bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of cognitive function in female rheumatoid arthritis patients: associations with cerebrovascular pathology, depression and anxiety
Authors: Oláh Csaba , Kardos Zsófia , Andrejkovics Mónika , Szarka Enikő , Hodosi Katalin , Domján Andrea , Sepsi Mariann , Sas Attila , Kostyál László , Fazekas Katalin , Flórián Ágnes , Lukács Katalin , Miksi Ágnes , Baráth Zsuzsanna , Kerekes György , Péntek Márta , Valikovics Attila , Tamási László , Bereczki Dániel , Szekanecz Zoltán
Published: September 2019

We assessed cognitive function of female rheumatoid arthritis (RA) patients and analyze the determinants, with special focus on cerebrovascular morphology. Sixty methotrexate (MTX-) or biologic-treated RA patients and 39 healthy controls were included in a cross-sectional study. Smoking habits, alcohol intake and time spent in education were recorded. Standard measures were performed to assess cognitive function (Montreal Cognitive Assessment, MOCA; Trail Making Test, TMT; Victoria Stroop Test, VST; Wechsler Adult Intelligence Scale, WAIS; Benton Visual Retention test, BVRT), depression (Beck Depression Inventory, BDI), anxiety (State-Trait Anxiety Inventory, STAIT/S) and general health status (Short Form 36, SF-36). Mean disease activity (28-joint Disease Activity Score, mDAS28; erythrocyte sedimentation rate, mESR; C-reactive protein, mCRP) of the past 12 months was calculated; anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were assessed. Cerebral vascular lesions and atrophy, carotid intima–media thickness (cIMT) and plaques, as well as median cerebral artery (MCA) circulatory reserve capacity (CRC) were assessed by brain magnetic resonance imaging (MRI), carotid ultrasound and transcranial Doppler, respectively. Cognitive function tests showed impairment in RA vs controls. Biologic- vs MTX-treated subgroups differed in TMT-A. Correlations were identified between cognitive function and depression/anxiety tests. WAIS, STAIS, STAIT and BDI correlated with most SF-36 domains. Numerous cognitive tests correlated with age and lower education. Some also correlated with disease duration, mESR and mDAS28. Regarding vascular pathophysiology, cerebral vascular lesions were associated with VST-A, carotid plaques with multiple cognitive parameters, while MCA and CRC with MOCA, BVRT and BDI. RA patients have significant cognitive impairment. Cognitive dysfunction may occur together with or independently of depression/anxiety. Older patients and those with lower education are at higher risk to develop cognitive impairment. Cognitive screening might be a useful tool to identify subgroups to be further investigated for cerebrovascular pathologies.
Portal flow modulation in living donor liver transplantation: review with a focus on splenectomy
Authors: Yoshizumi Tomoharu , Mori Masaki
Published: September 2019

Small-for-size graft (SFSG) syndrome after living donor liver transplantation (LDLT) is the dysfunction of a small graft, characterized by coagulopathy, cholestasis, ascites, and encephalopathy. It is a serious complication of LDLT and usually triggered by excessive portal flow transmitted to the allograft in the postperfusion setting, resulting in sinusoidal congestion and hemorrhage. Portal overflow injures the liver directly through nutrient excess, endothelial activation, and sinusoidal shear stress, and indirectly through arterial vasoconstriction. These conditions may be attenuated with portal flow modulation. Attempts have been made to control excessive portal flow to the SFSG, including simultaneous splenectomy, splenic artery ligation, hemi-portocaval shunt, and pharmacological manipulation, with positive outcomes. Currently, a donor liver is considered a SFSG when the graft-to-recipient weight ratio is less than 0.8 or the ratio of the graft volume to the standard liver volume is less than 40%. A strategy for transplanting SFSG safely into recipients and avoiding extensive surgery in the living donor could effectively address the donor shortage. We review the literature and assess our current knowledge of and strategies for portal flow modulation in LDLT.
Strong Pluralism, Coincident Objects and Haecceitism
Authors: Lenart Karol , Szachniewicz Artur
Published: September 2019

According to strong pluralism, objects distinct by virtue of their modal properties can coincide. The most common objection towards such view invokes the so-called Grounding Problem according to which the strong pluralist needs to explain what the grounds are for supposed modal differences between the coincidents. As recognized in the literature, the failure to provide an answer to the Grounding Problem critically undermines the plausibility of strong pluralism. Moreover, there are strong reasons to believe that strong pluralists cannot provide an explanation of the Grounding Problem. In this paper, we argue that strong pluralism can be motivated independently of the successful answer to the Grounding Problem. In order to achieve that aim, we provide a haecceitistic interpretation of strong pluralism according to which strong pluralism should be read as a position committed to the existence of primitive individuals, i.e., the individuals that have their criteria of individuation independently of their qualitative profiles. That said, we do not aim at defending haecceitism. Instead, our aim is rather modest: we want to provide a new way for the strong pluralist to supplement his view to make it more watertight.
Vocational identity of at-risk emerging adults and its relationship with individual characteristics
Authors: Keijzer Rineke , Admiraal Wilfried , Van der Rijst Roeland , Van Schooten Erik
Published: September 2019

