bluuebunny/crossref_metadata_2025 huggingface dataset:
High-resolution imaging mass spectrometry combined with transcriptomic analysis identified a link between fatty acid composition of phosphatidylinositols and the immune checkpoint pathway at the primary tumour site of breast cancer
Authors: Kawashima Masahiro , Tokiwa Mariko , Nishimura Tomomi , Kawata Yukiko , Sugimoto Masahiro , Kataoka Tatsuki R. , Sakurai Takaki , Iwaisako Keiko , Suzuki Eiji , Hagiwara Masatoshi , Harris Adrian L. , Toi Masakazu
Published: December 2019

Background

The fatty acid (FA) composition of phosphatidylinositols (PIs) is tightly regulated in mammalian tissue since its disruption impairs normal cellular functions. We previously found its significant alteration in breast cancer by using matrix-assisted laser desorption and ionisation imaging mass spectrometry (MALDI-IMS).

Methods

We visualised the histological distribution of PIs containing different FAs in 65 primary breast cancer tissues using MALDI-IMS and investigated its association with clinicopathological features and gene expression profiles.

Results

Normal ductal cells (n = 7) predominantly accumulated a PI containing polyunsaturated FA (PI-PUFA), PI(18:0/20:4). PI(18:0/20:4) was replaced by PIs containing monounsaturated FA (PIs-MUFA) in all non-invasive cancer cells (n = 12). While 54% of invasive cancer cells (n = 27) also accumulated PIs-MUFA, 46% of invasive cancer cells (n = 23) accumulated the PIs-PUFA, PI(18:0/20:3) and PI(18:0/20:4). The accumulation of PI(18:0/20:3) was associated with higher incidence of lymph node metastasis and activation of the PD-1-related immune checkpoint pathway. Fatty acid-binding protein 7 was identified as a putative molecule controlling PI composition.

Conclusions

MALDI-IMS identified PI composition associated with invasion and nodal metastasis of breast cancer. The accumulation of PI(18:0/20:3) could affect the PD-1-related immune checkpoint pathway, although its precise mechanism should be further validated.
Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin
Authors: Lord Simon R. , Collins Jennifer M. , Cheng Wei-Chen , Haider Syed , Wigfield Simon , Gaude Edoardo , Fielding Barbara A. , Pinnick Katherine E. , Harjes Ulrike , Segaran Ashvina , Jha Pooja , Hoefler Gerald , Pollak Michael N. , Thompson Alastair M. , Roy Pankaj G. , English Ruth. , Adams Rosie F. , Frezza Christian , Buffa Francesca M. , Karpe Fredrik , Harris Adrian L.
Published: December 2019

Background

Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy.

Methods

Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment.

Results

Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation.

Conclusions

We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations.

Clinical Trial Registration

NCT01266486.
Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy
Authors: Harris Adrian L.
Published: December 2019

Cancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.
Metabolism and cancer: the future is now
Authors: Frezza Christian
Published: December 2019

In the last decade, the field of cancer metabolism transformed itself from being a description of the metabolic features of cancer cells to become a key component of cellular transformation. Now, the potential role of this field in cancer biology is ready to be unravelled.
The epigenomic landscape of transposable elements across normal human development and anatomy
Authors: Pehrsson Erica C. , Choudhary Mayank N. K. , Sundaram Vasavi , Wang Ting
Published: December 2019

Transposable elements (TEs) have deposited functional regulatory elements throughout the human genome. Although most are silenced, certain TEs have been co-opted by the host. However, a comprehensive, multidimensional picture of the contribution of TEs to normal human gene regulation is still lacking. Here, we quantify the epigenomic status of TEs across human anatomy and development using data from the Roadmap Epigenomics Project. We find that TEs encompass a quarter of the human regulatory epigenome, and 47% of elements can be in an active regulatory state. We demonstrate that SINEs are enriched relative to other classes for active and transcribed marks, that TEs encompass a higher proportion of enhancer states in the hematopoietic lineage, and that DNA methylation of Alu elements decreases with age, corresponding with a loss of CpG islands. Finally, we identify TEs that may perform an evolutionarily conserved regulatory function, providing a systematic profile of TE activity in normal human tissue.
Efficient sky-blue perovskite light-emitting diodes via photoluminescence enhancement
Authors: Wang Qi , Wang Xiaoming , Yang Zhi , Zhou Ninghao , Deng Yehao , Zhao Jingjing , Xiao Xun , Rudd Peter , Moran Andrew , Yan Yanfa , Huang Jinsong
Published: December 2019

