bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduction in total and major cause-specific mortality from tobacco smoking cessation: a pooled analysis of 16 population-based cohort studies in Asia
Authors: Yang Jae Jeong , Yu Danxia , Shu Xiao-Ou , Wen Wanqing , Rahman Shafiur , Abe Sarah , Saito Eiko , Gupta Prakash C , He Jiang , Tsugane Shoichiro , Gao Yu-Tang , Yuan Jian-Min , Koh Woon-Puay , Sadakane Atsuko , Tomata Yasutake , Tsuji Ichiro , Sugawara Yumi , Matsuo Keitaro , Ahn Yoon-Ok , Park Sue K , Chen Yu , Inoue Manami , Kang Daehee , Zheng Wei ,   remaining authors are listed at the end of the paper
Published: April 2021

Background

Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia.

Methods

Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis.

Results

During a mean follow-up of 12.0 years, 108 287 deaths were ascertained—35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10–14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13–1.37) and 1.20 (1.02–1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15–19 years after smoking cessation [1.97 (1.41–2.73)], particularly among former heavy smokers [2.62 (1.71–4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries.

Conclusions

Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.
Explicit Plancherel Formula for the Space of Symplectic Forms
Authors: Lapid Erez , Offen Omer
Published: April 2021

We provide a Plancherel decomposition for the space of symplectic bilinear forms of rank $2n$ over a local non-Archimedean field $F$ in terms of that of $\operatorname{GL}_n(F)$.
Microbial-based magnetic nanoparticles production: a mini-review
Authors: Chmykhalo Victor , Belanova Anna , Belousova Mariya , Butova Vera , Makarenko Yuriy , Khrenkova Vera , Soldatov Alexander , Zolotukhin Peter
Published: April 2021

The ever-increasing biomedical application of magnetic nanoparticles (MNPs) implies increasing demand in their scalable and high-throughput production, with finely tuned and well-controlled characteristics. One of the options to meet the demand is microbial production by nanoparticles-synthesizing bacteria. This approach has several benefits over the standard chemical synthesis methods, including improved homogeneity of synthesis, cost-effectiveness, safety and eco-friendliness. There are, however, specific challenges emanating from the nature of the approach that are to be accounted and resolved in each manufacturing instance. Most of the challenges can be resolved by proper selection of the producing organism and optimizing cell culture and nanoparticles extraction conditions. Other issues require development of proper continuous production equipment, medium usage optimization and precursor ions recycling. This mini-review focuses on the related topics in microbial synthesis of MNPs: producing organisms, culturing methods, nanoparticles characteristics tuning, nanoparticles yield and synthesis timeframe considerations, nanoparticles isolation as well as on the respective challenges and possible solutions.
When text simplification is not enough: could a graph-based visualization facilitate consumers’ comprehension of dietary supplement information?
Authors: He Xing , Zhang Rui , Alpert Jordan , Zhou Sicheng , Adam Terrence J , Raisa Aantaki , Peng Yifan , Zhang Hansi , Guo Yi , Bian Jiang
Published: April 2021

Objective

Dietary supplements are widely used. However, dietary supplements are not always safe. For example, an estimated 23 000 emergency room visits every year in the United States were attributed to adverse events related to dietary supplement use. With the rapid development of the Internet, consumers usually seek health information including dietary supplement information online. To help consumers access quality online dietary supplement information, we have identified trustworthy dietary supplement information sources and built an evidence–based knowledge base of dietary supplement information—the integrated DIetary Supplement Knowledge base (iDISK) that integrates and standardizes dietary supplement related information across these different sources. However, as information in iDISK was collected from scientific sources, the complex medical jargon is a barrier for consumers’ comprehension. The objective of this study is to assess how different approaches to simplify and represent dietary supplement information from iDISK will affect lay consumers’ comprehension.

Materials and Methods

Using a crowdsourcing platform, we recruited participants to read dietary supplement information in 4 different representations from iDISK: (1) original text, (2) syntactic and lexical text simplification (TS), (3) manual TS, and (4) a graph–based visualization. We then assessed how the different simplification and representation strategies affected consumers’ comprehension of dietary supplement information in terms of accuracy and response time to a set of comprehension questions.

Results

With responses from 690 qualified participants, our experiments confirmed that the manual approach, as expected, had the best performance for both accuracy and response time to the comprehension questions, while the graph–based approach ranked the second outperforming other representations. In some cases, the graph–based representation outperformed the manual approach in terms of response time.