Vocational identity is a prerequisite for enhancing societal inclusion of at-risk emerging adults. School curricula and rebound programs need insights into individual differences of these youths to effectively foster their vocational identity. Identifying three aspects of vocational identity, a questionnaire study among at-risk emerging adults in The Netherlands (N = 996) examined the relationship between clusters of demographic, personality, self-sufficiency, self-competence, and school engagement characteristics and vocational identity performing blockwise entry analyses. Largest proportions of variance were explained by personality traits and, to a lesser extent, motivation, resilience, and valuing school outcome. These malleable characteristics offer opportunities for interventions.
Feasibility Study of the Enhancing Parenting Skills Programme
Authors: Williams Margiad E. , Hoare Zoe , Owen Dawn A. , Hutchings Judy
Published: September 2019

Objectives

This study reports on the feasibility and initial effectiveness of an individually delivered parent programme for parents of young children with behaviour problems. Whilst parenting programmes are known to be effective in reducing behaviour problems, numerous barriers can prevent families from accessing programmes. Individually delivered parent programmes may be more accessible. In the UK, health visitors provide support to all families with a child under 5 years of age and are ideally placed to deliver interventions for child behaviour problems.

Methods

Fifty-eight parents reporting children with behaviour problems were recruited from four areas to intervention (n = 29) and treatment as usual, wait-list control (n = 29) conditions. Feasibility outcomes included recruitment, retention, programme delivery, and satisfaction. Baseline and six-month post-randomisation follow-up measures were collected in parents’ homes and included parent-report measures of child behaviour, parenting skills, and parental mental health as well as an observation of parenting behaviour during a parent-child play task.

Results

Significant changes in child behaviour, lax parenting, and parental mental health were found for the whole sample but there were no significant differences between conditions. Recruitment and retention rates were lower than expected questioning the feasibility of delivering the parent programme as it is in existing services.

Conclusions

This paper provides limited evidence for the feasibility of the Enhancing Parenting Skills programme delivered in existing health services. Further feasibility work, particularly for recruitment and retention, would be needed before conducting a larger study to examine the effectiveness of the programme.
Achieving confidence in trace element analysis for nuclear forensic purposes: ICP-MS measurements using external calibration
Authors: Vesterlund Anna , Ramebäck Henrik
Published: September 2019

In this work, problems arising from performing trace element analysis using inductively coupled plasma—mass spectrometry with low measurement uncertainties are addressed. It is shown that some reference materials certified for massic concentration of lanthanides may have either deviating concentrations or underestimated measurement uncertainties. It is also shown that the choice of methods for sample preparation and linear regression to perform external calibration is affecting the outcome of the measurement results and their uncertainties. The results show that, from the selection of methods investigated in this work, the lowest measurement uncertainties can be achieved by using weighted linear regression to evaluate the calibration function and gravimetric dilutions of samples.
Mechanisms of Microscopic Displacement During Enhanced Oil Recovery in Mixed-Wet Rocks Revealed Using Direct Numerical Simulation
Authors: Akai Takashi , Alhammadi Amer M. , Blunt Martin J. , Bijeljic Branko
Published: September 2019

We demonstrate how to use numerical simulation models directly on micro-CT images to understand the impact of several enhanced oil recovery (EOR) methods on microscopic displacement efficiency. To describe the physics with high-fidelity, we calibrate the model to match a water-flooding experiment conducted on the same rock sample (Akai et al. in Transp Porous Media 127(2):393–414, 2019. 10.1007/s11242-018-1198-8). First we show comparisons of water-flooding processes between the experiment and simulation, focusing on the characteristics of remaining oil after water-flooding in a mixed-wet state. In both the experiment and simulation, oil is mainly present as thin oil layers confined to pore walls. Then, taking this calibrated simulation model as a base case, we examine the application of three EOR processes: low salinity water-flooding, surfactant flooding and polymer flooding. In low salinity water-flooding, the increase in oil recovery was caused by displacement of oil from the centers of pores without leaving oil layers behind. Surfactant flooding gave the best improvement in the recovery factor of 16% by reducing the amount of oil trapped by capillary forces. Polymer flooding indicated improvement in microscopic sweep efficiency at a higher capillary number, while it did not show an improvement at a low capillary number. Overall, this work quantifies the impact of different EOR processes on local displacement efficiency and establishes a workflow based on combining experiment and modeling to design optimal recovery processes.
Pore size distribution, their geometry and connectivity in deeply buried Paleogene Es1 sandstone reservoir, Nanpu Sag, East China
Authors: Kashif Muhammad , Cao Yingchang , Yuan Guanghui , Asif Muhammad , Javed Kamran , Mendez Jose Nicanor , Khan Danish , Miruo Lin
Published: September 2019

