bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility
Authors: Nguyen Quynh-Nhu , Zerafa Nadeen , Liew Seng H. , Morgan F. Hamish , Strasser Andreas , Scott Clare L. , Findlay Jock K. , Hickey Martha , Hutt Karla J.
Published: May 2018

Female gametes are stored in the ovary in structures called primordial follicles, the supply of which is non-renewable. It is well established that DNA-damaging cancer treatments can deplete the ovarian reserve of primordial follicles, causing premature ovarian failure and infertility. The precise mechanisms underlying this chemotherapy-driven follicle loss are unclear, and this has limited the development of targeted ovarian-protective agents. To address this fundamental knowledge gap, we used gene deletion mouse models to examine the role of the DNA damage-induced pro-apoptotic protein, PUMA, and its transcriptional activator TAp63, in primordial follicle depletion caused by treatment with cyclophosphamide or cisplatin. Cyclophosphamide caused almost complete destruction of the primordial follicle pool in adult wild-type (WT) mice, and a significant destructive effect was also observed for cisplatin. In striking contrast, Puma−/− mice retained 100% of their primordial follicles following either genotoxic treatment. Furthermore, elimination of PUMA alone completely preserved fertility in cyclophosphamide-treated mice, indicating that oocytes rescued from DNA damage-induced death can repair themselves sufficiently to support reproductive function and offspring health. Primordial follicles were also protected in TAp63−/− mice following cisplatin treatment, but not cyclophosphamide, suggesting mechanistic differences in the induction of apoptosis and depletion of the ovarian reserve in response to these different chemotherapies. These studies identify PUMA as a crucial effector of apoptosis responsible for depletion of primordial follicles following exposure to cyclophosphamide or cisplatin, and this indicates that inhibition of PUMA may be an effective ovarian-protective strategy during cancer treatment in women.
Transient modes of zeolite surface growth from 3D gel-like islands to 2D single layers
Authors: Kumar Manjesh , Choudhary Madhuresh K. , Rimer Jeffrey D.
Published: May 2018

Zeolite crystallization occurs by multifaceted processes involving molecule attachment and nonclassical pathways governed by the addition of amorphous precursors. Here, we use scanning probe microscopy to monitor zeolite LTA crystallization in situ with a spatiotemporal resolution that captures dynamic processes in real time. We report a distinctive pathway involving the formation of gel-like islands from supersaturated solutions comprised of (alumino)silicate molecules. Three-dimensional assembly and evolution of these islands constitutes a unique mode of growth that differs from classical theories. Time-resolved imaging also reveals that growth can occur by (nearly) oriented attachment. At later stages of crystallization, a progressive transition to lower supersaturation shifts growth to a layered mechanism involving two-dimensional nucleation and spreading of layers. Here, we show that LTA crystallization occurs by multiple pathways, thereby reconciling putative hypotheses of growth mechanisms while also highlighting new modes of nonclassical crystallization that may prove relevant to other zeolites and related materials.
STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap
Authors: Woroniuk Anna , Porter Andrew , White Gavin , Newman Daniel T. , Diamantopoulou Zoi , Waring Thomas , Rooney Claire , Strathdee Douglas , Marston Daniel J. , Hahn Klaus M. , Sansom Owen J. , Zech Tobias , Malliri Angeliki
Published: May 2018

The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap.
Intravital imaging by simultaneous label-free autofluorescence-multiharmonic microscopy
Authors: You Sixian , Tu Haohua , Chaney Eric J. , Sun Yi , Zhao Youbo , Bower Andrew J. , Liu Yuan-Zhi , Marjanovic Marina , Sinha Saurabh , Pu Yang , Boppart Stephen A.
Published: May 2018

Intravital microscopy (IVM) emerged and matured as a powerful tool for elucidating pathways in biological processes. Although label-free multiphoton IVM is attractive for its non-perturbative nature, its wide application has been hindered, mostly due to the limited contrast of each imaging modality and the challenge to integrate them. Here we introduce simultaneous label-free autofluorescence-multiharmonic (SLAM) microscopy, a single-excitation source nonlinear imaging platform that uses a custom-designed excitation window at 1110 nm and shaped ultrafast pulses at 10 MHz to enable fast (2-orders-of-magnitude improvement), simultaneous, and efficient acquisition of autofluorescence (FAD and NADH) and second/third harmonic generation from a wide array of cellular and extracellular components (e.g., tumor cells, immune cells, vesicles, and vessels) in living tissue using only 14 mW for extended time-lapse investigations. Our work demonstrates the versatility and efficiency of SLAM microscopy for tracking cellular events in vivo, and is a major enabling advance in label-free IVM.
Turbulent superstructures in Rayleigh-Bénard convection
Authors: Pandey Ambrish , Scheel Janet D. , Schumacher Jörg
Published: May 2018

Turbulent Rayleigh-Bénard convection displays a large-scale order in the form of rolls and cells on lengths larger than the layer height once the fluctuations of temperature and velocity are removed. These turbulent superstructures are reminiscent of the patterns close to the onset of convection. Here we report numerical simulations of turbulent convection in fluids at different Prandtl number ranging from 0.005 to 70 and for Rayleigh numbers up to 107. We identify characteristic scales and times that separate the fast, small-scale turbulent fluctuations from the gradually changing large-scale superstructures. The characteristic scales of the large-scale patterns, which change with Prandtl and Rayleigh number, are also correlated with the boundary layer dynamics, and in particular the clustering of thermal plumes at the top and bottom plates. Our analysis suggests a scale separation and thus the existence of a simplified description of the turbulent superstructures in geo- and astrophysical settings.
All-optical control of long-lived nuclear spins in rare-earth doped nanoparticles
Authors: Serrano D. , Karlsson J. , Fossati A. , Ferrier A. , Goldner P.
Published: May 2018