The efficiencies of green and red perovskite light-emitting diodes (PeLEDs) have been increased close to their theoretical upper limit, while the efficiency of blue PeLEDs is lagging far behind. Here we report enhancing the efficiency of sky-blue PeLEDs by overcoming a major hurdle of low photoluminescence quantum efficiency in wide-bandgap perovskites. Blending phenylethylammonium chloride into cesium lead halide perovskites yields a mixture of two-dimensional and three-dimensional perovskites, which enhances photoluminescence quantum efficiency from 1.1% to 19.8%. Adding yttrium (III) chloride into the mixture further enhances photoluminescence quantum efficiency to 49.7%. Yttrium is found to incorporate into the three-dimensional perovskite grain, while it is still rich at grain boundaries and surfaces. The yttrium on grain surface increases the bandgap of grain shell, which confines the charge carriers inside grains for efficient radiative recombination. Record efficiencies of 11.0% and 4.8% were obtained in sky-blue and blue PeLEDs, respectively.
Author Correction: Economic value of protected areas via visitor mental health
Authors: Buckley Ralf , Brough Paula , Hague Leah , Chauvenet Alienor , Fleming Chris , Roche Elisha , Sofija Ernesta , Harris Neil
Published: December 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development
Authors: Lampe Lena , Jentzsch Marius , Kierszniowska Sylwia , Levashina Elena A.
Published: December 2019

The blood-feeding behavior of Anopheles females delivers essential nutrients for egg development and drives parasite transmission between humans. Plasmodium growth is adapted to the vector reproductive cycle, but how changes in the reproductive cycle impact parasite development remains unclear. Here, we show that the bloodmeal-induced miR-276-5p fine-tunes the expression of branched-chain amino acid transferase to terminate the reproductive cycle. Silencing of miR-276 prolongs high rates of amino acid (AA) catabolism and increases female fertility, suggesting that timely termination of AA catabolism restricts mosquito investment into reproduction. Prolongation of AA catabolism in P. falciparum-infected females also compromises the development of the transmissible sporozoite forms. Our results suggest that Plasmodium sporogony exploits the surplus mosquito resources available after reproductive investment and demonstrate the crucial role of the mosquito AA metabolism in within-vector parasite proliferation and malaria transmission.
Tropical carbon sink accelerated by symbiotic dinitrogen fixation
Authors: Levy-Varon Jennifer H. , Batterman Sarah A. , Medvigy David , Xu Xiangtao , Hall Jefferson S. , van Breugel Michiel , Hedin Lars O.
Published: December 2019

A major uncertainty in the land carbon cycle is whether symbiotic nitrogen fixation acts to enhance the tropical forest carbon sink. Nitrogen-fixing trees can supply vital quantities of the growth-limiting nutrient nitrogen, but the extent to which the resulting carbon–nitrogen feedback safeguards ecosystem carbon sequestration remains unclear. We combine (i) field observations from 112 plots spanning 300 years of succession in Panamanian tropical forests, and (ii) a new model that resolves nitrogen and light competition at the scale of individual trees. Fixation doubled carbon accumulation in early succession and enhanced total carbon in mature forests by ~10% (~12MgC ha−1) through two mechanisms: (i) a direct fixation effect on tree growth, and (ii) an indirect effect on the successional sequence of non-fixing trees. We estimate that including nitrogen-fixing trees in Neotropical reforestation projects could safeguard the sequestration of 6.7 Gt CO2 over the next 20 years. Our results highlight the connection between functional diversity of plant communities and the critical ecosystem service of carbon sequestration for mitigating climate change.
Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retrospective cohort study
Authors: Lisspers Karin , Larsson Kjell , Janson Christer , Ställberg Björn , Tsiligianni Ioanna , Gutzwiller Florian S. , Mezzi Karen , Bjerregaard Bine Kjoeller , Jorgensen Leif , Johansson Gunnar
Published: December 2019

The present study aimed to generate real-world evidence regarding gender differences among chronic obstructive pulmonary disease (COPD) patients, especially as regards the diagnosis and outcomes in order to identify areas for improvement and management and optimize the associated healthcare resource allocation. ARCTIC is a large, real-world, retrospective cohort study conducted in Swedish COPD patients and a matched reference population from 52 primary care centers in 2000–2014. The incidence of COPD, prevalence of asthma and other comorbidities, risk of exacerbations, mortality rate, COPD drug prescriptions, and healthcare resource utilization were analyzed. In total, 17,479 patients with COPD were included in the study. During the study period, COPD was more frequent among women (53.8%) and women with COPD experienced more exacerbations vs. men (6.66 vs. 4.66). However, the overall mortality rate was higher in men compared with women (45% vs. 38%), but no difference for mortality due to COPD was seen between genders over the study period. Women seemed to have a greater susceptibility to asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, depression, and anxiety, but appeared less likely to have diabetes, kidney diseases, and cardiovascular diseases. Furthermore, women had a greater risk of COPD-related hospitalization and were likely to receive a significantly higher number of COPD drug prescriptions compared with men. These results support the need to reduce disease burden among women with COPD and highlight the role of healthcare professionals in primary care who should consider all these parameters in order to properly diagnose and treat women with COPD.
Mindfulness video game improves connectivity of the fronto-parietal attentional network in adolescents: A multi-modal imaging study
Authors: Patsenko Elena G. , Adluru Nagesh , Birn Rasmus M. , Stodola Diane E. , Kral Tammi R. A. , Farajian Reza , Flook Lisa , Burghy Cory A. , Steinkuehler Constance , Davidson Richard J.
Published: December 2019

