<p>We hypothesize morphogens to be transported on a vector field coincident with neuronal a... more <p>We hypothesize morphogens to be transported on a vector field coincident with neuronal axons (A), with hypothesized transport polarity as shown in (B). We further hypothesize that vector transport of morphogens occurs on aligned microtubule arrays in nerve axons (C, D). A regulatory network (E) integrates molecular-genetic interactions with vector transport in nerves to produce stable, self-assembling morphogen gradients consistent with planarian body-plan in homeostasis (F), and capable of responding to cutting event perturbations to establish new gradients (G). Head and tail regeneration are assumed to be related to concentrations of ERK and <i>β</i>-Cat, respectively (F, G, H). The percentage of regenerated heteromorphoses in a population was estimated from steady-state ERK and <i>β</i>-Cat gradients after cutting (G), where average morphogen concentration at wound edges (G <i>ii</i>, and <i>iii</i>) were used to define the probability of the blastema developing into a head or tail (G, H) using a Markov Chain Model for Regeneration (see text and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006904#pcbi.1006904.g003" target="_blank">Fig 3</a> for details). Head (G, transition ‘<i>i</i>’) and tail (G, transition ‘<i>iv</i>’) regions existing on a fragment prior to cutting were assumed to be terminally differentiated, and to therefore remain as head or tail in the regenerated fragment. In the regulatory network of E, blue lines with circular endpoints represent activating interaction, whereas red lines with flat-line ends represent an inhibitory relationship. Kinesin symbol on Hedgehog node, and dynein symbol on NRF, signify proposed transport of the respective factors. Hh—Hedgehog, Ptc—Patched, Wnt—Wingless/integrated (Wnt1 and Wnt11 combined), <i>β</i>-Cat—<i>β</i>-Catenin, ERK—extracellular-signal regulated kinase, cAMP—cyclic adenosine monophophate, NRF—Notum Regulating Factor.</p
The configuration file that can be used with BETSE to run the anterior-posterior polarity control... more The configuration file that can be used with BETSE to run the anterior-posterior polarity control network.
The role of endogenous bioelectricity in morphogenesis has recently been explored through the fin... more The role of endogenous bioelectricity in morphogenesis has recently been explored through the finite volume-based code BioElectric Tissue Simulation Engine . We extend this platform to electrostatic and osmotic forces due to bioelectrical ion fluxes, causing cell cluster deformation. We further account for mechanosensitive ion channels, which, gated by membrane tension, modulate ion fluxes and, ultimately, bioelectrical forces. We illustrate the potentialities of this combined model of actuation and sensing with reference to cancer progression, osmoregulation, symmetry breaking and long-range signalling. This suggests control strategies for the manipulation of cell networks in vivo .
The shape of an animal body plan is constructed from protein components encoded by the genome. Ho... more The shape of an animal body plan is constructed from protein components encoded by the genome. However, bioelectric networks composed of many cell types have their own intrinsic dynamics, and can drive distinct morphological outcomes during embryogenesis and regeneration. Planarian flatworms are a popular system for exploring body plan patterning due to their regenerative capacity, but despite considerable molecular information regarding stem cell differentiation and basic axial patterning, very little is known about how distinct head shapes are produced. Here, we show that after decapitation in G. dorotocephala, a transient perturbation of physiological connectivity among cells (using the gap junction blocker octanol) can result in regenerated heads with quite different shapes, stochastically matching other known species of planaria (S. mediterranea, D. japonica, and P. felina). We use morphometric analysis to quantify the ability of physiological network perturbations to induce different species-specific head shapes from the same genome. Moreover, we present a computational agent-based model of cell and physical dynamics during regeneration that quantitatively reproduces the observed shape changes. Morphological alterations induced in a genomically wild-type G. dorotocephala during regeneration include not only the shape of the head but also the morphology of the brain, the characteristic distribution of adult stem cells (neoblasts), and the bioelectric gradients of resting potential within the anterior tissues. Interestingly, the shape change is not permanent; after regeneration is complete, intact animals remodel back to G. dorotocephala-appropriate head shape within several weeks in a secondary phase of remodeling following initial complete regeneration. We present a conceptual model to guide future work to delineate the molecular mechanisms by which bioelectric networks stochastically select among a small set of discrete head morphologies. Taken together, these data and analyses shed light on important physiological modifiers of morphological information in dictating species-specific shape, and reveal them to be a novel instructive input into head patterning in regenerating planaria.