Nanoscale systems that coherently couple to light and possess spins offer key capabilities for quantum technologies. However, an outstanding challenge is to preserve properties, and especially optical and spin coherence lifetimes, at the nanoscale. Here, we report optically controlled nuclear spins with long coherence lifetimes (T2) in rare-earth-doped nanoparticles. We detect spins echoes and measure a spin coherence lifetime of 2.9 ± 0.3 ms at 5 K under an external magnetic field of 9 mT, a T2 value comparable to those obtained in bulk rare-earth crystals. Moreover, we achieve spin T2 extension using all-optical spin dynamical decoupling and observe high fidelity between excitation and echo phases. Rare-earth-doped nanoparticles are thus the only nano-material in which optically controlled spins with millisecond coherence lifetimes have been reported. These results open the way to providing quantum light-atom-spin interfaces with long storage time within hybrid architectures.
Budding-like division of all-aqueous emulsion droplets modulated by networks of protein nanofibrils
Authors: Song Yang , Michaels Thomas C. T. , Ma Qingming , Liu Zhou , Yuan Hao , Takayama Shuichi , Knowles Tuomas P. J. , Shum Ho Cheung
Published: May 2018

Networks of natural protein nanofibrils, such as cytoskeletal filaments, control the shape and the division of cells, yet mimicking this functionality in a synthetic setting has proved challenging. Here, we demonstrate that artificial networks of protein nanofibrils can induce controlled deformation and division of all-aqueous emulsion droplets with budding-like morphologies. We show that this process is driven by the difference in the immersional wetting energy of the nanofibril network, and that both the size and the number of the daughter droplets formed during division can be controlled by modulating the fibril concentration and the chemical properties of the fibril network. Our results demonstrate a route for achieving biomimetic division with synthetic self-assembling fibrils and offer an engineered approach to regulate the morphology of protein gels.
Increased glutarate production by blocking the glutaryl-CoA dehydrogenation pathway and a catabolic pathway involving l-2-hydroxyglutarate
Authors: Zhang Manman , Gao Chao , Guo Xiaoting , Guo Shiting , Kang Zhaoqi , Xiao Dan , Yan Jinxin , Tao Fei , Zhang Wen , Dong Wenyue , Liu Pan , Yang Chen , Ma Cuiqing , Xu Ping
Published: May 2018

Glutarate is a five carbon platform chemical produced during the catabolism of l-lysine. It is known that it can be catabolized through the glutaryl-CoA dehydrogenation pathway. Here, we discover that Pseudomonas putida KT2440 has an additional glutarate catabolic pathway involving l-2-hydroxyglutarate (l-2-HG), an abnormal metabolite produced from 2-ketoglutarate (2-KG). In this pathway, CsiD, a Fe2+/2-KG-dependent glutarate hydroxylase, is capable of converting glutarate into l-2-HG, and LhgO, an l-2-HG oxidase, can catalyze l-2-HG into 2-KG. We construct a recombinant strain that lacks both glutarate catabolic pathways. It can produce glutarate from l-lysine with a yield of 0.85 mol glutarate/mol l-lysine. Thus, l-2-HG anabolism and catabolism is a metabolic alternative to the glutaryl-CoA dehydrogenation pathway in P. putida KT2440; l-lysine can be both ketogenic and glucogenic.
In situ redox reactions facilitate the assembly of a mixed-valence metal-organic nanocapsule
Authors: Rathnayake Asanka S. , Fraser Hector W. L. , Brechin Euan K. , Dalgarno Scott J. , Baumeister Jakob E. , White Joshua , Rungthanaphatsophon Pokpong , Walensky Justin R. , Barnes Charles L. , Teat Simon J. , Atwood Jerry L.
Published: May 2018

C-alkylpyrogallol[4]arenes (PgCs) have been studied for their ability to form metal-organic nanocapsules (MONCs) through coordination to appropriate metal ions. Here we present the synthesis and characterization of an MnII/MnIII-seamed MONC in addition to its electrochemical and magnetic behavior. This MONC assembles from 24 manganese ions and 6 PgCs, while an additional metal ion is located on the capsule interior, anchored through the introduction of bridging nitrite ions. The latter originate from an in situ redox reaction that occurs during the self-assembly process, thus representing a new route to otherwise unobtainable nanocapsules.
Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR
Authors: Dai Yaxin , Zhang Aili , Shan Shan , Gong Zihua , Zhou Zheng
Published: May 2018

P53-binding protein 1 (53BP1) regulates the double-strand break (DSB) repair pathway choice. A recently identified 53BP1-binding protein Tudor-interacting repair regulator (TIRR) modulates the access of 53BP1 to DSBs by masking the H4K20me2 binding surface on 53BP1, but the underlying mechanism remains unclear. Here we report the 1.76-Å crystal structure of TIRR in complex with 53BP1 tandem Tudor domain. We demonstrate that the N-terminal region (residues 10–24) and the L8-loop of TIRR interact with 53BP1 Tudor through three loops (L1, L3, and L1′). TIRR recognition blocks H4K20me2 binding to 53BP1 Tudor and modulates 53BP1 functions in vivo. Structure comparisons identify a TIRR histidine (H106) that is absent from the TIRR homolog Nudt16, but essential for 53BP1 Tudor binding. Remarkably, mutations mimicking TIRR binding modules restore the disrupted binding of Nudt16-53BP1 Tudor. Our studies elucidate the mechanism by which TIRR recognizes 53BP1 Tudor and functions as a cellular inhibitor of the histone methyl-lysine readers.
Manipulation of skyrmion motion by magnetic field gradients
Authors: Zhang S. L. , Wang W. W. , Burn D. M. , Peng H. , Berger H. , Bauer A. , Pfleiderer C. , van der Laan G. , Hesjedal T.
Published: May 2018