Mindfulness training has been shown to improve attention and change the underlying brain substrates in adults. Most mindfulness training programs involve a myriad of techniques, and it is difficult to attribute changes to any particular aspect of the program. Here, we created a video game, Tenacity, which models a specific mindfulness technique – focused attention on one’s breathing – and assessed its potential to train an attentional network in adolescents. A combined analysis of resting state functional connectivity (rs-FC) and diffusion tensor imaging (DTI) yielded convergent results – change in communication within the left fronto-parietal network after two weeks of playing Tenacity compared to a control game. Rs-FC analysis showed greater connectivity between left dorsolateral prefrontal cortex (dlPFC) and left inferior parietal cortex (IPC) in the Tenacity group. Importantly, changes in left dlPFC – IPC rs-FC and changes in structural connectivity of the white matter tract that connects these regions –left superior longitudinal fasiculus (SLF) – were associated with changes in performance on an attention task. Finally, changes in left dlPFC – IPC rs-FC correlated with the change in left SLF structural connectivity as measured by fractional anisotropy (FA) in the Tenacity group only.
Genomic Landscape of Intramedullary Spinal Cord Gliomas
Authors: Zhang Ming , Iyer Rajiv R. , Azad Tej D. , Wang Qing , Garzon-Muvdi Tomas , Wang Joanna , Liu Ann , Burger Peter , Eberhart Charles , Rodriguez Fausto J. , Sciubba Daniel M. , Wolinsky Jean-Paul , Gokaslan Ziya , Groves Mari L. , Jallo George I. , Bettegowda Chetan
Published: December 2019

Intramedullary spinal cord tumors (IMSCTs) are rare neoplasms that have limited treatment options and are associated with high rates of morbidity and mortality. To better understand the genetic basis of these tumors we performed whole exome sequencing on 45 tumors and matched germline DNA, including twenty-nine spinal cord ependymomas and sixteen astrocytomas. Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts (e.g. glioblastoma) did not harbor the canonical mutations associated with their intracranial counterparts. Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides the framework to begin more biologically based therapeutic strategies.
The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development
Authors: Schmidt Ewoud R. E. , Kupferman Justine V. , Stackmann Michelle , Polleux Franck
Published: December 2019

Human-specific gene duplications (HSGDs) have recently emerged as key modifiers of brain development and evolution. However, the molecular mechanisms underlying the function of HSGDs remain often poorly understood. In humans, a truncated duplication of SRGAP2A led to the emergence of two human-specific paralogs: SRGAP2B and SRGAP2C. The ancestral copy SRGAP2A limits synaptic density and promotes maturation of both excitatory (E) and inhibitory (I) synapses received by cortical pyramidal neurons (PNs). SRGAP2C binds to and inhibits all known functions of SRGAP2A leading to an increase in E and I synapse density and protracted synapse maturation, traits characterizing human cortical neurons. Here, we demonstrate how the evolutionary changes that led to the emergence of SRGAP2 HSGDs generated proteins that, in neurons, are intrinsically unstable and, upon hetero-dimerization with SRGAP2A, reduce SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, despite only a few non-synonymous mutations specifically targeting arginine residues, SRGAP2C is unique compared to SRGAP2B in its ability to induce long-lasting changes in synaptic density throughout adulthood. These mutations led to the ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.
Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27
Authors: García-Gutiérrez Lucía , Bretones Gabriel , Molina Ester , Arechaga Ignacio , Symonds Catherine , Acosta Juan C. , Blanco Rosa , Fernández Adrián , Alonso Leticia , Sicinski Piotr , Barbacid Mariano , Santamaría David , León Javier
Published: December 2019

Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of the Cdk inhibitors p15 and p21 and the degradation of p27. The Myc-p27 antagonism has been shown to be relevant in human cancer. To be degraded, p27 must be phosphorylated at Thr-187 to be recognized by Skp2, a component of the ubiquitination complex. We previously described that Myc induces Skp2 expression. Here we show that not only Cdk2 but Cdk1 phosphorylates p27 at the Thr-187. Moreover, Myc induced p27 degradation in murine fibroblasts through Cdk1 activation, which was achieved by Myc-dependent cyclin A and B induction. In the absence of Cdk2, p27 phosphorylation at Thr-187 was mainly carried out by cyclin A2-Cdk1 and cyclin B1-Cdk1. We also show that Cdk1 inhibition was enough for the synthetic lethal interaction with Myc. This result is relevant because Cdk1 is the only Cdk strictly required for cell cycle and the reported synthetic lethal interaction between Cdk1 and Myc.
Boosted acceleration of protons by tailored ultra-thin foil targets
Authors: Kaymak Vural , Aktan Esin , Cerchez Mirela , Elkin Bentsian , Papenheim Marc , Prasad Rajendra , Pukhov Alexander , Scheer Hella-C. , Schroer Anna-Marie , Willi Oswald , Aurand Bastian
Published: December 2019

