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1.  Chronic Infection Depletes Hematopoietic Stem Cells Through Stress-Induced Terminal Differentiation 
Cell reports  2016;17(10):2584-2595.
Summary
Chronic infections affect a third of the world’s population and can cause bone marrow suppression, a severe condition that increases mortality from infection. To uncover the basis for infection-associated bone marrow suppression, we conducted repeated infection of WT mice with Mycobacterium avium. After 4–6 months, mice became pancytopenic. Their hematopoietic stem and progenitor cells (HSPCs) were severely depleted and displayed interferon gamma (IFNγ) signaling-dependent defects in self-renewal. There was no evidence of increased HSPC mobilization or apoptosis. However, consistent with known effects of IFNγ, transcriptome analysis pointed towards increased myeloid differentiation of HSPCs and revealed the transcription factor Batf2 as a potential mediator of IFNγ-induced HSPC differentiation. Gain and loss of function studies uncovered a role for Batf2 in myeloid differentiation in both murine and human systems. We thus demonstrate that chronic infection can deplete HSPCs and identify BATF2 as a mediator of infection-induced HSPC terminal differentiation.
Graphical Abstract
doi:10.1016/j.celrep.2016.11.031
PMCID: PMC5161248  PMID: 27926863
Hematopoietic stem cell; chronic infection; pancytopenia; bone marrow failure; interferon gamma; terminal differentiation
2.  Effect of chemotherapy exposure prior to pregnancy on fetal brain tissue and the potential protective role of quercetin 
Cytotechnology  2014;67(6):1031-1038.
Cyclophosphamide (CYC) and doxorubicin (DOX) are among the most effective and widely used anticancer chemotherapeutic drugs. Potential chemopreventive and chemotherapeutic functions have recently been attributed to flavonoids. We hypothesized that Quercetin (QR) would protect against the toxic effects of chemotherapeutic agents applied prior to pregnancy. Rats were treated with the chemotherapeutic drugs CYC (27 mg/kg) and DOX (1.8 mg/kg) applied in a single intraperitoneal dose once every 3 weeks for 10 weeks. QR was administered at a dose of 10 mg/kg/day by oral gavage. 48 h following the experimental chemotherapy exposure, female rats were transferred to cages containing male rat for mating. Fetal brain tissues were removed from fetuses extracted by cesarean section on the 20th day of gestation for evaluation of antioxidant parameters. A significant increase in superoxide dismutase and malondialdehyde activity was observed in CYC and DOX treatment groups relative to the control group (p < 0.05). Similarly, carnitine acylcarnitine translocase and Glutathione activity was significantly reduced in the CYC and DOX groups relative to the control group (p < 0.05). Our results indicate that the use of chemotherapeutic drugs before pregnancy can result in oxidative damage to fetal brain tissue. Therefore, women who have been exposed to chemotherapy and may become pregnant should be treated with antioxidant compounds such as QR to reduce the risk of damage to fetal brain tissues.
doi:10.1007/s10616-014-9742-z
PMCID: PMC4628923  PMID: 25260542
Chemotherapy; Cyclophosphamide; Doxorubicin; Fetal development; Quercetin
3.  Do state minimum markup/price laws work? Evidence from retail scanner data and TUS-CPS 
Tobacco Control  2016;25(Suppl 1):i52-i59.
Background
Minimum markup/price laws (MPLs) have been proposed as an alternative non-tax pricing strategy to reduce tobacco use and access. However, the empirical evidence on the effectiveness of MPLs in increasing cigarette prices is very limited. This study aims to fill this critical gap by examining the association between MPLs and cigarette prices.
Methods
State MPLs were compiled from primary legal research databases and were linked to cigarette prices constructed from the Nielsen retail scanner data and the self-reported cigarette prices from the Tobacco Use Supplement to the Current Population Survey. Multivariate regression analyses were conducted to examine the association between MPLs and the major components of MPLs and cigarette prices.
Results
The presence of MPLs was associated with higher cigarette prices. In addition, cigarette prices were higher, above and beyond the higher prices resulting from MPLs, in states that prohibit below-cost combination sales; do not allow any distributing party to use trade discounts to reduce the base cost of cigarettes; prohibit distributing parties from meeting the price of a competitor, and prohibit distributing below-cost coupons to the consumer. Moreover, states that had total markup rates >24% were associated with significantly higher cigarette prices.
