bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetosheath Microstructure: Mirror Mode Waves and Jets during Southward IP Magnetic Field
Authors: Blanco‐Cano X. , Preisser L. , Kajdič P. , Rojas‐Castillo D.
Published: August 2020

In the Earth's magnetosheath plasma waves, nonlinear structures associated with characteristic ion populations can occur. Understanding the interaction of the solar wind with the magnetosphere requires a deeper knowledge of the underlying magnetosheath kinetic microstructure. We study a 45 min interval when the MMS spacecraft observed a southward magnetic field (Bz < 0 nT) in the dayside magnetosheath. Using magnetic field and plasma data, we analyze three transient dynamic pressure enhancements identified as magnetosheath jets. The characteristics of these jets are different, suggesting different origins. While two of them, called J1 and J2, exhibit large increment in velocity and almost no density increment, the third jet (J3) shows large density enhancements with almost no velocity increment. The duration of J3 is ∼7 times longer than those of J1 and J2. J3 occurs at the region where the negative Bz becomes positive. Ion distributions inside the jets are different. J1 and J2 show a secondary field‐aligned beam, which is not present in J3, suggesting that magnetic reconnection at the magnetopause is responsible for their formation. Distributions inside J3 are more isotropic. B field and plasma signatures inside J3 correspond to the crossing of a sector boundary, similar to the heliospheric plasma sheet, suggesting that J3 forms by the evolution and interaction of a solar wind structure with the bow shock and magnetosheath. Fluctuations inside J3 have larger transverse components, although they propagate at large angles to B. In contrast, waves in regions between the jets are compressive and are identified as mirror mode waves.
Properties of Plasma Waves Observed Upstream From Mars
Authors: Halekas J. S. , Ruhunusiri S. , Vaisberg O. L. , Harada Y. , Espley J. R. , Mitchell D. L. , Mazelle C. , Romanelli N. , DiBraccio G. A. , Brain D. A.
Published: August 2020

We describe a new method to analyze the properties of plasma waves and apply it to observations made upstream from Mars by the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission. The slow measurement cadence of most charged particle instrumentation has limited the application of analysis techniques based on correlations between particle and magnetic field measurements. We show that we can extend the frequency range of applicability for these techniques, for a subset of waves that remain nearly coherent over multiple wave periods, by subsampling velocity distribution function measurements and binning them by the wave phase. This technique enables the computation of correlations and transport ratios for plasma waves previously inaccessible to this technique at Mars. By computing the cross helicity, we find that most identified waves propagate upstream in the plasma frame. This supports the conclusions of previous studies but enables a clearer determination of the intrinsic wave mode and characteristics. The intrinsic properties of observed waves with frequencies close to the proton cyclotron frequency have little spatial variability but do have large temporal variations, likely due to seasonal changes in the hydrogen exosphere. In contrast, the predominant characteristics of waves at higher frequencies have less temporal variability but more spatial variability. We find several indications of the presence of multiple wave modes in the lower frequency wave observations, with unusual wave properties observed for propagation parallel to the magnetic field and for background magnetic fields nearly perpendicular to the solar wind flow.
On‐Fault Geological Fingerprint of Earthquake Rupture Direction
Authors: Kearse J. , Kaneko Y.
Published: August 2020

How earthquake ruptures evolve and propagate are major outstanding questions in seismology. Our current understanding is limited to modern events captured by seismic networks, making it impossible to observe rupture propagation that occurred during earthquakes in the distant past. Here we propose a new method to discern the rupture propagation directions of past large earthquakes based on geological features preserved on fault slip planes. These features—called slickenlines—are striations formed during seismic slip and record dynamic fault movement during past surface‐breaking earthquakes. We develop a theoretical framework that links slickenline curvature with rupture mode and rupture propagation direction for all faulting types and test our model using a global catalogue of historical surface‐rupturing earthquakes with seismologically constrained rupture directions. Our results reveal that historical observations are consistent with theoretical predictions, thus providing a robust way to uncover the rupture directions of large earthquakes that lack instrumental data.
Analysis of Coupled Oceanic and Atmospheric Preconditioning for Primary Madden‐Julian Oscillation Events Across ENSO Phases
Authors: Shoup Casey G. , Roman‐Stork Heather L. , Subrahmanyam Bulusu
Published: August 2020

