bluuebunny/crossref_metadata_2025 huggingface dataset:
Salmonella Typhi Stool Shedding by Patients With Enteric Fever and Asymptomatic Chronic Carriers in an Endemic Urban Setting
Authors: Khanam Farhana , Darton Thomas C , Meiring James E , Kumer Sarker Protup , Kumar Biswas Prasanta , Bhuiyan Md Amirul Islam , Hasan Rajib Nazmul , Tonks Susan , Pollard Andrew J , Clemens John D , Qadri Firdausi
Published: September 2021

The burden of Salmonella enterica serotype Typhi (S. Typhi) shedding in stool and its contribution to transmission in endemic settings is unknown. During passive surveillance S. Typhi shedding was seen during convalescence in 332 bacteremic patient with typhoid, although none persisted at 1-year follow-up. Anti–virulence capsule (Vi)–immunoglobulin (Ig) G titers were measured in age-stratified cohort of serosurveillance participants. Systematic stool sampling of 303 participants with high anti–Vi-IgG titers identified 1 asymptomatic carrier with shedding. These findings suggest that ongoing S. Typhi transmission in this setting is more likely to occur from acute convalescent cases, although better approaches are needed to identify true chronic carriers in the community to enable typhoid elimination.
Nasopharyngeal Codetection of Haemophilus influenzae and Streptococcus pneumoniae Shapes Respiratory Syncytial Virus Disease Outcomes in Children
Authors: Diaz-Diaz Alejandro , Bunsow Eleonora , Garcia-Maurino Cristina , Moore-Clingenpeel Melissa , Naples Jeffrey , Juergensen Alexis , Mertz Sara , Wang Huanyu , Leber Amy L , Gern James , Hall Mark W , Cohen Daniel M , Ramilo Octavio , Mejias Asuncion
Published: September 2021

Background

The role of nasopharyngeal bacteria in respiratory syncytial virus (RSV) disease has been underestimated. We measured the frequency and burden of respiratory bacteria in the upper respiratory tract of infants with RSV infection over 7 respiratory seasons, and their impact on clinical outcomes.

Methods

Children <2 years old with mild (outpatients, n=115) or severe (inpatients, n=566) RSV infection, and matched healthy controls (n=161) were enrolled. Nasopharyngeal samples were obtained for RSV, Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and Haemophilus influenzae detection and quantitation by PCR. Multivariable models were constructed to identify variables predictive of severe disease.

Results

S. pneumoniae, H. influenzae, and M. catarrhalis, but not S. aureus, were detected more frequently in RSV-infected children (84%) than healthy controls (46%; P<.001). Detection of S. pneumoniae and/or H. influenzae was associated with fever, more frequent antibiotic treatment, worse radiologic findings, and higher neutrophil counts (P<.01). In adjusted analyses, S. pneumoniae/H. influenzae codetection was independentlyassociated with greater odds of hospitalization, higher disease severity scores, need for supplemental oxygen, and longer hospitalization.

Conclusions

Nasopharyngeal codetection of S. pneumoniae and H. influenzae in infants with RSV infection is associated with increased disease severity.
Telavancin pharmacokinetics in patients with chronic kidney disease receiving haemodialysis
Authors: Gharibian Katherine N , Lewis Susan J , Heung Michael , Segal Jonathan H , Salama Noha N , Mueller Bruce A
Published: September 2021

Background

Telavancin is a lipoglycopeptide antibiotic with limited pharmacokinetic data to guide drug dosing in patients receiving haemodialysis.

Objectives

This study characterized telavancin pharmacokinetics in patients receiving haemodialysis.