Magnetic skyrmions are particle-like, topologically protected magnetisation entities that are promising candidates as information carriers in racetrack memory. The transport of skyrmions in a shift-register-like fashion is crucial for their embodiment in practical devices. Here, we demonstrate that chiral skyrmions in Cu2OSeO3 can be effectively manipulated under the influence of a magnetic field gradient. In a radial field gradient, skyrmions were found to rotate collectively, following a given velocity–radius relationship. As a result of this relationship, and in competition with the elastic properties of the skyrmion lattice, the rotating ensemble disintegrates into a shell-like structure of discrete circular racetracks. Upon reversing the field direction, the rotation sense reverses. Field gradients therefore offer an effective handle for the fine control of skyrmion motion, which is inherently driven by magnon currents. In this scheme, no local electric currents are needed, thus presenting a different approach to shift-register-type operations based on spin transfer torque.
Conformation and dynamics of soluble repetitive domain elucidates the initial β-sheet formation of spider silk
Authors: Oktaviani Nur Alia , Matsugami Akimasa , Malay Ali D. , Hayashi Fumiaki , Kaplan David L. , Numata Keiji
Published: May 2018

The β-sheet is the key structure underlying the excellent mechanical properties of spider silk. However, the comprehensive mechanism underlying β-sheet formation from soluble silk proteins during the transition into insoluble stable fibers has not been elucidated. Notably, the assembly of repetitive domains that dominate the length of the protein chains and structural features within the spun fibers has not been clarified. Here we determine the conformation and dynamics of the soluble precursor of the repetitive domain of spider silk using solution-state NMR, far-UV circular dichroism and vibrational circular dichroism. The soluble repetitive domain contains two major populations: ~65% random coil and ~24% polyproline type II helix (PPII helix). The PPII helix conformation in the glycine-rich region is proposed as a soluble prefibrillar region that subsequently undergoes intramolecular interactions. These findings unravel the mechanism underlying the initial step of β-sheet formation, which is an extremely rapid process during spider silk assembly.
High pCO2-induced exopolysaccharide-rich ballasted aggregates of planktonic cyanobacteria could explain Paleoproterozoic carbon burial
Authors: Kamennaya Nina A. , Zemla Marcin , Mahoney Laura , Chen Liang , Holman Elizabeth , Holman Hoi-Ying , Auer Manfred , Ajo-Franklin Caroline M. , Jansson Christer
Published: May 2018

The contribution of planktonic cyanobacteria to burial of organic carbon in deep-sea sediments before the emergence of eukaryotic predators ~1.5 Ga has been considered negligible owing to the slow sinking speed of their small cells. However, global, highly positive excursion in carbon isotope values of inorganic carbonates ~2.22–2.06 Ga implies massive organic matter burial that had to be linked to oceanic cyanobacteria. Here to elucidate that link, we experiment with unicellular planktonic cyanobacteria acclimated to high partial CO2 pressure (pCO2) representative of the early Paleoproterozoic. We find that high pCO2 boosts generation of acidic extracellular polysaccharides (EPS) that adsorb Ca and Mg cations, support mineralization, and aggregate cells to form ballasted particles. The down flux of such self-assembled cyanobacterial aggregates would decouple the oxygenic photosynthesis from oxidative respiration at the ocean scale, drive export of organic matter from surface to deep ocean and sustain oxygenation of the planetary surface.
Author Correction: Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease
Authors: Di Pardo Alba , Amico Enrico , Basit Abdul , Armirotti Andrea , Joshi Piyush , Neely M. Diana , Vuono Romina , Castaldo Salvatore , Digilio Anna F. , Scalabrì Francesco , Pepe Giuseppe , Elifani Francesca , Madonna Michele , Jeong Se Kyoo , Park Bu-Mahn , D’Esposito Maurizio , Bowman Aaron B. , Barker Roger A. , Maglione Vittorio
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Analytical and toxicological evaluation of flavor chemicals in electronic cigarette refill fluids
Authors: Behar Rachel Z. , Luo Wentai , McWhirter Kevin J. , Pankow James F. , Talbot Prue
Published: May 2018