The Madden‐Julian Oscillation (MJO) is the dominant mode of air‐sea interaction over intraseasonal timescales. The effects of the MJO are well understood, but the initiation of the MJO remains less conclusive, particularly under El Niño Southern Oscillation (ENSO) conditions. Primary MJO events are those not immediately preceded by existing MJO activity of sufficient strength. As they are rare by definition, primary MJOs remain difficult to study, especially so when observations of events are scarce and of low spatiotemporal resolution. The advent of satellites allows for more expansive observations to be made more frequently than in situ methods, thus improving the observational capabilities of pre‐primary MJO conditions in the ocean and atmosphere. We examined oceanic and atmospheric intraseasonal signals preceding two primary MJO events during contrasting ENSO events in an attempt to bridge the connection between oceanic and atmospheric observations as potentially coupled trigger mechanisms. Satellite observations and model simulations of the central and western Indian Ocean show that intraseasonal peaks in absolute dynamic topography (ADT) and sea surface temperature (SST) upward of 1 to 2 weeks prior to the observed outgoing longwave radiation (OLR) minimum. Surface ocean warming moistens the near surface through anomalous surface fluxes, which destabilizes the lower atmosphere to deep convection. Low‐level moisture flux convergence (MFC) moistens the lower atmosphere prior to convective initiation, thus forcing an increase of total column moist static energy (MSE). Coupled midtropospheric cooling is observed that further destabilizes the atmosphere. Zonal shifts in contributing initiating parameters are observed during ENSO phases.
Correction: C-Peptide and leptin system in dichorionic, small and appropriate for gestational age twins—possible link to metabolic programming?
Authors: Lewandowski Krzysztof C. , Biesiada L. , Grzesiak M. , Sakowicz A.
Published: August 2020

The original version of this Article was updated shortly after publication to correct two mistakes.

Under Figure 2, “The results were recalculated accordingly: nanograms [ng] of studied protein per 100 μ” should read “The results were recalculated accordingly: picograms [pg] of studied protein per 100 μg”.
Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications
Authors: Wei Qinyao , Qian Yun , Yu Jun , Wong Chi Chun
Published: August 2020

Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.
Intracellular amorphous Ca-carbonate and magnetite biomineralization by a magnetotactic bacterium affiliated to the Alphaproteobacteria
Authors: Monteil Caroline L , Benzerara Karim , Menguy Nicolas , Bidaud Cécile C , Michot-Achdjian Emmanuel , Bolzoni Romain , Mathon François P , Coutaud Margot , Alonso Béatrice , Garau Camille , Jézéquel Didier , Viollier Eric , Ginet Nicolas , Floriani Magali , Swaraj Sufal , Sachse Martin , Busigny Vincent , Duprat Elodie , Guyot François , Lefevre Christopher T
Published: August 2020

Bacteria synthesize a wide range of intracellular submicrometer-sized inorganic precipitates of diverse chemical compositions and structures, called biominerals. Their occurrences, functions and ultrastructures are not yet fully described despite great advances in our knowledge of microbial diversity. Here, we report bacteria inhabiting the sediments and water column of the permanently stratified ferruginous Lake Pavin, that have the peculiarity to biomineralize both intracellular magnetic particles and calcium carbonate granules. Based on an ultrastructural characterization using transmission electron microscopy (TEM) and synchrotron-based scanning transmission X-ray microscopy (STXM), we showed that the calcium carbonate granules are amorphous and contained within membrane-delimited vesicles. Single-cell sorting, correlative fluorescent in situ hybridization (FISH), scanning electron microscopy (SEM) and molecular typing of populations inhabiting sediments affiliated these bacteria to a new genus of the Alphaproteobacteria. The partially assembled genome sequence of a representative isolate revealed an atypical structure of the magnetosome gene cluster while geochemical analyses indicate that calcium carbonate production is an active process that costs energy to the cell to maintain an environment suitable for their formation. This discovery further expands the diversity of organisms capable of intracellular Ca-carbonate biomineralization. If the role of such biomineralization is still unclear, cell behaviour suggests that it may participate to cell motility in aquatic habitats as magnetite biomineralization does.
Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218
Authors: Jurkiewicz Magdalena , Moser Dirk , Koller Antonius , Yu Lei , Chen Emily I. , Bennett David A. , Canli Turhan
Published: August 2020

Recent genome-wide studies have begun to identify gene variants, expression profiles, and regulators associated with neuroticism, anxiety disorders, and depression. We conducted a set of experimental cell culture studies of gene regulation by micro RNAs (miRNAs), based on genome-wide transcriptome, proteome, and miRNA expression data from twentypostmortemsamples of lateral amygdala from donors with known neuroticism scores. Using Ingenuity Pathway Analysis and TargetScan, we identified a list of mRNA–protein–miRNA sets whose expression patterns were consistent with miRNA-based translational repression, as a function of trait anxiety. Here, we focused on one gene from that list, which is of particular translational significance in Psychiatry: synaptic vesicle glycoprotein 2A (SV2A) is the binding site of the anticonvulsant drug levetiracetam ((S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide), which has shown promise in anxiety disorder treatments. We confirmed thatSV2Ais associated with neuroticism or anxiety using an original GWAS of a community cohort (N = 1,706), and cross-referencing a published GWAS of multiple cohorts (Ns ranging from 340,569 to 390,278).Postmortemamygdala expression profiling implicated three putative regulatory miRNAs to targetSV2A: miR-133a, miR-138, and miR-218. Moving from association to experimental causal testing in cell culture, we used a luciferase assay to demonstrate that miR-133a and miR-218, but not miR-138, significantly decreased relative luciferase activity from theSV2Adual-luciferase construct. In human neuroblastoma cells, transfection with miR-133a and miR-218 reduced both endogenousSV2AmRNA and protein levels, confirming miRNA targeting of theSV2Agene. This study illustrates the utility of combiningpostmortemgene expression data with GWAS to guide experimental cell culture assays examining gene regulatory mechanisms that may contribute to complex human traits. Identifying specific molecular mechanisms of gene regulation may be useful for future clinical applications in anxiety disorders or other forms of psychopathology.
The definition and measurement of heterogeneity
Authors: Nunes Abraham , Trappenberg Thomas , Alda Martin
Published: August 2020

