bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Predictive Model for Mortality in Hospitalized Patients With COVID-19
Authors: Niu Yuanyuan , Zhan Zan , Li Jianfeng , Shui Wei , Wang Changfeng , Xing Yanli , Zhang Changran
Published: January 2021

Introduction:

Early identification of patients with novel corona virus disease 2019 (COVID-19) who may be at high mortality risk is of great importance.

Methods:

In this retrospective study, we included all patients with COVID-19 at Huanggang Central Hospital from January 23 to March 5, 2020. Data on clinical characteristics and outcomes were compared between survivors and nonsurvivors. Univariable and multivariable logistic regression were used to explore risk factors associated with in-hospital death. A nomogram was established based on the risk factors selected by multivariable analysis.

Results:

A total of 150 patients were enrolled, including 31 nonsurvivors and 119 survivors. The multivariable logistic analysis indicated that increasing the odds of in-hospital death associated with higher Sequential Organ Failure Assessment score (odds ratio [OR], 3.077; 95% confidence interval [CI]: 1.848-5.122; P < 0.001), diabetes (OR, 10.474; 95% CI: 1.554-70.617; P = 0.016), and lactate dehydrogenase greater than 245 U/L (OR, 13.169; 95% CI: 2.934-59.105; P = 0.001) on admission. A nomogram was established based on the results of the multivariable analysis. The AUC of the nomogram was 0.970 (95% CI: 0.947-0.992), showing good accuracy in predicting the risk of in-hospital death.

Conclusions:

This finding would facilitate the early identification of patients with COVID-19 who have a high-risk for fatal outcome.
Applications of Robotics, Artificial Intelligence, and Digital Technologies During COVID-19: A Review
Authors: Zhao Zhuo , Ma Yangmyung , Mushtaq Adeel , Rajper Abdul M. Azam , Shehab Mahmoud , Heybourne Annabel , Song Wenzhan , Ren Hongliang , Tse Zion Tsz Ho
Published: January 2021

Many countries have enacted a quick response to the unexpected coronavirus disease 2019 (COVID-19) pandemic by using existing technologies. For example, robotics, artificial intelligence, and digital technology have been deployed in hospitals and public areas for maintaining social distancing, reducing person-to-person contact, enabling rapid diagnosis, tracking virus spread, and providing sanitation. In this study, 163 news articles and scientific reports on COVID-19-related technology adoption were screened, shortlisted, categorized by application scenario, and reviewed for functionality. Technologies related to robots, artificial intelligence, and digital technology were selected from the pool of candidates, yielding a total of 50 applications for review. Each case was analyzed for its engineering characteristics and potential impact on the COVID-19 pandemic. Finally, challenges and future directions regarding the response to this pandemic and future pandemics were summarized and discussed.
An analysis of funding patterns in development assistance for mental health: who, when, what, and where
Authors: Gribble Rebecca S. F. , Liese Bernhard H. , Wickremsinhe Marisha N.
Published: January 2021

Background

Mental health has recently gained increasing attention on global health and development agendas, including calls for an increase in international funding. Few studies have previously characterized official development assistance for mental health (DAMH) in a nuanced and differentiated manner in order to support future funding efforts.

Methods

Data from the Organisation for Economic Cooperation and Development Creditor Reporting System were obtained through keyword searches. Projects were manually reviewed and categorized into projects dedicated entirely to mental health and projects that mention mental health (as one of many aims). Analysis of donor, recipient, and sector characteristics within and between categories was undertaken cumulatively and yearly.

Findings

Between the two categories of official DAMH defined, characteristics differed in terms of largest donors, largest recipient countries and territories, and sector classification. However, across both categories there were clear and consistent findings: the top donors accounted for over 80% of all funding identified; the top recipients were predominantly conflict-affected countries and territories, or were receiving nations for conflict-affect refugees; and sector classification demonstrated shifting international development priorities and political drivers.