We report on a detailed experimental and numerical study on the boosted acceleration of protons from ultra-thin hemispherical targets utilizing multi-Joule short-pulse laser-systems. For a laser intensity of 1 × 1020 W/cm2 and an on-target energy of only 1.3 J with this setup a proton cut-off energy of 8.5 MeV was achieved, which is a factor of 1.8 higher compared to a flat foil target of the same thickness. While a boost of the acceleration process by additionally injected electrons was observed for sophisticated targets at high-energy laser-systems before, our studies reveal that the process can be utilized over at least two orders of magnitude in intensity and is therefore suitable for a large number of nowadays existing laser-systems. We retrieved a cut-off energy of about 6.5 MeV of proton energy per Joule of incident laser energy, which is a noticeable enhancement with respect to previous results employing this mechanism. The approach presented here has the advantage of using structure-wise simple targets and being sustainable for numerous applications and high repetition rate demands at the same time.
Heat dissipation in quasi-ballistic single-atom contacts at room temperature
Authors: Tsutsui Makusu , Chen Yu-Chang
Published: December 2019

We report on evaluations of local heating in Au single-atom chains at room temperature. We performed onsite thermometry of atomic-scale Au junctions under applied sinusoidal voltage of variable amplitudes. The AC approach enabled to preclude electromigration effects for characterizing the influence of energy dissipations on the lifetime. We elucidated nonlinear increase in the effective temperature of the current-carrying single-atom chains with the voltage amplitudes, which was attributed to subtle interplay between electron-phonon scattering and electron-mediated thermal transport in the quasi-ballistic conductor. We also found that only 0.2% of the electric power contributed to local heating while the majority was consumed at the diffusive bank. The present findings can be used for thermal management of future integrated nanoelectronics.
Long-term impact of oral surgery with or without amoxicillin on the oral microbiome-A prospective cohort study
Authors: Menon R. K. , Gomez A. , Brandt B. W. , Leung Y. Y. , Gopinath D. , Watt R. M. , Crielaard W. , Nelson K. E , Botelho M. G.
Published: December 2019

Routine postoperative antibiotic prophylaxis is not recommended for third molar extractions. However, amoxicillin still continues to be used customarily in several clinical practices worldwide to prevent infections. A prospective cohort study was conducted in cohorts who underwent third molar extractions with (group EA, n = 20) or without (group E, n = 20) amoxicillin (250 mg three times daily for 5 days). Further, a control group without amoxicillin and extractions (group C, n = 17) was included. Salivary samples were collected at baseline, 1-, 2-, 3-, 4-weeks and 3 months to assess the bacterial shift and antibiotic resistance gene changes employing 16S rRNA gene sequencing (Illumina-Miseq) and quantitative polymerase chain reaction. A further 6-month follow-up was performed for groups E and EA. Seven operational taxonomic units reported a significant change from baseline to 3 months for group EA (adjusted p < 0.05). No significant change in relative abundance of bacteria and β-lactamase resistance genes (TEM-1) was observed over 6 months for any group (adjusted p > 0.05). In conclusion, the salivary microbiome is resilient to an antibiotic challenge by a low-dose regimen of amoxicillin. Further studies evaluating the effect of routinely used higher dose regimens of amoxicillin on gram-negative bacteria and antibiotic resistance genes are warranted.
Rectal Cancer Invasiveness: Whole-Lesion Diffusion-Weighted Imaging (DWI) Histogram Analysis by Comparison of Reduced Field-of-View and Conventional DWI Techniques
Authors: Peng Yang , Tang Hao , Hu Xuemei , Shen Yaqi , Kamel Ihab , Li Zhen , Hu Daoyu
Published: December 2019