Conclusions

A hybrid approach that combines text and graph–based representations might be needed to accommodate consumers’ different information needs and information seeking behavior.
Midwives and Maternal Mortality: Evidence from a Midwifery Policy Experiment in 19th-century Sweden
Authors: Lorentzon Louise , Pettersson-Lidbom Per
Published: April 2021

This paper estimates the causal effect of a historical midwifery policy experiment on maternal mortality, infant mortality, and stillbirth during the period of 1830–1894 in Sweden. Exploiting sharp changes or “discontinuities” across time and place in the availability of trained and licensed midwives as an exogenous source of variation, we find that a doubling of trained midwives led to a 20%–40% reduction in maternal mortality and a 20% increase in the uptake of midwife-assisted homebirths. The results thus suggest that a 1% increase in the share of midwife-assisted homebirths decreased maternal mortality by as much as 2%, which is a remarkable finding given that midwife training was only 6–12 months at that time. The results of this study contribute to the current debate about the most effective strategy to reduce the unacceptably high rate of maternal mortality in many developing countries, especially in low-resource settings.
Idle Souls, Regulated Emotions of a Mind Industry: A new look at Ottoman materialism
Authors: Afacan Şeyma
Published: April 2021

The phenomenon of ‘materialism’ in the late Ottoman Empire has long been explained as the vehicle of fully-fledged modernization (i.e., Westernization and secularization) in allegedly essential opposition to tradition and religion. Amid growing intellectual interest in aspects of the individual such as mind, soul, brain, and emotions in the late Ottoman period, this paper shifts the explanatory focus from religious vs. nationalist ideologies to the discourse of ‘productivity’. It argues that before the discourse of national homogenization came to dominate intellectual writings in the late Ottoman Empire, a new language about the regulation of body and emotion was formulated with the aim of increasing labour productivity and rational conduct. The debate between materialism and spiritualism was embedded in this new language. The first section of the paper reviews relevant secondary literature to question what we know about the phenomenon of Ottoman materialism. The second moves on to the over-abundance of machine metaphors in materialist writings with particular focus on Abdullah Cevdet’s books on brain physiology, and in light of the spread of mechanistic views of human nature in the late nineteenth century. The final section presents Baha Tevfik’s problematization of sensibility (hassasiyet) as an obstacle to greater social harmony based on rational conduct as a case study of the regulation of emotion in the early 1910s, when interest in scientific and philosophical literature on human nature and the soul reached its zenith. This paper shows the ways in which Ottoman materialism became an important tool to imagine the individual as a unit of production, whose soul was rendered idle and whose emotions were subjected to regulation.
Oestrogen receptor alpha in papillary thyroid carcinoma: association with clinical features and BRAFV600E mutation
Authors: Liu Shiyang , Jiao Bo , Li Shuyu , Zhao Lu , Zheng Weihong , Wang Kun , Xu Jing , Tian Yao , Liu Chenguang , Gui Zhengwei , Zhang Lin
Published: April 2021

Background

Papillary thyroid cancer cells can express oestrogen receptor alpha, which is encoded by the ESR1 gene and may bind to oestrogen to induce the occurrence and development of papillary thyroid cancer. The BRAFV600E mutation is also an important biomarker for the occurrence and progression of papillary thyroid cancer. However, the association between the BRAFV600E mutation and oestrogen receptor alpha expression has not been identified. This study aims to investigate the association between ESR1 expression and the BRAFV600E mutation and its clinical significance.

Methods

Oestrogen receptor alpha and BRAFV600E proteins were detected by immunohistochemical staining of formalin-fixed paraffin-embedded thyroid tissues from 1105 patients with papillary thyroid cancer at our institution. Messenger RNA expression counts of ESR1 and clinicopathologic information were obtained from The Cancer Genome Atlas database.

Results

Oestrogen receptor alpha protein expression was significantly associated with BRAFV600E protein. The positive rate of oestrogen receptor alpha protein in papillary thyroid cancer patients was significantly higher in males, younger patients and patients with the multifocal type. In papillary thyroid cancer patients with positive BRAFV600E protein, oestrogen receptor alpha expression was significantly correlated with central lymph node metastasis. Data from the The Cancer Genome Atlas database also suggested that the ESR1 messenger RNA level was associated with the BRAFV600E mutation. Furthermore, classification analysis performed according to a tree-based classification method demonstrated that higher ESR1 messenger RNA expression indicated poorer overall survival in papillary thyroid cancer patients with the BRAFV600E mutation.

Conclusions

The percentage of BRAFV600E mutations is increased in patients with higher ESR1 messenger RNA levels, and the BRAFV600E protein might be co-expressed with oestrogen receptor alpha, which could be an indicator of cervical lymph node metastasis and poor overall survival in patients with papillary thyroid cancer.
Gender Differences in Treatment Allocation and Survival of Advanced Gastroesophageal Cancer: A Population-Based Study
Authors: Dijksterhuis Willemieke P M , Kalff Marianne C , Wagner Anna D , Verhoeven Rob H A , Lemmens Valery E P P , van Oijen Martijn G H , Gisbertz Suzanne S , van Berge Henegouwen Mark I , van Laarhoven Hanneke W M
Published: April 2021

Background

Biological sex and gender have been reported to affect incidence and overall survival (OS) of curatively treated gastroesophageal cancer. The aim of this study was to compare palliative treatment allocation and OS between women and men with advanced gastroesophageal cancer.