Conclusion

Across DAMH, significant amounts of funding are directed toward conflict settings and relevant emergency response by a small majority of donors. Our analysis demonstrated that, within minimal international assistance for mental health overall, patterns of donor, recipient, and sector characteristics favor emergency conflict-affected settings. Calls for increased funding should be grounded in understanding of funding drivers and directed toward both emergency and general health settings.
Magnetic field annihilation and charged particle acceleration in ultra-relativistic laser plasmas
Authors: Gu Yan-Jun , Bulanov Sergei V.
Published: January 2021

Magnetic reconnection driven by laser plasma interactions attracts great interests in the recent decades. Motivated by the rapid development of the laser technology, the ultra strong magnetic field generated by the laser-plasma accelerated electrons provides unique environment to investigate the relativistic magnetic field annihilation and reconnection. It opens a new way for understanding relativistic regimes of fast magnetic field dissipation particularly in space plasmas, where the large scale magnetic field energy is converted to the energy of the nonthermal charged particles. Here we review the recent results in relativistic magnetic reconnection based on the laser and collisionless plasma interactions. The basic mechanism and the theoretical model are discussed. Several proposed experimental setups for relativistic reconnection research are presented.
Mandrel degradation model of combined fast and slow processes
Authors: Zhu Yu , Liu Zheng , Yu Famin , Chen Qiang , Feng Wei , Zhang Zhanwen , Wang Zhigang
Published: January 2021

In this paper, we report the study of degradation for a kind of ideal mandrel material called poly-α-methylstyrene based on theoretical and experimental methods. First-principles calculations reveal two types of process: depolymerization and hydrogen-transfer-induced chain scission. The energy barrier for the former (0.68–0.82 eV) is smaller than that for most of the latter (1.39–4.23 eV). More importantly, reaction rates suggest that the former is fast whereas the latter is mostly slow, which can result in a difference of 5–31 orders of magnitude at 550 K. Furthermore, a thermogravimetric experiment shows that the activation energy of 2.53 eV for degradation is between those of fast and slow processes, corresponding to the theoretical average value of multiple reaction paths. Thus, a mandrel degradation model combining fast and slow processes is established at the atomic level. Our work provides a direction for research into the key technology of target fabrication in inertial confinement fusion.
THE ORDER OF REFLECTION
Authors: AGUILERA JUAN P.
Published: January 2021

Extending Aanderaa’s classical result that
$\pi ^{1}_{1} < \sigma ^{1}_{1}$
, we determine the order between any two patterns of iterated
$\Sigma ^{1}_{1}$
- and
$\Pi ^{1}_{1}$
-reflection on ordinals. We show that this order of linear reflection is a prewellordering of length
$\omega ^{\omega }$
. This requires considering the relationship between linear and some non-linear reflection patterns, such as
$\sigma \wedge \pi $
, the pattern of simultaneous
$\Sigma ^{1}_{1}$
- and
$\Pi ^{1}_{1}$
-reflection. The proofs involve linking the lengths of
$\alpha $
-recursive wellorderings to various forms of stability and reflection properties satisfied by ordinals
$\alpha $
within standard and non-standard models of set theory.
JUDICIAL EXPROPRIATION IN INTERNATIONAL INVESTMENT LAW
Authors: Prislan Vid
Published: January 2021

This article examines the notion of judicial takings in international law and its reflection in the practice of investment tribunals. It takes stock of the already significant body of arbitral jurisprudence dealing with expropriation claims grounded in, or relating to, the acts or omissions of courts, with a view to developing a coherent theory of judicial expropriations. It is suggested that, due to the courts’ specific role in the determination of the underlying proprietary rights that are the very object of international legal protection, judicial measures warrant different conceptual treatment from measures by other State organs. Traditional approaches to expropriation analysis do not take this sufficiently into account and therefore do not provide adequate tools for distinguishing legitimate judicial measures from undue interferences with investors’ rights. It is argued that a sui generis approach is hence needed: where proprietary rights are primarily affected by the impugned judicial action, it is first necessary to determine whether such action is itself wrongful under international law, for only then can it be treated as an act of expropriation. However, the proper analytical approach will ultimately depend on the circumstances of each case and traditional approaches, such as the sole effects doctrine, may still be appropriate where the judicial injury actually flows from wrongful legislative or executive conduct.
Interruptions: Affective futures and uncanny presences atGiemaš, Finnmark
Authors: Lien Marianne Elisabeth
Published: January 2021

This paper concerns affective relations and unexpected interruptions as the planned expansion of an extractive open-pit mining site gathers momentum. The site is a mountain in Varanger, North Norway, criss-crossed by a sand-coloured meshwork of roads that are part of the current infrastructure of a quartzite quarry. Recently purchased by Chinese investors, the mining company Elkem plans a massive expansion of the operations, which will interrupt a wide range of practices and projects, including the migratory movement of reindeer, as well as their grazing patterns. Known asGiemašamongst Sámi speakers, the mountain is also alluded to as a site of other powers, manifesting as unexpected accidents. In this article, I explore how the planned expansion evokes this contested site as more than a singular mountain, and how divergent epistemic formations interrupt the making of extractive resources in multiple ways.
Control of Teleoperation Systems in the Presence of Varying Transmission Delay, Non-passive Interaction Forces, and Model Uncertainty
Authors: Ebrahimi Bavili Robab , Akbari Ahmad , Mahboobi Esfanjani Reza
Published: January 2021