ABSTRACT Calcium phosphate coatings were prepared on magnesium substrates via a biomimetic coatin... more ABSTRACT Calcium phosphate coatings were prepared on magnesium substrates via a biomimetic coating process. The effects of a magnesium hydroxide pretreatment on the formation and the ultimate corrosion protection of the coatings were studied. The pretreatment layer was found to affect the amount of defects present in the coatings. Corrosion resistance of the coatings was studied in vitro using two simulated body fluids, 0.8% NaCl and Hanks solution. In NaCl, the resistance to corrosion of all samples decreases with time as corrosion proceeded through cracks and other defects in the coatings. Samples with no pretreatment displayed the highest corrosion resistance as these samples had the fewest defects in the coating. However, in Hanks solution, corrosion resistance increased with time due to additional nucleation of calcium phosphate from the fluid on to the substrate. In this solution, additional pretreatment time was beneficial to the overall corrosion resistance.
Magnesium (Mg) and its alloys have the potential to revolutionize orthopaedic implants as a biode... more Magnesium (Mg) and its alloys have the potential to revolutionize orthopaedic implants as a biodegradable metal implant; however, strategies are still needed to match its biodegradation rate with the healing rate of bone tissue. In this work, the in situ crystallization of calcium phosphates on pure Mg was developed as an easy and inexpensive method for controlling the corrosion rate
Fundamental mathematical relationships are widespread in biology yet there is little information ... more Fundamental mathematical relationships are widespread in biology yet there is little information on this topic with regard to human limb bone lengths and none related to human limb bone volumes. Forty-six sets of ipsilateral upper and lower limb long bones and third digit short bones were imaged by computed tomography. Maximum bone lengths were measured manually and individual bone volumes calculated from computed tomography images using a stereologic method. Length ratios of femur : tibia and humerus : ulna were remarkably similar (1.21 and 1.22, respectively) and varied little (<7%) between individuals. The volume ratio of femur : tibia was approximately half that of humerus : ulna (1.58 and 3.28, respectively; P < 0.0001). Lower limb bone volume ratios varied much more than upper limb ratios. The relationship between bone length and volume was found to be well described by power laws, with R 2 values ranging from 0.983 to 0.995. The most striking finding was a logarithmic periodicity in bone length moving from distal to proximal up the limb (upper limb k = 0.72, lower limb k = 0.93). These novel data suggest that human limb bone lengths and volumes follow fundamental and highly conserved mathematical relationships, which may contribute to our understanding of normal and disordered growth, stature estimation, and biomechanics.
Impurity centers associated with silicon have been observed in the phase mixture of silicon subst... more Impurity centers associated with silicon have been observed in the phase mixture of silicon substituted apatite (Si-Ap) and silicon stabilized tricalcium phosphate (Si-TCP) using electron spin resonance (ESR). Two unique centers occur upon addition of SiO 2 to the calcium phosphate system: an orthorhombic center with g-values 2.007270.0001, 2.002470.0001 and 2.000370.0001 (Si-h1) and a center with tetrahedral symmetry having g-values components 2.005470.0001 and 1.999270.0003 (Si-h2). Both centers are hypothesized to be characteristic of defects associated with silicon in the Si-Ap phase. Through comparison of the intensity of F-OH centers in undoped calcium hydroxyapatite (HA) prepared with various levels of OH occupancy, a relationship is demonstrated between the ESR intensity of an F-center signal with g ¼ 2.0019+0.0004 (F-OH) and the OH occupation of HA. Relative changes in the intensity of ESR signals Si-h1 and F-OH are consistent with a chemical model describing the substitution of SiO 4 4À for PO 4 3À in HA with the creation of OH À vacancies as charge compensation, resulting in a mixed phase composition of Si-Ap and Si-TCP that results when a hydroxyapatite precipitate (HA) is heated in the presence of added SiO 2 .