Conclusions
MPLs are an effective way to increase cigarette prices. The impact of MPLs can be further strengthened by imposing greater markup rates and by prohibiting coupon distribution, competitor price matching, and use of below-cost combination sales and trade discounts.
doi:10.1136/tobaccocontrol-2016-053093
PMCID: PMC5099228  PMID: 27697948
Price; Taxation; Public policy
4.  In a warmer Arctic, mosquitoes avoid increased mortality from predators by growing faster 
Climate change is altering environmental temperature, a factor that influences ectothermic organisms by controlling rates of physiological processes. Demographic effects of warming, however, are determined by the expression of these physiological effects through predator–prey and other species interactions. Using field observations and controlled experiments, we measured how increasing temperatures in the Arctic affected development rates and mortality rates (from predation) of immature Arctic mosquitoes in western Greenland. We then developed and parametrized a demographic model to evaluate how temperature affects survival of mosquitoes from the immature to the adult stage. Our studies showed that warming increased development rate of immature mosquitoes (Q10 = 2.8) but also increased daily mortality from increased predation rates by a dytiscid beetle (Q10 = 1.2–1.5). Despite increased daily mortality, the model indicated that faster development and fewer days exposed to predators resulted in an increased probability of mosquito survival to the adult stage. Warming also advanced mosquito phenology, bringing mosquitoes into phenological synchrony with caribou. Increases in biting pests will have negative consequences for caribou and their role as a subsistence resource for local communities. Generalizable frameworks that account for multiple effects of temperature are needed to understand how climate change impacts coupled human–natural systems.
doi:10.1098/rspb.2015.1549
PMCID: PMC4614756  PMID: 26378217
mosquitoes; Arctic; predator–prey interactions; thermal physiology
5.  A fatty cough 
Lipoid pneumonia is a rare form of pneumonia caused by accumulation of exogenous or endogenous lipids in the pulmonary system. Symptoms can often range from being asymptomatic to presenting with chest pain, fevers and shortness of breath. High resolution CT and bronchoalveolar lavage (BAL) remain important in establishing the diagnosis. The treatment of lipoid pneumonia includes stopping the offending agents and providing supportive therapy. The use of anti-inflammatory agents has shown some benefit in severe cases.
doi:10.4103/0970-2113.188976
PMCID: PMC5006336  PMID: 27625450
Diagnosis; fatty pneumonia; treatment
6.  Cancer and the arts: Johannes Brahms and the problem of pancreatic carcinoma 
ESMO Open  2016;1(4):e000095.
doi:10.1136/esmoopen-2016-000095
PMCID: PMC5070262  PMID: 27843636
Brahms
7.  Habitat use of bats in relation to wind turbines revealed by GPS tracking 
Scientific Reports  2016;6:28961.
Worldwide, many countries aim at countering global climate change by promoting renewable energy. Yet, recent studies highlight that so-called green energy, such as wind energy, may come at environmental costs, for example when wind turbines kill birds and bats. Using miniaturized GPS loggers, we studied how an open-space foraging bat with high collision risk with wind turbines, the common noctule Nyctalus noctula (Schreber, 1774), interacts with wind turbines. We compared actual flight trajectories to correlated random walks to identify habitat variables explaining the movements of bats. Both sexes preferred wetlands but used conventionally managed cropland less than expected based on availability. During midsummer, females traversed the land on relatively long flight paths and repeatedly came close to wind turbines. Their flight heights above ground suggested a high risk of colliding with wind turbines. In contrast, males recorded in early summer commuted straight between roosts and foraging areas and overall flew lower than the operating range of most turbine blades, suggesting a lower collision risk. Flight heights of bats suggest that during summer the risk of collision with wind turbines was high for most studied bats at the majority of currently installed wind turbines. For siting of wind parks, preferred bat habitats and commuting routes should be identified and avoided.
doi:10.1038/srep28961
PMCID: PMC4931514  PMID: 27373219
8.  Krüppel-like factor 4 promotes human osteosarcoma growth and metastasis via regulating CRYAB expression 
Oncotarget  2016;7(21):30990-31000.
Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, is an essential regulator in many cellular processes, including differentiation, proliferation, inflammation, pluripotency, and apoptosis. Along with these roles in normal cells and tissues, KLF4 has been reported as a tumor suppressor or an oncogene in many cancers. However, the role of KLF4 in osteosarcoma is largely unknown. Here we found the expression of KLF4 was significantly increased in human osteosarcoma tissues compared with the normal tissues. Elevated KLF4 promoted human osteosarcoma cell proliferation and metastasis. Subsequently, mechanistic studies revealed KLF4 specifically bound the promoter of CRYAB and upregulated CRYAB expression in human osteosarcoma cells. Moreover, we found that KLF4 enhanced osteosarcoma cell proliferation and migration via upregulating CRYAB. Therefore, our studies suggested KLF4 may be a potential target for human osteosarcoma therapy.
doi:10.18632/oncotarget.8824
PMCID: PMC5058733  PMID: 27105535
KLF4; osteosarcoma; migration; CRYAB; proliferation
9.  Renin–angiotensin system inhibitors protect against age-related changes in rat liver mitochondrial DNA content and gene expression 
Experimental gerontology  2008;43(10):919-928.
Chronic renin–angiotensin system inhibition protects against liver fibrosis, ameliorates age-associated mitochondrial dysfunction and increases rodent lifespan. We hypothesized that life-long angiotensin-II-mediated stimulation of oxidant generation might participate in mitochondrial DNA “common deletion” formation, and the resulting impairment of bioenergetic capacity. Enalapril (10 mg/kg/d) or losartan (30 mg/kg/d) administered during 16.5 months were unable to prevent the age-dependent accumulation of rat liver mitochondrial DNA “common deletion”, but attenuated the decrease of mitochondrial DNA content. This evidence – together with the enhancement of NRF-1 and PGC-1 mRNA contents – seems to explain why enalapril and losartan improved mitochondrial functioning and lowered oxidant production, since both the absolute number of mtDNA molecules and increased NRF-1 and PGC-1 transcription are positively related to mitochondrial respiratory capacity, and PGC-1 protects against increases in ROS production and damage. Oxidative stress evoked by abnormal respiratory function contributes to the pathophysiology of mitochondrial disease and human aging. If the present mitochondrial actions of renin–angiotensin system inhibitors are confirmed in humans they may modify the therapeutic significance of that strategy.
doi:10.1016/j.exger.2008.08.007
PMCID: PMC4871262  PMID: 18765277
Aging; Mitochondria DNA; Reactive oxygen species; Gene expression; Anti-aging; Antioxidant
10.  Pollen dispersal and breeding structure in a hawkmoth-pollinated Pampa grasslands species Petunia axillaris (Solanaceae) 
Annals of Botany  2015;115(6):939-948.
Background and Aims The evolution of selfing is one of the most common transitions in flowering plants, and this change in mating pattern has important systematic and ecological consequences because it often initiates reproductive isolation and speciation. Petunia axillaris (Solanaceae) includes three allopatric subspecies widely distributed in temperate South America that present different degrees of self-compatibity and incompatibility. One of these subspecies is co-distributed with P. exserta in a restricted area and presents a complex, not well-understood mating system. Artificial crossing experiments suggest a complex system of mating in this sympatric area. The main aims of this study were to estimate the pollen dispersal distance and to evaluate the breeding structure of P. axillaris subsp. axillaris, a hawkmoth-pollinated taxon from this sympatric zone.
Methods Pollen dispersal distance was compared with nearest-neighbours distance, and the differentiation in the pollen pool among mother plants was estimated. In addition, the correlation between genetic differentiation and spatial distance among plants was tested. All adult individuals (252) within a space of 2800 m2 and 15 open-pollinated progeny (285 seedlings) were analysed. Genetic analyses were based on 12 polymorphic microsatellite loci.
Key Results A high proportion of self-pollination was found, indicating a mixed-mating system. The maximum pollen dispersal distance was 1013 m, but most pollination events (96 %) occurred at a distance of 0 m, predominantly in an inbreeding system. Both parents among sampled individuals could be identifed in 60–85 % of the progeny.