Heterogeneity is an important concept in psychiatric research and science more broadly. It negatively impacts effect size estimates under case–control paradigms, and it exposes important flaws in our existing categorical nosology. Yet, our field has no precise definition of heterogeneity proper. We tend to quantify heterogeneity by measuring associated correlates such as entropy or variance: practices which are akin to accepting the radius of a sphere as a measure of its volume. Under a definition of heterogeneity as the degree to which a system deviates from perfect conformity, this paper argues that its proper measure roughly corresponds to the size of a system’s event/sample space, and has units known as numbers equivalent. We arrive at this conclusion through focused review of more than 100 years of (re)discoveries of indices by ecologists, economists, statistical physicists, and others. In parallel, we review psychiatric approaches for quantifying heterogeneity, including but not limited to studies of symptom heterogeneity, microbiome biodiversity, cluster-counting, and time-series analyses. We argue that using numbers equivalent heterogeneity measures could improve the interpretability and synthesis of psychiatric research on heterogeneity. However, significant limitations must be overcome for these measures—largely developed for economic and ecological research—to be useful in modern translational psychiatric science.
Bacterial lipopolysaccharide as negative predictor of gemcitabine efficacy in advanced pancreatic cancer – translational results from the AIO-PK0104 Phase 3 study
Authors: Guenther Michael , Haas Michael , Heinemann Volker , Kruger Stephan , Westphalen Christoph Benedikt , von Bergwelt-Baildon Michael , Mayerle Julia , Werner Jens , Kirchner Thomas , Boeck Stefan , Ormanns Steffen
Published: August 2020

Background

Gram-negative bacteria mediated gemcitabine resistance in pre-clinical models. We determined if intratumoural lipopolysaccharide (LPS) detection by immunohistochemistry is associated with outcome in advanced pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine and non-gemcitabine containing 1st-line chemotherapy.

Methods

We examined LPS on tumour tissue from 130 patients treated within the randomised AIO-PK0104 trial and a validation cohort (n = 113) and analysed the association of LPS detection to patient outcome according to treatment subgroups.

Results

In 24% of samples from the AIO-PK0104 study LPS was detected; in LPS-positive patients median OS was 4.4 months, compared to 7.3 months with LPS negative tumours (HR 1.732, p = 0.010). A difference in OS was detected in 1st-line gemcitabine-treated patients (n = 71; HR 2.377, p = 0.002), but not in the non-gemcitabine treatment subgroup (n = 59; HR 1.275, p = 0.478). Within the validation cohort, the LPS positivity rate was 23%, and LPS detection was correlated with impaired OS in the gemcitabine subgroup (n = 94; HR 1.993, p = 0.008) whereas no difference in OS was observed in the non-gemcitabine subgroup (n = 19; HR 2.596, p = 0.219).

Conclusions

The detection of intratumoural LPS as surrogate marker for gram-negative bacterial colonisation may serve as a negative predictor for gemcitabine efficacy in advanced PDAC.

Clinical trial registry

The Clinical trial registry identifier is NCT00440167.
Alcohol drinking and head and neck cancer risk: the joint effect of intensity and duration
Authors: Di Credico Gioia , Polesel Jerry , Dal Maso Luigino , Pauli Francesco , Torelli Nicola , Luce Daniele , Radoï Loredana , Matsuo Keitaro , Serraino Diego , Brennan Paul , Holcatova Ivana , Ahrens Wolfgang , Lagiou Pagona , Canova Cristina , Richiardi Lorenzo , Healy Claire M. , Kjaerheim Kristina , Conway David I. , Macfarlane Gary J. , Thomson Peter , Agudo Antonio , Znaor Ariana , Franceschi Silvia , Herrero Rolando , Toporcov Tatiana N. , Moyses Raquel A. , Muscat Joshua , Negri Eva , Vilensky Marta , Fernandez Leticia , Curado Maria Paula , Menezes Ana , Daudt Alexander W. , Koifman Rosalina , Wunsch-Filho Victor , Olshan Andrew F. , Zevallos Jose P. , Sturgis Erich M. , Li Guojun , Levi Fabio , Zhang Zuo-Feng , Morgenstern Hal , Smith Elaine , Lazarus Philip , La Vecchia Carlo , Garavello Werner , Chen Chu , Schwartz Stephen M. , Zheng Tongzhang , Vaughan Thomas L. , Kelsey Karl , McClean Michael , Benhamou Simone , Hayes Richard B. , Purdue Mark P. , Gillison Maura , Schantz Stimson , Yu Guo-Pei , Chuang Shu-Chun , Boffetta Paolo , Hashibe Mia , Yuan-Chin Amy Lee , Edefonti Valeria
Published: August 2020

Background

Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk.