The study of pore characteristics is of great importance in reservoir evaluation, especially in deeply buried sandstone. It controls the storage mechanism and reservoir fluid properties of the permeable horizons. The first member of Eocene Shahejie Formation (Es1) sandstone is classified as feldspathic litharenite and lithic arkose. The present research investigates the pore characteristics and reservoir features of the deeply buried sandstone reservoir of Es1 member of Shahejie Formation. The techniques including thin-section petrography, mercury injection capillary pressure (MICP), scanning electron microscopy and laser scanning confocal microscope images were used to demarcate the pores including primary intergranular pores and secondary intergranular, intragranular, dissolution and fracture pores. Mercury injection test and routine core analysis were led to demarcate the pore network characteristics of the studied reservoir. Pore size and pore throat size distribution are acquired from mercury injection test. Porosity values range from 0.5% to 30%, and permeability ranges 0.006–7000 mD. Pore radii of coarse-grained sandstone and fine-grained sandstone range from 0.2 to > 4 µm and 1 nm to 1.60 µm, respectively, by MICP analysis. The mineral composition also plays an important role in protecting the pores with pressure from failure. Fractured sandstone and coarse-grained sandstone consist of large and interconnected pores that enhance the reservoir porosity and permeability, whereas fine-grained sandstone and siltstone consist of numerous pores but not well interconnected, and so they consist of high porosity with low permeability.
Rounding based continuous data discretization for statistical disclosure control
Authors: Senavirathne Navoda , Torra Vicenç
Published: September 2019

“Rounding” can be understood as a way to coarsen continuous data. That is, low level and infrequent values are replaced by high-level and more frequent representative values. This concept is explored as a method for data privacy with techniques like rounding, microaggregation, and generalisation. This concept is explored as a method for data privacy in statistical disclosure control literature with perturbative techniques like rounding, microaggregation and non-perturbative methods like generalisation. Even though “rounding” is well known as a numerical data protection method, it has not been studied in depth or evaluated empirically to the best of our knowledge. This work is motivated by three objectives, (1) to study the alternative methods of obtaining the rounding values to represent a given continuous variable, (2) to empirically evaluate rounding as a data protection technique based on information loss (IL) and disclosure risk (DR), and (3) to analyse the impact of data rounding on machine learning based models. Here, in order to obtain the rounding values we consider discretization methods introduced in the unsupervised machine learning literature along with microaggregation and re-sampling based approaches. The results indicate that microaggregation based techniques are preferred over unsupervised discretization methods due to their fair trade-off between IL and DR.
3D geological modeling of the Upper Cretaceous reservoirs in GPT oil field, Abu Sennan area, Western Desert, Egypt
Authors: Abu-Hashish Mohamed F. , Wanas Hamdalla A. , Madian Emad
Published: September 2019

This study aims to construct 3D geological model using the integration of seismic data with well log data for reservoir characterization and development of the hydrocarbon potentialities of the Upper Cretaceous reservoirs of GPT oil field. 2D seismic data were used to construct the input interpreted horizon grids and fault polygons. The horizon which cut across the wells was used to perform a comprehensive petrophysical analysis. Structural and property modeling was distributed within the constructed 3D grid using different algorithms. The workflow of the 3D geological model comprises mainly the structural and property modeling. The structural model includes fault framework, pillar girding, skeleton girding, horizon modeling and zonation and layering modeling processes. It shows system of different oriented major and minor faults trending in NE–SW direction. The property modeling process was performed to populate the reservoir facies and petrophysical properties (volume of shale (Vsh), fluid saturations (SwandSh), total and effective porosities (ΦtandΦe), net to gross thickness and permeability) as extracted from the available petrophysical analysis of wells inside the structural model. The model represents a detailed zonation and layering configuration for the Khoman, Abu Roash and Bahariya formations. The 3D geological model helps in the field development and evaluates the hydrocarbon potentialities and optimizes production of the study area. It can be also used to predict reservoir shape and size, lateral continuity and degree of interconnectivity of the reservoir, as well as its internal heterogeneity.
Distribution and association of cancer with mortality in end-stage renal disease patients receiving dialysis
Authors: Chinnadurai Rajkumar , Flanagan Emma , Kalra Philip A.
Published: September 2019

Background and aims

Cancer in end-stage renal disease (ESRD) patients is an important comorbidity to be taken into consideration while planning for renal replacement therapy (RRT) options due to its associated increased mortality. This study aims to investigate the natural history and association of cancer with all-cause mortality in an ESRD population receiving dialysis.

Method

The study was conducted on 1271 ESRD patients receiving dialysis between January 2012 and December 2017. A comparative analysis was carried out between 119 patients with and 1152 without cancer history at entry into this study (baseline). A 1:2 (119 cancer: 238 no cancer) propensity score matched sample of 357 patients was also used for analysis. Cox-regression analysis was used to study the strength of the association between cancer and all-cause mortality. Kaplan–Meier (KM) analysis was used to demonstrate the difference in cumulative survival between the groups. A competing risk analysis was also carried out to calculate the probability of competing events (death, transplant and incident cancer).