Methods

Patients with an unresectable or metastatic esophageal (including cardia) adenocarcinoma (EAC) or squamous cell carcinoma (ESCC) or gastric adenocarcinoma (GAC) diagnosed in 2015-2018 were identified in the Netherlands Cancer Registry. Treatment allocation was compared using χ2 tests and multivariable logistic regression analyses, and OS using the Kaplan-Meier method with log-rank test and Cox proportional hazards analysis. All statistical tests were 2-sided.

Results

Of patients with EAC (n = 3077), ESCC (n = 794), and GAC (n = 1836), 18.0%, 39.4%, and 39.1% were women, respectively. Women less often received systemic treatment compared with men for EAC (42.7% vs 47.4%, P = .045) and GAC (33.8% vs 38.8%, P = .03) but not for ESCC (33.2% vs 39.5%, P = .07). Women had a lower probability of receiving systemic treatment for GAC in multivariable analyses (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.62 to 1.00) but not for EAC (OR = 0.86, 95% CI = 0.69 to 1.06) and ESCC (OR = 0.81, 95% CI = 0.57 to 1.14). Median OS was lower in women with EAC (4.4 vs 5.2 months, P = .04) but did not differ after adjustment for patient and tumor characteristics and systemic treatment administration.

Conclusions

We observed statistically significant and clinically relevant gender differences in systemic treatment administration and OS in advanced gastroesophageal cancer. Causes of these disparities may be sex based (ie, related to tumor biology) as well as gender based (eg, related to differences in treatment choices).
Arbitration as an Alternative Dispute Settlement Mechanism at the WTO
Authors: Grey Felicia A
Published: April 2021

This study examines the WTO provisions for arbitration and their underutilisation when compared with litigation. It specifically assesses Articles 21.3(c), 22.6 and 25 of the Dispute Settlement Understanding (DSU). Of these provisions for arbitration, DSU Article 21.3(c) is most often invoked, while Article 25 is seldomly used. The paralysis in the Appellate Body and the proposed Multi-Party Interim Appeal Arbitration Arrangement (MPIA) have renewed the WTO s attention on Article 25. The study examines this new feature and makes some projections about the WTO s future. It argues that there is a direct relationship between MPIA s success and Article 25's increased usage. There is a concern, however, about whether MPIA s success will disincentivise interest and urgency in resolving the Appellate Body's gridlock. While MPIA Members have signalled their commitment to resolving the issue, it remains to be seen whether this will happen and whether the Appellate Body will become functional once again.
Use of paclitaxel carried in lipid nanoparticles to treat aortic allograft transplantation in rats
Authors: Pepineli Rafael , Santana Alexandre C , Silva Filipe M O , Tavoni Thauany M , Stolf Noedir A G , Noronha Irene L , Maranhão Raul C
Published: April 2021

Objectives

The aim of this study was to test whether lipid core nanoparticles loaded with paclitaxel (LDE-PTX) protect rat aortic allograft from immunological damage.

Methods

Fisher and Lewis rats were used differing in minor histocompatibility loci. Sixteen Lewis rats were allocated to four-animal groups: SYNG (syngeneic), Lewis rats receiving aorta grafts from Lewis rats; ALLO (allogeneic), Lewis rats receiving aortas from Fisher rats; ALLO+LDE (allogeneic transplant treated with LDE), Lewis rats receiving aortas from Fisher rats, treated with LDE (weekly injection for 3 weeks); ALLO+LDE-PTX (allogeneic transplant treated with LDE-PTX), Lewis rats receiving aortas from Fisher rats treated with LDE-PTX (4 mg/kg weekly for 3 weeks). Treatments began on transplantation day.

Results

Thirty days post-transplantation, SYNG showed intact aortas. ALLO and ALLO+LDE presented intense neointimal formation. In ALLO+LDE-PTX, treatment inhibited neointimal formation; narrowing of aortic lumen was prevented in ALLO and ALLO+LDE. LDE-PTX strongly inhibited proliferation and intimal invasion by smooth muscle cells, diminished 4-fold presence of apoptotic/dead cells in the intima, reduced the invasion of aorta by macrophages and T-cells and gene expression of pro-inflammatory tumour necrosis factor-alpha (TNFα), interferon gamma (IFNγ) and interleukin-1 beta (IL-1β).

Conclusions

LDE-PTX was effective in preventing the vasculopathy associated with rejection and may offer a potent therapeutic tool for post-transplantation.
Home Away from Home: Examining Adolescent Refugees’ Well-Being in Australia
Authors: Mahadevan Renuka , Jayasinghe Maneka
Published: April 2021

This article examines the correlation of post-migration factors and in particular parental mental health with post-traumatic stress disorder (PTSD) and happiness levels of adolescent refugee migrants in Australia, with a special emphasis on associated age and gender differences. Data were sourced from the child module in the 2015–2016 Building a New Life in Australia data set. Results indicate that factors associated with happiness are quite different from those associated with PTSD and this varies across gender and the age groups of 11–14 and 15–17. For example, discrimination related to religion/culture and language have different correlation with boys’ and girls’ well-being measures. While father’s education and mental state have no significant association with any well-being measure, mothers’ education plays some role. Of concern is the intergenerational correlation of mother’s PTSD with their daughters. The results in this study caution against a one-size-fits-all approach to intervention and suggest that a targeted focus on older and younger adolescents further differentiated by gender is likely to be more effective.
Cyanoacrylate glue for closure of proximal enterocutaneous fistula: a case report
Authors: Alharbi Ahlam Hamed , Alotaibi Abdularahman M
Published: April 2021