To explore the role of whole-lesion histogram analysis of apparent diffusion coefficient (ADC) for discriminating between T stages of rectal carcinoma by comparison of reduced field-of-view (FOV) and conventional DWI techniques. 102 patients with rectal cancer were enrolled in this retrospective study. All patients received preoperative MR scan at 3 T, including reduced and full FOV DWI sequences. Histogram parameters from two DWI methods were calculated and correlated with histological T stage of rectal cancer. The diagnostic performance of individual parameter for differentiating stage pT1-2 and pT3-4 tumors from both DWI techniques was assessed by receiver operating characteristic curve analysis. There were significant differences for the parameters of ADCmean, 50th, 75th, 90th, 95th percentiles, skewness and kurtosis of both DWI sequences in patients with pT1-2 as compared to those with pT3-4 tumors (P < 0.05), in addition to parameters including ADCmin (P = 0.015) and 25th percentile (P = 0.006) from rFOV DWI. Correlations were noted between T staging and above histogram parameters from rFOV DWI (r: −0.741–0.682) and fFOV DWI (r: −0.449–0.449), besides parameters of ADCmin (0.370) and 25th percentile (−0.425) from rFOV DWI. The AUCs of 75th and 90th percentiles from rFOV DWI were significantly higher than that from fFOV DWI (P = 0.0410 and P = 0.0208). The whole-lesion histogram analysis based on rFOV DWI was overall more advantageous than the one based on fFOV DWI in differentiating T staging of rectal cancer and the 90th percentile ADC from rFOV DWI was the value with the highest AUC (0.932).
Quantum scale biomimicry of low dimensional growth: An unusual complex amorphous precursor route to TiO2 band confinement by shape adaptive biopolymer-like flexibility for energy applications
Authors: Choi Dahyun , Sonkaria Sanjiv , Fox Stephen J. , Poudel Shivraj , Kim Sung-yong , Kang Suhee , Kim Seheon , Verma Chandra , Ahn Sung Hoon , Lee Caroline Sunyong , Khare Varsha
Published: December 2019

Crystallization via an amorphous pathway is often preferred by biologically driven processes enabling living species to better regulate activation energies to crystal formation that are intrinsically linked to shape and size of dynamically evolving morphologies. Templated ordering of 3-dimensional space around amorphous embedded non-equilibrium phases at heterogeneous polymer─metal interfaces signify important routes for the genesis of low-dimensional materials under stress-induced polymer confinement. We report the surface induced catalytic loss of P=O ligands to bond activated aromatization of C−C C=C and Ti=N resulting in confinement of porphyrin-TiO2 within polymer nanocages via particle attachment. Restricted growth nucleation of TiO2 to the quantum scale (≤2 nm) is synthetically assisted by nitrogen, phosphine and hydrocarbon polymer chemistry via self-assembly. Here, the amorphous arrest phase of TiO2 is reminiscent of biogenic amorphous crystal growth patterns and polymer coordination has both a chemical and biomimetic significance arising from quantum scale confinement which is atomically challenging. The relative ease in adaptability of non-equilibrium phases renders host structures more shape compliant to congruent guests increasing the possibility of geometrical confinement. Here, we provide evidence for synthetic biomimicry akin to bio-polymerization mechanisms to steer disorder-to-order transitions via solvent plasticization-like behaviour. This challenges the rationale of quantum driven confinement processes by conventional processes. Further, we show the change in optoelectronic properties under quantum confinement is intrinsically related to size that affects their optical absorption band energy range in DSSC.
Transcranial direct current stimulation (tDCS) over vmPFC modulates interactions between reward and emotion in delay discounting
Authors: Manuel Aurélie L. , Murray Nicholas W. G. , Piguet Olivier
Published: December 2019

Delay discounting requires computing trade-offs between immediate-small rewards and later-larger rewards. Negative and positive emotions shift decisions towards more or less impulsive responses, respectively. Models have conceptualized this trade-off by describing an interplay between “emotional” and “rational” processes, with the former involved during immediate choices and relying on the ventromedial prefrontal cortex (vmPFC), and the latter involved in long-term choices and relying on the dorsolateral prefrontal cortex (dlPFC). Whether stimulation of the vmPFC modulates emotion-induced delay discounting remains unclear. We applied tDCS over the vmPFC in 20 healthy individuals during a delay discounting task following an emotional (positive, negative) or neutral induction. Our results showed that cathodal tDCS increased impulsivity after positive emotions in high impulsivity trials. For low impulsivity trials, anodal tDCS decreased impulsivity following neutral induction compared with emotional induction. Our findings demonstrate that the vmPFC integrates reward and emotion most prominently in situations of increased impulsivity, whereas when higher cognitive control is required the vmPFC appears to be less engaged, possibly due to recruitment of the dlPFC. Understanding how stimulation and emotion influence decision-making at the behavioural and neural levels holds promise to develop interventions to reduce impulsivity.
Formalin-induced and neuropathic pain altered time estimation in a temporal bisection task in rats
Authors: Liu Xinhe , Wang Ning , Wang Jinyan , Luo Fei
Published: December 2019