The sintering of silicon doped calcium phosphate ceramics prepared from a basic colloidal hydroxy... more The sintering of silicon doped calcium phosphate ceramics prepared from a basic colloidal hydroxyapatite (Ca 5 (PO 4) 3 OH or HA) precipitate mixed with silica over 800 1C yields a phase mixture of tricalcium phosphate phases (TCP) designated Si-TCP, b-TCP and a silicon substituted dehydrated apatite (Si-Ap). The Si-TCP phase is defined as a combination of a silicon stabilized TCP in which the silicon content attains a saturated value (Ca 3 (P 0.9 Si 0.1 O 3.95) 2 or Si-TCP sat) and a-TCP (Ca 3 (PO 4) 2). Si-TCP sat has the same crystalline space group (P2 1 /a) as a-TCP, but with characteristically different lattice parameters due to the substitution of silicon in tetrahedral phosphorus sites. The nucleation and growth kinetics of Si-TCP in samples of composition 0.2 mol SiO 2 :mol HA (0.2:1) and 1 mol SiO 2 :mol HA (1:1) can be understood in terms of the initial growth of a-TCP at a silica-HA interface followed by a transformation to Si-TCP sat or b-TCP. A thermodynamic model for the formation of Si-TCP sat predicts a nucleation temperature of 795 1C, in close agreement with experiment. If sufficient silicon is available, the a-TCP transforms to Si-TCP sat during extended sintering. In the absence of sufficient silicon, the a-TCP transforms to b-TCP.
As a lightweight metal with mechanical properties similar to natural bone, a natural ionic presen... more As a lightweight metal with mechanical properties similar to natural bone, a natural ionic presence with significant functional roles in biological systems, and in vivo degradation via corrosion in the electrolytic environment of the body, magnesium-based implants have the potential to serve as biocompatible, osteoconductive, degradable implants for load-bearing applications. This review explores the properties, biological performance, challenges and future directions of magnesium-based biomaterials.
Theoretical details relating to model details, ion channel, ion pump and transporter dynamics, an... more Theoretical details relating to model details, ion channel, ion pump and transporter dynamics, and BIGR network models that are presented in the main text.
Seminars in cell & developmental biology, Jan 30, 2018
Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medic... more Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medicine, evolutionary biology, morphogenetic engineering, robotics, and unconventional computation. Despite recent advances in the molecular genetics of stem cell differentiation, this model organism's remarkable anatomical homeostasis provokes us with truly fundamental puzzles about the origin of large-scale shape and its relationship to the genome. In this review article, we first highlight several deep mysteries about planarian regeneration in the context of the current paradigm in this field. We then review recent progress in understanding of the physiological control of an endogenous, bioelectric pattern memory that guides regeneration, and how modulating this memory can permanently alter the flatworm's target morphology. Finally, we focus on computational approaches that complement reductive pathway analysis with synthetic, systems-level understanding of morphological decision-...
Abstract: The shape of an animal body plan is constructed from protein components encoded by the ... more Abstract: The shape of an animal body plan is constructed from protein components encoded by the genome. However, bioelectric networks composed of many cell types have their own intrinsic dynamics, and can drive distinct morphological outcomes during embryogenesis and regeneration. Planarian flatworms are a popular system for exploring body plan patterning due to their regenerative capacity, but despite considerable molecular information regarding stem cell differentiation and basic axial patterning, very little is known about how distinct head shapes are produced. Here, we show that after decapitation in G. dorotocephala, a transient perturbation of physiological connectivity among cells (using the gap junction blocker octanol) can result in regenerated heads with quite different shapes, stochastically matching other known species of planaria (S. mediterranea, D. japonica, and P. felina). We use morphometric analysis to quantify the ability of physiological network perturbations to...
Resorbable silicon stabilized tricalcium phosphate (Si-TCP)-based bioceramics are characterized f... more Resorbable silicon stabilized tricalcium phosphate (Si-TCP)-based bioceramics are characterized from a biological perspective by measuring the intermolecular interaction force between osteopontin (OPN) protein and the material surface using atomic force microscopy (AFM). OPN protein was covalently bound to silicon nitride AFM tips and adsorption and adhesion forces were measured in an electrolyte with a composition similar to that of physiological fluids. A strong relationship exists between the adhesion force of OPN on the material surface, the number of adherent osteoclasts (OC) and the resorption of the material. OPN adhesion is strongest on hydroxyapatite (HA) surfaces, or in samples that induce a HA-like surface through a precipitation reaction in electrolytic media. It is proposed that the increased biological response of the Si-TCP phase can be attributed in part to its reactivity in a physiological electrolyte, which involves a rapid conversion to a calcium deficient HA phase with a corresponding increase in the adhesion strength of OPN to the material, with a consequentially higher OC resorption response.