Methods

Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking.

Results

For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx).

Conclusions

Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.
One-year mortality of colorectal cancer patients: development and validation of a prediction model using linked national electronic data
Authors: Cowling Thomas E. , Bellot Alexis , Boyle Jemma , Walker Kate , Kuryba Angela , Galbraith Sarah , Aggarwal Ajay , Braun Michael , Sharples Linda D. , van der Meulen Jan
Published: August 2020

Background

The existing literature does not provide a prediction model for mortality of all colorectal cancer patients using contemporary national hospital data. We developed and validated such a model to predict colorectal cancer death within 90, 180 and 365 days after diagnosis.

Methods

Cohort study using linked national cancer and death records. The development population included 27,480 patients diagnosed in England in 2015. The test populations were diagnosed in England in 2016 (n = 26,411) and Wales in 2015–2016 (n = 3814). Predictors were age, gender, socioeconomic status, referral source, performance status, tumour site, TNM stage and treatment intent. Cox regression models were assessed using Brier scores,c-indices and calibration plots.

Results

In the development population, 7.4, 11.7 and 17.9% of patients died from colorectal cancer within 90, 180 and 365 days after diagnosis. T4 versus T1 tumour stage had the largest adjusted association with the outcome (HR 4.67; 95% CI: 3.59–6.09).C-indices were 0.873–0.890 (England) and 0.856–0.873 (Wales) in the test populations, indicating excellent separation of predicted risks by outcome status. Models were generally well calibrated.

Conclusions

The model was valid for predicting short-term colorectal cancer mortality. It can provide personalised information to support clinical practice and research.
Is ovarian cancer surgery stuck in the dark ages?: a commentary piece reviewing surgical technologies
Authors: Phelps David L. , Saso Srdjan , Ghaem-Maghami Sadaf
Published: August 2020

Ovarian cancer surgery endeavours to remove all visible tumour deposits, and surgical technologies could potentially facilitate this aim. However, there appear to be barriers around the adoption of new technologies, and we hope this article provokes discussion within the specialty to encourage a forward-thinking approach to new-age surgical gynaecological oncology.
Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib
Authors: Sun Xin , Shu Yuhan , Yan Peiyi , Huang Hongliang , Gao Ruilan , Xu Mengting , Lu Liqin , Tian Jingkui , Huang Dongsheng , Zhang Jianbin
Published: August 2020

Anlotinib is a receptor tyrosine kinase inhibitor with potential anti-neoplastic and anti-angiogenic activities. It has been approved for the treatment of non-small-cell lung cancer. Lysosomes are acidic organelles and have been implicated in various mechanisms of cancer therapeutics. However, the effect of anlotinib on lysosomal function has not been investigated. In the present study, anlotinib induces apoptosis in human colon cancer cells. Through transcriptome sequencing, we found for the first time that anlotinib treatment upregulates ATP6V0E2 (ATPase H+Transporting V0 Subunit E2) and other lysosome-related genes expression in human colon cancer. In human colon cancer, we validated that anlotinib activates lysosomal function and enhances the fusion of autophagosomes and lysosomes. Moreover, anlotinib treatment is shown to inhibit mTOR (mammalian target of rapamycin) signaling and the activation of lysosomal function by anlotinib is mTOR dependent. Furthermore, anlotinib treatment activates TFEB, a key nuclear transcription factor that controls lysosome biogenesis and function. We found that anlotinib treatment promotes TFEB nuclear translocation and enhances its transcriptional activity. When TFEB or ATP6V0E2 are knocked down, the enhanced lysosomal function and autophagy by anlotinib are attenuated. Finally, inhibition of lysosomal function enhances anlotinib-induced cell death and tumor suppression, which may be attributed to high levels of ROS (reactive oxygen species). These findings suggest that the activation of lysosomal function protects against anlotinib-mediated cell apoptosis via regulating the cellular redox status. Taken together, our results provide novel insights into the regulatory mechanisms of anlotinib on lysosomes, and this information could facilitate the development of potential novel cancer therapeutic agents that inhibit lysosomal function.
USP7 negatively controls global DNA methylation by attenuating ubiquitinated histone-dependent DNMT1 recruitment
Authors: Li Jialun , Wang Ruiping , Jin Jianyu , Han Mengmeng , Chen Zhaosu , Gao Yingying , Hu Xueli , Zhu Haijun , Gao Huifang , Lu Kongbin , Shao Yanjiao , Lyu Cong , Lai Weiyi , Li Pishun , Hu Guang , Li Jiwen , Li Dali , Wang Hailin , Wu Qihan , Wong Jiemin
Published: August 2020