Enterocutaneous fistula (ECF) is a distressing complication. Commonly, it follows abdominal operations that require extensive adhesiolysis. Its management is challenging, burdening health systems. Complete healing can take several weeks. Several modalities have been described, with varying success rates. A 48-year-old male underwent a trauma laparotomy, with resection of a segment of the proximal bowel and anastomosis. He experienced an anastomosis leak, wound infection and ECF and was managed conservatively for 5 weeks with parenteral nutrition and bowel rest. He was then referred to us and treated with approximation sutures and cyanoacrylate adhesive. His wound was closed with a subcutaneous drain. He experienced complete healing of the fistula and wound after undergoing a minimally invasive approach using sutures and a cyanoacrylate sealant. Cyanoacrylate glue is a safe initial non-invasive treatment of low-output ECF. It can be selected over approximation sutures to ensure sealing of the tract before surgery.
The properties of polycyclic aromatic hydrocarbons in galaxies: constraints on PAH sizes, charge and radiation fields
Authors: Rigopoulou D , Barale M , Clary D C , Shan X , Alonso-Herrero A , García-Bernete I , Hunt L , Kerkeni B , Pereira-Santaella M , Roche P F
Published: April 2021

Based on theoretical spectra computed using Density Functional Theory we study the properties of polycyclic aromatic hydrocarbons (PAH). In particular using bin-average spectra of PAH molecules with varying number of carbons we investigate how the intensity of the mid-infrared emission bands, 3.3, 6.2, 7.7, and 11.3 $\mu$m, respond to changes in the number of carbons, charge of the molecule, and the hardness of the radiation field that impinges the molecule. We confirm that the 6.2/7.7 band ratio is a good predictor for the size of the PAH molecule (based on the number of carbons present). We also investigate the efficacy of the 11.3/3.3 ratio to trace the size of PAH molecules and note the dependence of this ratio on the hardness of the radiation field. While the ratio can potentially also be used to trace PAH molecular size, a better understanding of the impact of the underlying radiation field on the 3.3 $\mu$m feature and the effect of the extinction on the ratio should be evaluated. The newly developed diagnostics are compared to band ratios measured in a variety of galaxies observed with the Infrared Spectrograph on board the Spitzer Space Telescope. We demonstrate that the band ratios can be used to probe the conditions of the interstellar medium in galaxies and differentiate between environments encountered in normal star forming galaxies and active galactic nuclei. Our work highlights the immense potential that PAH observations with the James Webb Space Telescope will have on our understanding of the PAH emission itself and of the physical conditions in galaxies near and far.
Modelling neutron star–black hole binaries: future pulsar surveys and gravitational wave detectors
Authors: Chattopadhyay Debatri , Stevenson Simon , Hurley Jarrod R , Bailes Matthew , Broekgaarden Floor
Published: April 2021

Binaries comprised of a neutron star (NS) and a black hole (BH) have so far eluded observations as pulsars and with gravitational waves (GWs). We model the formation and evolution of these NS+BH binaries – including pulsar evolution – using the binary population synthesis code COMPAS. We predict the presence of a total of 50–2000 binaries containing a pulsar and a BH (PSR+BHs) in the Galactic field. We find the population observable by the next generation of radio telescopes, represented by the SKA and MeerKAT, current (LIGO/Virgo) and future (LISA) GW detectors. We conclude that the SKA will observe 1–80 PSR+BHs, with 0–4 binaries containing millisecond pulsars. MeerKAT is expected to observe 0–40 PSR+BH systems. Future radio detections of NS+BHs will constrain uncertain binary evolution processes such as BH natal kicks. We show that systems in which the NS formed first (NSBH) can be distinguished from those where the BH formed first (BHNS) by their pulsar and binary properties. We find 40 per cent of the LIGO/Virgo observed NS+BHs from a Milky Way like field population will have a chirp mass ≥3.0 M⊙. We estimate the spin distributions of NS+BHs with two models for the spins of BHs. The remnants of BHNS mergers will have a spin of ∼0.4, whilst NSBH merger remnants can have a spin of ∼0.6 or ∼0.9 depending on the model for BH spins. We estimate that approximately 25–1400 PSR+BHs will be radio alive whilst emitting GWs in the LISA frequency band, raising the possibility of joint observation by the SKA and LISA.
On dust evolution in planet-forming discs in binary systems – I. Theoretical and numerical modelling: radial drift is faster in binary discs
Authors: Zagaria Francesco , Rosotti Giovanni P , Lodato Giuseppe
Published: April 2021