Patients and methods

This was a Phase IV, prospective, open-label, single-centre, crossover pharmacokinetic study (ClinicalTrials.gov: NCT02392208). Eight subjects with end-stage kidney disease requiring maintenance haemodialysis (mean ± SD: 47 ± 20 years, 69.5 ± 17.1 kg) received 5 mg/kg telavancin IV 3 h before starting a 3.5 hour haemodialysis treatment with a high-permeability haemodialyser (haemodialysis period). After a 14 day washout period, a second 5 mg/kg dose was administered post-haemodialysis (control period). Telavancin plasma concentrations were measured over a 2 day period after each dose and non-compartmental pharmacokinetic analyses were performed.

Results

The geometric mean (GM) of telavancin overall clearance was 11.2 mL/h/kg (intrinsic clearance and dialytic clearance) in the haemodialysis period and 5.9 mL/h/kg (off-haemodialysis clearance) in the control period [GM ratio (GMR) = 1.89; 90% CI: 1.70–2.10; P < 0.01]. The GM t½ was 13.1 h when haemodialysis occurred 3 h post-dosing in the haemodialysis period but extended to 20.9 h with post-haemodialysis dosing in the control period (GMR = 0.63; 90% CI: 0.54–0.73; P < 0.01). The GM of telavancin plasma concentrations removed by haemodialysis was 27.7%. The GMR of peak plasma concentration and volume of distribution of the haemodialysis period and the control period were 0.88 (90% CI: 0.79–0.98; P = 0.08) and 1.17 (90% CI: 1.05–1.30; P = 0.048), respectively.

Conclusions

Haemodialysis with high-permeability haemodialysers removes telavancin considerably (∼⅓ of body load). Telavancin 5 mg/kg every 48 h post-haemodialysis dosing is recommended, but dose adjustments may be warranted if haemodialysis starts within 3 h of telavancin administration.
Facultative Parthenogenesis in California Condors
Authors: Ryder Oliver A , Thomas Steven , Judson Jessica Martin , Romanov Michael N , Dandekar Sugandha , Papp Jeanette C , Sidak-Loftis Lindsay C , Walker Kelli , Stalis Ilse H , Mace Michael , Steiner Cynthia C , Chemnick Leona G
Published: September 2021

Parthenogenesis is a relatively rare event in birds, documented in unfertilized eggs from columbid, galliform, and passerine females with no access to males. In the critically endangered California condor, parentage analysis conducted utilizing polymorphic microsatellite loci has identified two instances of parthenogenetic development from the eggs of two females in the captive breeding program, each continuously housed with a reproductively capable male with whom they had produced offspring. Paternal genetic contribution to the two chicks was excluded. Both parthenotes possessed the expected male ZZ sex chromosomes and were homozygous for all evaluated markers inherited from their dams. These findings represent the first molecular marker-based identification of facultative parthenogenesis in an avian species, notably of females in regular contact with fertile males, and add to the phylogenetic breadth of vertebrate taxa documented to have reproduced via asexual reproduction.
Increased precipitation magnifies the effects of N addition on performance of invasive plants in subtropical native communities
Authors: Li Xiang-Qin , Tang Sai-Chun , Pan Yu-Mei , Wei Chun-Qiang , Lü Shi-Hong
Published: September 2021

Nitrogen (N) deposition, precipitation and their interaction affect plant invasions in temperate ecosystems with limiting N and water resources, but whether and how they affect plant invasions in subtropical native communities with abundant N and precipitation remains unclear.

We constructed in situ artificial communities with 12 common native plant species in a subtropical system and introduced four common invasive plant species and their native counterparts to these communities. We compared plant growth and establishment of introduced invasive species and native counterparts in communities exposed to ambient (CK), N addition (N+), increased precipitation (P+) and N addition plus increased precipitation (P+N+). We also investigated the density and aboveground biomass of communities under such conditions.