Thousands of electronic cigarette refill fluids are commercially available. The concentrations of nicotine and the solvents, but not the flavor chemicals, are often disclosed on product labels. The purpose of this study was to identify and quantify flavor chemicals in 39 commercial refill fluids that were previously evaluated for toxicity. Twelve flavor chemicals were identified with concentrations ≥1 mg/ml: cinnamaldehyde, menthol, benzyl alcohol, vanillin, eugenol, p-anisaldehyde, ethyl cinnamate, maltol, ethyl maltol, triacetin, benzaldehyde, and menthone. Transfer of these flavor chemicals into aerosols made at 3V and 5V was efficient (mean transfer = 98%). We produced lab-made refill fluids containing authentic standards of each flavor chemical and analyzed the toxicity of their aerosols produced at 3V and 5V using a tank Box Mod device. Over 50% of the refill fluids in our sample contained high concentrations of flavor chemicals that transferred efficiently to aerosols at concentrations that produce cytotoxicity. When tested with two types of human lung cells, the aerosols made at 5V were generally more toxic than those made at 3V. These data will be valuable for consumers, physicians, public health officials, and regulatory agencies when discussing potential health concerns relating to flavor chemicals in electronic cigarette products.
Leukocyte mono-immunoglobulin-like receptor 8 (LMIR8)/CLM-6 is an FcRγ-coupled receptor selectively expressed in mouse tissue plasmacytoid dendritic cells
Authors: Kaitani Ayako , Izawa Kumi , Maehara Akie , Isobe Masamichi , Takamori Ayako , Matsukawa Toshihiro , Takahashi Mariko , Yamanishi Yoshinori , Oki Toshihiko , Yamada Hiromichi , Nagamine Masakazu , Uchida Shino , Uchida Koichiro , Ando Tomoaki , Maeda Keiko , Nakano Nobuhiro , Shimizu Toshiaki , Takai Toshiyuki , Ogawa Hideoki , Okumura Ko , Kitamura Toshio , Kitaura Jiro
Published: May 2018

Plasmacytoid dendritic cells (pDCs) produce large amounts of type-I interferon (IFN) in response to viral infection or self nucleic acids. Leukocyte mono-immunoglobulin-like receptor 8 (LMIR8), also called CMRF-35-like molecule-6 (CLM-6), is a putative activating receptor among mouse LMIR/CLM/CD300 members; however, the expression and function of LMIR8 remain unclear. Here, we characterize mouse LMIR8 as a pDC receptor. Analysis of Flag-tagged LMIR8-transduced bone marrow (BM)-derived mast cells demonstrated that LMIR8 can transmit an activating signal by interacting with immunoreceptor tyrosine-based activating motif (ITAM)-containing FcRγ. Flow cytometric analysis using a specific antibody for LMIR8 showed that LMIR8 expression was restricted to mouse pDCs residing in BM, spleen, or lymph node. FcRγ deficiency dampened surface expression of LMIR8 in mouse pDCs. Notably, LMIR8 was detected only in pDCs, irrespective of TLR9 stimulation, suggesting that LMIR8 is a suitable marker for pDCs in mouse tissues; LMIR8 is weakly expressed in Flt3 ligand-induced BM-derived pDCs (BMpDCs). Crosslinking of transduced LMIR8 in BMpDCs with anti-LMIR8 antibody did not induce IFN-α production, but rather suppressed TLR9-mediated production of IFN-α. Taken together, these observations indicate that LMIR8 is an FcRγ-coupled receptor selectively expressed in mouse tissue pDCs, which might suppress pDC activation through the recognition of its ligands.
Does “a picture is worth 1000 words” apply to iconic Chinese words? Relationship of Chinese words and pictures
Authors: Lo Shih-Yu , Yeh Su-Ling
Published: May 2018

The meaning of a picture can be extracted rapidly, but the form-to-meaning relationship is less obvious for printed words. In contrast to English words that follow grapheme-to-phoneme correspondence rule, the iconic nature of Chinese words might predispose them to activate their semantic representations more directly from their orthographies. By using the paradigm of repetition blindness (RB) that taps into the early level of word processing, we examined whether Chinese words activate their semantic representations as directly as pictures do. RB refers to the failure to detect the second occurrence of an item when it is presented twice in temporal proximity. Previous studies showed RB for semantically related pictures, suggesting that pictures activate their semantic representations directly from their shapes and thus two semantically related pictures are represented as repeated. However, this does not apply to English words since no RB was found for English synonyms. In this study, we replicated the semantic RB effect for pictures, and further showed the absence of semantic RB for Chinese synonyms. Based on our findings, it is suggested that Chinese words are processed like English words, which do not activate their semantic representations as directly as pictures do.
Linking drug target and pathway activation for effective therapy using multi-task learning
Authors: Yang Mi , Simm Jaak , Lam Chi Chung , Zakeri Pooya , van Westen Gerard J. P. , Moreau Yves , Saez-Rodriguez Julio
Published: May 2018

Despite the abundance of large-scale molecular and drug-response data, the insights gained about the mechanisms underlying treatment efficacy in cancer has been in general limited. Machine learning algorithms applied to those datasets most often are used to provide predictions without interpretation, or reveal single drug-gene association and fail to derive robust insights. We propose to use Macau, a bayesian multitask multi-relational algorithm to generalize from individual drugs and genes and explore the interactions between the drug targets and signaling pathways’ activation. A typical insight would be: “Activation of pathway Y will confer sensitivity to any drug targeting protein X”. We applied our methodology to the Genomics of Drug Sensitivity in Cancer (GDSC) screening, using gene expression of 990 cancer cell lines, activity scores of 11 signaling pathways derived from the tool PROGENy as cell line input and 228 nominal targets for 265 drugs as drug input. These interactions can guide a tissue-specific combination treatment strategy, for example suggesting to modulate a certain pathway to maximize the drug response for a given tissue. We confirmed in literature drug combination strategies derived from our result for brain, skin and stomach tissues. Such an analysis of interactions across tissues might help target discovery, drug repurposing and patient stratification strategies.
Single-shot 3D coherent diffractive imaging of core-shell nanoparticles with elemental specificity
Authors: Pryor Alan , Rana Arjun , Xu Rui , Rodriguez Jose A. , Yang Yongsoo , Gallagher-Jones Marcus , Jiang Huaidong , Kanhaiya Krishan , Nathanson Michael , Park Jaehyun , Kim Sunam , Kim Sangsoo , Nam Daewoong , Yue Yu , Fan Jiadong , Sun Zhibin , Zhang Bosheng , Gardner Dennis F. , Dias Carlos Sato Baraldi , Joti Yasumasa , Hatsui Takaki , Kameshima Takashi , Inubushi Yuichi , Tono Kensuke , Lee Jim Yang , Yabashi Makina , Song Changyong , Ishikawa Tetsuya , Kapteyn Henry C. , Murnane Margaret M. , Heinz Hendrik , Miao Jianwei
Published: May 2018