Many stars are in binaries or higher order multiple stellar systems. Although in recent years a large number of binaries have been proven to host exoplanets, how planet formation proceeds in multiple stellar systems has not been studied much yet from the theoretical standpoint. In this paper, we focus on the evolution of the dust grains in planet-forming discs in binaries. We take into account the dynamics of gas and dust in discs around each component of a binary system under the hypothesis that the evolution of the circumprimary and the circumsecondary discs is independent. It is known from previous studies that the secular evolution of the gas in binary discs is hastened due to the tidal interactions with their hosting stars. Here, we prove that binarity affects dust dynamics too, possibly in a more dramatic way than the gas. In particular, the presence of a stellar companion significantly reduces the amount of solids retained in binary discs because of a faster, more efficient radial drift, ultimately shortening their lifetime. We prove that how rapidly discs disperse depends both on the binary separation, with discs in wider binaries living longer, and on the disc viscosity. Although the less-viscous discs lose high amounts of solids in the earliest stages of their evolution, they are dissipated slowly, while those with higher viscosities show an opposite behaviour. The faster radial migration of dust in binary discs has a striking impact on planet formation, which seems to be inhibited in this hostile environment, unless other disc substructures halt radial drift further in. We conclude that if planetesimal formation were viable in binary discs, this process would take place on very short time-scales.
Iblis, Abraham, and Teleological Suspensions
Authors: Hudson Hud
Published: April 2021

In this essay, I shall scold a Jinn, recommend a position in Islamic theology to my Muslim neighbors, explore a famous dilemma recounted in Genesis, and participate in a debate occasioned by an interpretive puzzle in Kierkegaard studies. I investigate two opposed ways of understanding the phrase, ‘the teleological suspension of the ethical’, offer some critical remarks on the interpretation of that phrase in Kierkegaard’s Fear and Trembling, and defend a range of considerations that speak in favor of one of the options over the other. Finally, I show how one may invoke my preferred interpretation to confront the puzzle common to Jewish, Christian, and Islamic theology presented by the story of Abraham and the binding of Isaac and also how a related strategy can be invoked to address the story of Iblis and the puzzle peculiar to Islamic theology to which it gives rise.
Intermolecular dark resonance energy transfer (DRET): upgrading fluorogenic DNA sensing
Authors: Barnoin Guillaume , Shaya Janah , Richert Ludovic , Le Hoang-Ngoan , Vincent Steve , Guérineau Vincent , Mély Yves , Michel Benoît Y , Burger Alain
Published: April 2021

The sensitivity of FRET-based sensing is usually limited by the spectral overlaps of the FRET donor and acceptor, which generate a poor signal-to-noise ratio. To overcome this limitation, a quenched donor presenting a large Stokes shift can be combined with a bright acceptor to perform Dark Resonance Energy Transfer (DRET). The consequent fluorogenic response from the acceptor considerably improves the signal-to-noise ratio. To date, DRET has mainly relied on a donor that is covalently bound to the acceptor. In this context, our aim was to develop the first intermolecular DRET pair for specific sensing of nucleic acid sequences. To this end, we designed DFK, a push–pull probe based on a fluorenyl π-platform that is strongly quenched in water. DFK was incorporated into a series of oligonucleotides and used as a DRET donor with Cy5-labeled complementary sequences. In line with our expectations, excitation of the dark donor in the double-labeled duplex switched on the far-red Cy5 emission and remained free of cross-excitation. The DRET mechanism was supported by time-resolved fluorescence measurements. This concept was then applied with binary probes, which confirmed the distance dependence of DRET as well as its potency in detecting sequences of interest with low background noise.
A nucleotide-sensing endonuclease from the Gabija bacterial defense system
Authors: Cheng Rui , Huang Fengtao , Wu Hui , Lu Xuelin , Yan Yan , Yu Bingbing , Wang Xionglue , Zhu Bin
Published: April 2021

The arms race between bacteria and phages has led to the development of exquisite bacterial defense systems including a number of uncharacterized systems distinct from the well-known restriction-modification and CRISPR/Cas systems. Here, we report functional analyses of the GajA protein from the newly predicted Gabija system. The GajA protein is revealed as a sequence-specific DNA nicking endonuclease unique in that its activity is strictly regulated by nucleotide concentration. NTP and dNTP at physiological concentrations can fully inhibit the robust DNA cleavage activity of GajA. Interestingly, the nucleotide inhibition is mediated by an ATPase-like domain, which usually hydrolyzes ATP to stimulate the DNA cleavage when associated with other nucleases. These features suggest a mechanism of the Gabija defense in which an endonuclease activity is suppressed under normal conditions, while it is activated by the depletion of NTP and dNTP upon the replication and transcription of invading phages. This work highlights a concise strategy to utilize a DNA nicking endonuclease for phage resistance via nucleotide regulation.
DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion
Authors: Silva-Pinheiro Pedro , Pardo-Hernández Carlos , Reyes Aurelio , Tilokani Lisa , Mishra Anup , Cerutti Raffaele , Li Shuaifeng , Rozsivalova Dieu-Hien , Valenzuela Sebastian , Dogan Sukru A , Peter Bradley , Fernández-Silva Patricio , Trifunovic Aleksandra , Prudent Julien , Minczuk Michal , Bindoff Laurence , Macao Bertil , Zeviani Massimo , Falkenberg Maria , Viscomi Carlo
Published: April 2021

Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the PolgA449T/A449T mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POLγB, the accessory subunit of the POLγ holoenzyme. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POLγB acts to stabilize POLγA and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POLγ subunits. We suggest that targeting POLγA turnover can be exploited as a target for the development of future therapies.
Development and Validation of a Multivariable Prediction Model for Missed HIV Health Care Provider Visits in a Large US Clinical Cohort
Authors: Pettit April C , Bian Aihua , Schember Cassandra O , Rebeiro Peter F , Keruly Jeanne C , Mayer Kenneth H , Mathews W Christopher , Moore Richard D , Crane Heidi M , Geng Elvin , Napravnik Sonia , Shepherd Bryan E , Mugavero Michael J
Published: April 2021

Background

Identifying individuals at high risk of missing HIV care provider visits could support proactive intervention. Previous prediction models for missed visits have not incorporated data beyond the individual level.

Methods

We developed prediction models for missed visits among people with HIV (PWH) with ≥1 follow-up visit in the Center for AIDS Research Network of Integrated Clinical Systems from 2010 to 2016. Individual-level (medical record data and patient-reported outcomes), community-level (American Community Survey), HIV care site–level (standardized clinic leadership survey), and structural-level (HIV criminalization laws, Medicaid expansion, and state AIDS Drug Assistance Program budget) predictors were included. Models were developed using random forests with 10-fold cross-validation; candidate models with the highest area under the curve (AUC) were identified.

Results

Data from 382 432 visits among 20 807 PWH followed for a median of 3.8 years were included; the median age was 44 years, 81% were male, 37% were Black, 15% reported injection drug use, and 57% reported male-to-male sexual contact. The highest AUC was 0.76, and the strongest predictors were at the individual level (prior visit adherence, age, CD4+ count) and community level (proportion living in poverty, unemployed, and of Black race). A simplified model, including readily accessible variables available in a web-based calculator, had a slightly lower AUC of .700.

Conclusions

Prediction models validated using multilevel data had a similar AUC to previous models developed using only individual-level data. The strongest predictors were individual-level variables, particularly prior visit adherence, though community-level variables were also predictive. Absent additional data, PWH with previous missed visits should be prioritized by interventions to improve visit adherence.
Diabetic ketoacidosis at presentation of type 1 diabetes in children in Canada during the COVID-19 pandemic
Authors: Sellers Elizabeth A C , Pacaud Danièle
Published: April 2021

Type 1 diabetes is a common chronic illness in childhood. Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes. Early recognition of symptoms of diabetes and immediate initiation of treatment are important factors in preventing DKA at first presentation. We describe the numbers of children presenting with DKA at initial diagnosis across eight Canadian paediatric centres during the COVID-19 pandemic (March 15, 2020 to July 31, 2020) and compare this to the same time period in 2019. Comparing the pre-COVID to the COVID-19 time period, presentation in DKA increased from 36.4% to 55.0% (P<0.0001) and presentation in severe DKA from 37.0% to 48.3% (P=0.044). These findings are concerning and emphasize the importance of awareness of the signs and symptoms of diabetes. In addition, these findings raise concern about access to appropriate and timely care during the COVID-19 pandemic.
Making the ‘Green Revolution’ Truly Green: Improving Crop Nitrogen Use Efficiency
Authors: Wang Fanmiao , Yoshida Hideki , Matsuoka Makoto
Published: April 2021

Traditional breeding for high-yielding crops has mainly relied on the widespread cultivation of gibberellin (GA)-deficient semi-dwarf varieties, as dwarfism increases lodging resistance and allows for high nitrogen use, resulting in high grain yield. Although the adoption of semi-dwarf varieties in rice and wheat breeding brought big success to the ‘Green Revolution’ in the 20th century, it consequently increased the demand for nitrogen-based fertilizer, which causes severe threat to ecosystems and sustainable agriculture. To make the ‘Green Revolution’ truly green, it is necessary to develop new varieties with high nitrogen use efficiency (NUE). Under this demand, research on NUE, mainly for rice, has made great strides in the last decade. This mini-review focuses on three aspects of recent epoch-making findings on rice breeding for high NUE. The first one on ‘NUE genes related to GA signaling’ shows how promising it is to improve NUE in semi-dwarf Green Revolution varieties. The second aspect centers around the nitrate transporter1.1B, NRT1.1B; studies have revealed a nutrient signaling pathway through the discovery of the nitrate-NRT1.1B-SPX4-NLP3 cascade. The last one is based on the recent finding that the teosinte branched1, cycloidea, proliferating cell factor (TCP)-domain protein 19 underlies the genomic basis of geographical adaptation to soil nitrogen; OsTCP19 regulates the expression of a key transacting factor, DLT/SMOS2, which participates in the signaling of four different phytohormones, GA, auxin, brassinosteroid and strigolactone. Collectively, these breakthrough findings represent a significant step toward breeding high-NUE rice in the future.
The Unicellular Red AlgaCyanidioschyzon merolae—The Simplest Model of a Photosynthetic Eukaryote
Authors: Miyagishima Shin-Ya , Tanaka Kan
Published: April 2021