Previous studies have implicated an essential role for UHRF1-mediated histone H3 ubiquitination in recruiting DNMT1 to replication sites for DNA maintenance methylation during S phase of the cell cycle. However, the regulatory mechanism on UHRF1-mediated histone ubiquitination is not clear. Here we present evidence that UHRF1 and USP7 oppositely control ubiquitination of histones H3 and H2B in S phase of the cell cycle and that DNMT1 binds both ubiquitinated H3 and H2B. USP7 knockout markedly increased the levels of ubiquitinated H3 and H2B in S phase, the association of DNMT1 with replication sites and importantly, led to a progressive increase of global DNA methylation shown with increased cell passages. Using DNMT3A/DNMT3B/USP7 triple knockout cells and various DNA methylation analyses, we demonstrated that USP7 knockout led to an overall elevation of DNA methylation levels. Mechanistic study demonstrated that USP7 suppresses DNMT1 recruitment and DNA methylation through its deubiquitinase activity and the interaction with DNMT1. Altogether our study provides evidence that USP7 is a negative regulator of global DNA methylation and that USP7 protects the genome from excessive DNA methylation by attenuating histone ubiquitination-dependent DNMT1 recruitment.
Myofiber necroptosis promotes muscle stem cell proliferation via releasing Tenascin-C during regeneration
Authors: Zhou Shen’ao , Zhang Wei , Cai Gaihong , Ding Yingzhe , Wei Caixia , Li Sheng , Yang Yu , Qin Jie , Liu Dan , Zhang Hao , Shao Xiexiang , Wang Jianhua , Wang Hongye , Yang Wenjun , Wang Huating , Chen She , Hu Ping , Sun Liming
Published: August 2020

Necroptosis, a form of programmed cell death, is characterized by the loss of membrane integrity and release of intracellular contents, the execution of which depends on the membrane-disrupting activity of the Mixed Lineage Kinase Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers committed MLKL-dependent necroptosis after muscle injury. Either pharmacological inhibition of the necroptosis upstream kinase Receptor Interacting Protein Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to significant muscle regeneration defects. By releasing factors into the muscle stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to be critical for MuSC proliferation. The temporary expression of TNC in myofibers is tightly controlled by necroptosis; the extracellular release of TNC depends on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR) signaling pathway in MuSCs through its N-terminus assembly domain together with the EGF-like domain. These findings indicate that necroptosis plays a key role in promoting MuSC proliferation to facilitate muscle regeneration.
Grid cells are modulated by local head direction
Authors: Gerlei Klara , Passlack Jessica , Hawes Ian , Vandrey Brianna , Stevens Holly , Papastathopoulos Ioannis , Nolan Matthew F.
Published: August 2020

Grid and head direction codes represent cognitive spaces for navigation and memory. Pure grid cells generate grid codes that have been assumed to be independent of head direction, whereas conjunctive cells generate grid representations that are tuned to a single head direction. Here, we demonstrate that pure grid cells also encode head direction, but through distinct mechanisms. We show that individual firing fields of pure grid cells are tuned to multiple head directions, with the preferred sets of directions differing between fields. This local directional modulation is not predicted by previous continuous attractor or oscillatory interference models of grid firing but is accounted for by models in which pure grid cells integrate inputs from co-aligned conjunctive cells with firing rates that differ between their fields. We suggest that local directional signals from grid cells may contribute to downstream computations by decorrelating different points of view from the same location.
Tissue sodium excess is not hypertonic and reflects extracellular volume expansion
Authors: Rossitto Giacomo , Mary Sheon , Chen Jun Yu , Boder Philipp , Chew Khai Syuen , Neves Karla B. , Alves Rheure L. , Montezano Augusto C. , Welsh Paul , Petrie Mark C. , Graham Delyth , Touyz Rhian M. , Delles Christian
Published: August 2020

Our understanding of Na+ homeostasis has recently been reshaped by the notion of skin as a depot for Na+ accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na+ could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na+ excess upon high Na+ intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.e. a shift in the extracellular-to-intracellular compartments, due to a reduction of the intracellular or accumulation of water-paralleled Na+ in the extracellular space. We also demonstrate that this accumulation is unlikely to justify the observed development of experimental hypertension if it were water-independent. Finally, we show that this isotonic skin Na+ excess, reflecting subclinical oedema, occurs in hypertensive patients and in association with aging. The implications of our findings, questioning previous assumptions but also reinforcing the importance of tissue Na+ excess, are both mechanistic and clinical.
Feedback-controlled active brownian colloids with space-dependent rotational dynamics
Authors: Fernandez-Rodriguez Miguel Angel , Grillo Fabio , Alvarez Laura , Rathlef Marco , Buttinoni Ivo , Volpe Giovanni , Isa Lucio
Published: August 2020

The non-thermal nature of self-propelling colloids offers new insights into non-equilibrium physics. The central mathematical model to describe their trajectories is active Brownian motion, where a particle moves with a constant speed, while randomly changing direction due to rotational diffusion. While several feedback strategies exist to achieve position-dependent velocity, the possibility of spatial and temporal control over rotational diffusion, which is inherently dictated by thermal fluctuations, remains untapped. Here, we decouple rotational diffusion from thermal fluctuations. Using external magnetic fields and discrete-time feedback loops, we tune the rotational diffusivity of active colloids above and below its thermal value at will and explore a rich range of phenomena including anomalous diffusion, directed transport, and localization. These findings add a new dimension to the control of active matter, with implications for a broad range of disciplines, from optimal transport to smart materials.
Preventing and treating PTSD-like memory by trauma contextualization
Authors: Al Abed Alice Shaam , Ducourneau Eva-Gunnel , Bouarab Chloé , Sellami Azza , Marighetto Aline , Desmedt Aline
Published: August 2020