Conclusions The results show that most pollen dispersal in the hawkmoth-pollinated P. axillaris subsp. axillaris occurs within populations and there is a high proportion of inbreeding. This mating system appears to favour species integrity in a secondary contact zone with the congener species P. exserta.
doi:10.1093/aob/mcv025
PMCID: PMC4407064  PMID: 25808656
Pollen dispersal; breeding structure; Petunia axillaris; P. exserta; Solanaceae; Pampas; selfing; inbreeding; genetic structure; microsatellites; hawkmoth pollination; gene flow
11.  Inflammageing assessed by MMP9 in normal Japanese individuals and the patients with Werner syndrome 
Summary
Age-associated minor inflammation: inflammageing may explain human ageing mechanism(s). Our previous study reported a significant increase in the serum level of highly sensitive C-reactive protein (hsCRP) with normal ageing and the patients with Werner syndrome (WS). To further study the minor inflammatory condition associated with ageing, another possible ageing biomarker: matrix metalloproteinase-9 (MMP9) was examined in the sera from 217 normal Japanese individuals aged between 1 and 100 years and 41 mutation-proven Japanese WS aged between 32 and 70 years. MMP9 was assayed by ELISA. The serum level of MMP9 was elevated significantly (p < 0.001) with normal ageing from both sexes as hsCRP. In contrast to normal ageing, the serum MMP9 level in WS decreased significantly with calendar age (p < 0.05). The MMP9 level (ng/mL) in WS (147.2 ± 28.5) was not significantly different in comparison with those from age-matched normal adult population aged between 25 and 70 years (109.1 ± 9.4), nor normal elderly population aged between 71 and 100 years (179.9 ± 16.1). Although both normal ageing and WS were associated with minor inflammation, the inflammatory parameters such as serum MMP9 and hsCRP changed differently between normal ageing and WS. The WS-specific chronic inflammation including skin ulcer and diabetes mellitus may contribute the different behavior of both ageing biomarkers from normal ageing.
doi:10.5582/irdr.2016.01028
PMCID: PMC4869575  PMID: 27195193
Aging; C-reactive protein (CRP); inflammageing; matrix metalloproteinase-9 (MMP9); Werner syndrome
12.  Viral Activation of Cellular Metabolism 
Virology  2015;0:609-618.
To ensure optimal environments for their replication and spread, viruses have evolved to alter many host cell pathways. In the last decade, metabolomic studies have shown that eukaryotic viruses induce large-scale alterations in host cellular metabolism. Most viruses examined to date induce aerobic glycolysis also known as the Warburg effect. Many viruses tested also induce fatty acid synthesis as well as glutaminolysis. These modifications of carbon source utilization by infected cells can increase available energy for virus replication and virion production, provide specific cellular substrates for virus particles and create viral replication niches while increasing infected cell survival. Each virus species also likely requires unique metabolic changes for successful spread and recent research has identified additional virus-specific metabolic changes induced by many virus species. A better understanding of the metabolic alterations required for each virus may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways.
doi:10.1016/j.virol.2015.02.038
PMCID: PMC4424078  PMID: 25812764
13.  Mode engineering for realistic quantum-enhanced interferometry 
Nature Communications  2016;7:11411.
Quantum metrology overcomes standard precision limits by exploiting collective quantum superpositions of physical systems used for sensing, with the prominent example of non-classical multiphoton states improving interferometric techniques. Practical quantum-enhanced interferometry is, however, vulnerable to imperfections such as partial distinguishability of interfering photons. Here we introduce a method where appropriate design of the modal structure of input photons can alleviate deleterious effects caused by another, experimentally inaccessible degree of freedom. This result is accompanied by a laboratory demonstration that a suitable choice of spatial modes combined with position-resolved coincidence detection restores entanglement-enhanced precision in the full operating range of a realistic two-photon Mach–Zehnder interferometer, specifically around a point which otherwise does not even attain the shot-noise limit due to the presence of residual distinguishing information in the spectral degree of freedom. Our method highlights the potential of engineering multimode physical systems in metrologic applications.