Several species of unicellular eukaryotic algae exhibit relatively simple genomic and cellular architecture. Laboratory cultures of these algae grow faster than plants and often provide homogeneous cellular populations exposed to an almost equal environment. These characteristics are ideal for conducting experiments at the cellular and subcellular levels. Many microalgal lineages have recently become genetically tractable, which have started to evoke new streams of studies. Among such algae, the unicellular red alga Cyanidioschyzon merolae is the simplest organism; it possesses the minimum number of membranous organelles, only 4,775 protein-coding genes in the nucleus, and its cell cycle progression can be highly synchronized with the diel cycle. These properties facilitate diverse omics analyses of cellular proliferation and structural analyses of the intracellular relationship among organelles. C. merolae cells lack a rigid cell wall and are thus relatively easily disrupted, facilitating biochemical analyses. Multiple chromosomal loci can be edited by highly efficient homologous recombination. The procedures for the inducible/repressive expression of a transgene or an endogenous gene in the nucleus and for chloroplast genome modification have also been developed. Here, we summarize the features and experimental techniques of C. merolae and provide examples of studies using this alga. From these studies, it is clear that C. merolae—either alone or in comparative and combinatory studies with other photosynthetic organisms—can provide significant insights into the biology of photosynthetic eukaryotes.
Increased Drought Resistance 1 Mutation Increases Drought Tolerance of Upland Rice by Altering Physiological and Morphological Traits and Limiting ROS Levels
Authors: Zu Xiaofeng , Lu Yanke , Wang Qianqian , La Yumei , Hong Xinyue , Tan Feng , Niu Jiayu , Xia Huihui , Wu Yufeng , Zhou Shaoxia , Li Kun , Chen Huhui , Qiang Sheng , Rui Qi , Wang Huaqi , La Honggui
Published: April 2021

To discover new mutants conferring enhanced tolerance to drought stress, we screened a mutagenized upland rice (Oryza sativa) population (cv. IAPAR9) and identified a mutant, named idr1-1 (increased drought resistance 1-1), with obviously increased drought tolerance under upland field conditions. The idr1-1 mutant possessed a significantly enhanced ability to tolerate high-drought stresses. Map-based cloning revealed that the gene LOC_Os05g26890, residing in the mapping region of IDR1 locus, carried a single-base deletion in the idr1-1 mutant. IDR1 encodes the Gα subunit of the heterotrimeric G protein (also known as RGA1), and this protein was localized in nucleus and to plasma membrane or cell periphery. Further investigations indicated that the significantly increased drought tolerance in idr1-1 mutants stemmed from a range of physiological and morphological changes, including greater leaf potentials, increased proline contents, heightened leaf thickness and upregulation of antioxidant-synthesizing and drought-induced genes, under drought-stressed conditions. Especially, reactive oxygen species (ROS) production might be remarkably impaired, while ROS-scavenging ability appeared to be markedly enhanced due to significantly elevated expression of ROS-scavenging enzyme genes in idr1-1 mutants under drought-stressed conditions. In addition, idr1-1 mutants showed reduced expression of OsBRD1. Altogether, these results suggest that mutation of IDR1 leads to alterations in multiple layers of regulations, which ultimately leads to changes in the physiological and morphological traits and limiting of ROS levels, and thereby confers obviously increased drought tolerance to the idr1-1 mutant.
Late Triassic Orogenic Assembly of the Tibetan Plateau: Constraints from Magmatism and Metamorphism in the East Lhasa Terrane
Authors: Chen Yanfei , Zhang Zeming , Palin Richard M , Tian Zuolin , Xiang Hua , Dong Xin , Ding Huixia , Qin Shengkai , Li Yunshuai
Published: April 2021

The early Mesozoic evolution of the Lhasa terrane, which represents a major component of the Himalayan–Tibetan orogen, remains highly controversial. In particular, geological units and events documented either side of the eastern Himalayan syntaxis (EHS) are poorly correlated. Here, we report new petrological, geochemical and geochronological data for cogenetic peraluminous S-type granites and metamorphic rocks (gneiss and schist) from the Motuo–Bomi–Chayu region of the eastern Lhasa terrane, located on the eastern flank of the EHS. Zircon U–Pb dating indicates that these units record both Late Triassic magmatic (216–206 Ma) and metamorphic (209–198 Ma) episodes. The granites were derived from a Paleoproterozoic crustal source with negative zircon εHf(t) values (–5·5 to –16·6) and TDM2 model ages of 1·51–1·99 Ga, and are interpreted to have formed by crustal anatexis of nearby metasediments during collisional orogeny and crustal thickening. The gneisses and schists experienced similar upper amphibolite-facies peak metamorphism and associated partial melting, followed by decompressional cooling and retrograde metamorphism. These rocks were buried to lower-crustal depths and then exhumed to the surface in a collisional orogenic setting during plate convergence. From comparison of these data with those for other metamorphic belts with similar grades and ages, and association of coeval granitic magmatism widespread in the central–east Lhasa terrane, we propose that the studied cogenetic magmatism and metamorphism in the Motuo–Bomi–Chayu region records Late Triassic accretion of the North Lhasa and South Lhasa terranes, which represents the first evidence of the Paleo-Tethys Ocean closure in this part of Asia. These data provide new constraints on the spatial and temporal evolution of the Paleo-Tethyan Wilson Cycle and provide a ‘missing link’ to correlate the geology and tectonic history of the Lhasa terrane continental crust on either side of the EHS.
Egg production and hatching patterns of Acartia erythraea (Copepoda, Calanoida), with a note on its two egg types, in a eutrophic bay in Korea
Authors: Choi Seo Yeol , Jang Min-Chul , Youn Seok Hyun , Seo Min Ho , Soh Ho Young
Published: April 2021