Post-traumatic stress disorder (PTSD) is characterized by emotional hypermnesia on which preclinical studies focus so far. While this hypermnesia relates to salient traumatic cues, partial amnesia for the traumatic context can also be observed. Here, we show in mice that contextual amnesia is causally involved in PTSD-like memory formation, and that treating the amnesia by re-exposure to all trauma-related cues cures PTSD-like hypermnesia. These findings open a therapeutic perspective based on trauma contextualization and the underlying hippocampal mechanisms.
Possible itinerant excitations and quantum spin state transitions in the effective spin-1/2 triangular-lattice antiferromagnet Na2BaCo(PO4)2
Authors: Li N. , Huang Q. , Yue X. Y. , Chu W. J. , Chen Q. , Choi E. S. , Zhao X. , Zhou H. D. , Sun X. F.
Published: August 2020

The most fascinating feature of certain two-dimensional (2D) gapless quantum spin liquid (QSL) is that their spinon excitations behave like the fermionic carriers of a paramagnetic metal. The spinon Fermi surface is then expected to produce a linear increase of the thermal conductivity with temperature that should manifest via a residual value (κ0/T) in the zero-temperature limit. However, this linear in T behavior has been reported for very few QSL candidates. Here, we studied the ultralow-temperature thermal conductivity of an effective spin-1/2 triangular QSL candidate Na2BaCo(PO4)2, which has an antiferromagnetic order at very low temperature (TN ~ 148 mK), and observed a finite κ0/T extrapolated from the data above TN. Moreover, while approaching zero temperature, it exhibits series of quantum spin state transitions with applied field along the c axis. These observations indicate that Na2BaCo(PO4)2 possibly behaves as a gapless QSL with itinerant spin excitations above TN and its strong quantum spin fluctuations persist below TN.
Targeting of intracellular Ca2+ stores as a therapeutic strategy against age-related neurotoxicities
Authors: Goldberg Joshua , Currais Antonio , Ates Gamze , Huang Ling , Shokhirev Maxim , Maher Pamela , Schubert David
Published: August 2020

Calcium dysregulation often underlies pathologies associated with aging and age-associated neurodegenerative diseases. Cells express a unique pattern of Ca2+channels and pumps geared to fulfill specific physiological requirements and there is a decline in the fidelity of these processes with age and age-associated diseases. J147 is an Alzheimer’s disease (AD) drug candidate that was identified using a phenotypic screening platform based upon age-related brain toxicities that are mediated by changes in calcium metabolism. The molecular target for J147 is the α-F1-ATP synthase (ATP5A). J147 has therapeutic efficacy in multiple mouse models of AD and accelerated aging and extends life span in flies. A bioinformatics analysis of gene expression in rapidly aging SAMP8 mice during the last quadrant of their life span shows that J147 has a significant effect on ion transport pathways that are changed with aging, making their expression look more like that of younger animals. The molecular basis of these changes was then investigated in cell culture neurotoxicity assays that were the primary screen in the development of J147. Here we show that J147 and its molecular target, ATP synthase, regulate the maintenance of store-operated calcium entry (SOCE) and cell death during acute neurotoxicity.
Akinetic rigid symptoms are associated with decline in a cortical motor network in Parkinson’s disease
Authors: Kann Sarah J. , Chang Chiapei , Manza Peter , Leung Hoi-Chung
Published: August 2020

The akinetic/rigid (AR) motor subtype of Parkinson’s Disease is associated with increased rates of motor and cognitive decline. Cross-sectional studies examining the neural correlates of AR have found abnormalities in both subcortical and cortical networks involved in motor planning and execution relative to controls. To better understand how these cross-sectional findings are implicated in the unique decline associated with the AR subtype, we examined whether baseline AR symptoms are associated with longitudinal decline of these networks, in contrast to other motor symptoms such as tremor. Using whole brain multiple regression analyses we found that worse AR symptoms at baseline were associated with greater gray matter loss over four years in superior parietal and paracentral lobules and motor cortex. These regions also showed altered connectivity patterns with posterior parietal, premotor, pre-supplementary motor area and dorsolateral prefrontal regions in association with AR symptoms across subjects. Thus, AR symptoms are related to gray matter decline and aberrant functional connectivity in a network of frontal-parietal regions critical for motor planning and execution. These structural and functional abnormalities may therefore be implicated in the more aggressive course of decline associated with the AR relative to tremor-dominant subtype.
Structured-light surface scanning system to evaluate breast morphology in standing and supine positions
Authors: Tong Olivia L. H. , Chamson-Reig Astrid , Yip Lawrence C. M. , Brackstone Muriel , Diop Mamadou , Carson Jeffrey J. L.
Published: August 2020

