Forcing nonperiodicity with a single tile

An aperiodic prototile is a shape for which infinitely many copies can be arranged to fill Euclidean space completely with no overlaps, but not in a periodic pattern. Tiling theorists refer to such a prototile as an "einstein" (a German pun on "one stone"). The possible existence of an einstein has been pondered ever since Berger's discovery of large set of prototiles that in combination can tile the plane only in a nonperiodic way. In this article we review and clarify some features of a prototile we recently introduced that is an einstein according to a reasonable definition. [This abstract does not appear in the published article.]Comment: 18 pages, 10 figures. This article has been substantially revised and accepted for publication in the Mathematical Intelligencer and is scheduled to appear in Vol 33. Citations to and quotations from this work should reference that publication. If you cite this work, please check that the published form contains precisely the material to which you intend to refe

Insulin Solution Stability and Biocompatibility with Materials Used for an Implantable Insulin Delivery Device Using Reverse Phase HPLC Methods

open access articleAbstract: Insulin (Humulin® R IU500) has been delivered from an implantable artificial pancreas in diabetic rats and pigs. The artificial pancreas which was implanted in the peritoneum was fabricated from several biocompatible materials such as polycarbonate, stainless steel, polyurethane, titanium and a polyurethane resin. The device also contains a glucose responsive smart gel which controls the di usion of insulin dependent on the surrounding glucose environment. As the insulin reservoir is refillable and in contact with the device materials, assessing its biocompatibility with these various device component materials was conducted. Insulin can undergo chemical degradation mainly via a deamidation reaction on glutamine and asparagine residues rendering its biological hormone functionality. Two Reverse Phase High Performance Liquid Chromatography (RP-HPLC) methods were developed and validated for detection of insulin and degradant Asn A21 desamido insulin (method A) and insulin and degradant Asn B3 desamido insulin (method B). Material biocompatibility studies show that stainless steel and titanium are suitable for an implantable insulin delivery device design over a 31-day period. The use of polycarbonate and polyurethane could be considered if the insulin reservoir in the device was only to remain in the device for less than 11 days after which time there is a loss in cresol which acts in a protective capacity for insulin stability

An aperiodic hexagonal tile

We show that a single prototile can fill space uniformly but not admit a periodic tiling. A two-dimensional, hexagonal prototile with markings that enforce local matching rules is proven to be aperiodic by two independent methods. The space--filling tiling that can be built from copies of the prototile has the structure of a union of honeycombs with lattice constants of $2^n a$, where $a$ sets the scale of the most dense lattice and $n$ takes all positive integer values. There are two local isomorphism classes consistent with the matching rules and there is a nontrivial relation between these tilings and a previous construction by Penrose. Alternative forms of the prototile enforce the local matching rules by shape alone, one using a prototile that is not a connected region and the other using a three--dimensional prototile.Comment: 32 pages, 24 figures; submitted to Journal of Combinatorial Theory Series A. Version 2 is a major revision. Parts of Version 1 have been expanded and parts have been moved to a separate article (arXiv:1003.4279

Glucose lowering strategies with insulin

open access journalPeople with type 1 diabetes must use insulin and a large fraction of those with type 2 condition also do so. Many therefore struggle with the unpredictable balancing of insulin dose with calorie intake and utility. A healthy pancreas makes meticulous adjustment on a continuous basis that present therapeutic insulin administration cannot match. However, much progress has been made to make it simpler to inject both background and fast-acting boost insulins with a view to better mimicking normal pancreatic output. The present fast insulins are reviewed with accent on the primary amino acid structures of the biosynthetic types that diffuse more quickly than regular insulin that associates in hexamers. This makes boost doses kinetically and clinically more effective, allowing people to inject better estimated boost and corrective doses. Formulation advances are discussed for their present and potential contributions. The newer slow-acting insulins are also described and compared, their advantage also being kinetic with a lower likelihood of inducing overnight hypoglycaemia when used optimally. Finally, the appreciation of the advantages of alternative routes of administration such as oral and peritoneal are included in this review because of the possibility of altering the hepatic to peripheral ratio, the reasons for which are more effective but less obesogenic insulin activity. The logistics of oral insulin are summarised in terms of the risks to the insulin structure, the facilitation of paracellular uptake at the apical surface and the paradoxically advantageous hepatic first pass. Other non-invasive routes are also included in the review

