bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational inference of physical spatial organization of eukaryotic genomes
Authors: Xu Bingxiang , Zhang Zhihua
Published: November 2016

Background

Chromosomes are packed in the cell’s nucleus, and chromosomal conformation is critical to nearly all intranuclear biological reactions, including gene transcription and DNA replication. Nevertheless, chromosomal conformation is largely a mystery in terms of its formation and the regulatory machinery that accesses it.

Results

Thanks to recent technological developments, we can now probe chromatin interaction in substantial detail, boosting research interest in modeling genome spatial organization. Here, we review the current computational models that simulate chromosome dynamics, and explain the physical and topological properties of chromosomal conformation, as inferred from these newly generated data.

Conclusion

Novel models shall be developed to address questions beyond averaged structure in the near further.
Rethinking pathology in adolescent self‐harm: Towards a more complex understanding of risk factors
Authors: Stanford Sarah , Jones Michael P. , Hudson Jennifer L.
Published: November 2016

Researchers have begun to consider whether there may be more than one psychological profile to describe adolescents who engage in self‐harm. Limited past research suggests multiple different profiles. Australian high school students (n = 1,521, age 11–19, 56.4% female) completed an online questionnaire reporting risk and protective factors and self‐harm frequency. Non‐hierarchical cluster analysis allocated 256 students who reported 6‐month self‐harm to mutually exclusive profiles based on psychological similarity. Five distinct psychological profiles were identified: 1) Psychologically 'normal'; 2) Anxiety symptoms; 3) Impulsive; 4) Pathological; and 5) Pathological‐Impulsive. The proportion of adolescents that reported 11 or more episodes of self‐harm varied from 5.7% in the psychologically 'Normal' group to 27.7% in the 'Pathological‐ Impulsive' group. These results indicate that multiple psychological profiles exist. Adolescents with different risk factors may require disparate strategies for treatment and prevention. Given the variability in profiles, screening may assist in detecting adolescents who self‐harm.
Mesozoic granitoids in the structure of the Bezymyannyi metamorphic-core complex (western Transbaikalia)
Authors: Donskaya T.V. , Gladkochub D.P. , Mazukabzov A.M. , Wang T. , Guo L. , Rodionov N.V. , Demonterova E.I.
Published: November 2016

We performed geological, geochronological, and isotope-geochemical studies of two tectonized-granite bodies intruding the rocks of the lower plate of the Bezymyannyi metamorphic-core complex (MCC) (western Transbaikalia). The U–Pb zircon age of sheared granites sampled on the periphery of the Bezymyannyi MCC near the detachment zone is 202 ± 2 Ma (LA–ICP-MS). The U–Pb dating (SHRIMP-II) of zircon grains from gneissic granite intruding the rocks of the lower plate in the central zone of the Bezymyannyi MCC has yielded an age of 165 ± 2 Ma. The sheared granites dated at 202 Ma (Late Triassic) have low contents of Nb and Ta and high contents of Sr and Ba, probably inherited from magmatic subduction-related sources. These granites are characterized by εNd(T) = –3.7, which, along with the high contents of K2O and medium contents of Th, testifies to the presence of continental-crust material in their source. Thus, they formed, most likely, from a mixed mantle–crust source. The studied granites, like other Triassic igneous rocks in Transbaikalia, might have originated in the suprasubduction setting during the evolution of the active continental margin of the Siberian continent. The gneissic granites dated at 165 Ma (Middle Jurassic) have high contents of K2O, Rb, and Th, are depleted in Nb, and are characterized by εNd(T) = 0 and a negative Eu anomaly on the REE patterns. They formed, most likely, from an intermediate–felsic crustal source. These Middle Jurassic granites, like other small Jurassic granitoid massifs spatially associated with MCCs in western Transbaikalia, intruded in the western part of the Mongol–Okhotsk Ocean after its closure, during the change of the subduction regime for the collisional one. The studied Late Triassic granites of the Bezymyannyi MCC cannot be associated with MCCs in Transbaikalia because their intrusion was related to the subduction of the oceanic plate of the Mongol–Okhotsk Ocean beneath the Siberian continent. The Middle Jurassic granites of the Bezymyannyi MCC, together with other small Jurassic granitoid massifs, can be classified as prekinematic intrusions formed earlier than MCCs in western Transbaikalia. However, it is unlikely that their intrusion caused a large-scale crustal extension in Transbaikalia.
Planning Clinical Research
Authors: Parker Robert A. , Berman Nancy G.
Published: November 2016

Planning a clinical study is much more than determining the basic study design. Who will you be studying? How do you plan to recruit your study subjects? How do you plan to retain them in the study? What data do you plan to collect? How will you obtain this data? How will you minimize bias? All these decisions must be consistent with the ethical considerations of studying people. This book teaches how to choose the best design for your question. Drawing on their many years working in clinical research, Nancy G. Berman and Robert A. Parker guide readers through the essential elements of study planning to help get them started. The authors offer numerous examples to illustrate the key decisions needed, describing what works, what does not work, and why. Written specifically for junior investigators beginning their research careers, this guide will also be useful to senior investigators needing to review specific topics.
Is prosodic production driven by lexical development? Longitudinal evidence from babble and words
Authors: DE CLERCK ILKE , PETTINATO MICHÈLE , VERHOEVEN JO , GILLIS STEVEN
Published: November 2016