We report 3D coherent diffractive imaging (CDI) of Au/Pd core-shell nanoparticles with 6.1 nm spatial resolution with elemental specificity. We measured single-shot diffraction patterns of the nanoparticles using intense x-ray free electron laser pulses. By exploiting the curvature of the Ewald sphere and the symmetry of the nanoparticle, we reconstructed the 3D electron density of 34 core-shell structures from these diffraction patterns. To extract 3D structural information beyond the diffraction signal, we implemented a super-resolution technique by taking advantage of CDI’s quantitative reconstruction capabilities. We used high-resolution model fitting to determine the Au core size and the Pd shell thickness to be 65.0 ± 1.0 nm and 4.0 ± 0.5 nm, respectively. We also identified the 3D elemental distribution inside the nanoparticles with an accuracy of 3%. To further examine the model fitting procedure, we simulated noisy diffraction patterns from a Au/Pd core-shell model and a solid Au model and confirmed the validity of the method. We anticipate this super-resolution CDI method can be generally used for quantitative 3D imaging of symmetrical nanostructures with elemental specificity.
Anatomy of interfacial spin-orbit coupling in Co/Pd multilayers using X-ray magnetic circular dichroism and first-principles calculations
Authors: Okabayashi Jun , Miura Yoshio , Munekata Hiro
Published: May 2018

Element-specific orbital magnetic moments and their anisotropies in perpendicularly magnetised Co/Pd multilayers are investigated using Co L-edge and Pd M-edge angle-dependent x-ray magnetic circular dichroism. We show that the orbital magnetic moments in Co are anisotropic, whereas those in Pd are isotropic. The first-principles density-functional-theory calculations also suggest that the Co/Pd interfacial orbital magnetic moments in Co are anisotropic and contribute to the perpendicular magnetic anisotropy (PMA), and that the isotropic ones in Pd manipulates the Co orbitals at the interface through proximity effects. Orbital-resolved anatomy of Co/Pd interfaces reveals that the orbital moment anisotropy in Co and spin-flipped transition related to the magnetic dipoles in Pd are essential for the appearance of PMA.
Probiotic supplementation and associated infant gut microbiome and health: a cautionary retrospective clinical comparison
Authors: Quin C. , Estaki M. , Vollman D. M. , Barnett J. A. , Gill S. K. , Gibson D. L.
Published: May 2018

While probiotics are a multi-billion dollar industry, there is little evidence to show that supplementing infants provides any health benefits. We conducted an observational study where 35 of 86 participating mothers self-administered probiotics during breastfeeding, as well as directly to their infants. The primary objective was to determine if probiotic exposure influenced the infants’ fecal microbiome while the secondary objective assessed associated changes to the mothers’ breast milk immunity and infant health. Analysis of infant fecal microbiome throughout the first 6 months of life revealed that probiotics were associated with higher abundances of Bifidobacterium at week 1 only. Short-chain fatty acid production and predicted metagenomic functions of the microbial communities were not altered. While probiotics did not alter breast milk immune markers, fecal sIgA responses were higher among probiotic supplemented infants. Surprisingly, this was not associated with better health outcomes, as the probiotic cohort had higher incidences of mucosal-associated illnesses as toddlers. This retrospective clinical comparison suggests that probiotic exposure during infancy has limited effects on gut microbial composition yet is associated with increased infection later in life. These correlative findings caution against probiotic supplementation during infancy until rigorous controlled follow-up studies determining their safety and efficacy have occurred.
Cortical BOLD responses to moderate- and high-speed motion in the human visual cortex
Authors: Mikellidou Kyriaki , Frijia Francesca , Montanaro Domenico , Greco Vincenzo , Burr David C. , Morrone Maria Concetta
Published: May 2018

We investigated the BOLD response of visual cortical and sub-cortical regions to fast drifting motion presented over wide fields, including the far periphery. Stimuli were sinusoidal gratings of 50% contrast moving at moderate and very high speeds (38 and 570 °/s), projected to a large field of view (~60°). Both stimuli generated strong and balanced responses in the lateral geniculate nucleus and the superior colliculus. In visual cortical areas, responses were evaluated at three different eccentricities: central 0–15°; peripheral 20–30°; and extreme peripheral 30–60°. “Ventral stream” areas (V2, V3, V4) preferred moderate-speeds in the central visual field, while motion area MT+ responded equally well to both speeds at all eccentricities. In all other areas and eccentricities BOLD responses were significant and equally strong for both types of moving stimuli. Support vector machine showed that the direction of the fast-speed motion could be successfully decoded from the BOLD response in all visual areas, suggesting that responses are mediated by motion mechanisms rather than being an unspecific preference for fast rate of flicker. The results show that the visual cortex responds to very fast motion, at speeds generated when we move our eyes rapidly, or when moving objects pass by closely.
Outer Membrane Vesicles from Neisseria Meningitidis (Proteossome) Used for Nanostructured Zika Virus Vaccine Production
Authors: Martins Paula , Machado Daisy , Theizen Thais Holtz , Guarnieri João Paulo Oliveira , Bernardes Bruno Gaia , Gomide Gabriel Piccirillo , Corat Marcus Alexandre Finzi , Abbehausen Camilla , Módena José Luiz Proença , Melo Carlos Fernando Odir Rodrigues , Morishita Karen Noda , Catharino Rodrigo Ramos , Arns Clarice Weis , Lancellotti Marcelo
Published: May 2018