This paper addresses robust stability and position tracking problems in teleoperation systems subject to varying delay in the communication medium, uncertainties in the models of manipulators, and non-passive interaction forces in the terminations. Fixed-structure nonlinear control law is developed based on the notion of Interconnection and Damping Assignment Passivity-Based Control (IDA-PBC) scheme. Then, utilizing the Lyapunov–Krasovskii theorem, sufficient conditions are derived in terms of Linear Matrix Inequalities (LMIs) to tune the controller parameters. Differently from literature, the objectives are achieved without requirement for any passive parts in the model of interaction forces. Comparative simulations and experimental results demonstrate the applicability and superiority of the proposed method.
Dynamic Modeling and Optimal Control of a Novel Microswimmer with Gimbal Based Disks
Authors: Nickandish Ali , Nejat Pishkenari Hossein
Published: January 2021

We have introduced a new low-Reynolds-number microrobot with high 3D maneuverability. Our novel proposed microrobot has a higher rank of the controllability matrix with respect to the previous microswimmers which makes it capable of performing complex motions in space. In this study, governing equations of the microswimmer’s motion have been derived and simulated. Subsequently, we have proposed a cascade optimal control technique to control the swimmer trajectory. In the proposed control scheme, the actuation is provided in a way that an exponential stability on the system trajectory error as well as minimum fluctuations of control signals are achieved.
A cellular automaton-based model of ship traffic flow in busy waterways
Authors: Qi Le , Ji Yuanyuan , Balling Robert , Xu Wenhai
Published: January 2021

In busy waterways, spatial-temporal discretisation, safe distance and collision avoidance timing are three of the core components of ship traffic flow modelling based on cellular automata. However, these components are difficult to determine in ship traffic simulations because the size, operation and manoeuvrability vary between ships. To solve these problems, a novel traffic flow model is proposed. Firstly, a spatial-temporal discretisation method based on the concept of a standard ship is presented. Secondly, the update rules for ships’ motion are built by considering safe distance and collision avoidance timing, in which ship operation and manoeuvrability are thoroughly considered. We demonstrate the effectiveness of our model, which is implemented through simulating ship traffic flow in a waterway of the Yangtze River, China. By comparing the results with actual observed ship traffic data, our model shows that the behaviours and the characteristics of ships’ motions can be represented very well, which also can be further used to reveal the mechanism that affects the efficiency and safety of ship traffic.
Predictors of professional commitment for Chinese new generation cohorts in a sample of seafaring officers
Authors: Jia Xiaohui
Published: January 2021

This study aims to examine the predictors of professional commitment of the Chinese new generation, divided into post-80s and post-90s cohorts. A questionnaire survey was employed to collect data from Chinese seafaring officers of these cohorts. The results through hierarchical regression analysis present the two cohorts as having both similar and different predictors. The main difference is that company management and policies positively drive the post-80s cohort to work at sea but not the post-90s. The main similarity is that the work itself is the most important predictor for both cohorts. This study contributes to helping maritime companies to estimate the possibility of Chinese new generation officers quitting sea jobs and can be of value to both managers and authorities as they seek to comprehend the generational dynamic features to better cope with the problem of shortage of younger qualified officers.
Abundance and habitat associations of the globally endangered Giant NuthatchSitta magnain Southern Shan State, Myanmar
Authors: HTIKE THURA SOE MIN , ROUND PHILIP D. , SAVINI TOMMASO , TANTIPISANUH NARUEMON , NGOPRASERT DUSIT , GALE GEORGE A.
Published: January 2021