This study investigated the relation between lexical development and the production of prosodic prominence in disyllabic babble and words. Monthly recordings from nine typically developing Belgian-Dutch-speaking infants were analyzed from the onset of babbling until a cumulative vocabulary of 200 words was reached. The differentiation between the two syllables of isolated disyllabic utterances was computed for f0, intensity, and duration measurements. Results showed that the ambient trochaic pattern emerged in babble, but became enhanced in words. Words showed more prosodic differentiation in terms of f0 and intensity and a more even duration ratio. Age or vocabulary size did not predict the expansion of f0 or intensity in words, whereas vocabulary size was related to the production of more even-timed syllables. The findings are discussed in terms of lexicalist accounts of phonetic development and a potential phonetic highlighting function of first words.
Trade-offs and synergies between carbon, forest diversity and forest products in Nepal community forests
Authors: RANA EAK , THWAITES RIK , LUCK GARY
Published: November 2016

Reducing emissions from deforestation and forest degradation, the sustainable management of forests and the conservation and enhancement of forest carbon stocks in developing countries (‘REDD+’) aims to improve local livelihoods and conserve plant diversity while limiting carbon emissions. Yet trade-offs and synergies that exist between supporting livelihoods, protecting plant diversity and maintaining forest ecosystem services are poorly documented. We used forest inventory data and community-group records to assess trade-offs and synergies between carbon, plant diversity and forest products in 19 community forests managed under REDD+ in Nepal. Trade-offs were prevalent for carbon, whereby community forests with relatively high carbon values had relatively low values for plant diversity or forest products provision, and vice versa. Synergies occurred between plant diversity and forest products provision (fuelwood and fodder), suggesting that forests with relatively high plant diversity values were also important for providing critical forest products to local communities. This study shows that conserving forests for carbon should not impinge greatly on the flow of forest resources to at least some local communities; however, promoting carbon storage will not necessarily protect plant diversity. These findings should help guide future REDD+ policy for community forests.
THE PHILLIPS CURVE AND AN ASSUMED UNIQUE MACROECONOMIC EQUILIBRIUM IN HISTORICAL CONTEXT
Authors: Lipsey Richard G.
Published: November 2016

An early post-WWII debate concerned the most desirable demand and inflationary pressures at which to run the economy. Context was provided by Keynesian theory devoid of a full employment equilibrium and containing its mainly forgotten, but still relevant, microeconomic underpinnings. A major input came with the estimates provided by the original Phillips curve. The debate seemed to be rendered obsolete by the curve’s expectations-augmented version with its natural rate of unemployment, and associated unique equilibrium GDP, as the only values consistent with stable inflation. The current behavior of economies with the successful inflation targeting is inconsistent with this natural-rate view, but is consistent with evolutionary theory in which economies have a wide range of GDP-compatible stable inflation. Now the early post-WWII debates are seen not to be as misguided as they appeared to be when economists came to accept the assumptions implicit in the expectations-augmented Phillips curve.
Genetic and Environmental Influences on General Skin Traits: Healthy Twins and Families in Korea
Authors: Suh Young Ju , Shin Jeonghyun , Kang Moonil , Park Hyun Ju , Lee Kayoung , Song Yun-Mi , Sung Joohon
Published: November 2016

Family study can provide estimates of overall genetic influences on a particular trait because family relationships provide accurate measures of average genetic sharing. However, evidence of genetic contributions to skin phenotypes is limited, which may preclude genetic studies to identify genetic variants or to understand underlying molecular biology of skin traits. This study aimed to estimate genetic and environmental contributions to selected dermatologic phenotypes, that is, to melanin index, sebum secretion, and skin humidity level in a Korean twin-family cohort. We investigated more than 2,000 individuals from 486 families, including 388 monozygotic twin pairs and 82 dizygotic twin pairs. Variance component method was used to estimate genetic influences in terms of heritability. Heritability of skin melanin index, sebum secretion, and skin humidity (arm and cheek) were estimated to be 0.44 [95% CI 0.38–0.49], 0.21 [95% CI 0.16–0.26], 0.13 [95% CI 0.07–0.18], and 0.11 [95% CI 0.06–0.16] respectively, after adjusting for confounding factors. Our findings suggest that genetics play a major role on skin melanin index, but only mild roles on sebum secretion and humidity. Sebum secretion and skin humidity are controlled predominantly by environmental factors notably on shared environments among family members. We expect that our findings add insight to determinants of common dermatologic traits, and serve as a reference for biologic studies.
Der Migrationshintergrund in multikulturellen Pflegearrangements
Authors: Krobisch Verena , Sonntag Pia-Theresa , Gül Kübra , Aronson Polina , Schenk Liane
Published: November 2016