Peptides as probes for G protein signal transduction

Triggered by agonist binding to cell surface receptors, the heterotrimeric G proteins dissociate into [alpha] and [beta][gamma] subunits, each activating distinct second messenger pathways. Peptides from the primary sequences of receptors, G proteins, and effectors have been used to study the molecular interactions between these proteins. Receptor-derived peptides from the second, third and fourth intracellular loops and certain naturally occurring peptides antagonize G protein interactions and can directly activate G protein. These peptides bind to G protein sites that include the N and C terminal regions of the [alpha] subunit and a yet to be identified region of the [beta] subunit. Peptides have also been useful in characterizing G protein-effector interactions. The identification of the contact sites between proteins involved in G protein signal transduction should aid in the development of non-peptide mimetic therapeutics which could specifically modify G protein-mediated cellular responses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31230/1/0000133.pd

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophy in vivo. Collectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux

Engineering Cowpea Mosaic Virus RNA-2 into a Vector to Express Heterologous Proteins in Plants

AbstractA series of new cowpea mosaic virus (CPMV) RNA-2-based expression vectors were designed. The jellyfish green fluorescent protein (GFP) was introduced between the movement protein (MP) and the large (L) coat protein or downstream of the small (S) coat protein. Release of the GFP inserted between the MP and L proteins was achieved by creating artificial processing sites each side of the insert, either by duplicating the MP-L cleavage site or by introducing a sequence encoding the foot-and-mouth disease virus (FMDV) 2A catalytic peptide. Eight amino acids derived from the C-terminus of the MP and 14–19 amino acids from the N-terminus of the L coat protein were necessary for efficient processing of the artificial Gln/Met sites. Insertion of the FMDV 2A sequence at the C-terminus of the GFP resulted in a genetically stable construct, which produced particles containing about 10 GFP-2A-L fusion proteins. Immunocapture experiments indicated that some of the GFP is present on the virion surface. Direct fusion of GFP to the C-terminus of the S coat protein resulted in a virus which was barely viable. However, when the sequence of GFP was linked to the C-terminus by an active FMDV 2A sequence, a highly infectious construct was obtained

Thermoresponsive Gels

An invited review and relates to the responsive gel used in the "artificial pancreas" work og INsmart, DMU. This article is an Open Access journal.Thermoresponsive gelling materials constructed from natural and synthetic polymers can be used to provide triggered action and therefore customised products such as drug delivery and regenerative medicine types as well as for other industries. Some materials give Arrhenius-type viscosity changes based on coil to globule transitions. Others produce more counterintuitive responses to temperature change because of agglomeration induced by enthalpic or entropic drivers. Extensive covalent crosslinking superimposes complexity of response and the upper and lower critical solution temperatures can translate to critical volume temperatures for these swellable but insoluble gels. Their structure and volume response confer advantages for actuation though they lack robustness. Dynamic covalent bonding has created an intermediate category where shape moulding and self-healing variants are useful for several platforms. Developing synthesis methodology—for example, Reversible Addition Fragmentation chain Transfer (RAFT) and Atomic Transfer Radical Polymerisation (ATRP)—provides an almost infinite range of materials that can be used for many of these gelling systems. For those that self-assemble into micelle systems that can gel, the upper and lower critical solution temperatures (UCST and LCST) are analogous to those for simpler dispersible polymers. However, the tuned hydrophobic-hydrophilic balance plus the introduction of additional pH-sensitivity and, for instance, thermochromic response, open the potential for coupled mechanisms to create complex drug targeting effects at the cellular level