The Giant NuthatchSitta magnais a globally endangered species presumed to be declining, for which basic parameters of population and habitat associations remain largely unquantified. We focused on Myanmar, which potentially constitutes ~30% of the Giant Nuthatch global range and yet lacks recently published records. Our objectives were to survey key potential Giant Nuthatch localities in, or near, historical locations in Southern Shan State, assess its population status, and quantify habitat associations. Preliminary locality surveys focused on four potential forest patches, assessed by walking approximately 40 km of trails. The species was found in only one of the four localities (Mt. Ashae Myin Anauk Myin [AMAM]), an 18 km2forest patch in Pindaya and Lawksawk Townships. Here, point counts and vegetation surveys were conducted at 46 locations using an adaptive cluster sampling design. N-mixture models were applied to estimate abundance and identify habitat variables correlated with abundance and detection probability. We also conducted a brief quantitative assessment of tree use and foraging behaviour during one breeding season. Our population estimate for AMAM was 56 individuals (95% CI 25–128) based on a sampled area of 3.25 km2. Abundance was positively associated with larger diameter trees, a higher proportion of pine and oak combined based on their total basal area, and negatively correlated with elevation. Foraging data suggested that Giant Nuthatch preferred to feed on trunks and large branches of larger diameter pines and Fagaceae trees. Based on the estimated population size, AMAM is probably a globally significant locality for Giant Nuthatch and the only confirmed locality in Myanmar since 1992 but is threatened by agricultural expansion. More detailed understanding of the habitat requirements of this endangered species and an assessment of its distribution at the landscape-level, especially in Shan State, would increase the precision of global population estimates.
Sustainability and wellbeing: the dynamic relationship between subjective wellbeing and sustainability indicators
Authors: Qasim Mubashir , Grimes Arthur
Published: January 2021

We analyse the relationship between individuals' subjective wellbeing (SWB) and measures of their country's sustainability. SWB data are sourced from the World Values Survey; sustainability is measured by ecological footprint (EF) and by components of the World Bank's adjusted net savings (ANS) series. ANS, a measure of weak sustainability, represents changes in a country's capital stock including financial, physical, human and natural capital. We show that an increase in strong sustainability, measured by EF and by ANS's natural capital component, is associated with reductions in SWB over the next decade followed by a rebound in SWB over the subsequent decade. We show also that the perfect substitutability assumptions on which ANS is calculated do not hold. Our findings highlight an important political challenge: governments that run sustainable policies may decrease the near-term wellbeing of citizens. This can reduce government's short-term popularity even though the improved sustainability may raise future wellbeing.
How does air pollution affect housing rental prices in Chile? An economic assessment of PM2.5 concentration across Chilean communes
Authors: Gómez Katty , Iturra Victor
Published: January 2021

This paper addresses a serious environmental concern in Chile: PM2.5 concentration, a health threat especially affecting the population living in the central and southern communes of Chile. Using housing data for 312 spatial units, along with interpolation techniques to predict air pollution for communes with missing information, we find that, on average, 1 μg/m3 increase in PM2.5 produces a decrease of 4.1 per cent in housing rental prices. These estimates also show an important upward bias in the estimated coefficient when the endogeneity of air pollution is not addressed. An average Chilean household would be willing to pay US$12.31 per month for a one-unit reduction in PM2.5 concentration. Similar monetary values have been found in previous studies for both México and Chile. As with PM2.5 concentration, the average marginal willingness to pay exhibits marked differences across communes. From these results, the study addresses some policy implications and proposes avenues for future research.
ON A CERTAIN LOCAL IDENTITY FOR LAPID–MAO’S CONJECTURE AND FORMAL DEGREE CONJECTURE : EVEN UNITARY GROUP CASE
Authors: Morimoto Kazuki
Published: January 2021

Lapid and Mao formulated a conjecture on an explicit formula of Whittaker–Fourier coefficients of automorphic forms on quasi-split reductive groups and metaplectic groups as an analogue of the Ichino–Ikeda conjecture. They also showed that this conjecture is reduced to a certain local identity in the case of unitary groups. In this article, we study the even unitary-group case. Indeed, we prove this local identity over p-adic fields. Further, we prove an equivalence between this local identity and a refined formal degree conjecture over any local field of characteristic zero. As a consequence, we prove a refined formal degree conjecture over p-adic fields and get an explicit formula of Whittaker–Fourier coefficients under certain assumptions.
LOSIK CLASSES FOR CODIMENSION-ONE FOLIATIONS
Authors: Bazaikin Yaroslav V. , Galaev Anton S.
Published: January 2021