Quantum interferometry suffers from residual distinguishability between input photons. Here, the authors show theoretically and experimentally, in a two-photon measurement, how to overcome this by manipulating additional degrees of freedom.
doi:10.1038/ncomms11411
PMCID: PMC4855535  PMID: 27125782
14.  Wnt signaling in cancer stem cells and colon cancer metastasis 
F1000Research  2016;5:F1000 Faculty Rev-699.
Overactivation of Wnt signaling is a hallmark of colorectal cancer (CRC). The Wnt pathway is a key regulator of both the early and the later, more invasive, stages of CRC development. In the normal intestine and colon, Wnt signaling controls the homeostasis of intestinal stem cells (ISCs) that fuel, via proliferation, upward movement of progeny cells from the crypt bottom toward the villus and differentiation into all cell types that constitute the intestine. Studies in recent years suggested that cancer stem cells (CSCs), similar to ISCs of the crypts, consist of a small subpopulation of the tumor and are responsible for the initiation and progression of the disease. Although various ISC signature genes were also identified as CRC markers and some of these genes were even demonstrated to have a direct functional role in CRC development, the origin of CSCs and their contribution to cancer progression is still debated. Here, we describe studies supporting a relationship between Wnt-regulated CSCs and the progression of CRC.
doi:10.12688/f1000research.7579.1
PMCID: PMC4841194  PMID: 27134739
Wnt; colorectal cancer; intestinal stem cells; cancer stem cells; β-catenin; Lgr5
15.  Understanding the pathogenesis of abdominal aortic aneurysms 
Summary
An aortic aneurysm is a dilatation in which the aortic diameter is ≥ 3.0 cm. If left untreated, the aortic wall continues to weaken and becomes unable to withstand the forces of the luminal blood pressure resulting in progressive dilatation and rupture, a catastrophic event associated with a mortality of 50 – 80%. Smoking and positive family history are important risk factors for the development of abdominal aortic aneurysms (AAA). Several genetic risk factors have also been identified. On the histological level, visible hallmarks of AAA pathogenesis include inflammation, smooth muscle cell apoptosis, extracellular matrix degradation, and oxidative stress. We expect that large genetic, genomic, epigenetic, proteomic and metabolomic studies will be undertaken by international consortia to identify additional risk factors and biomarkers, and to enhance our understanding of the pathobiology of AAA. Collaboration between different research groups will be important in overcoming the challenges to develop pharmacological treatments for AAA.
doi:10.1586/14779072.2015.1074861
PMCID: PMC4829576  PMID: 26308600
embryologic origin; extracellular matrix; genetic susceptibility; risk factors; smoking; epigenetics; animal models; inflammation; doxycycline; matrix metalloproteinases
16.  Pathways Regulating Spheroid Formation of Human Follicular Thyroid Cancer Cells under Simulated Microgravity Conditions: A Genetic Approach 
Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS) and spheroid non-forming (AD) thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line) after a 24 h-exposure on the Random Positioning Machine (RPM) and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis) and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation.
doi:10.3390/ijms17040528
PMCID: PMC4848984  PMID: 27070589
thyroid cancer; simulated microgravity; random positioning machine; pathway studio; caveolin-1; vascular endothelial growth factor; matrix metalloproteinases; growth
17.  Active and Repressive Chromatin-Associated Proteome after MPA Treatment and the Role of Midkine in Epithelial Monolayer Permeability 
Mycophenolic acid (MPA) is prescribed to maintain allografts in organ-transplanted patients. However, gastrointestinal (GI) complications, particularly diarrhea, are frequently observed as a side effect following MPA therapy. We recently reported that MPA altered the tight junction (TJ)-mediated barrier function in a Caco-2 cell monolayer model system. This study investigates whether MPA induces epigenetic changes which lead to GI complications, especially diarrhea. Methods: We employed a Chromatin Immunoprecipitation-O-Proteomics (ChIP-O-Proteomics) approach to identify proteins associated with active (H3K4me3) as well as repressive (H3K27me3) chromatin histone modifications in MPA-treated cells, and further characterized the role of midkine, a H3K4me3-associated protein, in the context of epithelial monolayer permeability. Results: We identified a total of 333 and 306 proteins associated with active and repressive histone modification marks, respectively. Among them, 241 proteins were common both in active and repressive chromatin, 92 proteins were associated exclusively with the active histone modification mark, while 65 proteins remained specific to repressive chromatin. Our results show that 45 proteins which bind to the active and seven proteins which bind to the repressive chromatin region exhibited significantly altered abundance in MPA-treated cells as compared to DMSO control cells. A number of novel proteins whose function is not known in bowel barrier regulation were among the identified proteins, including midkine. Our functional integrity assays on the Caco-2 cell monolayer showed that the inhibition of midkine expression prior to MPA treatment could completely block the MPA-mediated increase in barrier permeability. Conclusions: The ChIP-O-Proteomics approach delivered a number of novel proteins with potential implications in MPA toxicity. Consequently, it can be proposed that midkine inhibition could be a potent therapeutic approach to prevent the MPA-mediated increase in TJ permeability and leak flux diarrhea in organ transplant patients.