Results

At baseline, 10.1% of the cohort had a history of cancer (current and past) with the annual incident rate being 1.3%. Urological cancers were the leading site of cancer. The median age of our cohort was 63 years with a predominance of males (63%) and Caucasians (79%). The majority (69%) of the cohort were receiving haemodialysis. 47% had a history of diabetes with 88% being hypertensive. During a median follow-up of 28 months, the proportion of deaths observed was similar between the groups in the matched sample (cancer 49.6 versus no-cancer 52.1%, p value 0.77). In a univariable Cox-regression model, there was no significant association between cancer and all-cause mortality (HR 1.28; 95% CI 0.97–1.67; p = 0.07). The KM estimates showed similar observations in the cumulative survival between the groups (matched sample log-rank, p value 0.85). In competing risk analysis, the cumulative probability of death at 5 years was non-significantly higher in the cancer group (cancer group 64% vs no cancer group 51%, p value 0.16).

Conclusions

In our real-world multi-morbid dialysis cohort of 119 cancer patients, baseline cancer history did not prove to be an independent risk factor for all-cause mortality in the first 5 years of follow-up, suggesting the need for a case-by-case approach in provision of RRT options, including transplantation.
Drug Nanorod-Mediated Intracellular Delivery of microRNA-101 for Self-sensitization via Autophagy Inhibition
Authors: Xin Xiaofei , Du Xiaoqing , Xiao Qingqing , Azevedo Helena S. , He Wei , Yin Lifang
Published: September 2019

Autophagy is closely related to the drug resistance and metastasis in cancer therapy. Nanoparticle-mediated co-delivery of combinatorial therapy with small-molecular drugs and nucleic acids is promising to address drug resistance. Here, a drug-delivering-drug (DDD) platform consisting of anti-tumor-drug nanorods as a vehicle for cytosol delivery of nucleic acid (miR-101) with potent autophagic-inhibition activity is reported for combinatorial therapy. The developed 180-nm nanoplatform, with total drug loading of up to 66%, delivers miR-101 to cancer cells, with threefold increase in intracellular level compared to conventional gene carriers and inhibits the autophagy significantly, along with above twofold reduction in LC3II mRNA and approximately fivefold increase in p62 mRNA over the control demonstrated in the results in vivo. And in turn, the delivery of miR-101 potentiates the drug’s ability to kill cancer cells, with a threefold increase in apoptosis over that of chemotherapy alone. The anti-tumor study in vivo indicates the combined therapy that enables a reduction of 80% in tumor volume and > twofold increase in apoptosis than of the single-drug strategy. In summary, via the carrier-free strategy of DDD, this work provides a delivery platform that can be easily customized to overcome drug resistance and facilitates the delivery of combined therapy of small-molecular drugs and nucleic acids.
Convergence to equilibrium for the solution of the full compressible Navier-Stokes equations
Authors: Zhang Zhifei , Zi Ruizhao
Published: September 2019

We study the convergence to equilibrium for the full compressible Navier-Stokes equations on the torus

\mathbb{T}^{3}

. Under the conditions that both the density
ρ
and the temperature
θ
possess uniform in time positive lower and upper bounds, it is shown that global regular solutions converge to equilibrium with exponential rate. We improve the previous result obtained by Villani in (2009) [28] on two levels: weaker conditions on solutions and faster decay rates.
Cannabis in the Treatment of Traumatic Brain Injury: A Primer for Clinicians
Authors: Grenier Karl , Ponnambalam Fallon , Lee David , Lauwers Rebecca , Bhalerao Shree
Published: September 2019

Our clinical experience at a specialized brain injury clinic suggests that numerous patients with traumatic brain injury (TBI) are using cannabis to alleviate their symptoms. While this patient population often inquires about the evidence of using cannabis post-head injury for the neurosensory, neurocognitive, and neuropsychiatric sequelae, most health professionals have little to no knowledge of this evidence. Given the recent legalization of recreational cannabis in Canada, questions and guidance related to cannabis use following a TBI are likely to become more common. This article reviews the evidence for cannabis use in psychiatric disorders with or without TBI. Overall, we found that the evidence for the use of cannabis among TBI patients is sparse and that patients tend to have little knowledge of the proven benefits and diverse effects of cannabis use. We feel this paper can serve as a stepping stone for future studies that explore the impact of cannabis use in a TBI population and can guide clinicians in advising their patients.
Creating and testing a GCP game in an asynchronous course environment: The game and future plans
Authors: Jones Carolynn T. , Jester Penelope , Croker Jennifer A. , Fritter Jessica , Roche Cathy , Wallace Brian , Westfall Andrew O. , Redden David T. , Willig James
Published: September 2019

Introduction:

The National Institute of Health has mandated good clinical practice (GCP) training for all clinical research investigators and professionals. We developed a GCP game using the Kaizen-Education platform. The GCP Kaizen game was designed to help clinical research professionals immerse themselves into applying International Conference on Harmonization GCP (R2) guidelines in the clinical research setting through case-based questions.