Following Losik’s approach to Gelfand’s formal geometry, certain characteristic classes for codimension-one foliations coming from the Gelfand-Fuchs cohomology are considered. Sufficient conditions for nontriviality in terms of dynamical properties of generators of the holonomy groups are found. The nontriviality for the Reeb foliations is shown; this is in contrast with some classical theorems on the Godbillon-Vey class; for example, the Mizutani-Morita-Tsuboi theorem about triviality of the Godbillon-Vey class of foliations almost without holonomy is not true for the classes under consideration. It is shown that the considered classes are trivial for a large class of foliations without holonomy. The question of triviality is related to ergodic theory of dynamical systems on the circle and to the problem of smooth conjugacy of local diffeomorphisms. Certain classes are obstructions for the existence of transverse affine and projective connections.
ATIYAH CLASS AND CHERN CHARACTER FOR GLOBAL MATRIX FACTORISATIONS
Authors: Kim Bumsig , Polishchuk Alexander
Published: January 2021

We define the Atiyah class for global matrix factorisations and use it to give a formula for the categorical Chern character and the boundary-bulk map for matrix factorisations, generalising the formula in the local case obtained in [12]. Our approach is based on developing the Lie algebra analogies observed by Kapranov [7] and Markarian [9].
Observations of Particle Loss due to Injection‐Associated Electromagnetic Ion Cyclotron Waves
Authors: Kim Hyomin , Schiller Quintin , Engebretson Mark J. , Noh Sungjun , Kuzichev Ilya , Lanzerotti Louis J. , Gerrard Andrew J. , Kim Khan‐Hyuk , Lessard Marc R. , Spence Harlan E. , Lee Dae‐Young , Matzka Jürgen , Fromm Tanja
Published: January 2021

We report on observations of electromagnetic ion cyclotron (EMIC) waves and their interactions with injected ring current particles and high energy radiation belt electrons. The magnetic field experiment aboard the twin Van Allen Probes spacecraft measured EMIC waves near L = 5.5–6. Particle data from the spacecraft show that the waves were associated with particle injections. The wave activity was also observed by a ground‐based magnetometer near the spacecraft geomagnetic footprint over a more extensive temporal range. Phase space density profiles, calculated from directional differential electron flux data from Van Allen Probes, show that there was a significant energy‐dependent relativistic electron dropout over a limited L‐shell range during and after the EMIC wave activity. In addition, the NOAA spacecraft observed relativistic electron precipitation associated with the EMIC waves near the footprint of the Van Allen Probes spacecraft. The observations suggest EMIC wave‐induced relativistic electron loss in the radiation belt.
Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions
Authors: Pantano Francesco , Croset Martine , Driouch Keltouma , Bednarz-Knoll Natalia , Iuliani Michele , Ribelli Giulia , Bonnelye Edith , Wikman Harriet , Geraci Sandra , Bonin Florian , Simonetti Sonia , Vincenzi Bruno , Hong Saw See , Sousa Sofia , Pantel Klaus , Tonini Giuseppe , Santini Daniele , Clézardin Philippe
Published: January 2021

Bone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.
PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer
Authors: Yin Xin-Ke , Wang Yun-Long , Wang Fei , Feng Wei-Xing , Bai Shao-Mei , Zhao Wan-Wen , Feng Li-Li , Wei Ming-Biao , Qin Cao-Litao , Wang Fang , Chen Zhi-Li , Yi Hong-Jun , Huang Yan , Xie Pei-Yi , Kim Taewan , Wang Ying-Nai , Hou Jun-Wei , Li Chia-Wei , Liu Quentin , Fan Xin-Juan , Hung Mien-Chie , Wan Xiang-Bo
Published: January 2021

Arginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.
Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway
Authors: Huang Xin , Hou Yichao , Weng Xiaoling , Pang Wenjing , Hou Lidan , Liang Yu , Wang Yu , Du Leilei , Wu Tianqi , Yao Mengfei , Wang Jianhua , Meng Xiangjun
Published: January 2021

Exploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis–mediated aerobic glycolysis pathway.
Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers
Authors: Zhou Min , Yuan Jianlong , Deng Yaqi , Fan Xianqun , Shen Jianfeng
Published: January 2021