doi:10.3390/ijms17040597
PMCID: PMC4849051  PMID: 27104530
mycophenolic acid; midkine; iMDK; tight junctions
18.  An extensive program of periodic alternative splicing linked to cell cycle progression 
eLife  null;5:e10288.
Progression through the mitotic cell cycle requires periodic regulation of gene function at the levels of transcription, translation, protein-protein interactions, post-translational modification and degradation. However, the role of alternative splicing (AS) in the temporal control of cell cycle is not well understood. By sequencing the human transcriptome through two continuous cell cycles, we identify ~1300 genes with cell cycle-dependent AS changes. These genes are significantly enriched in functions linked to cell cycle control, yet they do not significantly overlap genes subject to periodic changes in steady-state transcript levels. Many of the periodically spliced genes are controlled by the SR protein kinase CLK1, whose level undergoes cell cycle-dependent fluctuations via an auto-inhibitory circuit. Disruption of CLK1 causes pleiotropic cell cycle defects and loss of proliferation, whereas CLK1 over-expression is associated with various cancers. These results thus reveal a large program of CLK1-regulated periodic AS intimately associated with cell cycle control.
DOI: http://dx.doi.org/10.7554/eLife.10288.001
eLife digest
Mitosis is a key step in the normal life cycle of a cell, during which one cell divides into two new cells. As a cell progresses through the cell cycle, it must carefully regulate its gene activity to switch particular genes on or off at specific moments. When a gene is activated its sequence is first copied into a temporary molecule called a transcript. These transcripts are then edited to form templates to build proteins. One way that a transcript can be edited is via a process called alternative splicing, in which different pieces of the transcript are cut and pasted together to form different versions of the final template. This allows different instructions to be obtained from a single gene, introducing an added layer of biological complexity. However, the role of alternative splicing in the timing of key events of the cell life cycle is not well understood.
Dominguez et al. have now looked for the genes that undergo alternative splicing during the cell cycle. The sequences of gene transcripts produced within human cells were collected while the cells went through two rounds of division. This approach revealed that around 1,300 genes are spliced in different ways at different stages of each cell cycle. Many of these genes were known to play roles in controlling the cell’s life cycle, but few of the genes showed large changes in the amount of total transcript that is generated over time.
Dominguez et al. also showed that an enzyme called CLK1 influences about half of the 1,300 periodically spliced genes during the cell cycle. The production of CLK1 is itself carefully controlled throughout the cell cycle, and the enzyme’s activity prevents its own overproduction. Further experiments showed that blocking CLK1’s activity while a cell is replicating its DNA halts the cell cycle, but blocking this enzyme’s activity after the cell had replicated its DNA did not. Given this pivotal role in the cell cycle, Dominguez et al. also examined the role of CLK1 in cancer cells and found that high levels of CLK1 in tumours were linked to lower survival rates. These findings indicate that CLK1 warrants further investigation, particularly in relation to its role in cancer.