Limited methods exist to aid in deciding the appropriate donor limb lengths in bilateral upper li... more Limited methods exist to aid in deciding the appropriate donor limb lengths in bilateral upper limb amputees qualifying for vascularized composite allotransplantation. We hypothesized mathematical equations could be created using long bone length ratios, and applied to radiographs, to approximate the patient's limb length prior to amputation. A data set of 30 skeletons' unilateral upper limb long bones measured using osteometric board and calipers was used. Anatomic segment ratios were calculated based on humerus length after multivariate linear regression analysis. For clinical application testing, 5 cadavers' upper limbs were radiographed. Radiographic bone lengths were then measured along the long axis of each long bone. These measured radiographic lengths were then compared with the predicted bone lengths, generated from the skeleton data set ratios, for each cadaver. The chi-square goodness-of-fit test showed excellent fit ( P < .01) between the predicted and rad...
Progress in biophysics and molecular biology, Jan 5, 2018
Positional information describes pre-patterns of morphogenetic substances that alter spatio-tempo... more Positional information describes pre-patterns of morphogenetic substances that alter spatio-temporal gene expression to instruct development of growth and form. A wealth of recent data indicate bioelectrical properties, such as the transmembrane potential (V), are involved as instructive signals in the spatiotemporal regulation of morphogenesis. However, the mechanistic relationships between V and molecular positional information are only beginning to be understood. Recent advances in computational modeling are assisting in the development of comprehensive frameworks for mechanistically understanding how endogenous bioelectricity can guide anatomy in a broad range of systems. V represents an extraordinarily strong electric field (∼1.0 × 10 V/m) active over the thin expanse of the plasma membrane, with the capacity to influence a variety of downstream molecular signaling cascades. Moreover, in multicellular networks, intercellular coupling facilitated by gap junction channels may ind...
<p>We hypothesize morphogens to be transported on a vector field coincident with neuronal a... more <p>We hypothesize morphogens to be transported on a vector field coincident with neuronal axons (A), with hypothesized transport polarity as shown in (B). We further hypothesize that vector transport of morphogens occurs on aligned microtubule arrays in nerve axons (C, D). A regulatory network (E) integrates molecular-genetic interactions with vector transport in nerves to produce stable, self-assembling morphogen gradients consistent with planarian body-plan in homeostasis (F), and capable of responding to cutting event perturbations to establish new gradients (G). Head and tail regeneration are assumed to be related to concentrations of ERK and <i>β</i>-Cat, respectively (F, G, H). The percentage of regenerated heteromorphoses in a population was estimated from steady-state ERK and <i>β</i>-Cat gradients after cutting (G), where average morphogen concentration at wound edges (G <i>ii</i>, and <i>iii</i>) were used to define the probability of the blastema developing into a head or tail (G, H) using a Markov Chain Model for Regeneration (see text and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006904#pcbi.1006904.g003" target="_blank">Fig 3</a> for details). Head (G, transition ‘<i>i</i>’) and tail (G, transition ‘<i>iv</i>’) regions existing on a fragment prior to cutting were assumed to be terminally differentiated, and to therefore remain as head or tail in the regenerated fragment. In the regulatory network of E, blue lines with circular endpoints represent activating interaction, whereas red lines with flat-line ends represent an inhibitory relationship. Kinesin symbol on Hedgehog node, and dynein symbol on NRF, signify proposed transport of the respective factors. Hh—Hedgehog, Ptc—Patched, Wnt—Wingless/integrated (Wnt1 and Wnt11 combined), <i>β</i>-Cat—<i>β</i>-Catenin, ERK—extracellular-signal regulated kinase, cAMP—cyclic adenosine monophophate, NRF—Notum Regulating Factor.</p
The configuration file that can be used with BETSE to run the anterior-posterior polarity control... more The configuration file that can be used with BETSE to run the anterior-posterior polarity control network.