Zusammenfassung. Hintergrund: Migration befördert die Zunahme multikultureller Pflegearrangements. Welche Akzeptanz diese Versorgungsbeziehungen auf Nutzerseite finden, ist kaum erforscht. Ziel: Untersucht wird, ob und inwiefern für ältere Türkeistämmige ein gemeinsamer Migrations- bzw. soziokultureller Hintergrund mit den Pflegefachpersonen relevant ist. Methode: Im Sinne einer Datentriangulation wurden Ergebnisse einer qualitativen und quantitativen Studie zu Pflegeerwartungen älterer Türkeistämmiger zusammengeführt. Die Datengrundlage bilden leitfadengestützte Interviews und Fragebogen-Interviews. Die Auswertung erfolgte mittels dokumentarischer Methode nach Bohnsack sowie deskriptiver und multivariater Analysen. Ergebnisse: Eine Berücksichtigung kulturell- und migrationsbedingter Aspekte in der Pflege ist für die Mehrheit der Befragten bedeutsam. Mehr als drei Viertel erachten Türkischkenntnisse der Pflegefachpersonen als ein Merkmal guter Pflege. Dabei kommt es ihnen auf die Möglichkeit zur sachlichen, aber auch zur kulturell geprägten intuitiven Kommunikation in der Muttersprache an. Ein geringer Grad an Deutschkenntnissen, eine türkisch geprägte Identität sowie das weibliche Geschlecht sind mit einem Bedarf an migrationssensibler Pflege assoziiert. Schlussfolgerungen: Ein gemeinsamer soziokultureller Hintergrund mit den Pflegefachpersonen und die gemeinsame Muttersprache scheinen für ältere Türkeistämmige eine Voraussetzung für gute Pflege. Weitere Forschung sollte klären, unter welchen Bedingungen multikulturelle Pflegekonstellationen in dieser Gruppe auf Akzeptanz stoßen.
Tick microbiome and pathogen acquisition altered by host blood meal
Authors: Swei Andrea , Kwan Jessica Y
Published: November 2016

Lyme disease, a zoonotic disease, is the most prevalent vector-borne disease in the Northern Hemisphere. Diversity of the vector (tick) microbiome can impact pathogen transmission, yet the biotic and abiotic factors that drive microbiome diversity are largely unresolved, especially under natural, field conditions. We describe the microbiome of Ixodes pacificus ticks, the vector for Lyme disease in the western United States, and show a strong impact of host blood meal identity on tick microbiome species richness and composition. Western fence lizards, a host that is refractory to the Lyme disease pathogen, significantly reduces microbiome diversity in ticks relative to ticks that feed on a mammalian reservoir host. Host blood meal-driven reduction of tick microbiome diversity may have lifelong repercussions on I. pacificus vector competency and ultimately disease dynamics.
Positive and strongly relaxed purifying selection drive the evolution of repeats in proteins
Authors: Persi Erez , Wolf Yuri I. , Koonin Eugene V
Published: November 2016

Protein repeats are considered hotspots of protein evolution, associated with acquisition of new functions and novel phenotypic traits, including disease. Paradoxically, however, repeats are often strongly conserved through long spans of evolution. To resolve this conundrum, it is necessary to directly compare paralogous (horizontal) evolution of repeats within proteins with their orthologous (vertical) evolution through speciation. Here we develop a rigorous methodology to identify highly periodic repeats with significant sequence similarity, for which evolutionary rates and selection (dN/dS) can be estimated, and systematically characterize their evolution. We show that horizontal evolution of repeats is markedly accelerated compared with their divergence from orthologues in closely related species. This observation is universal across the diversity of life forms and implies a biphasic evolutionary regime whereby new copies experience rapid functional divergence under combined effects of strongly relaxed purifying selection and positive selection, followed by fixation and conservation of each individual repeat.
Structure and biodiversity of coralligenous assemblages dominated by the precious red coral Corallium rubrum over broad spatial scales
Authors: Casas-Güell Edgar , Cebrian Emma , Garrabou Joaquim , Ledoux Jean-Baptiste , Linares Cristina , Teixidó Núria
Published: November 2016

Data on species diversity and structure in coralligenous outcrops dominated by Corallium rubrum are lacking. A hierarchical sampling including 3 localities and 9 sites covering more than 400 km of rocky coasts in NW Mediterranean, was designed to characterize the spatial variability of structure, composition and diversity of perennial species inhabiting coralligenous outcrops. We estimated species/taxa composition and abundance. Eight morpho-functional groups were defined according to their life span and growth to characterize the structural complexity of the outcrops. The species composition and structural complexity differed consistently across all spatial scales considered. The lowest and the highest variability were found among localities (separated by >200 km) and within sites (separated by 1–5 km), respectively supporting differences in diversity indices. The morpho-functional groups displayed a consistent spatial arrangement in terms of the number, size and shape of patches across study sites. These results contribute to filling the gap on the understanding of assemblage composition and structure and to build baselines to assess the response of this of this highly threatened habitat to anthropogenic disturbances.
Robustness of a Topologically Protected Surface State in a Sb2Te2Se Single Crystal
Authors: Lee Chao-Kuei , Cheng Cheng-Maw , Weng Shih-Chang , Chen Wei-Chuan , Tsuei Ku-Ding , Yu Shih-Hsun , Chou Mitch Ming-Chi , Chang Ching-Wen , Tu Li-Wei , Yang Hung-Duen , Luo Chih-Wei , Gospodinov Marin M.
Published: November 2016