DOI: http://dx.doi.org/10.7554/eLife.10288.002
doi:10.7554/eLife.10288
PMCID: PMC4884079  PMID: 27015110
alternative splicing; cancer genomic; cell cycle; Human
19.  Significance of the actual nonlinear slope geometry for catastrophic failure in submarine landslides 
A simple approach to slope stability analysis of naturally occurring, mild nonlinear slopes is proposed through extension of shear band propagation (SBP) theory. An initial weak zone appears in the steepest part of the slope where the combined action of gravity and seismic loads overcomes the degraded peak shear resistance of the soil. If the length of this steepest part is larger than the critical length, the shear band will propagate into the quasi-stable parts of the slope, where the gravitational and seismically induced shear stresses are smaller than the peak but larger than the residual shear strength of the soil. Growth of a shear band is strongly dependent on the shape of the slope, seismic parameters and the strength of soil and less dependent on the slope inclination and the sensitivity of clay. For the slope surface with faster changing inclination, the criterion is more sensitive to the changes of the parameters. Accounting for the actual nonlinear slope geometry eliminates the main challenge of the SBP approach—determination of the length of the initial weak zone, because the slope geometry can be readily obtained from submarine site investigations. It also helps to identify conditions for the early arrest of the shear band, before failure in the sliding layer or a change in loading or excess pore water pressures occurs. The difference in the size of a landslide predicted by limiting equilibrium and SBP approaches can reach orders of magnitude, potentially providing an explanation for the immense dimensions of many observed submarine landslides that may be caused by local factors acting over a limited portion of the slope.
doi:10.1098/rspa.2014.0772
PMCID: PMC4353042  PMID: 25792958
submarine landslides; shear band propagation; geomorphology
20.  Adolescent sleep patterns in humans and laboratory animals 
Hormones and behavior  2013;64(2):270-279.
One of the defining characteristics of adolescence in humans is a large shift in the timing and structure of sleep. Some of these changes are easily observable at the behavioral level, such as a shift in sleep patterns from a relatively morning to a relatively evening chronotype. However, there are equally large changes in the underlying architecture of sleep, including a > 60% decrease in slow brain wave activity, which may reflect cortical pruning. In this review we examine the developmental forces driving adolescent sleep patterns using a cross-species comparison. We find that behavioral and physiological sleep parameters change during adolescence in non-human mammalian species, ranging from primates to rodents, in a manner that is often hormone-dependent. However, the overt appearance of these changes is species-specific, with polyphasic sleepers, such as rodents, showing a phase-advance in sleep timing and consolidation of daily sleep/wake rhythms. Using the classic two-process model of sleep regulation, we demonstrate via a series of simulations that many of the species-specific characteristics of adolescent sleep patterns can be explained by a universal decrease in the build-up and dissipation of sleep pressure. Moreover, and counterintuitively, we find that these changes do not necessitate a large decrease in overall sleep need, fitting the adolescent sleep literature. We compare these results to our previous review detailing evidence for adolescent changes in the regulation of sleep by the circadian timekeeping system (Hagenauer and Lee, 2012), and suggest that both processes may be responsible for adolescent sleep patterns.
doi:10.1016/j.yhbeh.2013.01.013
PMCID: PMC4780325  PMID: 23998671
Adolescent; Puberty; Sleep; Chronotype; Circadian; Homeostasis; Two-process model; Hormone; Development; Rodent
21.  Tight-binding approach to penta-graphene 
Scientific Reports  2016;6:22672.
We introduce an effective tight-binding model to discuss penta-graphene and present an analytical solution. This model only involves the π-orbitals of the sp2-hybridized carbon atoms and reproduces the two highest valence bands. By introducing energy-dependent hopping elements, originating from the elimination of the sp3-hybridized carbon atoms, also the two lowest conduction bands can be well approximated - but only after the inclusion of a Hubbard onsite interaction as well as of assisted hopping terms. The eigenfunctions can be approximated analytically for the effective model without energy-dependent hopping elements and the optical absorption is discussed. We find large isotropic absorption ranging from 7.5% up to 24% for transitions at the Γ-point.
doi:10.1038/srep22672
PMCID: PMC4778137  PMID: 26940279
22.  Insights into Cullin-RING E3 ubiquitin ligase recruitment: Structure of the VHL–EloBC–Cul2 complex 
Summary
The von Hippel-Lindau tumor suppressor protein (VHL) recruits a Cullin 2 (Cul2) E3 ubiquitin ligase to downregulate HIF-1α, an essential transcription factor for the hypoxia response. Mutations in VHL lead to VHL disease and renal cell carcinomas. Inhibition of this pathway to upregulate erythropoietin production is a promising new therapy to treat ischemia and chronic anemia. Here we report the crystal structure of VHL bound to a Cul2 N-terminal domain, Elongin B (EloB), and Elongin C (EloC). Cul2 interacts with both the VHL BC box and cullin box and a novel EloC site. Comparison to other cullin E3 ligase structures shows that there is a conserved, yet flexible, cullin recognition module and that cullin selectivity is influenced by distinct electrostatic interactions. Our structure provides a structural basis for the study of the pathogenesis of VHL disease and the rationale design of novel compounds that may modulate cullin–substrate receptor interactions.