Methods:

Students were invited to participate in the GCP Kaizen game as part of their 100% online academic Masters during the Spring 2019 semester. The structure of the game consisted of 75 original multiple choice and 25 repeated questions stemming from fictitious vignettes that were distributed across 10 weeks. Each question presented a teachable rationale after the answers were submitted. At the end of the game, a satisfaction survey was issued to collect player satisfaction data on the game platform, content, experience as well as perceptions of GCP learning and future GCP concept application.

Results:

There were 71 total players who participated and answered at least one question. Of those, 53 (75%) answered all 100 questions. The game had a high Cronbach’s alpha, and item analyses provided information on question quality, thus assisting us in future quality edits before re-testing and wider dissemination.

Conclusions:

The GCP Kaizen game provides an alternative method for mandated GCP training using principles of gamification. It proved to be a reliable and an effective educational method with high player satisfaction.
Respiratory viral surveillance of healthcare personnel and patients at an adult long-term care facility
Authors: O’Neil Caroline A. , Kim Lindsay , Prill Mila M. , Talbot H. Keipp , Whitaker Brett , Sakthivel Senthilkumar K. , Zhang Yange , Zhang Jing , Tong Suxiang , Stone Nimalie , Garg Shikha , Gerber Susan I. , Babcock Hilary M.
Published: September 2019

We conducted active surveillance of acute respiratory viral infections (ARIs) among residents and healthcare personnel (HCP) at a long-term care facility during the 2015–2016 respiratory illness season. ARIs were observed among both HCP and patients, highlighting the importance of including HCP in surveillance programs.
Is carrot consumption associated with a decreased risk of lung cancer? A meta-analysis of observational studies
Authors: Xu Hongbin , Jiang Heng , Yang Wei , Song Fujian , Yan Shijiao , Wang Chao , Fu Wenning , Li Hui , Lyu Chuanzhu , Gan Yong , Lu Zuxun
Published: September 2019

Findings of epidemiological studies regarding the association between carrot consumption and lung cancer risk remain inconsistent. The present study aimed to summarise the current epidemiological evidence concerning carrot intake and lung cancer risk with a meta-analysis. We conducted a meta-analysis of case–control and prospective cohort studies, and searched PubMed and Embase databases from their inception to April 2018 without restriction by language. We also reviewed reference lists from included articles. Prospective cohort or case–control studies reporting OR or relative risk with the corresponding 95 % CI of the risk lung cancer for the highest compared with the lowest category of carrot intake. A total of eighteen eligible studies (seventeen case–control studies and one prospective cohort study) were included, involving 202 969 individuals and 5517 patients with lung cancer. The pooled OR of eighteen studies for lung cancer was 0·58 (95 % CI 0·45, 0·74) by comparing the highest category with the lowest category of carrot consumption. Based on subgroup analyses for the types of lung cancer, we pooled that squamous cell carcinoma (OR 0·52, 95 % CI 0·19, 1·45), small-cell carcinoma (OR 0·43, 95 % CI 0·12, 1·59), adenocarcinoma (OR 0·34, 95 % CI 0·15, 0·79), large-cell carcinoma (OR 0·40, 95 % CI 0·10, 1·57), squamous and small-cell carcinoma (OR 0·85, 95 % CI 0·45, 1·62), adenocarcinoma and large-cell carcinoma (OR 0·20, 95 % CI 0·02, 1·70) and mixed types (OR 0·61, 95 % CI 0·46, 0·81). Exclusion of any single study did not materially alter the pooled OR. Integrated epidemiological evidence from observational studies supported the hypothesis that carrot consumption may decrease the risk of lung cancer, especially for adenocarcinoma.
Zaha Hadid’s Center for Contemporary Art and the perils of new museum architecture
Authors: Merrill Elizabeth M.
Published: September 2019

As epitomised in the works of Renzo Piano, Frank Gehry, and Daniel Libeskind, the ‘new museum’ of art claims its own architectural typology. With asymmetrical silhouettes, gallery spaces that eschew the much derided ‘white cube’, and cleverly conceived circulation systems, the new museum has been heralded as revolutionising the display of art. Yet its function extends beyond the display and conservation of art. The new art museum is conceived as a multifaceted cultural centre – a public forum – where art and culture are democratised, and families, scholars, students, tourists, and teachers come together. At the same time, the new museum competes with other entertainment venues on a commercial level. As a cultural factory replete with an ambitious programme of temporary exhibitions, media facilities, restaurants, and shops, the new museum emphasises consumption as much as it does contemplation. In fact, the array of non-artrelated diversions contained in the new museum is often more important to the institution’s success than the art itself.
“Glass Pearls” in Clamshells Point to Ancient Meteor Impact
Authors: Crowell Rachel
Published: September 2019

