bluuebunny/crossref_metadata_2025_split huggingface dataset:
The definition and measurement of heterogeneity
Authors: Nunes Abraham , Trappenberg Thomas , Alda Martin 
Published: August 2020

AbstractHeterogeneity 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

Abstract
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

Abstract
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

AbstractBackgroundThe 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.MethodsCohort 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.ResultsIn 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.ConclusionsThe 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

SummaryOvarian 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

AbstractAnlotinib 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

AbstractPrevious 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

AbstractNecroptosis, 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

AbstractGrid 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

AbstractOur 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

AbstractThe 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

AbstractPost-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

AbstractThe 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

AbstractCalcium 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

AbstractThe 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.