Breast shapes are affected by gravitational loads and deformities. Measurements obtained in the standing position may not correlate well with measurements in the supine position, which is more representative of patient position during breast surgery. A dual color 3D surface imaging system capable of scanning patients in both supine and standing positions was developed to evaluate the effect of changes in body posture on breast morphology. The system was evaluated with  breast phantoms to assess accuracy, then tested on ten subjects in three body postures to assess its effectiveness as a clinical tool. The accuracy of the system was within 0.4 mm on average across the model. For the human study, there was no effect of body posture on breast volumes (p value > 0.05), but we observed an effect of completeness of breast scans on body posture (p value  < 0.05). Post-hoc tests showed that the supine position and the standing position with hands at the waist differed significantly (p value  < 0.05). This study shows that the system can quantitatively evaluate the effect of subject postures, and thereby has the potential to be used to investigate peri-operative changes in breast morphology.
Programmed death ligand-1 (PD-L1) expression in meningioma; prognostic significance and its association with hypoxia and NFKB2 expression
Authors: Karimi Shirin , Mansouri Sheila , Mamatjan Yasin , Liu Jeff , Nassiri Farshad , Suppiah Suganth , Singh Olivia , Aldape Kenneth , Zadeh Gelareh
Published: August 2020

Management of clinically aggressive meningiomas is a considerable challenge. PD-L1 induced immune suppression has increasingly gained attention in clinical management of cancer; however, to date, the clinical significance and regulatory mechanisms of PD-L1 in meningioma is not yet fully characterized. We sought to characterize PD-L1 expression in meningioma and elucidate its regulatory mechanisms. Immunohistochemical staining of PD-L1 expression in meningiomas showed 43% positivity in both tumor and immune cells and we observed intra and inter tumoral heterogeneity. Univariate and multivariate analyses confirmed that PD-L1 protein expression is an independent prognostic marker for worse recurrence free survival in meningioma. Furthermore, our transcriptomic analysis revealed a strong association between PD-L1 expression and that of NFKB2 and carbonic anhydrase 9 (CA9). We also demonstrated that both of these markers, when co-expressed with PD-L1, predict tumor progression. Our studies on several meningioma cell lines cultured in hypoxic conditions validated the association of CA9 and PD-L1 expression. Here we show the clinical significance of PD-L1 in meningioma as a marker that can predict tumor recurrence. We also show an association PD-L1 expression with NFKB2 expression and its induction under hypoxic conditions. These findings may open new avenues of molecular investigation in pathogenesis of meningioma.
Author Correction: Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model
Authors: Kumar Prashant , Achieng Angela O. , Rajendran Vinoth , Ghosh Prahlad C. , Singh Brajendra K. , Rawat Manmeet , Perkins Douglas J. , Kempaiah Prakasha , Rathi Brijesh
Published: August 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
A biphasic nanohydroxyapatite/calcium sulphate carrier containing Rifampicin and Isoniazid for local delivery gives sustained and effective antibiotic release and prevents biofilm formation
Authors: Qayoom Irfan , Verma Rahul , Murugan Prem Anand , Raina Deepak Bushan , Teotia Arun Kumar , Matheshwaran Saravanan , Nair Nisanth N. , Tägil Magnus , Lidgren Lars , Kumar Ashok
Published: August 2020

Long term multiple systemic antibiotics form the cornerstone in the treatment of bone and joint tuberculosis, often combined with local surgical eradication. Implanted carriers for local drug delivery have recently been introduced to overcome some of the limitations associated with conventional treatment strategies. In this study, we used a calcium sulphate hemihydrate (CSH)/nanohydroxyapatite (nHAP) based nanocement (NC) biomaterial as a void filler as well as a local delivery carrier of two standard of care tuberculosis drugs, Rifampicin (RFP) and Isoniazid (INH). We observed that the antibiotics showed different release patterns where INH showed a burst release of 67% and 100% release alone and in combination within one week, respectively whereas RFP showed sustained release of 42% and 49% release alone and in combination over a period of 12 weeks, respectively indicating different possible interactions of antibiotics with nHAP. The interactions were studied using computational methodology, which showed that the binding energy of nHAP with RFP was 148 kcal/mol and INH was 11 kcal/mol, thus varying substantially resulting in RFP being retained in the nHAP matrix. Our findings suggest that a biphasic ceramic based drug delivery system could be a promising treatment alternative to bone and joint TB.
Signatures of local adaptation in the spatial genetic structure of the ascidian Pyura chilensis along the southeast Pacific coast
Authors: Segovia Nicolás I. , González-Wevar Claudio A. , Haye Pilar A.
Published: August 2020