The role of endogenous bioelectricity in morphogenesis has recently been explored through the fin... more The role of endogenous bioelectricity in morphogenesis has recently been explored through the finite volume-based code BioElectric Tissue Simulation Engine . We extend this platform to electrostatic and osmotic forces due to bioelectrical ion fluxes, causing cell cluster deformation. We further account for mechanosensitive ion channels, which, gated by membrane tension, modulate ion fluxes and, ultimately, bioelectrical forces. We illustrate the potentialities of this combined model of actuation and sensing with reference to cancer progression, osmoregulation, symmetry breaking and long-range signalling. This suggests control strategies for the manipulation of cell networks in vivo .
The shape of an animal body plan is constructed from protein components encoded by the genome. Ho... more The shape of an animal body plan is constructed from protein components encoded by the genome. However, bioelectric networks composed of many cell types have their own intrinsic dynamics, and can drive distinct morphological outcomes during embryogenesis and regeneration. Planarian flatworms are a popular system for exploring body plan patterning due to their regenerative capacity, but despite considerable molecular information regarding stem cell differentiation and basic axial patterning, very little is known about how distinct head shapes are produced. Here, we show that after decapitation in G. dorotocephala, a transient perturbation of physiological connectivity among cells (using the gap junction blocker octanol) can result in regenerated heads with quite different shapes, stochastically matching other known species of planaria (S. mediterranea, D. japonica, and P. felina). We use morphometric analysis to quantify the ability of physiological network perturbations to induce different species-specific head shapes from the same genome. Moreover, we present a computational agent-based model of cell and physical dynamics during regeneration that quantitatively reproduces the observed shape changes. Morphological alterations induced in a genomically wild-type G. dorotocephala during regeneration include not only the shape of the head but also the morphology of the brain, the characteristic distribution of adult stem cells (neoblasts), and the bioelectric gradients of resting potential within the anterior tissues. Interestingly, the shape change is not permanent; after regeneration is complete, intact animals remodel back to G. dorotocephala-appropriate head shape within several weeks in a secondary phase of remodeling following initial complete regeneration. We present a conceptual model to guide future work to delineate the molecular mechanisms by which bioelectric networks stochastically select among a small set of discrete head morphologies. Taken together, these data and analyses shed light on important physiological modifiers of morphological information in dictating species-specific shape, and reveal them to be a novel instructive input into head patterning in regenerating planaria.
ABSTRACT Calcium phosphate coatings were prepared on magnesium substrates via a biomimetic coatin... more ABSTRACT Calcium phosphate coatings were prepared on magnesium substrates via a biomimetic coating process. The effects of a magnesium hydroxide pretreatment on the formation and the ultimate corrosion protection of the coatings were studied. The pretreatment layer was found to affect the amount of defects present in the coatings. Corrosion resistance of the coatings was studied in vitro using two simulated body fluids, 0.8% NaCl and Hanks solution. In NaCl, the resistance to corrosion of all samples decreases with time as corrosion proceeded through cracks and other defects in the coatings. Samples with no pretreatment displayed the highest corrosion resistance as these samples had the fewest defects in the coating. However, in Hanks solution, corrosion resistance increased with time due to additional nucleation of calcium phosphate from the fluid on to the substrate. In this solution, additional pretreatment time was beneficial to the overall corrosion resistance.
Magnesium (Mg) and its alloys have the potential to revolutionize orthopaedic implants as a biode... more Magnesium (Mg) and its alloys have the potential to revolutionize orthopaedic implants as a biodegradable metal implant; however, strategies are still needed to match its biodegradation rate with the healing rate of bone tissue. In this work, the in situ crystallization of calcium phosphates on pure Mg was developed as an easy and inexpensive method for controlling the corrosion rate
Fundamental mathematical relationships are widespread in biology yet there is little information ... more Fundamental mathematical relationships are widespread in biology yet there is little information on this topic with regard to human limb bone lengths and none related to human limb bone volumes. Forty-six sets of ipsilateral upper and lower limb long bones and third digit short bones were imaged by computed tomography. Maximum bone lengths were measured manually and individual bone volumes calculated from computed tomography images using a stereologic method. Length ratios of femur : tibia and humerus : ulna were remarkably similar (1.21 and 1.22, respectively) and varied little (<7%) between individuals. The volume ratio of femur : tibia was approximately half that of humerus : ulna (1.58 and 3.28, respectively; P < 0.0001). Lower limb bone volume ratios varied much more than upper limb ratios. The relationship between bone length and volume was found to be well described by power laws, with R 2 values ranging from 0.983 to 0.995. The most striking finding was a logarithmic periodicity in bone length moving from distal to proximal up the limb (upper limb k = 0.72, lower limb k = 0.93). These novel data suggest that human limb bone lengths and volumes follow fundamental and highly conserved mathematical relationships, which may contribute to our understanding of normal and disordered growth, stature estimation, and biomechanics.