The increase of Zika virus (ZIKV) infections in Brazil in the last two years leaves a prophylactic measures on alert for this new and emerging pathogen. Concerning of our positive experience, we developed a new prototype using Neisseria meningitidis outer membrane vesicles (OMV) on ZIKV cell growth in a fusion of OMV in the envelope of virus particles. The fusion of nanoparticles resulting from outer membrane vesicles of N. meningitidis with infected C6/36 cells line were analyzed by Nano tracking analysis (NTA), zeta potential, differential light scattering (DLS), scan and scanning transmission eletronic microscopy (SEM and STEM) and high resolution mass spectometry (HRMS) for nanostructure characterization. Also, the vaccination effects were viewed by immune response in mice protocols immunization (ELISA and inflammatory chemokines) confirmed by Zika virus soroneutralization test. The results of immunizations in mice showed that antibody production had a titer greater than 1:160 as compared to unvaccinated mice. The immune response of the adjuvant and non-adjuvant formulation activated the cellular immune response TH1 and TH2. In addition, the serum neutralization was able to prevent infection of virus particles in the glial tumor cell model (M059J). This research shows efficient strategies without recombinant technology or DNA vaccines.
Rate and Temporal Coding Mechanisms in the Anterior Cingulate Cortex for Pain Anticipation
Authors: Urien Louise , Xiao Zhengdong , Dale Jahrane , Bauer Elizabeth P. , Chen Zhe , Wang Jing
Published: May 2018

Pain is a complex sensory and affective experience. Through its anticipation, animals can learn to avoid pain. Much is known about passive avoidance during a painful event; however, less is known about active pain avoidance. The anterior cingulate cortex (ACC) is a critical hub for affective pain processing. However, there is currently no mechanism that links ACC activities at the cellular level with behavioral anticipation or avoidance. Here we asked whether distinct populations of neurons in the ACC can encode information for pain anticipation. We used tetrodes to record from ACC neurons during a conditioning assay to train rats to avoid pain. We found that in rats that successfully avoid acute pain episodes, neurons that responded to pain shifted their firing rates to an earlier time, whereas neurons that responded to the anticipation of pain increased their firing rates prior to noxious stimulation. Furthermore, we found a selected group of neurons that shifted their firing from a pain-tuned response to an anticipatory response. Unsupervised learning analysis of ensemble spike activity indicates that temporal spiking patterns of ACC neurons can indeed predict the onset of pain avoidance. These results suggest rate and temporal coding schemes in the ACC for pain avoidance.
Local field potential decoding of the onset and intensity of acute pain in rats
Authors: Zhang Qiaosheng , Xiao Zhengdong , Huang Conan , Hu Sile , Kulkarni Prathamesh , Martinez Erik , Tong Ai Phuong , Garg Arpan , Zhou Haocheng , Chen Zhe , Wang Jing
Published: May 2018

Pain is a complex sensory and affective experience. The current definition for pain relies on verbal reports in clinical settings and behavioral assays in animal models. These definitions can be subjective and do not take into consideration signals in the neural system. Local field potentials (LFPs) represent summed electrical currents from multiple neurons in a defined brain area. Although single neuronal spike activity has been shown to modulate the acute pain, it is not yet clear how ensemble activities in the form of LFPs can be used to decode the precise timing and intensity of pain. The anterior cingulate cortex (ACC) is known to play a role in the affective-aversive component of pain in human and animal studies. Few studies, however, have examined how neural activities in the ACC can be used to interpret or predict acute noxious inputs. Here, we recorded in vivo extracellular activity in the ACC from freely behaving rats after stimulus with non-noxious, low-intensity noxious, and high-intensity noxious stimuli, both in the absence and chronic pain. Using a supervised machine learning classifier with selected LFP features, we predicted the intensity and the onset of acute nociceptive signals with high degree of precision. These results suggest the potential to use LFPs to decode acute pain.
Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity
Authors: Hartman Jessica H. , Smith Latasha L. , Gordon Kacy L. , Laranjeiro Ricardo , Driscoll Monica , Sherwood David R. , Meyer Joel N.
Published: May 2018