The highly heterogeneous Humboldt Current System (HCS) and the 30°S transition zone on the southeast Pacific coast, represent an ideal scenario to test the influence of the environment on the spatial genomic structure in marine near-shore benthic organisms. In this study, we used seascape genomic tools to evaluate the genetic structure of the commercially important ascidian Pyura chilensis, a species that exhibits a low larval transport potential but high anthropogenic dispersal. A recent study in this species recorded significant genetic differentiation across a transition zone around 30°S in putatively adaptive SNPs, but not in neutral ones, suggesting an important role of environmental heterogeneity in driving genetic structure. Here, we aim to understand genomic-oceanographic associations in P. chilensis along the Southeastern Pacific coast using two combined seascape genomic approaches. Using 149 individuals from five locations along the HCS, a total of 2,902 SNPs were obtained by Genotyping-By-Sequencing, of which 29–585 were putatively adaptive loci, depending on the method used for detection. In adaptive loci, spatial genetic structure was better correlated with environmental differences along the study area (mainly to Sea Surface Temperature, upwelling-associated variables and productivity) than to the geographic distance between sites. Additionally, results consistently showed the presence of two groups, located north and south of 30°S, which suggest that local adaptation processes seem to allow the maintenance of genomic differentiation and the spatial genomic structure of the species across the 30°S biogeographic transition zone of the Humboldt Current System, overriding the homogenizing effects of gene flow.
C24:0 and C24:1 sphingolipids in cholesterol-containing, five- and six-component lipid membranes
Authors: González-Ramírez Emilio J. , García-Arribas Aritz B. , Sot Jesús , Goñi Félix M. , Alonso Alicia
Published: August 2020

The biophysical properties of sphingolipids containing lignoceric (C24:0) or nervonic (C24:1) fatty acyl residues have been studied in multicomponent lipid bilayers containing cholesterol (Chol), by means of confocal microscopy, differential scanning calorimetry and atomic force microscopy. Lipid membranes composed of dioleoyl phosphatidylcholine and cholesterol were prepared, with the addition of different combinations of ceramides (C24:0 and/or C24:1) and sphingomyelins (C24:0 and/or C24:1). Results point to C24:0 sphingolipids, namely lignoceroyl sphingomyelin (lSM) and lignoceroyl ceramide (lCer), having higher membrane rigidifying properties than their C24:1 homologues (nervonoyl SM, nSM, or nervonoyl Cer, nCer), although with a similar strong capacity to induce segregated gel phases. In the case of the lSM-lCer multicomponent system, the segregated phases have a peculiar fibrillar or fern-like morphology. Moreover, the combination of C24:0 and C24:1 sphingolipids generates interesting events, such as a generalized bilayer dynamism/instability of supported planar bilayers. In some cases, these sphingolipids give rise to exothermic curves in thermograms. These peculiar features were not present in previous studies of C24:1 combined with C16:0 sphingolipids. Conclusions of our study point to nSM as a key factor governing the relative distribution of ceramides when both lCer and nCer are present. The data indicate that lCer could be easier to accommodate in multicomponent bilayers than its C16:0 counterpart. These results are relevant for events of membrane platform formation, in the context of sphingolipid-based signaling cascades.
Public institutions’ capacities regarding climate change adaptation and risk management support in agriculture: the case of Punjab Province, Pakistan
Authors: Khan Nasir Abbas , Gao Qijie , Abid Muhammad
Published: August 2020

Public institutions could play an important role in building agricultural resilience to climate change by providing information and technology support to farmers. This study takes the case of Pakistan to investigate the perspective and capacities of public institutions as well as to identify gaps in current institutional arrangements in dealing and managing climate change in the agriculture sector. For this purpose, 53 office bearers from thirteen public institutions in Punjab province of Pakistan were interviewed using a semi-structured questionnaire to collect data on climate knowledge, training, coordination, and resource availability. The study uses an index-based approach to calculate Institutional Capacity Indices (ICI) based on selected seven indicators. The results of the index analysis show that institutions have the least financial capacity, followed by lacking physical and human resources. Whereas results show high index value for perception and knowledge, indicating a good understanding of climate change at the institutional level. The overall ICI index value indicates a medium level capacity of institutions in dealing with climate change. Moreover, the study shows that gaps in management, non-availability of financial and physical resources, and lack of training are the key bottlenecks for limited adaptation support from public institutions. This study highlights the importance of reducing gaps so that institutions could play their role in building the resilience of the agriculture sector to climate change.
Effects of conical intersections on hyperfine quenching of hydroxyl OH in collision with an ultracold Sr atom
Authors: Li Ming , Kłos Jacek , Petrov Alexander , Li Hui , Kotochigova Svetlana
Published: August 2020

The effect of conical intersections (CIs) on electronic relaxation, transitions from excited states to ground states, is well studied, but their influence on hyperfine quenching in a reactant molecule is not known. Here, we report on ultracold collision dynamics of the hydroxyl free-radical OH with Sr atoms leading to quenching of OH hyperfine states. Our quantum-mechanical calculations of this process reveal that quenching is efficient due to anomalous molecular dynamics in the vicinity of the conical intersection at collinear geometry. We observe wide scattering resonance features in both elastic and inelastic rate coefficients at collision energies below$$k_{\text {B}}\times 10 \, \hbox {mK}$$kB×10mK. They are identified as eitherp- ord-wave shape resonances. We also describe the electronic potentials relevant for these non-reactive collisions, their diabatization procedure, as well as the non-adiabatic coupling between the diabatic potentials near the CIs.