Impurity centers associated with silicon have been observed in the phase mixture of silicon subst... more Impurity centers associated with silicon have been observed in the phase mixture of silicon substituted apatite (Si-Ap) and silicon stabilized tricalcium phosphate (Si-TCP) using electron spin resonance (ESR). Two unique centers occur upon addition of SiO 2 to the calcium phosphate system: an orthorhombic center with g-values 2.007270.0001, 2.002470.0001 and 2.000370.0001 (Si-h1) and a center with tetrahedral symmetry having g-values components 2.005470.0001 and 1.999270.0003 (Si-h2). Both centers are hypothesized to be characteristic of defects associated with silicon in the Si-Ap phase. Through comparison of the intensity of F-OH centers in undoped calcium hydroxyapatite (HA) prepared with various levels of OH occupancy, a relationship is demonstrated between the ESR intensity of an F-center signal with g ¼ 2.0019+0.0004 (F-OH) and the OH occupation of HA. Relative changes in the intensity of ESR signals Si-h1 and F-OH are consistent with a chemical model describing the substitution of SiO 4 4À for PO 4 3À in HA with the creation of OH À vacancies as charge compensation, resulting in a mixed phase composition of Si-Ap and Si-TCP that results when a hydroxyapatite precipitate (HA) is heated in the presence of added SiO 2 .
The sintering of silicon doped calcium phosphate ceramics prepared from a basic colloidal hydroxy... more The sintering of silicon doped calcium phosphate ceramics prepared from a basic colloidal hydroxyapatite (Ca 5 (PO 4) 3 OH or HA) precipitate mixed with silica over 800 1C yields a phase mixture of tricalcium phosphate phases (TCP) designated Si-TCP, b-TCP and a silicon substituted dehydrated apatite (Si-Ap). The Si-TCP phase is defined as a combination of a silicon stabilized TCP in which the silicon content attains a saturated value (Ca 3 (P 0.9 Si 0.1 O 3.95) 2 or Si-TCP sat) and a-TCP (Ca 3 (PO 4) 2). Si-TCP sat has the same crystalline space group (P2 1 /a) as a-TCP, but with characteristically different lattice parameters due to the substitution of silicon in tetrahedral phosphorus sites. The nucleation and growth kinetics of Si-TCP in samples of composition 0.2 mol SiO 2 :mol HA (0.2:1) and 1 mol SiO 2 :mol HA (1:1) can be understood in terms of the initial growth of a-TCP at a silica-HA interface followed by a transformation to Si-TCP sat or b-TCP. A thermodynamic model for the formation of Si-TCP sat predicts a nucleation temperature of 795 1C, in close agreement with experiment. If sufficient silicon is available, the a-TCP transforms to Si-TCP sat during extended sintering. In the absence of sufficient silicon, the a-TCP transforms to b-TCP.
As a lightweight metal with mechanical properties similar to natural bone, a natural ionic presen... more As a lightweight metal with mechanical properties similar to natural bone, a natural ionic presence with significant functional roles in biological systems, and in vivo degradation via corrosion in the electrolytic environment of the body, magnesium-based implants have the potential to serve as biocompatible, osteoconductive, degradable implants for load-bearing applications. This review explores the properties, biological performance, challenges and future directions of magnesium-based biomaterials.
Theoretical details relating to model details, ion channel, ion pump and transporter dynamics, an... more Theoretical details relating to model details, ion channel, ion pump and transporter dynamics, and BIGR network models that are presented in the main text.