Research suggests that the spherical structures, smaller than grains of sand, may be microtektites, but additional investigations are needed to verify their identity.
Therapeutic targeting of the PI4K2A/PKR lysosome network is critical for misfolded protein clearance and survival in cancer cells
Authors: Pataer Apar , Ozpolat Bulent , Shao RuPing , Cashman Neil R. , Plotkin Steven S. , Samuel Charles E. , Lin Steven H. , Kabil Nashwa N. , Wang Jing , Majidi Mourad , Fang Bingliang , Roth Jack A. , Vaporciyan Ara A. , Wistuba Ignacio I. , Hung Mien-Chie , Swisher Stephen G.
Published: September 2019

The role of RNA-dependent protein kinase R (PKR) and its association with misfolded protein expression in cancer cells are unclear. Herein we report that PKR regulates misfolded protein clearance by preventing it release through exosomes and promoting lysosomal degradation of misfolded prion proteins in cancer cells. We demonstrated that PKR contributes to the lysosome function and regulates misfolded prion protein clearance. We hypothesized that PKR-associated lysosome function is critical for cancer but not normal cell survival, representing an effective approach for highly targeted cancer therapy. In screening a compound library, we identified two PKR-associated compounds 1 and 2 (Pac 1 and 2) did not affect normal cells but selectively induced cell death in cancer cells depending on their PKR expression status. Pac 1 significantly inhibited the growth of human lung and breast xenograft tumors in mice with no toxicity. Pac 1 binds to PI4K2A and disrupts the PKR/PI4K2A-associated lysosome complex, contributing to destabilization of cancer cell lysosomes and triggering cell death. We observed that PKR and PI4K2A play significant prognostic roles in breast cancer patients. These results demonstrate that targeting of a PI4K2A/PKR lysosome complex may be an effective approach for cancer therapy.
FRQ-CK1 interaction determines the period of circadian rhythms in Neurospora
Authors: Liu Xiao , Chen Ahai , Caicedo-Casso Angélica , Cui Guofei , Du Mingjian , He Qun , Lim Sookkyung , Kim Hang J. , Hong Christian I. , Liu Yi
Published: September 2019

Circadian clock mechanisms have been extensively investigated but the main rate-limiting step that determines circadian period remains unclear. Formation of a stable complex between clock proteins and CK1 is a conserved feature in eukaryotic circadian mechanisms. Here we show that the FRQ-CK1 interaction, but not FRQ stability, correlates with circadian period in Neurospora circadian clock mutants. Mutations that specifically affect the FRQ-CK1 interaction lead to severe alterations in circadian period. The FRQ-CK1 interaction has two roles in the circadian negative feedback loop. First, it determines the FRQ phosphorylation profile, which regulates FRQ stability and also feeds back to either promote or reduce the interaction itself. Second, it determines the efficiency of circadian negative feedback process by mediating FRQ-dependent WC phosphorylation. Our conclusions are further supported by mathematical modeling and in silico experiments. Together, these results suggest that the FRQ-CK1 interaction is a major rate-limiting step in circadian period determination.
Microscale residual stresses in additively manufactured stainless steel
Authors: Chen Wen , Voisin Thomas , Zhang Yin , Forien Jean-Baptiste , Spadaccini Christopher M. , McDowell David L. , Zhu Ting , Wang Y. Morris
Published: September 2019

Additively manufactured (AM) metallic materials commonly possess substantial microscale internal stresses that manifest as intergranular and intragranular residual stresses. However, the impact of these residual stresses on the mechanical behaviour of AM materials remains unexplored. Here we combine in situ synchrotron X-ray diffraction experiments and computational modelling to quantify the lattice strains in different families of grains with specific orientations and associated intergranular residual stresses in an AM 316L stainless steel under uniaxial tension. We measure pronounced tension–compression asymmetries in yield strength and work hardening for as-printed stainless steel, and show they are associated with back stresses originating from heterogeneous dislocation distributions and resultant intragranular residual stresses. We further report that heat treatment relieves microscale residual stresses, thereby reducing the tension–compression asymmetries and altering work-hardening behaviour. This work establishes the mechanistic connections between the microscale residual stresses and mechanical behaviour of AM stainless steel.
Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells
Authors: Hernando-Herraez Irene , Evano Brendan , Stubbs Thomas , Commere Pierre-Henri , Jan Bonder Marc , Clark Stephen , Andrews Simon , Tajbakhsh Shahragim , Reik Wolf
Published: September 2019

Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions. We find context-dependent alterations of DNA methylation in aged stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is associated with the degradation of coherent transcriptional networks during stem cell ageing. Furthermore, our observations also shed light on the mechanisms underlying the DNA methylation clock.
Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology
Authors: Takeda Andrew J. , Maher Timothy J. , Zhang Yu , Lanahan Stephen M. , Bucklin Molly L. , Compton Susan R. , Tyler Paul M. , Comrie William A. , Matsuda Makoto , Olivier Kenneth N. , Pittaluga Stefania , McElwee Joshua J. , Long Priel Debra A. , Kuhns Douglas B. , Williams Roger L. , Mustillo Peter J. , Wymann Matthias P. , Koneti Rao V. , Lucas Carrie L.
Published: September 2019