The impact of moderate combination exercise on HbA1c, IL-6, and TNF in type 2 diabetic and non-diabetic subjects: an interventional non-randomized clinical trial

open access articleIntroduction: The main causes of worldwide increase in prevalence of type 2 diabetes are the daily consumption of excessive number of calories and sedentary lifestyle. Diabetes is usually accompanied by hypertension, lipid disorders and obesity that are considered as risk factors for developing diabetes. This study is designed to assess the benefit of a combined exercise programme (cardio “aerobic” and resistance) on HbA1c and the inflammatory markers (IL-6, and TNF) in type 2 diabetic (T2D) and non-diabetic (ND) subjects. Materials and methods: This is an interventional non randomized clinical trial conducted from 2016 to 2019 at exercise physiology laboratory at De Montfort University (DMU). Our target volunteers are T2D (HbA1c > 6.4), and ND (HbA1c < 5.8) with age group from 18-60 years old who are fit and able to do exercise. No restriction on weight. HbA1c, weight, BMI, waist and lung capacity were measured at baseline and at the 12th exercise session. In each exercise session the participant performed a combined exercise program consists of 30 min of resistance exercise followed by 20 min moderate cycling to be done twice a week for 6 weeks. Results: We enrolled 17 T2D intervention group 4 female and 13 male and 8 ND control group 5 female and 3 male. In both groups there was a significant reduction in HbA1c level after 6 weeks (P= 0.000). In T2D there were a significant weight reduction that decreased from (92.0± 4.3) to (90.0±4.5), (P< 0.001), BMI reduction that decreased from (30.8± 1.0) to (30.2± 0.9), (P< 0.001). In ND, the changes in weight reduction and BMI level were not significant. In T2D the changes in IL-6 level were only significant after the last exercise session. It was increased from 1.79±0.4 to 3.88±1.9 pg/ml (P=0.002), while it was not significant in ND group. In T2D and ND subjects, the changes in TNF level were insignificant. Conclusion: Development of combination exercise programs as a non-pharmacological intervention for diabetic and non-diabetic population are essential to decrease the prevalence of diabetes worldwide. In addition to conduction of public awareness events for proper implementation

Germline deletion of FAK-related non-kinase delays post-natal cardiomyocyte mitotic arrest

The cardiomyocyte phenotypic switch from a proliferative to terminally differentiated state impacts normal heart development and pathologic myocardial remodeling, yet the signaling mechanisms that regulate this vital process are incompletely understood. Studies from our lab and others indicate that focal adhesion kinase (FAK) is a critical regulator of cardiac growth and remodeling and we found that expression of the endogenous FAK inhibitor, FAK-related non kinase (FRNK) coincided with postnatal cardiomyocyte arrest. Mis-expression of FRNK in the embryonic heart led to pre-term lethality associated with reduced cardiomyocyte proliferation and led us to speculate that the postnatal FRNK surge might be required to promote quiescence in this growth promoting environment. Herein, we provide strong evidence that endogenous FRNK contributes to post-mitotic arrest. Depletion of FRNK promoted DNA synthesis in post-natal day (P) 10 hearts accompanied by a transient increase in DNA content and multi-nucleation by P14, indicative of DNA replication without cell division. Interestingly, a reduction in tri- and tetra-nucleated cardiomyocytes, concomitant with an increase in bi-nucleated cells by P21, indicated the possibility that FRNK-depleted cardiomyocytes underwent eventual cytokinesis. In support of this conclusion, Aurora B-labeled central spindles (a hallmark of cytokinesis) were observed in tetra-nucleated P20 FRNK−/− but not wt cardiomyocytes, while no evidence of apoptosis was observed. Moreover, hearts from FRNK null mice developed ventricular enlargement that persisted until young adulthood which resulted from myocyte expansion rather than myocyte hypertrophy or interstitial growth. These data indicate that endogenous FRNK serves an important role in limiting DNA synthesis and regulating the un-coupling between DNA synthesis and cytokinesis in the post-natal myocardium