Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model

Bone tissue has an exceptional quality to regenerate to native tissue in response to injury. However, the fracture repair process requires mechanical stability or a viable biological microenvironment or both to ensure successful healing to native tissue. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. Preclinical and clinical studies using biologic agents like recombinant bone morphogenetic proteins have demonstrated an efficacy similar or better than that of autologous bone graft in acute fracture healing. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications.     

Targeting the cell cycle in breast cancer: towards the next phase

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.     

Disposition of Mulberry Pollen in the Human Respiratory System: A Mathematical Model

Inhaled particle deposition sites must be identified to effectively treat human airway diseases. We have determined distribution patterns of a selected aeroallergen, mulberry pollen, among human extrathoracic (ET: i.e., oronasopharyngeal) regions and the lung. A predictive model validated by inhalation exposure data from human subjects was utilized. Deposition locations were primarily functions of (1) mulberry particle parameters (geometric size, 11–18 μm; shape, spherical; and density, 1.14 g cm^?3), and (2) mode of breathing. In the general population, two styles of inhalation are prevalent, normal augmentors (NAs) and mouth breathers (MBs). Their clinical definitions are based on intra-ET airflow divisions. For a NA-mode breathing sedentary (minute ventilation = V_E = 10 L min^?1) adult, 93% of inhaled mulberry pollen was removed by the ET compartment and 7% collected within the lung. For a MB, the respective deposition efficiencies were 75% and 25%. To apply the model, we used a daily springtime mulberry pollen concentration of 1748 grains m^?3 and an exposure time of 0.5 hour to calculate actual doses for the respiratory system. Under the stipulated conditions, a MB would inhale 524 pollen grains per day and 131 would be deposited in the lung; the value is 37 grains for a NA. Preliminary epidemiological results suggest 15% of the study population are MBs in whom such pollen deposits are likely contributors to airway disease.     

Importance of pollen grain volumes for calculating bee diets

Pollen grains harvested by bees differ greatly in volume, thus pollen grains contribute differentially to larval and imaginal nutritional ecology, and ultimately to bee fitness. Simple proportions are inadequate when disentangling the importance of various pollen taxa found on foraging bees, their scopal loads or in their nest provisions. Disparate volumes of pollen grains are an essential feature to be considered in any foraging or dietary study. To document the importance of pollen volume on diet we mixed equal amounts (by weight) of ten morphologically diverse pollen taxa commonly collected by honey bees in the Sonoran desert of Arizona. These taxa were: Cereus giganteus, Ephedra trifurca, Fouquieria splendens, Helianthus annuus, Prosopis juliflora, and Simmondsia chinensis. Additionally, a small grain, Solanum rostratum, and two large grains, Cucurbita foetidissima and Opuntia phaeacantha, rarely harvested by honey bees, were included in the mixture. The mixture was inoculated with calibrated spore tablets, acetolyzed, counted, and % volumes calculated. Pollen grain numbers obtained from the middle of the coverslip were compared with those along the coverslip edge (x²) with no apparent statistically significant difference. The percent by pollen grain number was compared with percentage by pollen grain volume using a Chi-square test.     

Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms

Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca(2+) concentration ([Ca(2+)](i)) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca(2+) handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current (I(Ca,L)) density (-0.964 +/- 0.172 vs. -0.745 +/- 0.128 pA/pF at +10 mV) and Na(+)/Ca(2+) exchanger (NCX) currents (2.1 +/- 0.8 vs. 2.3 +/- 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca(2+)](i) was depressed (at +10 mV, 0.72 +/- 0.07 and 0.56 +/- 0.04 microM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca(2+) spark amplitudes (P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca(2+) in myocytes isolated from failing vs. control hearts (P < 0.05). mRNA levels of the alpha(1C)-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts (P < 0.05). alpha(1C) protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated (P < 0.05), while NCX protein was significantly upregulated (P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca(2+) uptake and release synergistically contribute to the depressed [Ca(2+)](i) and the altered AP profile phenotype.     

Bradykinin-related peptides, including a novel structural variant, (Val1)-bradykinin, from the skin secretion of Guenther's frog, Hylarana guentheri and their molecular precursors

Multiple bradykinin-related peptides including a novel bradykinin structural variant, (Val(1))-bradykinin, have been identified from the defensive skin secretion of Guenther's frog, Hylarana guentheri by a tandem mass spectrometry method. Subsequently, four different preprobradykinin cDNAs, which encoded multiple bradykinin copies and its structural variants, were consistently cloned from a skin derived cDNA library. These preprobradykinin cDNAs showed little structural similarity with mammalian kininogens and the kininogens from the skin of toads, but have regions that are highly conserved in the kininogens from another ranid frog, Odorrana schmackeri. Alignment of these preprobradykinins revealed that preprobradykinin 1, 2 and 3 may derive from a single gene by alternative exon splicing.     

Prion gene (PRNP) haplotype variation in United States goat breeds (Open Access publication)

Scrapie eradication efforts cost 18 million dollars annually in the United States and rely heavily upon PRNP genotyping of sheep. Genetic resistance might reduce goat scrapie and limit the risk of goats serving as a scrapie reservoir, so PRNP coding sequences were examined from 446 goats of 10 breeds, 8 of which had not been previously examined at PRNP. The 10 observed alleles were all related to one of two central haplotypes by a single amino acid substitution. At least five of these alleles (M142, R143, S146, H154, and K222) have been associated with increased incubation time or decreased odds of scrapie. To the best of our knowledge, neither S146 nor K222 has been found in any goats with scrapie, though further evaluation will be required to demonstrate true resistance. S146 was more common, present in several breeds at widely varying frequencies, while K222 was observed only in two dairy breeds at low frequency. Overall, this study provides frequency data on PRNP alleles in US goats, shows the pattern of relationships between haplotypes, and demonstrates segregation of multiple scrapieassociated alleles in several breeds not examined before at PRNP.     

香菇的学名及其在当代真菌分类中的位置

本文综述了香菇(Lentinula edodes)的分类历史,确认其在蘑菇目(Agaricales)Tricholomataceae科下的分类地位,并证实了它与多孔菌目(Poriales)Lentinaceae科的Lentinus属没有联系。根据《真菌、地衣汉语学名命名法规》,作者讨论了译为“香菇属”的Lentinus和“小香菇属”的Lentinellus两属的汉语学名问题,提出Lentinus的汉语学名应订正为“韧伞属”,Lentinellus为“螺壳菌属”。香菇所在的Lentinula属的汉语学名建议为“木菇属”。