the vessel wall is a flat impenetrable homogeneous surface. While this is a good first approximation, especially for larger vessels, the vessel wall is typically coated by a flexible, porous endothelial glycocalyx or endothelial surface layer (ESL) that is on the order of 0.5–1 µm thick. To better understand the possible effects of this layer on RBC partitioning, a diverging capillary bifurcation is analyzed using a flexible, two-dimensional model. In addition, the model is also used to investigate RBC deformation and RBC penetration of the ESL region when ESL properties are varied. The RBC is represented using interconnected viscoelastic elements. Stokes flow equations (viscous flow) model the surrounding fluid. The flow in the ESL is modeled using the Brinkman approximation for porous media with a corresponding hydraulic resistivity. The ESL’s resistance to compression is modeled using an osmotic pressure difference. One cell passes through the bifurcation at a time, so there are no cell–cell interactions. A range of physiologically relevant hydraulic resistivities and osmotic pressure differences are explored. Decreasing hydraulic resistivity and/or decreasing osmotic pressure differences (ESL resistance to compression) produced four behaviors: (1) RBC partitioning nonuniformity increased slightly; (2) RBC deformation decreased; (3) RBC velocity decreased relative to blood flow velocity; and (4) RBCs penetrated more deeply into the ESL. Decreasing the ESL’s resistance to flow and/or compression to pathological levels could lead to more frequent cell adhesion and clotting as well as impaired vascular regulation due to weaker ATP and nitric oxide release. Potential mechanisms that can contribute to these behaviors are also discussed.

     

Congruence between cytochrome oxidase I (COI) and morphological data in Anuraphis spp. (Hemiptera,Aphididae) with a comparison between the utility of the 5’ barcode and 3’ COI regions

The discrimination of species in the genus Anuraphis is particularly difficult due to the overlap of morphological characters. In this study, we used the 5’ (barcode) and 3’ regions of cytochrome oxidase I (COI) to test their utility in the identification of species in this genus as well as closely related species. Both regions were useful to discriminate all the species tested. However the non-barcode 3’ region resulted in higher resolution and support for species relationships when the data were analyzed using both Maximum Likelihood and MrBayes. We propose the development of an integrated database that encompasses morphological, molecular, life-cycle, host plant and bibliographic information to facilitate and increase the accuracy of aphid identification.     

Maintenance of CMV-specific CD8+ T cell responses and the relationship of IL-27 to IFN-γ levels with aging

We investigated whether healthy young (age ? 40) and elderly (age ? 65) people infected with cytomegalovirus (CMV) had similar levels of CD8⁺ T cell cytokine production and proliferation in response to an immunodominant CMV pp65 peptide pool given the role of CD8⁺ T cells in controlling viral infection and the association of CMV with immunosenescence. Plus, we determined the effects of aging and CMV-infectious status on plasma levels of IL-27, an innate immune cytokine with pro- and anti-inflammatory properties, as well as on its relationship to IFN-γ in that IL-27 can promote the production of IFN-γ. The results of our study show that young and elderly people had similar levels of CD8⁺ T cell proliferation, and IFN-γ and TNF-α production in response to CMV pp65 peptides. Plasma levels of IL-27 were similar between the two groups although CMV-infected young and elderly people had a trend toward increased levels of IL-27. Regardless of aging and CMV-infectious status, plasma levels of IL-27 correlated highly with plasma levels of IFN-γ. These findings suggest the maintenance of CMV pp65-specific CD8⁺ T cell proliferation and cytokine production with aging as well as the sustaining of circulatory IL-27 levels and its biological link to IFN-γ in young and elderly people irrespective of CMV infection.     

On the Value of Taxonomy,Phylogeny, and Systematics to Orchid Conservation: Implications for China’s Yachang Orchid Reserve

Orchid classification has undergone a series of significant changes during the past decade as molecular phylogenetic studies have examined relationships at all taxonomic levels in the family. Today, the 750 genera and 25,000 species of Orchidaceae are organized into five subfamilies, the two largest of which (Epidendroideae and Orchidoideae) are further divided into 19 tribes and 43 subtribes. Whereas some of these groups are relatively small in terms of total species numbers, and may be of little horticultural or medicinal value, they are especially important for understanding orchid evolution and may deserve to be conserved for this reason alone. The question of which orchids to conserve is a complex one, but the science of systematics, including taxonomy and phylogenetics, has an undeniable role to play in answering that question. Among the many ways that phylogenetic trees can assist biologists in setting conservation priorities are by: 1) guiding taxonomists in naming species, which is essential for creating checklists within floras, monographs, and inventories; 2) discovering overlooked, rare or cryptic species that deserve recognition and protection; 3) determining whether or not a taxon is actually a species or simply a variant or hybrid; 4) predicting species that may be of value to humans for economic value; 5) identifying species that may have particularly important scientific value for better understanding the biology of plants. In the same way that we cannot protect all habitats, we may not be able to save every orchid species. Priorities must be established. The Yachang Orchid Reserve has been recognized as important not only because of the number of individual orchid plants that grow there, but also because of its great orchid diversity. Diversity is a product of evolution by natural selection, and the science of phylogenetics has a role to play in better understanding that process.