A topological insulator (TI) is a quantum material in a new class with attractive properties for physical and technological applications. Here we derive the electronic structure of highly crystalline Sb2Te2Se single crystals studied with angle-resolved photoemission spectra. The result of band mapping reveals that the Sb2Te2Se compound behaves as a p-type semiconductor and has an isolated Dirac cone of a topological surface state, which is highly favored for spintronic and thermoelectric devices because of the dissipation-less surface state and the decreased scattering from bulk bands. More importantly, the topological surface state and doping level in Sb2Te2Se are difficult to alter for a cleaved surface exposed to air; the robustness of the topological surface state defined in our data indicates that this Sb2Te2Se compound has a great potential for future atmospheric applications.
Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β
Authors: Jiang Chunming , Zhu Wei , Yan Xiang , Shao Qiuyuan , Xu Biao , Zhang Miao , Gong Rujun
Published: November 2016

Acute kidney injury (AKI) remains challenging for clinical practice and poses a risk of developing progressive chronic kidney disease (CKD) with no definitive treatment available yet. Tanshinone IIA, an active ingredient of Chinese herbal Salvia miltiorrhiza, has been widely used in Asia for the remarkable organoprotective activities. Its effect on established AKI, however, remains unknown. In mice with folic acid-induced AKI, delayed treatment with Tanshinone IIA, commenced early or late after injury, diminished renal expression of kidney injury markers, reduced apoptosis and improved kidney dysfunction, concomitant with mitigated histologic signs of AKI to CKD transition, including interstitial fibrosis and tubular atrophy, and with an ameliorated inflammatory infiltration in tubulointerstitium and a favored M2-skewed macrophage polarization. Mechanistically, Tanshinone IIA blunted glycogen synthase kinase (GSK)3β overactivity and hyperactivation of its downstream mitogen-activated protein kinases that are centrally implicated in renal fibrogenesis and inflammation. Inhibition of GSK3β is likely a key mechanism mediating the therapeutic activity of Tanshinone IIA, because sodium nitroprusside, a GSK3β activator, largely offset its renoprotective effect. In confirmatory studies, rescue treatment with Tanshinone IIA likewise ameliorated ischemia/reperfusion-induced kidney destruction in mice. Our data suggest that Tanshinone IIA represents a valuable treatment that improves post-AKI kidney salvage via targeting GSK3β.
Precise identification of Dirac-like point through a finite photonic crystal square matrix
Authors: Dong Guoyan , Zhou Ji , Yang Xiulun , Meng Xiangfeng
Published: November 2016

The phenomena of the minimum transmittance spectrum or the maximum reflection spectrum located around the Dirac frequency have been observed to demonstrate the 1/L scaling law near the Dirac-like point through the finite ribbon structure. However, so far there is no effective way to identify the Dirac-like point accurately. In this work we provide an effective measurement method to identify the Dirac-like point accurately through a finite photonic crystal square matrix. Based on the Dirac-like dispersion achieved by the accidental degeneracy at the centre of the Brillouin zone of dielectric photonic crystal, both the simulated and experimental results demonstrate that the transmittance spectra through a finite photonic crystal square matrix not only provide the clear evidence for the existence of Dirac-like point but also can be used to identify the precise location of Dirac-like point by the characteristics of sharp cusps embedded in the extremum spectra surrounding the conical singularity.
LUC7L3/CROP inhibits replication of hepatitis B virus via suppressing enhancer II/basal core promoter activity
Authors: Li Yuan , Ito Masahiko , Sun Suofeng , Chida Takeshi , Nakashima Kenji , Suzuki Tetsuro
Published: November 2016

The core promoter of hepatitis B virus (HBV) genome is a critical region for transcriptional initiation of 3.5 kb, pregenome and precore RNAs and for the viral replication. Although a number of host-cell factors that potentially regulate the viral promoter activities have been identified, the molecular mechanisms of the viral gene expression, in particular, regulatory mechanisms of the transcriptional repression remain elusive. In this study, we identified LUC7 like 3 pre-mRNA splicing factor (LUC7L3, also known as hLuc7A or CROP) as a novel interacting partner of HBV enhancer II and basal core promoter (ENII/BCP), key elements within the core promoter, through the proteomic screening and found that LUC7L3 functions as a negative regulator of ENII/BCP. Gene silencing of LUC7L3 significantly increased expression of the viral genes and antigens as well as the activities of ENII/BCP and core promoter. In contrast, overexpression of LUC7L3 inhibited their activities and HBV replication. In addition, LUC7L3 possibly contributes to promotion of the splicing of 3.5 kb RNA, which may also be involved in negative regulation of the pregenome RNA level. This is the first to demonstrate the involvement of LUC7L3 in regulation of gene transcription and in viral replication.
Atomistic switch of giant magnetoresistance and spin thermopower in graphene-like nanoribbons
Authors: Zhai Ming-Xing , Wang Xue-Feng
Published: November 2016