Acartia erythraea, a copepod species commonly found in the summer, was sampled weekly using a conical net, in Gamak Bay (southern Korea) from 19 July to 14 November 2013. Egg production rate (EPR) and hatching success rate (HS) were estimated weekly during the study period, for egg types with distinct surface morphologies, i.e. smooth or spiny. EPR ranged from 1.0 to 25.0 eggs female−1 day−1 with a mean of 12.0 eggs female−1 day−1. The weight-specific growth rate (WSGR) ranged from 0.01 to 0.19 day−1 with a mean value of 0.09 day−1. Of these, all the eggs were smooth until August, whereas spiny eggs were produced from September, and the spiny eggs contributed 88% of the total eggs in November. Both egg types hatched within 12 to 48 h, and the average HS was 80% or higher. The EPR and WSGR were significantly related to water temperature but weakly related to chlorophyll-a concentration. Contrary to previous studies, our findings suggest that it is impossible to determine whether an egg is subitaneous or diapause based on the egg surface structure. Spines on the surface of A. erythraea eggs in Gamak Bay could be an adaptation to seasonal variations and a rapidly changing coastal environment.
Lest We Forget: Learn from Out-of-Sample Forecast Errors When Optimizing Portfolios
Authors: Barroso Pedro , Saxena Konark
Published: April 2021

Portfolio optimization often struggles in realistic out-of-sample contexts. We deconstruct this stylized fact by comparing historical forecasts of portfolio optimization inputs with subsequent out-of-sample values. We confirm that historical forecasts are imprecise guides of subsequent values, but we discover the resultant forecast errors are not entirely random. They have predictable patterns and can be partially reduced using their own history. Learning from past forecast errors to calibrate inputs (akin to empirical Bayesian learning) generates portfolio performance that reinforces the case for optimization. Furthermore, the portfolios achieve performance that meets expectations, a desirable yet elusive feature of optimization methods.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Myeloproliferative neoplasms and clonal haematopoiesis in patients with giant cell arteritis: a case–control and exploratory study
Authors: Papo Matthias , Friedrich Chloé , Delaval Laure , Boysson Hubert de , Viallard Jean-François , Bachmeyer Claude , Sené Thomas , Humbert Sébastien , Duffau Pierre , Contis Anne , Agard Christian , Gombert Bruno , Puyade Mathieu , Foucher Aurélie , Alary Anne-Sophie , Danlos François-Xavier , Régent Alexis , Mouthon Luc , Guillevin Loïc , Samson Maxime , Kosmider Olivier , Terrier Benjamin ,   the French Vasculitis Study Group
Published: April 2021

Objectives

GCA is a large vessel vasculitis for which triggering factors remain unknown. Clonal haematopoiesis (CH) was associated with atherosclerosis through the induction of inflammation in myeloid cells, and data suggest that CH expansion and inflammation may support each other to induce a pro-inflammatory loop. Our objective was to describe the impact of JAK2p.V617F-mutated myeloproliferative neoplasms (MPNs) on GCA and to screen MPN-free patients for CH mutations.

Methods

We performed a retrospective case–control study comparing the characteristics of 21 GCA patients with MPN and 42 age- and gender-matched GCA patients without MPN. Also, 18 GCA patients were screened for CH through next-generation sequencing (NGS).

Results

The most frequent associated MPN was essential thrombocythaemia (ET; n = 11). Compared with controls, GCA patients with MPN had less-frequent cephalic symptoms (71.4 vs 97.6%; P = 0.004) and higher platelet counts at baseline [485 × 109/l (interquartile range 346–586) vs 346 (296–418); P = 0.02]. There was no difference between groups for other clinical features. Overall survival was significantly shorter in patients with MPN compared with controls [hazard ratio 8.2 (95% CI 1.2, 56.6); P = 0.03]. Finally, screening for CH using NGS in 15 GCA patients without MPN revealed CH in 33%.

Conclusion

GCA patients with MPN display higher platelet counts and shorter overall survival than controls. This association is not fortuitous, given the possible pathophysiological relationship between the two diseases. CH was found in one-third of GCA patients, which may be higher than the expected prevalence for a similar age, and should be confirmed in a larger cohort.