Time perception is an important ability that is related closely to humans’ and animals’ daily activities. It can be distorted by various emotional states. In human studies, experimental pain has been shown to prolong the perception of time. However, related animal studies are lacking. In this study, we used a temporal bisection task to investigate how acute inflammatory pain (induced by hind-paw formalin injection) and chronic neuropathic pain [induced by spinal nerve ligation (SNL)] affected time perception in rats. Rats were trained to recognize “short” (1200-ms) and “long” (2400-ms) anchor-duration pure tones and were rewarded for corresponding lever presses. During testing, rats perceived a series of intermediate-duration and anchor-duration pure tones, and selected levers corresponding to the “short” and “long” tones. After formalin injection, rats gave more “long” lever-press responses than after saline injection. The point of subjective equality after formalin injection also increased, suggesting that formalin-induced acute pain extended time perception. In contrast, rats that had undergone SNL gave fewer “long” lever-press responses compared with the sham surgery group. This animal study suggests that formalin-induced pain and neuropathic pain may have different effects on time perception.
A change in the zinc ion concentration reflects the maturation of insulin-producing cells generated from adipose-derived mesenchymal stem cells
Authors: Ohta Shogo , Ikemoto Tetsuya , Wada Yuma , Saito Yu , Yamada Shinichiro , Imura Satoru , Morine Yuji , Shimada Mitsuo
Published: December 2019

The generation of insulin-producing cells (IPCs) from pluripotent stem cells could be a breakthrough treatment for type 1 diabetes. However, development of new techniques is needed to exclude immature cells for clinical application. Dithizone staining is used to evaluate IPCs by detecting zinc. We hypothesised that zinc ion (Zn2+) dynamics reflect the IPC maturation status. Human adipose-derived stem cells were differentiated into IPCs by our two-step protocol using two-dimensional (2D) or 3D culture. The stimulation indexes of 2D -and 3D-cultured IPCs on day 21 were 1.21 and 3.64 (P < 0.05), respectively. The 3D-cultured IPCs were stained with dithizone during culture, and its intensity calculated by ImageJ reached the peak on day 17 (P < 0.05). Blood glucose levels of streptozotocin-induced diabetic nude mice were normalised (4/4,100%) after transplantation of 96 3D-cultured IPCs. Zn2+ concentration changes in the medium of 3D cultures had a negative value in the early period and a large positive value in the latter period. This study suggests that Zn2+ dynamics based on our observations and staining of zinc transporters have critical roles in the differentiation of IPCs, and that their measurement might be useful to evaluate IPC maturation as a non-destructive method.
Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model
Authors: Gallardo-Orihuela Andrea , Hervás-Corpión Irati , Hierro-Bujalance Carmen , Sanchez-Sotano Daniel , Jiménez-Gómez Gema , Mora-López Francisco , Campos-Caro Antonio , Garcia-Alloza Monica , Valor Luis M.
Published: December 2019

Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients.
Strain-Engineered Tetragonal Phase and Ferroelectricity in GdMnO3 Thin Films Grown on SrTiO3 (001)
Authors: Machado P. , Figueiras F. G. , Vilarinho R. , Fernandes J. R. A. , Tavares P. B. , Soares M. Rosário , Cardoso S. , Silva J. P. B. , Almeida A. , Moreira J. Agostinho
Published: December 2019

A previously unreported tetragonal phase has been discovered in a epitaxially strained GdMnO3 thin films deposited on (001)-oriented SrTiO3 substrates by radio frequency (RF) magnetron sputtering. The tetragonal axis of the films grown up to a 35 nm thickness is perpendicular to the film surface and the basal lattice parameters are imposed by the cubic structure of the substrate. Furthermore, the emergence of a spontaneous electric polarization below ~32 K points to the stabilization of an improper ferroelectric phase at low temperatures, which is not observed in bulk GdMnO3. This work shows how strain engineering can be used to tailor the structure and properties of strongly correlated oxides.
Asthma and/or hay fever as predictors of fertility/impaired fecundity in U.S. women: National Survey of Family Growth
Authors: Turkeltaub Paul C. , Lockey Richard F. , Holmes Katie , Friedmann Erika
Published: December 2019

This study addresses whether asthma and/or hay fever predict fertility and impaired fecundity. The lifetime number of pregnancies (fertility) and spontaneous pregnancy losses (impaired fecundity) in 10,847 women representative of the U.S. population 15 to 44 years of age with histories of diagnosed asthma and/or hay fever are analyzed in the 1995 National Survey of Family Growth using multivariable Poisson regression with multiple covariates and adjustments for complex sampling. Smokers have significantly increased fertility compared to nonsmokers. Smokers with asthma only have significantly increased fertility compared to other smokers. Higher fertility is associated with impaired fecundity (ectopic pregnancy, miscarriage, stillbirth). Women with asthma (with and without hay fever) have significantly higher pregnancy losses than women without asthma. With increasing number of pregnancies, smokers have increased pregnancy losses compared to nonsmokers. Smokers, especially those with asthma only, have increased fertility and require special attention as to their family planning needs, reproductive health, and smoking cessation. Women with asthma, regardless of number of pregnancies, and smokers with higher numbers of pregnancies have high risk pregnancies that require optimal asthma/medical management prenatally and throughout pregnancy. Whether a proinflammatory asthma endotype underlies both the increased fertility and impaired fecundity associated with age and smoking is discussed.
Pharmacological myeloperoxidase (MPO) inhibition in an obese/hypertensive mouse model attenuates obesity and liver damage, but not cardiac remodeling
Authors: Piek Arnold , Koonen Debby P. Y. , Schouten Elisabeth-Maria , Lindtstedt Eva L. , Michaëlsson Erik , de Boer Rudolf A. , Silljé Herman H. W.
Published: December 2019