Seminars in cell & developmental biology, Jan 30, 2018
Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medic... more Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medicine, evolutionary biology, morphogenetic engineering, robotics, and unconventional computation. Despite recent advances in the molecular genetics of stem cell differentiation, this model organism's remarkable anatomical homeostasis provokes us with truly fundamental puzzles about the origin of large-scale shape and its relationship to the genome. In this review article, we first highlight several deep mysteries about planarian regeneration in the context of the current paradigm in this field. We then review recent progress in understanding of the physiological control of an endogenous, bioelectric pattern memory that guides regeneration, and how modulating this memory can permanently alter the flatworm's target morphology. Finally, we focus on computational approaches that complement reductive pathway analysis with synthetic, systems-level understanding of morphological decision-...
Abstract: The shape of an animal body plan is constructed from protein components encoded by the ... more Abstract: The shape of an animal body plan is constructed from protein components encoded by the genome. However, bioelectric networks composed of many cell types have their own intrinsic dynamics, and can drive distinct morphological outcomes during embryogenesis and regeneration. Planarian flatworms are a popular system for exploring body plan patterning due to their regenerative capacity, but despite considerable molecular information regarding stem cell differentiation and basic axial patterning, very little is known about how distinct head shapes are produced. Here, we show that after decapitation in G. dorotocephala, a transient perturbation of physiological connectivity among cells (using the gap junction blocker octanol) can result in regenerated heads with quite different shapes, stochastically matching other known species of planaria (S. mediterranea, D. japonica, and P. felina). We use morphometric analysis to quantify the ability of physiological network perturbations to...
Resorbable silicon stabilized tricalcium phosphate (Si-TCP)-based bioceramics are characterized f... more Resorbable silicon stabilized tricalcium phosphate (Si-TCP)-based bioceramics are characterized from a biological perspective by measuring the intermolecular interaction force between osteopontin (OPN) protein and the material surface using atomic force microscopy (AFM). OPN protein was covalently bound to silicon nitride AFM tips and adsorption and adhesion forces were measured in an electrolyte with a composition similar to that of physiological fluids. A strong relationship exists between the adhesion force of OPN on the material surface, the number of adherent osteoclasts (OC) and the resorption of the material. OPN adhesion is strongest on hydroxyapatite (HA) surfaces, or in samples that induce a HA-like surface through a precipitation reaction in electrolytic media. It is proposed that the increased biological response of the Si-TCP phase can be attributed in part to its reactivity in a physiological electrolyte, which involves a rapid conversion to a calcium deficient HA phase with a corresponding increase in the adhesion strength of OPN to the material, with a consequentially higher OC resorption response.
Limited methods exist to aid in deciding the appropriate donor limb lengths in bilateral upper li... more Limited methods exist to aid in deciding the appropriate donor limb lengths in bilateral upper limb amputees qualifying for vascularized composite allotransplantation. We hypothesized mathematical equations could be created using long bone length ratios, and applied to radiographs, to approximate the patient's limb length prior to amputation. A data set of 30 skeletons' unilateral upper limb long bones measured using osteometric board and calipers was used. Anatomic segment ratios were calculated based on humerus length after multivariate linear regression analysis. For clinical application testing, 5 cadavers' upper limbs were radiographed. Radiographic bone lengths were then measured along the long axis of each long bone. These measured radiographic lengths were then compared with the predicted bone lengths, generated from the skeleton data set ratios, for each cadaver. The chi-square goodness-of-fit test showed excellent fit ( P < .01) between the predicted and rad...
Progress in biophysics and molecular biology, Jan 5, 2018
Positional information describes pre-patterns of morphogenetic substances that alter spatio-tempo... more Positional information describes pre-patterns of morphogenetic substances that alter spatio-temporal gene expression to instruct development of growth and form. A wealth of recent data indicate bioelectrical properties, such as the transmembrane potential (V), are involved as instructive signals in the spatiotemporal regulation of morphogenesis. However, the mechanistic relationships between V and molecular positional information are only beginning to be understood. Recent advances in computational modeling are assisting in the development of comprehensive frameworks for mechanistically understanding how endogenous bioelectricity can guide anatomy in a broad range of systems. V represents an extraordinarily strong electric field (∼1.0 × 10 V/m) active over the thin expanse of the plasma membrane, with the capacity to influence a variety of downstream molecular signaling cascades. Moreover, in multicellular networks, intercellular coupling facilitated by gap junction channels may ind...
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Papers by Alexis Pietak