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations inPIK3CGresulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-dependent manner upon TLR stimulation.Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.
MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates
Authors: Aron Badin Romina , Bugi Aurore , Williams Susannah , Vadori Marta , Michael Marie , Jan Caroline , Nassi Alberto , Lecourtois Sophie , Blancher Antoine , Cozzi Emanuele , Hantraye Philippe , Perrier Anselme L.
Published: September 2019

Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington’s disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain.
Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore
Authors: Urbani Andrea , Giorgio Valentina , Carrer Andrea , Franchin Cinzia , Arrigoni Giorgio , Jiko Chimari , Abe Kazuhiro , Maeda Shintaro , Shinzawa-Itoh Kyoko , Bogers Janna F. M. , McMillan Duncan G. G. , Gerle Christoph , Szabò Ildikò , Bernardi Paolo
Published: September 2019

The molecular identity of the mitochondrial megachannel (MMC)/permeability transition pore (PTP), a key effector of cell death, remains controversial. By combining highly purified, fully active bovine F-ATP synthase with preformed liposomes we show that Ca2+ dissipates the H+ gradient generated by ATP hydrolysis. After incorporation of the same preparation into planar lipid bilayers Ca2+ elicits currents matching those of the MMC/PTP. Currents were fully reversible, were stabilized by benzodiazepine 423, a ligand of the OSCP subunit of F-ATP synthase that activates the MMC/PTP, and were inhibited by Mg2+ and adenine nucleotides, which also inhibit the PTP. Channel activity was insensitive to inhibitors of the adenine nucleotide translocase (ANT) and of the voltage-dependent anion channel (VDAC). Native gel-purified oligomers and dimers, but not monomers, gave rise to channel activity. These findings resolve the long-standing mystery of the MMC/PTP and demonstrate that Ca2+ can transform the energy-conserving F-ATP synthase into an energy-dissipating device.
Damage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut
Authors: Patel Parthive H. , Pénalva Clothilde , Kardorff Michael , Roca Marianne , Pavlović Bojana , Thiel Anja , Teleman Aurelio A. , Edgar Bruce A.
Published: September 2019

Epithelia are exposed to diverse types of stress and damage from pathogens and the environment, and respond by regenerating. Yet, the proximal mechanisms that sense epithelial damage remain poorly understood. Here we report that p38 signaling is activated in adult Drosophila midgut enterocytes in response to diverse stresses including pathogenic bacterial infection and chemical and mechanical insult. Two upstream kinases, Ask1 and Licorne (MKK3), are required for p38 activation following infection, oxidative stress, detergent exposure and wounding. Ask1-p38 signaling in enterocytes is required upon infection to promote full intestinal stem cell (ISC) activation and regeneration, partly through Upd3/Jak-Stat signaling. Furthermore, reactive oxygen species (ROS) produced by the NADPH oxidase Nox in enterocytes, are required for p38 activation in enterocytes following infection or wounding, and for ISC activation upon infection or detergent exposure. We propose that Nox-ROS-Ask1-MKK3-p38 signaling in enterocytes integrates multiple different stresses to induce regeneration.
The role of highly oxygenated organic molecules in the Boreal aerosol-cloud-climate system
Authors: Roldin Pontus , Ehn Mikael , Kurtén Theo , Olenius Tinja , Rissanen Matti P. , Sarnela Nina , Elm Jonas , Rantala Pekka , Hao Liqing , Hyttinen Noora , Heikkinen Liine , Worsnop Douglas R. , Pichelstorfer Lukas , Xavier Carlton , Clusius Petri , Öström Emilie , Petäjä Tuukka , Kulmala Markku , Vehkamäki Hanna , Virtanen Annele , Riipinen Ilona , Boy Michael
Published: September 2019

Over Boreal regions, monoterpenes emitted from the forest are the main precursors for secondary organic aerosol (SOA) formation and the primary driver of the growth of new aerosol particles to climatically important cloud condensation nuclei (CCN). Autoxidation of monoterpenes leads to rapid formation of Highly Oxygenated organic Molecules (HOM). We have developed the first model with near-explicit representation of atmospheric new particle formation (NPF) and HOM formation. The model can reproduce the observed NPF, HOM gas-phase composition and SOA formation over the Boreal forest. During the spring, HOM SOA formation increases the CCN concentration by ~10 % and causes a direct aerosol radiative forcing of −0.10 W/m2. In contrast, NPF reduces the number of CCN at updraft velocities < 0.2 m/s, and causes a direct aerosol radiative forcing of +0.15 W/m2. Hence, while HOM SOA contributes to climate cooling, NPF can result in climate warming over the Boreal forest.
Massive computational acceleration by using neural networks to emulate mechanism-based biological models
Authors: Wang Shangying , Fan Kai , Luo Nan , Cao Yangxiaolu , Wu Feilun , Zhang Carolyn , Heller Katherine A. , You Lingchong
Published: September 2019

