2-(Trimethylammonium) Ethyl (R)-3-Methoxy-3-oxo-2-Stearamidopropyl Phosphate Suppresses Osteoclast Maturation and Bone Resorption by Targeting Macrophage-Colony Stimulating Factor Signaling

2-(Trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient megakaryopoiesis. Here, we show that (R)-TEMOSPho blocks osteoclast maturation from progenitor cells of hematopoietic origin, as well as blocking the resorptive function of mature osteoclasts. The inhibitory effect of (R)-TEMOSPho on osteoclasts was due to a disruption of the actin cytoskeleton, resulting from impaired downstream signaling of c-Fms, a receptor for macrophage-colony stimulating factor linked to c-Cbl, phosphoinositol-3-kinase (PI3K), Vav3, and Rac1. In addition, (R)-TEMOSPho blocked inflammation-induced bone destruction by reducing the numbers of osteoclasts produced in mice. Thus, (R)-TEMOSPho may represent a promising new class of antiresorptive drugs for the treatment of bone loss associated with increased osteoclast maturation and activity.     

Mitochondrial DNA Copy Number in Peripheral Blood and Melanoma Risk

Mitochondrial DNA (mtDNA) copy number in peripheral blood has been suggested as risk modifier in various types of cancer. However, its influence on melanoma risk is unclear. We evaluated the association between mtDNA copy number in peripheral blood and melanoma risk in 500 melanoma cases and 500 healthy controls from an ongoing melanoma study. The mtDNA copy number was measured using real-time polymerase chain reaction. Overall, mean mtDNA copy number was significantly higher in cases than in controls (1.15 vs 0.99, P<0.001). Increased mtDNA copy number was associated with a 1.45-fold increased risk of melanoma (95% confidence interval: 1.12-1.97). Significant joint effects between mtDNA copy number and variables related to pigmentation and history of sunlight exposure were observed. This study supports an association between increased mtDNA copy number and melanoma risk that is independent on the known melanoma risk factors (pigmentation and history of sunlight exposure).     

The sequence specificity of alkylation for a series of benzoic acid mustard and imidazole-containing distamycin analogues: the importance of local sequence conformation.

The covalent sequence specificity of a series of nitrogen mustard and imidazole-containing analogues of distamycin was determined using modified sequencing techniques. The analogues tether benzoic acid mustard (BAM) and possess either one, two or three imidazole units. Examination of the alkylation specificity revealed that BAM produced guanine-N7 lesions in a pattern similar to conventional nitrogen mustards. The monoimidazole-BAM conjugate also produced guanine-N7 alkylation in a similar pattern to BAM, but at a 100-fold lower dose. The diimidazole and triimidazole conjugates did not produce detectable guanine-N7 alkylation but only alkylated at selected sites in the minor groove. Unexpectedly, the alkylation specificity at equivalent doses was nearly identical to that found for the previously reported pyrrole-BAM conjugates. The consensus sequence, 5'-TTTTGPuwas strongly alkylated by the triimidazole conjugate in preference to other similar sites including three occurrences of 5'-TTTTAA. Footprinting studies were carried out to examine the non-covalent DNA binding interactions. These studies revealed that the tripyrrole- BAM conjugate bound non-covalently to the same AT-rich sites as distamycin. In contrast, whereas the Im3lexitropsin bound non-covalently to GC-rich sequences, the triimidazole-BAM conjugate did not detectably footprint to either GC- or AT-rich regions at equivalent doses. The results indicate that the alkylation event is not solely dictated by the non-covalent binding and might be influenced by a unique sequence dependent conformational feature of the consensus sequence 5'-TTTTGPu.     

Metaphysics to the rescue?: Four-dimensionalism and the twinning argument against conceptionism

The view that human beings begin to exist at fertilization (namely conceptionism) faces a serious challenge from the twinning argument, that identical twins coming from the same zygote must be numerically distinct from the zygote and so did not exist at fertilization. Recently, some philosophers have claimed that the twinning argument rests on a particular metaphysical theory of persistence, namely endurantism, on which a human being, for example, is wholly present at every moment of her existence. And we can easily refute the argument, they claim, by employing perdurantism or exdurantism, according to which a human being is a temporally extended entity with temporal parts or a momentarily existing stage who has other momentarily existing stages as counterparts. I argue that such claims are mistaken. The twinning argument does not rest on endurantism and can be formulated in terms of perdurantism to provide a good reason for perdurantists to reject conceptionism. And exdurantism does not have any advantage in defending conceptionism either, for it already concedes more than what the twinning argument aims to show.     