Mammalian SWI/SNF complex is a key chromatin remodeler that reshapes nucleosomes and regulates DNA accessibility. Mutations in SWI/SNF subunits are found in a broad spectrum of human cancers; however, the mechanisms of how these aberrations of SWI/SNF complex would impact tumorigenesis and cancer therapeutics remain to be elucidated. Studies have demonstrated that immune checkpoint blockade (ICB) therapy is promising in cancer treatment. Nevertheless, suitable biomarkers that reliably predict the clinical response to ICB are still lacking. Emerging evidence has suggested that SWI/SNF components play novel roles in the regulation of anti-tumor immunity, and SWI/SNF deficiency can be therapeutically targeted by ICB. These findings manifest the prominence of the SWI/SNF complex as a stratification biomarker that predicts treatment (therapeutic) response to ICB. In this review, we summarize the recent advances in ICB therapy by harnessing the cancer-specific vulnerability elicited by SWI/SNF deficiency. We provide novel insights into a comprehensive understanding of the underlying mechanisms by which SWI/SNF functions as a modulator of anti-tumor immunity.
Phosphorus deficiencies invoke optimal allocation of exoenzymes by ectomycorrhizas
Authors: Meeds Justin A , Kranabetter J Marty , Zigg Ieva , Dunn Dave , Miros François , Shipley Paul , Jones Melanie D
Published: January 2021

Ectomycorrhizal (EM) fungi can acquire phosphorus (P) through the production of extracellular hydrolytic enzymes (exoenzymes), but it is unclear as to the manner and extent native EM fungal communities respond to declining soil P availability. We examined the activity of six exoenzymes (xylosidase, N-acetyl glucosaminidase, β-glucosidase, acid phosphomonoesterase, acid phosphodiesterase [APD], laccase) from EM roots of Pseudotsuga menzesii across a soil podzolization gradient of coastal British Columbia. We found that APD activity increased fourfold in a curvilinear association with declining inorganic P. Exoenzyme activity was not related to organic P content, but at a finer resolution using 31P-NMR, there was a strong positive relationship between APD activity and the ratio of phosphodiesters to orthophosphate of surface organic horizons (forest floors). Substantial increases (two- to fivefold) in most exoenzymes were aligned with declining foliar P concentrations of P. menzesii, but responses were statistically better in relation to foliar nitrogen (N):P ratios. EM fungal species with consistently high production of key exoenzymes were exclusive to Podzol plots. Phosphorus deficiencies in relation to N limitations may provide the best predictor of exoenzyme investment, reflecting an optimal allocation strategy for EM fungi. Resource constraints contribute to species turnover and the assembly of distinct, well-adapted EM fungal communities.
When less is more: regarding the use of chest X-ray instead of computed tomography in screening for pulmonary metastasis in postmolar gestational trophoblastic neoplasia
Authors: Braga Antonio , Elias Kevin Meyer , Horowitz Neil Stuart , Berkowitz Ross Stuart
Published: January 2021

We discuss the use of chest computed tomography (CT) in the initial screening for gestational trophoblastic neoplasia (GTN) metastases. Chest CT does not influence overall treatment outcome or the time to remission. We endorse the FIGO recommendation for the screening of GTN metastases should be done with chest X-ray.
Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing
Authors: Mazzurana Luca , Czarnewski Paulo , Jonsson Viktor , Wigge Leif , Ringnér Markus , Williams Teresa C. , Ravindran Avinash , Björklund Åsa K. , Säfholm Jesper , Nilsson Gunnar , Dahlén Sven-Erik , Orre Ann-Charlotte , Al-Ameri Mamdoh , Höög Charlotte , Hedin Charlotte , Szczegielniak Sylwester , Almer Sven , Mjösberg Jenny
Published: January 2021

The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in colon and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2+ and CRTH2− ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-δ rearrangement. Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.
Establishment of intestinal organoid cultures modeling injury-associated epithelial regeneration
Authors: Qu Molong , Xiong Liang , Lyu Yulin , Zhang Xiannian , Shen Jie , Guan Jingyang , Chai Peiyuan , Lin Zhongqing , Nie Boyao , Li Cheng , Xu Jun , Deng Hongkui
Published: January 2021

The capacity of 3D organoids to mimic physiological tissue organization and functionality has provided an invaluable tool to model development and disease in vitro. However, conventional organoid cultures primarily represent the homeostasis of self-organizing stem cells and their derivatives. Here, we established a novel intestinal organoid culture system composed of 8 components, mainly including VPA, EPZ6438, LDN193189, and R-Spondin 1 conditioned medium, which mimics the gut epithelium regeneration that produces hyperplastic crypts following injury; therefore, these organoids were designated hyperplastic intestinal organoids (Hyper-organoids). Single-cell RNA sequencing identified different regenerative stem cell populations in our Hyper-organoids that shared molecular features with in vivo injury-responsive Lgr5+ stem cells or Clu+ revival stem cells. Further analysis revealed that VPA and EPZ6438 were indispensable for epigenome reprogramming and regeneration in Hyper-organoids, which functioned through epigenetically regulating YAP signaling. Furthermore, VPA and EPZ6438 synergistically promoted regenerative response in gut upon damage in vivo. In summary, our results demonstrated a new in vitro organoid model to study epithelial regeneration, highlighting the importance of epigenetic reprogramming that pioneers tissue repair.
AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells
Authors: Wang Shuai , Qiu Zongyang , Hou Yingnan , Deng Xiya , Xu Wei , Zheng Tingting , Wu Peihan , Xie Shaofang , Bian Weixiang , Zhang Chong , Sun Zewei , Liu Kunpeng , Shan Chao , Lin Aifu , Jiang Shibo , Xie Youhua , Zhou Qiang , Lu Lu , Huang Jing , Li Xu
Published: January 2021