We demonstrate that the giant magnetoresistance can be switched off (on) in even- (odd-) width zigzag graphene-like nanoribbons by an atomistic gate potential or edge disorder inside the domain wall in the antiparallel (ap) magnetic configuration. A strong magneto-thermopower effect is also predicted that the spin thermopower can be greatly enhanced in the ap configuration while the charge thermopower remains low. The results extracted from the tight-binding model agree well with those obtained by first-principles simulations for edge doped graphene nanoribbons. Analytical expressions in the simplest case are obtained to facilitate qualitative analyses in general contexts.
Glycation potentiates neurodegeneration in models of Huntington’s disease
Authors: Vicente Miranda Hugo , Gomes Marcos António , Branco-Santos Joana , Breda Carlo , Lázaro Diana F. , Lopes Luísa Vaqueiro , Herrera Federico , Giorgini Flaviano , Outeiro Tiago Fleming
Published: November 2016

Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington’s disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD.
Size Switchable Supramolecular Nanoparticle Based on Azobenzene Derivative within Anionic Pillar[5]arene
Authors: Zhang Cai-Cai , Li Sheng-Hua , Zhang Cui-Fang , Liu Yu
Published: November 2016

A photo/thermal-switchable supramolecular nanoparticles assembly has been constructed based on an inclusion complex between anionic pillar[5]arene 2C-WP5A and azobenzene derivative Azo-py-OMe (G). The novel anionic pillar[5]arene-based host-guest inclusion complexation was investigated by the 1H NMR titration, 2D ROESY and isothermal titration microcalorimetry (ITC) showing high association constant (Ka) of (2.60 ± 0.06) × 104 M−1 with 1:1 binding stoichiometry. Furthermore, the supramolecular nanoparticles assembly can be conveniently obtained from G and a small amount of 2C-WP5A in aqueous solution, which was so-called “host induced aggregating (HIA)”. The size and morphology of the supramolecular nanoparticles assembly were characterized by TEM and DLS. As a result of the photo/thermal-isomerization of G included in the cavity of 2C-WP5A, the size of these nanoparticles could reversibly change from ~800 nm to ~250 nm, which could switch the solution of this assembly from turbid to clear.
Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin
Authors: Chen Ling-Chun , Chen Yin-Chen , Su Chia-Yu , Wong Wan-Ping , Sheu Ming-Thau , Ho Hsiu-O
Published: November 2016

Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders.
A biodiversity hotspot losing its top predator: The challenge of jaguar conservation in the Atlantic Forest of South America
Authors: Paviolo Agustin , De Angelo Carlos , Ferraz Katia M. P. M. B. , Morato Ronaldo G. , Martinez Pardo Julia , Srbek-Araujo Ana C. , Beisiegel Beatriz de Mello , Lima Fernando , Sana Denis , Xavier da Silva Marina , Velázquez Myriam C. , Cullen Laury , Crawshaw Jr Peter , Jorge María Luisa S. P. , Galetti Pedro M. , Di Bitetti Mario S. , de Paula Rogerio Cunha , Eizirik Eduardo , Aide T. Mitchell , Cruz Paula , Perilli Miriam L. L. , Souza Andiara S. M. C. , Quiroga Verónica , Nakano Eduardo , Ramírez Pinto Fredy , Fernández Sixto , Costa Sebastian , Moraes Jr Edsel A. , Azevedo Fernando
Published: November 2016

The jaguar is the top predator of the Atlantic Forest (AF), which is a highly threatened biodiversity hotspot that occurs in Brazil, Paraguay and Argentina. By combining data sets from 14 research groups across the region, we determine the population status of the jaguar and propose a spatial prioritization for conservation actions. About 85% of the jaguar’s habitat in the AF has been lost and only 7% remains in good condition. Jaguars persist in around 2.8% of the region, and live in very low densities in most of the areas. The population of jaguars in the AF is probably lower than 300 individuals scattered in small sub-populations. We identified seven Jaguar Conservation Units (JCUs) and seven potential JCUs, and only three of these areas may have ≥50 individuals. A connectivity analysis shows that most of the JCUs are isolated. Habitat loss and fragmentation were the major causes for jaguar decline, but human induced mortality is the main threat for the remaining population. We classified areas according to their contribution to jaguar conservation and we recommend management actions for each of them. The methodology in this study could be used for conservation planning of other carnivore species.
Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons
Authors: Ohtake Yosuke , Wong Daniella , Abdul-Muneer P. M. , Selzer Michael E. , Li Shuxin
Published: November 2016

Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice. We demonstrate that both receptors share certain signaling pathways (RhoA, Akt and Erk), but also use distinct signals to mediate CSPG actions. Activation of PTPσ by CSPGs selectively inactivated CRMP2, APC, S6 kinase and CREB. By contrast LAR activation inactivated PKCζ, cofilin and LKB1. For the first time, we propose a model of the signaling pathways downstream of these two CSPG receptors. We also demonstrate that deleting both receptors exhibits additive enhancement of axon growth in adult neuronal cultures in vitro. Our findings elucidate the novel downstream pathways of CSPGs and suggest potential synergy of blocking their two PTP receptors.
ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions
Authors: Sharma Krishna Rakesh , Heckler Karl , Stoll Sandra J. , Hillebrands Jan-Luuk , Kynast Katharina , Herpel Esther , Porubsky Stefan , Elger Marlies , Hadaschik Boris , Bieback Karen , Hammes Hans-Peter , Nawroth Peter P. , Kroll Jens
Published: November 2016

Engulfment and cell motility 1 (ELMO1) functions as a guanine exchange factor for Rac1 and was recently found to protect endothelial cells from apoptosis. Genome wide association studies suggest that polymorphisms within human elmo1 act as a potential contributing factor for the development of diabetic nephropathy. Yet, the function of ELMO1 with respect to the glomerulus and how this protein contributes to renal pathology was unknown. Thus, this study aimed to identify the role played by ELMO1 in renal development in zebrafish, under hyperglycaemic conditions, and in diabetic nephropathy patients. In zebrafish, hyperglycaemia did not alter renal ELMO1 expression. However, hyperglycaemia leads to pathophysiological and functional alterations within the pronephros, which could be rescued via ELMO1 overexpression. Zebrafish ELMO1 crispants exhibited a renal pathophysiology due to increased apoptosis which could be rescued by the inhibition of apoptosis. In human samples, immunohistochemical staining of ELMO1 in nondiabetic, diabetic and polycystic kidneys localized ELMO1 in glomerular podocytes and in the tubules. However, ELMO1 was not specifically or distinctly regulated under either one of the disease conditions. Collectively, these results highlight ELMO1 as an important factor for glomerular protection and renal cell survival via decreasing apoptosis, especially under diabetic conditions.
Fatal Community-acquired Pneumonia in Children Caused by Re-emergent Human Adenovirus 7d Associated with Higher Severity of Illness and Fatality Rate
Authors: Yu Zhiwu , Zeng Zhiwei , Zhang Jing , Pan Yuxian , Chen Manjun , Guo Yonghui , Yu Nan , Chodosh James , Fu Ning , Che Xiaoyan , Zhang Qiwei
Published: November 2016

Human adenoviruses (HAdVs) are highly contagious pathogens causing acute respiratory disease (ARD), such as community-acquired pneumonia. HAdV-7d, a re-emergent genomic variant, has been recently reported in Asia and the United States after a several-decade absence. However, whether HAdV-7d is associated with higher severity than other types is currently unclear. In this study, the clinical and epidemiological investigation showed that fever, cough, and sore throat were the three most common respiratory symptoms of HAdV infections. HAdV-7 caused longer duration of fever, higher morbidity of tachypnea/dyspnea, pleural effusion, diarrhea, hepatosplenomegaly, consciousness alteration, as well as higher rates of pneumonia, mechanical ventilation and higher fatality rate (28.6%) than other types, particularly HAdV-3 and HAdV-2. The genomes of seven HAdV-7d isolates from mild, severe, and fatal cases were sequenced and highly similar with each other. Surprisingly, two isolates (2011, 2012) had 100% identical genomes with an earlier strain from a fatal ARD outbreak in China (2009), which elucidates the virus origin and confirms the unexpected HAdV genomic conservation and stability. Phylogenetic analysis indicated that L1 52/55-kDa DNA packaging protein may be associated with the higher severity of illness and fatality rate of HAdV-7. Clinicians need to be aware of HAdVs in children with ARD.
Deletion of Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology
Authors: Arango-Lievano Margarita , Peguet Camille , Catteau Matthias , Parmentier Marie-Laure , Wu Synphen , Chao Moses V , Ginsberg Stephen D. , Jeanneteau Freddy
Published: November 2016

Glucocorticoid resistance is a risk factor for Alzheimer’s disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeling synaptic structure and plasticity. The goal of this study is to test the role of the BDNF-dependent pathway on glucocorticoid signaling in a mouse model of glucocorticoid resistance. We report that deletion of GR phosphorylation at BDNF-responding sites and downstream signaling via the MAPK-phosphatase DUSP1 triggers tau phosphorylation and dendritic spine atrophy in mouse cortex. In human cortex, DUSP1 protein expression correlates with tau phosphorylation, synaptic defects and cognitive decline in subjects diagnosed with AD. These findings provide evidence for a causal role of BDNF-dependent GR signaling in tau neuropathology and indicate that DUSP1 is a potential target for therapeutic interventions.
Analysis of Microarray Data on Gene Expression and Methylation to Identify Long Non-coding RNAs in Non-small Cell Lung Cancer
Authors: Feng Nannan , Ching Travers , Wang Yu , Liu Ben , Lin Hongyan , Shi Oumin , Zhang Xiaohong , Zheng Min , Zheng Xin , Gao Ming , Zheng Zhi-jie , Yu Herbert , Garmire Lana , Qian Biyun
Published: November 2016