A New Electrolyte Formulation for Securing High Temperature Cycling and Storage Performances of Na‐Ion Batteries

The Na‐ion battery is recognized as a possible alternative to the Li‐ion battery for applications where power and cost override energy density performance. However, the increasing instability of their electrolyte with temperature is still problematic. Thus, a central question remains how to design Na‐based electrolytes. Here, the discovery of a Na‐based electrolyte formulation is reported which enlists four additives (vinylene carbonate, succinonitrile, 1,3‐propane sultone, and sodium difluoro(oxalate)borate) in proper quantities that synergistically combine their positive attributes to enable a stable solid electrolyte interphase at both negative and positive electrodes surface at 55 °C. Moreover, the role of each additive that consists in producing specific NaF coatings, thin elastomers, sulfate‐based deposits, and so on via combined impedance and X‐ray photoelectron spectroscopy is rationalized. It is demonstrated that empirical electrolyte design rules previously established for Li‐ion technology together with theoretical guidance is vital in the quest for better Na‐based electrolytes that can be extended to other chemistries. Overall, this finding, which is implemented to 18 650 cells, widens the route to the rapid development of the Na‐ion technology based on Na₃V₂(PO₄)₂F₃/C chemistry.     

Zwitterions for Organic/Perovskite Solar Cells,Light‐Emitting Devices,and Lithium Ion Batteries: Recent Progress and Perspectives

Zwitterions, a class of materials that contain covalently bonded cations and anions, have been extensively studied in the past decades owing to their special features, such as excellent solubility in polar solvents, for solution processing and dipole formation for the transfer of carriers and ions. Recently, zwitterions have been developed as electrode modifiers for organic solar cells (OSCs), perovskite solar cells (PVSCs), and organic light‐emitting devices (OLEDs), as well as electrolyte additives for lithium ion batteries (LIBs). With the rapid advances of zwitterionic materials, high‐performance devices have been constructed with enhanced efficiencies by introducing them as interface layers and electrolyte additives. In this review, recent progress in OSCs, PVSCs, OLEDs, and LIBs by using zwitterions is highlighted. The authors also elaborate the role of various zwitterionic materials as interfacial layers and additives for highly efficient OSCs, PVSCs, OLEDs, and LIBs. This article presents an overview of device performance of zwitterionic materials. The structure–property relationship is also discussed. Finally, the prospects of zwitterion materials are also addressed.     

Space use and genetic structure do not maintain color polymorphism in a species with alternative behavioral strategies

Space use including territoriality and spatial arrangement within a population can reveal important information on the nature, dynamics, and evolutionary maintenance of alternative strategies in color polymorphic species. Despite the prevalence of color polymorphic species as model systems in evolutionary biology, the interaction between space use and genetic structuring of morphs within populations has rarely been examined. Here, we assess the spatial and genetic structure of male throat color morphs within a population of the tawny dragon lizard, Ctenophorus decresii. Male color morphs do not differ in morphology but differ in aggressive and antipredator behaviors as well as androgen levels. Despite these behavioral and endocrine differences, we find that color morphs do not differ in territory size, with their spatial arrangement being essentially random with respect to each other. There were no differences in genetic diversity or relatedness between morphs; however, there was significant, albeit weak, genetic differentiation between morphs, which was unrelated to geographic distance between individuals. Our results indicate potential weak barriers to gene flow between some morphs, potentially due to nonrandom pre‐ or postcopulatory mate choice or postzygotic genetic incompatibilities. However, space use, spatial structure, and nonrandom mating do not appear to be primary mechanisms maintaining color polymorphism in this system, highlighting the complexity and variation in alternative strategies associated with color polymorphism.