The current coronavirus disease 2019 (COVID-19) pandemic presents a global public health challenge. The viral pathogen responsible, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to the host receptor ACE2 through its spike (S) glycoprotein, which mediates membrane fusion and viral entry. Although the role of ACE2 as a receptor for SARS-CoV-2 is clear, studies have shown that ACE2 expression is extremely low in various human tissues, especially in the respiratory tract. Thus, other host receptors and/or co-receptors that promote the entry of SARS-CoV-2 into cells of the respiratory system may exist. In this study, we found that the tyrosine-protein kinase receptor UFO (AXL) specifically interacts with the N-terminal domain of SARS-CoV-2 S. Using both a SARS-CoV-2 virus pseudotype and authentic SARS-CoV-2, we found that overexpression of AXL in HEK293T cells promotes SARS-CoV-2 entry as efficiently as overexpression of ACE2, while knocking out AXL significantly reduces SARS-CoV-2 infection in H1299 pulmonary cells and in human primary lung epithelial cells. Soluble human recombinant AXL blocks SARS-CoV-2 infection in cells expressing high levels of AXL. The AXL expression level is well correlated with SARS-CoV-2 S level in bronchoalveolar lavage fluid cells from COVID-19 patients. Taken together, our findings suggest that AXL is a novel candidate receptor for SARS-CoV-2 which may play an important role in promoting viral infection of the human respiratory system and indicate that it is a potential target for future clinical intervention strategies.
A three-dimensional in vitro model of the peripheral nervous system
Authors: Park Sunghee Estelle , Ahn Jinchul , Jeong Hyo-Eun , Youn Inchan , Huh Dongeun , Chung Seok
Published: January 2021

Recent advances in three-dimensional (3D) cell culture models developed on organ-on-a-chip or microfluidic devices have shown their capability to recapitulate the in vivo microenvironment as well as their potential as tools in biomedical research. Here, we present an in vitro model of the peripheral nervous system (PNS) by establishing a coculture model of motor neurons (MNs) and Schwann cells (SCs) in a 3D environment in a microengineered extracellular matrix hydrogel scaffold. The collagen scaffold placed at the center of the microdevice provided a 3D cellular microenvironment where the axons of MNs were allowed to actively interact with SCs during their growth and maturation. By treating the MN–SC coculture model with ascorbic acid, we were able to model the myelination process in the PNS, which was evidenced by the increased expression of myelin markers in SCs. Moreover, we show that this can be reversed by treating myelinated nerve fibers with glial growth factor (neuregulin-1 isoform) to potentially block the formation of the myelin sheath and induce demyelination. Our 3D cell culture model may be used to achieve active control of the myelinating and demyelinating processes in the PNS and thus may offer new opportunities to study pathophysiological processes involved in motor neuron diseases by in vitro modeling.
Bridgin connects the outer kinetochore to centromeric chromatin
Authors: Sridhar Shreyas , Hori Tetsuya , Nakagawa Reiko , Fukagawa Tatsuo , Sanyal Kaustuv
Published: January 2021