To identify what long non-coding RNAs (lncRNAs) are involved in non-small cell lung cancer (NSCLC), we analyzed microarray data on gene expression and methylation. Gene expression chip and HumanMethylation450BeadChip were used to interrogate genome-wide expression and methylation in tumor samples. Differential expression and methylation were analyzed through comparing tumors with adjacent non-tumor tissues. LncRNAs expressed differentially and correlated with coding genes and DNA methylation were validated in additional tumor samples using RT-qPCR and pyrosequencing. In vitro experiments were performed to evaluate lncRNA’s effects on tumor cells. We identified 8,500 lncRNAs expressed differentially between tumor and non-tumor tissues, of which 1,504 were correlated with mRNA expression. Two of the lncRNAs, LOC146880 and ENST00000439577, were positively correlated with expression of two cancer-related genes, KPNA2 and RCC2, respectively. High expression of LOC146880 and ENST00000439577 were also associated with poor survival. Analysis of lncRNA expression in relation to DNA methylation showed that LOC146880 expression was down-regulated by DNA methylation in its promoter. Lowering the expression of LOC146880 or ENST00000439577 in tumor cells could inhibit cell proliferation, invasion and migration. Analysis of microarray data on gene expression and methylation allows us to identify two lncRNAs, LOC146880 and ENST00000439577, which may promote the progression of NSCLC.
Nitrogen-induced metabolic changes and molecular determinants of carbon allocation in Dunaliella tertiolecta
Authors: Tan Kenneth Wei Min , Lin Huixin , Shen Hui , Lee Yuan Kun
Published: November 2016

Certain species of microalgae are natural accumulators of lipids, while others are more inclined to store starch. However, what governs the preference to store lipids or starch is not well understood. In this study, the microalga Dunaliella tertiolecta was used as a model to study the global gene expression profile regulating starch accumulation in microalgae. D. tertiolecta, when depleted of nitrogen, produced only 1% of dry cell weight (DCW) in neutral lipids, while starch was rapidly accumulated up to 46% DCW. The increased in starch content was accompanied by a coordinated overexpression of genes shunting carbon towards starch synthesis, a response not seen in the oleaginous microalgae Nannochloropsis oceanica, Chlamydomonas reinhardtii or Chlorella vulgaris. Genes in the central carbon metabolism pathways, particularly those of the tricarboxylic acid cycle, were also simultaneously upregulated, indicating a robust interchange of carbon skeletons for anabolic and catabolic processes. In contrast, fatty acid and triacylglycerol synthesis genes were downregulated or unchanged, suggesting that lipids are not a preferred form of storage in these cells. This study reveals the transcriptomic influence behind storage reserve allocation in D. tertiolecta and provides valuable insights into the possible manipulation of genes for engineering microorganisms to synthesize products of interest.
The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells
Authors: Rahman Md. Mostafizur , Prünte Laura , Lebender Leonard F. , Patel Brijeshkumar S. , Gelissen Ingrid , Hansbro Philip M. , Morris Jonathan C. , Clark Andrew R. , Verrills Nicole M. , Ammit Alaina J.
Published: November 2016

Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E2 (PGE2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism.
How a High-Gradient Magnetic Field Could Affect Cell Life
Authors: Zablotskii Vitalii , Polyakova Tatyana , Lunov Oleg , Dejneka Alexandr
Published: November 2016

The biological effects of high-gradient magnetic fields (HGMFs) have steadily gained the increased attention of researchers from different disciplines, such as cell biology, cell therapy, targeted stem cell delivery and nanomedicine. We present a theoretical framework towards a fundamental understanding of the effects of HGMFs on intracellular processes, highlighting new directions for the study of living cell machinery: changing the probability of ion-channel on/off switching events by membrane magneto-mechanical stress, suppression of cell growth by magnetic pressure, magnetically induced cell division and cell reprograming, and forced migration of membrane receptor proteins. By deriving a generalized form for the Nernst equation, we find that a relatively small magnetic field (approximately 1 T) with a large gradient (up to 1 GT/m) can significantly change the membrane potential of the cell and thus have a significant impact on not only the properties and biological functionality of cells but also cell fate.
Phosphorus K4 Crystal: A New Stable Allotrope
Authors: Liu Jie , Zhang Shunhong , Guo Yaguang , Wang Qian
Published: November 2016