Exercise and caloric restriction improve health, including reducing risk of cardiovascular disease, neurological disease, and cancer. However, molecular mechanisms underlying these protections are poorly understood, partly due to the cost and time investment of mammalian long-term diet and exercise intervention studies. We subjected Caenorhabditis elegans nematodes to a 6-day, twice daily swimming exercise regimen, during which time the animals also experienced brief, transient food deprivation. Accordingly, we included a non-exercise group with the same transient food deprivation, a non-exercise control with ad libitum access to food, and a group that exercised in food-containing medium. Following these regimens, we assessed mitochondrial health and sensitivity to mitochondrial toxicants. Exercise protected against age-related decline in mitochondrial morphology in body-wall muscle. Food deprivation increased organismal basal respiration; however, exercise was the sole intervention that increased spare respiratory capacity and proton leak. We observed increased lifespan in exercised animals compared to both control and transiently food-deprived nematodes. Finally, exercised animals (and to a lesser extent, transiently food-deprived animals) were markedly protected against lethality from acute exposures to the mitotoxicants rotenone and arsenic. Thus, swimming exercise and brief food deprivation provide effective intervention in C. elegans, protecting from age-associated mitochondrial decline and providing resistance to mitotoxicant exposures.
Targeted delivery of fluorogenic peptide aptamers into live microalgae by femtosecond laser photoporation at single-cell resolution
Authors: Maeno Takanori , Uzawa Takanori , Kono Izumi , Okano Kazunori , Iino Takanori , Fukita Keisuke , Oshikawa Yuki , Ogawa Taro , Iwata Osamu , Ito Takuro , Suzuki Kengo , Goda Keisuke , Hosokawa Yoichiroh
Published: May 2018

Microalgae-based metabolic engineering has been proven effective for producing valuable substances such as food supplements, pharmaceutical drugs, biodegradable plastics, and biofuels in the past decade. The ability to accurately visualize and quantify intracellular metabolites in live microalgae is essential for efficient metabolic engineering, but remains a major challenge due to the lack of characterization methods. Here we demonstrate it by synthesizing fluorogenic peptide aptamers with specific binding affinity to a target metabolite and delivering them into live microalgae by femtosecond laser photoporation at single-cell resolution. As a proof-of-principle demonstration of our method, we use it to characterizeEuglena gracilis, a photosynthetic unicellular motile microalgal species, which is capable of producing paramylon (a carbohydrate granule similar to starch). Specifically, we synthesize a peptide aptamer containing a paramylon-binding fluorescent probe, 7-nitrobenzofurazan, and introduce it intoE. graciliscells one-by-one by suppressing their mobility with mannitol and transiently perforating them with femtosecond laser pulses at 800 nm for photoporation. To demonstrate the method’s practical utility in metabolic engineering, we perform spatially and temporally resolved fluorescence microscopy of single live photoporatedE. graciliscells under different culture conditions. Our method holds great promise for highly efficient microalgae-based metabolic engineering.
Morphological and functional effects of graphene on the synthesis of uranium carbide for isotopes production targets
Authors: Biasetto L. , Corradetti S. , Carturan S. , Eloirdi R. , Amador-Celdran P. , Staicu D. , Blanco O. Dieste , Andrighetto A.
Published: May 2018

The development of tailored targets for the production of radioactive isotopes represents an active field in nuclear research. Radioactive beams find applications in nuclear medicine, in astrophysics, matter physics and materials science. In this work, we study the use of graphene both as carbon source for UO2 carbothermal reduction to produce UCx targets, and also as functional properties booster. At fixed composition, the UCx target grain size, porosity and thermal conductivity represent the three main points that affect the target production efficiency. UCx was synthesized using both graphite and graphene as the source of carbon and the target properties in terms of composition, grain size, porosity, thermal diffusivity and thermal conductivity were studied. The main output of this work is related to the remarkable enhancement achieved in thermal conductivity, which can profitably improve thermal dissipation during operational stages of UCx targets.
Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice
Authors: Hu Zhaoyang , Wei Wei , Zhou Leng , Chen Mou , Abbott Geoffrey W.
Published: May 2018

Sudden cardiac death (SCD) is associated with both electrical and ischemic substrates, and is a major cause of ischemic heart disease mortality worldwide. Male sex predisposes to SCD but the underlying mechanisms are incompletely understood. KCNE4, a cardiac arrhythmia-associated potassium channel β-subunit, is upregulated by 5α-dihydrotestosterone (DHT). Thus, ventricular Kcne4 expression is low in young adult female mice, but high in males and postmenopausal (12+ months) females. Despite causing a sex-independent electrical substrate at 13 months of age (22% QT prolongation in both males and females; P < 0.01), Kcne4 deletion preferentially predisposed aged male mice to ischemia/reperfusion (IR)-provoked ventricular tachyarrhythmias. Interestingly, Kcne4 deletion caused baseline induction of cardioprotective RISK and SAFE pathways in 13-m-old female, but not male, mice. IR-invoked RISK/SAFE induction was also deficient in male but not female Kcne4−/− mice. Pharmacological inhibition of RISK/SAFE pathways in Kcne4−/− females eliminated sex-specific differences in IR-invoked tachyarrhythmia predisposition. Furthermore, castration of Kcne4−/− males eliminated sex-specific differences in both baseline and post-IR RISK/SAFE pathway induction, and tachyarrhythmia predisposition. Our results demonstrate for the first time that male sex can predispose in aged mice to dangerous ventricular tachyarrhythmias despite sex-independent electrical and ischemic substrates, because of testosterone-dependent impairment of RISK/SAFE pathway induction.
Habituation of phase-locked local field potentials and gamma-band oscillations recorded from the human insula
Authors: Liberati Giulia , Algoet Maxime , Klöcker Anne , Ferrao Santos Susana , Ribeiro-Vaz Jose Geraldo , Raftopoulos Christian , Mouraux André
Published: May 2018