Lifestyle factors are important drivers of chronic diseases, including cardiovascular syndromes, with low grade inflammation as a central player. Attenuating myeloperoxidase (MPO) activity, an inflammatory enzyme associated with obesity, hypertension and heart failure, could have protective effects on multiple organs. Herein, the effects of the novel oral available MPO inhibitor AZM198 were studied in an obese/hypertensive mouse model which displays a cardiac phenotype. Eight week old male C57BL6/J mice received 16 weeks of high fat diet (HFD) combined with angiotensin II (AngII) infusion during the last 4 weeks, with low fat diet and saline infusion as control. Treated animals showed therapeutic AZM198 levels (2.1 µM), corresponding to 95% MPO inhibition. AZM198 reduced elevated circulating MPO levels in HFD/AngII mice to normal values. Independent of food intake, bodyweight increase and fat accumulation were attenuated by AZM198, alongside with reduced visceral adipose tissue (VAT) inflammation and attenuated severity of nonalcoholic steatohepatitis. The HFD/AngII perturbation caused impaired cardiac relaxation and contraction, and increased cardiac hypertrophy and fibrosis. AZM198 treatment did, however, not improve these cardiac parameters. Thus, AZM198 had positive effects on the main lipid controlling tissues in the body, namely adipose tissue and liver. This did, however, not directly result in improved cardiac function.
Nitrogen and phosphorus addition differentially affect plant ecological stoichiometry in desert grassland
Authors: Li Lei , Liu Bo , Gao Xiaopeng , Li Xiangyi , Li Chengdao
Published: December 2019

Plant C:N:P stoichiometric relations drive powerful constraints on ecological interactions and processes. However, information about plant stoichiometric responses to N and P availability in desert grassland is limited. We conducted two field experiments with 7 levels of N (from 0.5 g to 24 g N ∙ m−2 yr−1) and P (from 0.05 g to 3.2 g P ∙ m−2 yr−1) additions in a desert grassland of Kunlun Mountain in the northwest of China to investigate the effects of these addition rates on the N and P stoichiometry of the dominant grass species Seriphidium korovinii. Nitrogen and P additions both affected plant stoichiometry. N addition suppressed P concentrations, whereas P addition had no effect on plant N concentrations. The N:P ratios of green aboveground biomass (AGB) were positively correlated with N addition ranging from 14.73 to 29.08, whereas those for P additions decreased ranging from 14.73 to 8.29. N concentrations were positively correlated with soil available N:P ratios, whereas, P concentrations were negatively correlated with soil availably N:P. Our results suggest that chemistry and stoichiometry of S. korovinii was directly affected by soil nutrient availability. Soil N availability affects S. korovinii stoichiometry to a greater extent that does soil P availability in this ecosystem. These findings suggest that N-deposition could affect the stoichiometry of this desert grassland ecosystem, and thereby potentially alter litter decomposition, plant community composition, nutrient cycling, and food-web dynamics of these desert ecosystems.
The association of Dietary Approach to Stop Hypertension (DASH) diet with metabolic healthy and metabolic unhealthy obesity phenotypes
Authors: Farhadnejad Hossein , Darand Mina , Teymoori Farshad , Asghari Golaleh , Mirmiran Parvin , Azizi Fereidoun
Published: December 2019

The current study aimed at investigating the association between Dietary Approach to Stop Hypertension (DASH) diet and odds of obesity phenotypes, is a cross sectional study conducted on 3218 Iranian overweight or obese participants (BMI >25 kg/m2), aged ≥20 years, who participated in the fourth phase (2009–2011) of the Tehran Lipid and Glucose Study. Using a valid and reliable food-frequency questionnaire, DASH diet scores between 8 and 40 points were determined. Obesity phenotypes including metabolic unhealthy obesity (MUHO) and metabolic healthy obesity (MHO) were defined using criteria of the Joint International statement(JIS) for metabolic syndrome. Multivariable logistic regression was used to determine the odds ratio (OR) for obesity phenotypes according to the tertiles of the DASH diet. Mean ± SD age of participants (43.5% male) was 39.2 ± 9.5 years and median (25–75 interquartile range) DASH diet score was 24 (21–27); percentages of MHO and MUHO subjects were 33.4 and 66.6%, respectively. In the multivariable adjusted model, after controlling for age, sex, BMI, physical activity, smoking status, socioeconomic status, and energy intake, participants in the highest tertile of DASH diet had lower odds of MUHO (OR:0.79;95%CI:0.64–0.98), in comparison to those in the lowest one (P for trend = 0.040). Our findings indicate that adherence to DASH diet may be favourable in prevention of metabolic abnormalities in overweight and obese individuals.
Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner
Authors: Shiratori Reika , Furuichi Kenta , Yamaguchi Masashi , Miyazaki Natsumi , Aoki Haruna , Chibana Hiroji , Ito Kousei , Aoki Shigeki
Published: December 2019

Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.
Identification of the core bacteria in rectums of diarrheic and non-diarrheic piglets
Authors: Sun Jing , Du Lei , Li XiaoLei , Zhong Hang , Ding Yuchun , Liu Zuohua , Ge Liangpeng
Published: December 2019

Porcine diarrhea is a global problem that leads to large economic losses of the porcine industry. There are numerous factors related to piglet diarrhea, and compelling evidence suggests that gut microbiota is vital to host health. However, the key bacterial differences between non-diarrheic and diarrheic piglets are not well understood. In the present study, a total of 85 commercial piglets at three pig farms in Sichuan Province and Chongqing Municipality, China were investigated. To accomplish this, anal swab samples were collected from piglets during the lactation (0–19 days old in this study), weaning (20–21 days old), and post-weaning periods (22–40 days), and fecal microbiota were assessed by 16S rRNA gene V4 region sequencing using the Illumina Miseq platform. We found age-related biomarker microbes in the fecal microbiota of diarrheic piglets. Specifically, the family Enterobacteriaceae was a biomarker of diarrheic piglets during lactation (cluster A, 7–12 days old), whereas the Bacteroidales family S24–7 group was found to be a biomarker of diarrheic pigs during weaning (cluster B, 20–21 days old). Co-correlation network analysis revealed that the genus Escherichia-Shigella was the core component of diarrheic microbiota, while the genus Prevotellacea UCG-003 was the key bacterium in non-diarrheic microbiota of piglets in Southwest China. Furthermore, changes in bacterial metabolic function between diarrheic piglets and non-diarrheic piglets were estimated by PICRUSt analysis, which revealed that the dominant functions of fecal microbes were membrane transport, carbohydrate metabolism, amino acid metabolism, and energy metabolism. Remarkably, genes related to transporters, DNA repair and recombination proteins, purine metabolism, ribosome, secretion systems, transcription factors, and pyrimidine metabolism were decreased in diarrheic piglets, but no significant biomarkers were found between groups using LEfSe analysis.
The Association of Low Admission Serum Creatinine with the Risk of Respiratory Failure Requiring Mechanical Ventilation: A Retrospective Cohort Study
Authors: Thongprayoon Charat , Cheungpasitporn Wisit , Chewcharat Api , Mao Michael A. , Thirunavukkarasu Sorkko , Kashani Kianoush B.
Published: December 2019

To assess the association between low serum creatinine (SCr) value at admission and the risk of respiratory failure requiring mechanical ventilation in hospitalized patients. A retrospective cohort study was conducted at a tertiary referral hospital. All hospitalized adult patients from 2011 through 2013 who had an admission SCr value were included in this study. Patients who were mechanically ventilated at the time of admission were excluded. Admission creatinine was stratified into 7 groups: ≤0.4, 0.5–0.6, 0.7–0.8, 0.9–1.0, 1.1–1.2, 1.3–1.4, and ≥1.5 mg/dL. The primary outcome was the occurrence of respiratory failure requiring mechanical ventilation during hospitalization. Logistic regression analysis was used to assess the independent risk of respiratory failure based on various admission SCr, using SCr of 0.7–0.8 mg/dL as the reference group in the analysis of all patients and female subgroup and of 0.9–1.0 mg/dL in analysis of male subgroup. A total of 67,045 eligible patients, with the mean admission SCr of 1.0 ± 0.4 mg/dL, were studied. Of these patients, 799 (1.1%) had admission SCr of ≤0.4 mg/dL, and 2886 (4.3%) developed respiratory failure requiring mechanical ventilation during hospitalization. The U-curve relationship between admission SCr and respiratory failure during hospitalization was observed, with the nadir incidence of in-hospital respiratory failure in SCr of 0.7–0.8 mg/dL and increased in-hospital respiratory failure associated with both reduced and elevated admission SCr. After adjustment for confounders, very low admission SCr of ≤0.4 mg/dL was significantly associated with increased in-hospital respiratory failure (OR 3.11; 95% CI 2.33–4.17), exceeding the risk related to markedly elevated admission SCr of ≥1.5 mg/dL (OR 1.61; 95% CI 1.39–1.85). The association remained significant in the subgroup analysis of male and female patients. Low SCr value at admission is independently associated with increased in-hospital respiratory failure requiring mechanical ventilation in hospitalized patients.