The intriguing properties of phosphorene motivate scientists to further explore the structures and properties of phosphorus materials. Here, we report a new allotrope named K4 phosphorus composed of three-coordinated phosphorus atoms in non-layered structure which is not only dynamically and mechanically stable, but also possesses thermal stability comparable to that of the orthorhombic black phosphorus (A17). Due to its unique configuration, K4 phosphorus exhibits exceptional properties: it possesses a band gap of 1.54 eV which is much larger than that of black phosphorus (0.30 eV), and it is stiffer than black phosphorus. The band gap of the newly predicted phase can be effectively tuned by appling hydrostastic pressure. In addition, K4 phosphorus exibits a good light absorption in visible and near ultraviolet region. These findings add additional features to the phosphorus family with new potential applications in nanoelectronics and nanomechanics.
Rapid and efficient CRISPR/Cas9 gene inactivation in human neurons during human pluripotent stem cell differentiation and direct reprogramming
Authors: Rubio Alicia , Luoni Mirko , Giannelli Serena G. , Radice Isabella , Iannielli Angelo , Cancellieri Cinzia , Di Berardino Claudia , Regalia Giulia , Lazzari Giovanna , Menegon Andrea , Taverna Stefano , Broccoli Vania
Published: November 2016

The CRISPR/Cas9 system is a rapid and customizable tool for gene editing in mammalian cells. In particular, this approach has widely opened new opportunities for genetic studies in neurological disease. Human neurons can be differentiated in vitro from hPSC (human Pluripotent Stem Cells), hNPCs (human Neural Precursor Cells) or even directly reprogrammed from fibroblasts. Here, we described a new platform which enables, rapid and efficient CRISPR/Cas9-mediated genome targeting simultaneously with three different paradigms for in vitro generation of neurons. This system was employed to inactivate two genes associated with neurological disorder (TSC2 and KCNQ2) and achieved up to 85% efficiency of gene targeting in the differentiated cells. In particular, we devised a protocol that, combining the expression of the CRISPR components with neurogenic factors, generated functional human neurons highly enriched for the desired genome modification in only 5 weeks. This new approach is easy, fast and that does not require the generation of stable isogenic clones, practice that is time consuming and for some genes not feasible.
Identifying and Quantifying Allosteric Drug Function
Authors: Kenakin Terry
Published: November 2016

Allosteric molecules are fundamentally different from molecules that bind to the natural receptor binding pockets for endogenous hormones and neurotransmitters and this gives them a unique repertoire of dose-response behaviors. The underlying principle that differentiates allosteric from orthosteric molecules is the concept of permissiveness. Specifically, allosteric ligands may permit some aspects of the receptor system to function; in contrast, orthosteric ligands do not. Orthosteric ligands are pre-emptive in that if an orthosteric ligand is bound to the natural receptor binding site, then no other molecule can bind to the receptor, i.e. steric hindrance prevents further interaction. This being the case, the ligand-bound species are somewhat uniform, with respect to different orthosteric ligands, in that the observed properties are related only to the bound new molecule and not to the endogenous natural ligand. For instance, a β-blocker such as propranolol pre-empts the binding of natural catchecholamines in the same way as does the orthosteric β-blocker pindolol; the differences in this regard only relate to potency. The important difference between orthosteric and allosteric systems is that, in orthosteric systems there never is a pharmacologically relevant receptor species with both the orthosteric ligand and natural ligand bound simultaneously. In contrast, the pharmacologically relevant receptor species in allosteric systems has both the allosteric and the natural ligand bound simultaneously. This permissive nature makes allosteric receptor systems extremely flexible with respect to the fine tuning of receptor function. Within the repertoire of allosteric receptor behaviors lie a number of behaviors that can appear to be identical to the behaviors seen with orthosteric molecules. Failure to recognize which of these modes of action are operative with respect to drug action can lead to dissimulations in the interpretation of drug behavior. Therefore, it is important to determine whether a ligand interaction is orthosteric or allosteric in nature. Clearly if potentiation of effect is observed, this can only occur allosterically. However, allosteric antagonism can appear identical to simple competitive antagonism if it is surmountable (no depression of maximal response), and orthosteric non-competitive antagonism if it is insurmountable (depressed maximal response).
Examining Allosterism in a Dimeric G-Protein-Coupled Receptor Context
Authors: Giraldo Jesús , Ortiz Jordi , Dalton James , Zhou Bin
Published: November 2016

G-protein-coupled receptor (GPCR) allosterism is examined by comparing structure–function relationships in monomeric and dimeric receptor arrangements. The metabotropic glutamate receptors are chosen as a paradigm of dimeric receptors because there are no doubts about their dimeric nature both from structural and functional data. A number of mathematical models are revisited. The selected models offer a quantitative description of pharmacological properties, providing a mechanistic explanation of receptor subunits cross-talk and ligand cooperativity; thus, bringing in a conceptual framework for fitting experimental data and simulating mechanistic hypotheses. Further work is needed combining experimental (crystallography, nuclear magnetic resonance, fluorescence and bioluminescence) and theoretical (mathematics and computational-chemistry) efforts to fully understand the complex behaviour of GPCR allosteric machinery.