Salient nociceptive and non-nociceptive stimuli elicit low-frequency local field potentials (LFPs) in the human insula. Nociceptive stimuli also elicit insular gamma-band oscillations (GBOs), possibly preferential for thermonociception, which have been suggested to reflect the intensity of perceived pain. To shed light on the functional significance of these two responses, we investigated whether they would be modulated by stimulation intensity and temporal expectation – two factors contributing to stimulus saliency. Insular activity was recorded from 8 depth electrodes (41 contacts) implanted in the left insula of 6 patients investigated for epilepsy. Thermonociceptive, vibrotactile, and auditory stimuli were delivered using two intensities. To investigate the effects of temporal expectation, the stimuli were delivered in trains of three identical stimuli (S1-S2-S3) separated by a constant 1-s interval. Stimulation intensity affected intensity of perception, the magnitude of low-frequency LFPs, and the magnitude of nociceptive GBOs. Stimulus repetition did not affect perception. In contrast, both low-frequency LFPs and nociceptive GBOs showed a marked habituation of the responses to S2 and S3 as compared to S1 and, hence, a dissociation with intensity of perception. Most importantly, although insular nociceptive GBOs appear to be preferential for thermonociception, they cannot be considered as a correlate of perceived pain.
Caldera unrest driven by CO2-induced drying of the deep hydrothermal system
Authors: Moretti R. , Troise C. , Sarno F. , De Natale G.
Published: May 2018

Interpreting volcanic unrest is a highly challenging and non-unique problem at calderas, since large hydrothermal systems may either hide or amplify the dynamics of buried magma(s). Here we use the exceptional ground displacement and geochemical datasets from the actively degassing Campi Flegrei caldera (Southern Italy) to show that ambiguities disappear when the thermal evolution of the deep hydrothermal system is accurately tracked. By using temperatures from the CO2-CH4 exchange of 13C and thermodynamic analysis of gas ascending in the crust, we demonstrate that after the last 1982–84 crisis the deep hydrothermal system evolved through supercritical conditions under the continuous isenthalpic inflow of hot CO2-rich gases released from the deep (~8 km) magma reservoir of regional size. This resulted in the drying of the base of the hot hydrothermal system, no more buffered along the liquid-vapour equilibrium, and excludes any shallow arrival of new magma, whose abundant steam degassing due to decompression would have restored liquid-vapour equilibrium. The consequent CO2-infiltration and progressive heating of the surrounding deforming rock volume cause the build-up of pore pressure in aquifers, and generate the striking temporal symmetry that characterizes the ongoing uplift and the post-1984 subsidence, both originated by the same but reversed deformation mechanism.
E2F signature is predictive for the pancreatic adenocarcinoma clinical outcome and sensitivity to E2F inhibitors, but not for the response to cytotoxic-based treatments
Authors: Lan Wenjun , Bian Benjamin , Xia Yi , Dou Samir , Gayet Odile , Bigonnet Martin , Santofimia-Castaño Patricia , Cong Mei , Peng Ling , Dusetti Nelson , Iovanna Juan
Published: May 2018

The main goal of this study was to find out strategies of clinical relevance to classify patients with a pancreatic ductal adenocarcinoma (PDAC) for individualized treatments. In the present study a set of 55 patient-derived xenografts (PDX) were obtained and their transcriptome were analyzed by using an Affymetrix approach. A supervised bioinformatics-based analysis let us to classify these PDX in two main groups named E2F-highly dependent and E2F-lowly dependent. Afterwards their characterization by using a Kaplan-Meier analysis demonstrated that E2F high patients survived significantly less than E2F low patients (9.5 months vs. 16.8 months; p = 0.0066). Then we tried to establish if E2F transcriptional target levels were associated to the response to cytotoxic treatments by comparing the IC50 values of E2F high and E2F low cells after gemcitabine, 5-fluorouracil, oxaliplatin, docetaxel or irinotecan treatment, and no association was found. Then we identified an E2F inhibitor compound, named ly101-4B, and we observed that E2F-higly dependent cells were more sensitive to its treatment (IC50 of 19.4 ± 1.8 µM vs. 44.1 ± 4.4 µM; p = 0.0061). In conclusion, in this work we describe an E2F target expression-based classification that could be predictive for patient outcome, but more important, for the sensitivity of tumors to the E2F inhibitors as a treatment. Finally, we can assume that phenotypic characterization, essentially by an RNA expression analysis of the PDAC, can help to predict their clinical outcome and their response to some treatments when are rationally selected.
Optimization of Transcranial Direct Current Stimulation of Dorsolateral Prefrontal Cortex for Tinnitus: A Non-Linear Dose-Response Effect
Authors: Shekhawat Giriraj Singh , Vanneste Sven
Published: May 2018

Neuromodulation is defined as the process of augmenting neuroplasticity via invasive or non-invasive methods. Tinnitus is the perception of sound in the absence of its external source. The objective of this study was to optimize the parameters of transcranial direct current stimulation (tDCS) of dorsolateral prefrontal cortex (DLPFC) for tinnitus suppression. The following factors were optimized in the dose-response design (n = 111): current intensity (1.5 mA or 2 mA), stimulation duration (20 min or 30 min), and number of stimulation sessions (2, 4, 6, 8, or 10), with a 3–4 day washout period between each session. Participants underwent a minimum of 2 sessions in 1 week or maximum of 10 sessions in 5 weeks’ time. Tinnitus loudness was measured in pre-post design using a 10-point numeric rating scale. There was a significant reduction in tinnitus loudness after tDCS of DLPFC. There was no significant difference between the intensity and duration of stimulation. As the number of sessions increased, there was a higher reduction in the tinnitus loudness; however, this effect plateaued after 6 sessions.