The microtubule-binding outer kinetochore is coupled to centromeric chromatin through CENP-CMif2, CENP-TCnn1, and CENP-UAme1 linker pathways originating from the constitutive centromere associated network (CCAN) of the inner kinetochore. Here, we demonstrate the recurrent loss of most CCAN components, including certain kinetochore linkers during the evolution of the fungal phylum of Basidiomycota. By kinetochore interactome analyses in a model basidiomycete and human pathogen Cryptococcus neoformans, a forkhead-associated domain containing protein “bridgin” was identified as a kinetochore component along with other predicted kinetochore proteins. In vivo and in vitro functional analyses of bridgin reveal its ability to connect the outer kinetochore with centromeric chromatin to ensure accurate chromosome segregation. Unlike established CCAN-based linkers, bridgin is recruited at the outer kinetochore establishing its role as a distinct family of kinetochore proteins. Presence of bridgin homologs in non-fungal lineages suggests an ancient divergent strategy exists to bridge the outer kinetochore with centromeric chromatin.
Survey data and human computation for improved flu tracking
Authors: Wojcik Stefan , Bijral Avleen S. , Johnston Richard , Lavista Ferres Juan M. , King Gary , Kennedy Ryan , Vespignani Alessandro , Lazer David
Published: January 2021

While digital trace data from sources like search engines hold enormous potential for tracking and understanding human behavior, these streams of data lack information about the actual experiences of those individuals generating the data. Moreover, most current methods ignore or under-utilize human processing capabilities that allow humans to solve problems not yet solvable by computers (human computation). We demonstrate how behavioral research, linking digital and real-world behavior, along with human computation, can be utilized to improve the performance of studies using digital data streams. This study looks at the use of search data to track prevalence of Influenza-Like Illness (ILI). We build a behavioral model of flu search based on survey data linked to users’ online browsing data. We then utilize human computation for classifying search strings. Leveraging these resources, we construct a tracking model of ILI prevalence that outperforms strong historical benchmarks using only a limited stream of search data and lends itself to tracking ILI in smaller geographic units. While this paper only addresses searches related to ILI, the method we describe has potential for tracking a broad set of phenomena in near real-time.
Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site
Authors: Mendes Vitor , Green Simon R. , Evans Joanna C. , Hess Jeannine , Blaszczyk Michal , Spry Christina , Bryant Owain , Cory-Wright James , Chan Daniel S-H. , Torres Pedro H. M. , Wang Zhe , Nahiyaan Navid , O’Neill Sandra , Damerow Sebastian , Post John , Bayliss Tracy , Lynch Sasha L. , Coyne Anthony G. , Ray Peter C. , Abell Chris , Rhee Kyu Y. , Boshoff Helena I. M. , Barry Clifton E. , Mizrahi Valerie , Wyatt Paul G. , Blundell Tom L.
Published: January 2021

Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.
Disease risk scores for skin cancers
Authors: Fontanillas Pierre , Alipanahi Babak , Furlotte Nicholas A. , Johnson Michaela , Wilson Catherine H. ,   23andMe Research Team, Agee Michelle , Bell Robert K. , Bryc Katarzyna , Elson Sarah L. , Hinds David A. , Huber Karen E. , Kleinman Aaron , Litterman Nadia K. , McCreight Jennifer C. , McIntyre Matthew H. , Mountain Joanna L. , Noblin Elizabeth S. , Northover Carrie A. M. , Sathirapongsasuti J. Fah , Sazonova Olga V. , Shelton Janie F. , Shringarpure Suyash , Tian Chao , Tung Joyce Y. , Vacic Vladimir , Pitts Steven J. , Gentleman Robert , Auton Adam
Published: January 2021

We trained and validated risk prediction models for the three major types of skin cancer— basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma—on a cross-sectional and longitudinal dataset of 210,000 consented research participants who responded to an online survey covering personal and family history of skin cancer, skin susceptibility, and UV exposure. We developed a primary disease risk score (DRS) that combined all 32 identified genetic and non-genetic risk factors. Top percentile DRS was associated with an up to 13-fold increase (odds ratio per standard deviation increase >2.5) in the risk of developing skin cancer relative to the middle DRS percentile. To derive lifetime risk trajectories for the three skin cancers, we developed a second and age independent disease score, called DRSA. Using incident cases, we demonstrated that DRSA could be used in early detection programs for identifying high risk asymptotic individuals, and predicting when they are likely to develop skin cancer. High DRSA scores were not only associated with earlier disease diagnosis (by up to 14 years), but also with more severe and recurrent forms of skin cancer.
Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
Authors: Gong Qin , Robinson Kim , Xu Chenrui , Huynh Phuong Thao , Chong Kelvin Han Chung , Tan Eddie Yong Jun , Zhang Jiawen , Boo Zhao Zhi , Teo Daniel Eng Thiam , Lay Kenneth , Zhang Yaming , Lim John Soon Yew , Goh Wah Ing , Wright Graham , Zhong Franklin L. , Reversade Bruno , Wu Bin
Published: January 2021

Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.