For many biological applications, exploration of the massive parametric space of a mechanism-based model can impose a prohibitive computational demand. To overcome this limitation, we present a framework to improve computational efficiency by orders of magnitude. The key concept is to train a neural network using a limited number of simulations generated by a mechanistic model. This number is small enough such that the simulations can be completed in a short time frame but large enough to enable reliable training. The trained neural network can then be used to explore a much larger parametric space. We demonstrate this notion by training neural networks to predict pattern formation and stochastic gene expression. We further demonstrate that using an ensemble of neural networks enables the self-contained evaluation of the quality of each prediction. Our work can be a platform for fast parametric space screening of biological models with user defined objectives.
R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon
Authors: Harnack Christine , Berger Hilmar , Antanaviciute Agne , Vidal Ramon , Sauer Sascha , Simmons Alison , Meyer Thomas F. , Sigal Michael
Published: September 2019

The colonic epithelial turnover is driven by crypt-base stem cells that express the R-spondin receptor Lgr5. Signals that regulate epithelial regeneration upon stem cell injury are largely unknown. Here, we explore the dynamics of Wnt signaling in the colon. We identify two populations of cells with active Wnt signaling: highly proliferative Lgr5+/Axin2+ cells, as well as secretory Lgr5−/Axin2+ cells. Upon Lgr5+ cell depletion, these cells are recruited to contribute to crypt regeneration. Chemical injury induced by DSS leads to a loss of both Lgr5+ cells and Axin2+ cells and epithelial regeneration is driven by Axin2− cells, including differentiated Krt20+ surface enterocytes. Regeneration requires stromal Rspo3, which is present at increased levels upon injury and reprograms Lgr5− but Lgr4+ differentiated cells. In contrast, depletion of stromal Rspo3 impairs crypt regeneration, even upon mild injury. We demonstrate that Rspo3 is essential for epithelial repair via induction of Wnt signaling in differentiated cells.
Low CO2 levels of the entire Pleistocene epoch
Authors: Da Jiawei , Zhang Yi Ge , Li Gen , Meng Xianqiang , Ji Junfeng
Published: September 2019

Quantifying ancient atmosphericpCO2provides valuable insights into the interplay between greenhouse gases and global climate. Beyond the 800-ky history uncovered by ice cores, discrepancies in both the trend and magnitude ofpCO2changes remain among different proxy-derived results. The traditional paleosolpCO2paleobarometer suffers from largely unconstrained soil-respired CO2concentration (S(z)). Using finely disseminated carbonates precipitated in paleosols from the Chinese Loess Plateau, here we identified that theirS(z) can be quantitatively constrained by soil magnetic susceptibility. Based on this approach, we reconstructedpCO2during 2.6–0.9 Ma, which documents overall lowpCO2levels (<300 ppm) comparable with ice core records, indicating that the Earth system has operated under late PleistocenepCO2levels for an extended period. ThepCO2levels do not show statistically significant differences across the mid-Pleistocene Transition (ca. 1.2–0.8 Ma), suggesting that CO2is probably not the driver of this important climate change event.
Structural color three-dimensional printing by shrinking photonic crystals
Authors: Liu Yejing , Wang Hao , Ho Jinfa , Ng Ryan C. , Ng Ray J. H. , Hall-Chen Valerian H. , Koay Eleen H. H. , Dong Zhaogang , Liu Hailong , Qiu Cheng-Wei , Greer Julia R. , Yang Joel K. W.
Published: September 2019

The coloration of some butterflies, Pachyrhynchus weevils, and many chameleons are notable examples of natural organisms employing photonic crystals to produce colorful patterns. Despite advances in nanotechnology, we still lack the ability to print arbitrary colors and shapes in all three dimensions at this microscopic length scale. Here, we introduce a heat-shrinking method to produce 3D-printed photonic crystals with a 5x reduction in lattice constants, achieving sub-100-nm features with a full range of colors. With these lattice structures as 3D color volumetric elements, we printed 3D microscopic scale objects, including the first multi-color microscopic model of the Eiffel Tower measuring only 39 µm tall with a color pixel size of 1.45 µm. The technology to print 3D structures in color at the microscopic scale promises the direct patterning and integration of spectrally selective devices, such as photonic crystal-based color filters, onto free-form optical elements and curved surfaces.
Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling
Authors: Li Nan , Wang Yifan , Neri Shinya , Zhen Yuanli , Fong Lon Wolf R. , Qiao Yawei , Li Xu , Chen Zhen , Stephan Clifford , Deng Weiye , Ye Rui , Jiang Wen , Zhang Shuxing , Yu Yonghao , Hung Mien-Chie , Chen Junjie , Lin Steven H.
Published: September 2019

The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.