A new correction procedure for calibrating dental caries frequency

The incisors and canines and the premolars and molars show differential resistance to cariogenic factors. The anterior teeth have a lower caries frequency than the posterior teeth. However, these tooth classes are lost differentially in postmortem stages due to their anatomical structures. This differential postmortem tooth loss distorts proportions between the anterior and posterior tooth classes. The disproportionality can affect the calculation of total caries prevalence. In this paper, we propose a new calibration procedure which removes this disproportionality and call it the proportional correction factor. For this procedure, the caries rates of anterior and posterior teeth are corrected by multiplying the anterior teeth by three-eighths and the posterior teeth by five-eighths. These fractions are derived from the human dental formula which contains three anterior and five posterior teeth by side. The correction factor is more effective if the proportion of anterior to the posterior teeth is extremely distorted. When this procedure is used with the caries correction factor, it provides a useful way to approach to an almost true caries prevalence. Am J Phys Anthropol 108:237–240, 1999. © 1999 Wiley-Liss, Inc.     

Drug screening of α-amylase inhibitors as candidates for treating diabetes

In the present study, the identification of potential α-amylase inhibitors is explored as a potential strategy for treating type-2 diabetes mellitus. A computationally driven approach using molecular docking was employed to search for new α-amylase inhibitors. The interactions of potential drugs with the enzyme's active site were investigated and compared with the contacts established by acarbose (a reference drug for α-amylase inhibition) in the crystallographic structure 1B2Y. For this active site characterization, both molecular docking and molecular dynamics simulations were performed, and the residues involved in the α-amylase–acarbose complex were considered to analyse the potential drug's interaction with the enzyme. Two potential α-amylase inhibitors (AN-153I105594 and AN-153I104845) have been selected following this computational strategy. Both compounds established a large number of interactions with key binding site α-amylase amino acids and obtained a comparable docking score concerning the reference drug (acarbose). Aiming to further analyse candidates' properties, their ADME (absorption, distribution, metabolism, excretion) parameters, druglikeness, organ toxicity, toxicological endpoints and median lethal dose (LD₅₀) were estimated. Overall estimations are promising for both candidates, and in silico toxicity predictions suggest that a low toxicity should be expected.     

Pregnenolone Protects Mouse Hippocampal (HT-22) Cells against Glutamate and Amyloid Beta Protein Toxicity

In the present work we have examined whether the neurosteroid pregnenolone has any neuroprotective effects against glutamate and amyloid beta protein neurotoxicity using immortalized clonal mouse hippocampal cell line (HT-22). The neurosteroid pregnenolone protects HT-22 cells against both 5 mM glutamate and 2 M amyloid beta protein induced cell death in a concentration dependent manner. Optimum protection was attained at 500 nM pregnenolone, against both 5 mM glutamate as well as 2 M amyloid beta protein induced HT-22 cell death. Furthermore, using confocal immunoflourescence microscopy we observed that 20 hours of treatment with 5 mM glutamate resulted in intense nuclear localization of the glucocorticoid receptor (GR) in HT-22 cells as compared to control untreated cells. Interestingly, 500 nM pregnenolone treatment for 24 hours, followed by 20 hours treatment with 5 mM glutamate resulted in dramatic reduction in GR nuclear localization. These results show that (i) pregnenolone has neuroprotective effects against both glutamate and amyloid beta protein neuropathology and (ii) prevention of glucocorticoid receptor (GR) localization to the nucleus may be involved in the observed neuroprotective effects of pregnenolone against glutamate neurotoxicity.     

The Antibiotic Efflux Protein TolC Is a Highly Evolvable Target under Colicin E1 or TLS Phage Selection

Bacteriophages and bacterial toxins are promising antibacterial agents to treat infections caused by multidrug-resistant (MDR) bacteria. In fact, bacteriophages have recently been successfully used to treat life-threatening infections caused by MDR bacteria (Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, et al. 2017. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother. 61(10); Chan BK, Turner PE, Kim S, Mojibian HR, Elefteriades JA, Narayan D. 2018. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health. 2018(1):60–66; Petrovic Fabijan A, Lin RCY, Ho J, Maddocks S, Ben Zakour NL, Iredell JR, Westmead Bacteriophage Therapy Team. 2020. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol. 5(3):465–472). One potential problem with using these antibacterial agents is the evolution of resistance against them in the long term. Here, we studied the fitness landscape of the Escherichia coli TolC protein, an outer membrane efflux protein that is exploited by a pore forming toxin called colicin E1 and by TLS phage (Pagie L, Hogeweg P. 1999. Colicin diversity: a result of eco-evolutionary dynamics. J Theor Biol. 196(2):251–261; Andersen C, Hughes C, Koronakis V. 2000. Chunnel vision. Export and efflux through bacterial channel-tunnels. EMBO Rep. 1(4):313–318; Koronakis V, Andersen C, Hughes C. 2001. Channel-tunnels. Curr Opin Struct Biol. 11(4):403–407; Czaran TL, Hoekstra RF, Pagie L. 2002. Chemical warfare between microbes promotes biodiversity. Proc Natl Acad Sci U S A. 99(2):786–790; Cascales E, Buchanan SK, Duché D, Kleanthous C, Lloubès R, Postle K, Riley M, Slatin S, Cavard D. 2007. Colicin biology. Microbiol Mol Biol Rev. 71(1):158–229). By systematically assessing the distribution of fitness effects of ∼9,000 single amino acid replacements in TolC using either positive (antibiotics and bile salts) or negative (colicin E1 and TLS phage) selection pressures, we quantified evolvability of the TolC. We demonstrated that the TolC is highly optimized for the efflux of antibiotics and bile salts. In contrast, under colicin E1 and TLS phage selection, TolC sequence is very sensitive to mutations. Finally, we have identified a large set of mutations in TolC that increase resistance of E. coli against colicin E1 or TLS phage without changing antibiotic susceptibility of bacterial cells. Our findings suggest that TolC is a highly evolvable target under negative selection which may limit the potential clinical use of bacteriophages and bacterial toxins if evolutionary aspects are not taken into account.     

Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}

Transgenic mice overexpressing the inflammatory cytokine TNF-alpha in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-alpha mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n = 8/32) in TNF1.6 but not in control mice (n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca(2+) normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca(2+) handling. Thus abnormalities in action potential propagation and Ca(2+) handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.     

Synthesis,Spectroscopic Analysis,and in Vitro/in Silico Biological Studies of Novel Piperidine Derivatives Heterocyclic Schiff-Mannich Base Compounds

In the present study, 3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones ( S1-8 ) were synthesized by treating 4-hydroxybenzaldehyde ( B ) with eight different 3-substitued-4-amino-4,5-dihydro-1H-1,2,4-triazole-5-ones ( T1-8 ) in acetic acid medium, separately. The synthesized Schiff bases ( S ) were reacted with formaldehyde and secondary amine such as 4-piperidinecarboxyamide to afford novel heterocyclic bases. 3-Substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones ( T ) were treated with 4-piperidinecarboxyamide in the presence of formaldehyde to synthesize eight new 1-(4-piperidinecarboxyamide-1-yl - methyl)-3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones ( M1-8 ). The structure characterization of compounds was carried out using ¹H-NMR, IR, HR-MS, and ¹³C-NMR spectroscopic methods. The inhibitory properties of the newly synthesized compounds were calculated against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione S-transferase (GST) enzymes. Ki values were calculated in the range of 20.06±3.11–36.86±6.17 μM for GST, 17.87±2.91–30.53±4.25 μM for AChE, 9.08±0.69–20.02±2.88 μM for BChE, respectively, Besides, IC₅₀ values were also calculated. Best binding scores of -inhibitors against used enzymes were calculated as −12.095 kcal/mol, −12.775 kcal/mol, and −9.336 kcal/mol, respectively. While 5-oxo-triazole piperidine-4-carboxamide moieties have a critical role in the inhibition of AChE and GST enzymes, hydroxy benzyl moiety is important for BChE enzyme inhibition.     

Regulation and phylogeny of skeletal muscle regeneration

One of the most fascinating questions in regenerative biology is why some animals can regenerate injured structures while others cannot. Skeletal muscle has a remarkable capacity to regenerate even after repeated traumas, yet limited information is available on muscle repair mechanisms and how they have evolved. For decades, the main focus in the study of muscle regeneration was on muscle stem cells, however, their interaction with their progeny and stromal cells is only starting to emerge, and this is crucial for successful repair and re-establishment of homeostasis after injury. In addition, numerous murine injury models are used to investigate the regeneration process, and some can lead to discrepancies in observed phenotypes. This review addresses these issues and provides an overview of some of the main regulatory cellular and molecular players involved in skeletal muscle repair.     

Increased glucose oxidation in H-FABP null soleus muscle is associated with defective triacylglycerol accumulation and mobilization, but not with the defect of exogenous fatty acid oxidation

Heart-type fatty acid-binding protein (H-FABP) is a major fatty acid-binding factor in skeletal muscles. Genetic lack of H-FABP severely impairs the esterification and oxidation of exogenous fatty acids in soleus muscles isolated from chow-fed mice (CHOW-solei) and high fat diet-fed mice (HFD-solei), and prevents the HFD-induced accumulation of muscle triacylglycerols (TAGs). Here, we examined the impact of H-FABP deficiency on the relationship between fatty acid utilization and glucose oxidation. Glucose oxidation was measured in isolated soleus muscles in the presence or absence of 1 mM palmitate (simple protocol) or in the absence of fatty acid after preincubation with 1 mM palmitate (complex protocol). With the simple protocol, the mutation slightly reduced glucose oxidation in CHOW-muscles, but markedly increased it in HFD-muscles; unexpectedly, this pattern was not altered by the addition of palmitate, which reduced glucose oxidation in both CHOW- and HFD-solei irrespective of the mutation. In the complex protocol, the mutation first inhibited the synthesis and accumulation of TAGs and then their mobilization; with this protocol, the mutation increased glucose oxidation in both CHOW- and HFD-solei. We conclude: (i) H-FABP mediates a non-acute inhibition of muscle glucose oxidation by fatty acids, likely by enabling both the accumulation and mobilization of a critical mass of muscle TAGs; (ii) H-FABP does not mediate the acute inhibitory effect of extracellular fatty acids on muscle glucose oxidation; (iii) H-FABP affects muscle glucose oxidation in opposing ways, with inhibition prevailing at high muscle TAG contents.