doi:10.1016/j.str.2014.12.014
PMCID: PMC4351159  PMID: 25661653
23.  To what degree is palliative care integrated in guidelines and pathways for adult cancer patients in Europe: a systematic literature review 
BMC Palliative Care  2016;15:26.
Background
Palliative Care (PC) aims to improve the quality of life for patients with cancer and their families and its benefits have been demonstrated by several studies. The objective of this systematic review is to assess the integration of PC in the content of guidelines/pathways of adult cancer patients in Europe.
Methods
We included studies of adult patients with cancer published from 01/01/1995 and 31/12/2013 in Europe in six languages. We searched nine electronic databases, hand-searched six journals and also performed citation tracking. Studies were ranked using Emanuel’s Integrated Palliative Care (IPC) criteria, a tool containing 11 domains to assess PC content in guidelines. Two reviewers screened the results and narrative synthesis has been employed.
Results
We identified a total of 28,277 potentially relevant articles from which 637 were eligible for full-text screening. The final review included 60 guidelines and 14 pathways. Eighty percent (80 %) of the guidelines/pathways emphasize a holistic approach and 66 % focus on PC interventions aimed at reducing suffering. Fifty seven percent (57 %) did not discuss referral criteria for PC. Of all studies, five fulfilled at least 10/11 IPC criteria. Differences existed with regard to the referral criteria for bereavement care and the continuous adjustment of goals of care.
Conclusion
Overall, most of the identified guidelines/pathways highlighted the importance of the holistic approach of IPC. The studies that were found to fulfil at least 10/11 Emanuel’s IPC criteria could serve as benchmarks of IPC.
doi:10.1186/s12904-016-0100-0
PMCID: PMC4778279  PMID: 26940753
Delivery of Health Care; Integrated; Palliative care; Medical oncology; Systematic review; Guidelines; Pathways
24.  Day-to-Day Inconsistency in Parent Knowledge: Links with Youth Health and Parents’ Stress 
Purpose
Considerable evidence documents the linkages between higher levels of parental knowledge about youth activities and positive youth outcomes. This study investigated how day-to-day inconsistency in parental knowledge of youth activities was linked to youth behavioral, psychological, and physical health as well as parents’ stress.
Methods
Participants were employees in the Information Technology division of a Fortune 500 company and their children (N =129, Mean age youth = 13.39 years, 55% female). Data were collected from parents and youth via separate workplace and in-home surveys as well as telephone diary surveys on 8 consecutive evenings. We assessed day-to-day inconsistency in parental knowledge across these eight calls.
Results
Parents differed in their knowledge from day to day almost as much as their average knowledge scores differed from those of other parents. Controlling for mean levels of knowledge, youth whose parents exhibited more knowledge inconsistency reported more physical health symptoms (e.g., colds, flu). Knowledge inconsistency was also associated with more risky behavior for girls but greater psychological well-being for older adolescents. Parents who reported more stressors also had higher knowledge inconsistency.
Conclusions
Assessing only average levels of parental knowledge does not fully capture how this parenting dimension is associated with youth health. Consistent knowledge may promote youth physical health and less risky behavior for girls. Yet knowledge inconsistency also may reflect normative increases in autonomy as it was positively associated with psychological well-being for older adolescents. Given the linkages between parental stress and knowledge inconsistency, parent interventions should include stress-management components.
doi:10.1016/j.jadohealth.2014.11.017
PMCID: PMC4338414  PMID: 25703318
parental knowledge; daily diary; physical health; risky behavior; psychological well-being
25.  Zinc1 
Advances in Nutrition  2015;6(2):224-226.
doi:10.3945/an.114.006874
PMCID: PMC4352181  PMID: 25770261

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