P+ alone did not enhance the performance of invasive species or native counterparts. N+ enhanced only the aboveground biomass and relative density of invasive species. P+N+ enhanced the growth and establishment performance of both invasive species and native counterparts. Most growth and establishment parameters of invasive species were greater than those of native counterparts under N+, P+ and P+N+ conditions. The density and aboveground biomass of native communities established by invasive species were significantly lower than those of native communities established by native counterparts under P+N+ conditions. These results suggest that P+ may magnify the effects of N+ on performance of invasive species in subtropical native communities where N and water are often abundant, which may help to understand the effect of global change on plant invasion in subtropical ecosystems.
Self-calibrating the look-elsewhere effect: fast evaluation of the statistical significance using peak heights
Authors: Bayer Adrian E , Seljak Uroš , Robnik Jakob
Published: September 2021

In experiments where one searches a large parameter space for an anomaly, one often finds many spurious noise-induced peaks in the likelihood. This is known as the look-elsewhere effect, and must be corrected for when performing statistical analysis. This paper introduces a method to calibrate the false alarm probability (FAP), or p-value, for a given dataset by considering the heights of the highest peaks in the likelihood. Specifically, we derive an equation relating the global p-value to the rank and height of local maxima. In the simplest form of self-calibration, the look-elsewhere-corrected $\chi^2$ of a physical peak is approximated by the $\chi^2$ of the peak minus the $\chi^2$ of the highest noise-induced peak, with accuracy improved by considering lower peaks. In contrast to alternative methods, this approach has negligible computational cost as peaks in the likelihood are a byproduct of every peak-search analysis. We apply to examples from astronomy, including planet detection, periodograms, and cosmology.
Regular and chaotic orbits in axisymmetric stellar systems
Authors: Pascale Raffaele , Nipoti Carlo , Ciotti Luca
Published: September 2021

The gravitational potentials of realistic galaxy models are in general non-integrable, in the sense that they admit orbits that do not have three independent isolating integrals of motion and are therefore chaotic. However, if chaotic orbits are a small minority in a stellar system, it is expected that they have negligible impact on the main dynamical properties of the system. In this paper, we address the question of quantifying the importance of chaotic orbits in a stellar system, focusing, for simplicity, on axisymmetric systems. Chaotic orbits have been found in essentially all (non-Stäckel) axisymmetric gravitational potentials in which they have been looked for. Based on the analysis of the surfaces of section, we add new examples to those in the literature, finding chaotic orbits, as well as resonantly trapped orbits among regular orbits, in Miyamoto-Nagai, flattened logarithmic and shifted Plummer axisymmetric potentials. We define the fractional contributions in mass of chaotic (ξc) and resonantly trapped (ξt) orbits to a stellar system of given distribution function (DF), which are very useful quantities, for instance in the study of the dispersal of stellar streams of galaxy satellites. As a case study, we measure ξc and ξt in two axisymmetric stellar systems obtained by populating flattened logarithmic potentials with the Evans ergodic DF, finding ξc ∼ 10−4 − 10−3 and ξt ∼ 10−2 − 10−1.
Plasma screening of nuclear fusion reactions in liquid layers of compact degenerate stars: a first-principle study
Authors: Baiko D A
Published: September 2021

A reliable description of nuclear fusion reactions in inner layers of white dwarfs and envelopes of neutron stars is important for realistic modelling of a wide range of observable astrophysical phenomena from accreting neutron stars to Type Ia supernovae. We study the problem of screening of the Coulomb barrier impeding the reactions by a plasma surrounding the fusing nuclei. Numerical calculations of the screening factor are performed from the first principles with the aid of quantum-mechanical path integrals in the model of a one-component plasma of atomic nuclei for temperatures and densities typical for dense liquid layers of compact degenerate stars. We do not rely on various quasi-classic approximations widely used in the literature, such as factoring out the tunnelling process, tunnelling in an average spherically symmetric mean-force potential, usage of classic free energies and pair correlation functions, linear mixing rule, and so on. In general, a good agreement with earlier results from the thermonuclear limit to Γ ∼ 100 is found. For a very strongly coupled liquid 100 ≲ Γ ≤ 175, a deviation from currently used parametrizations of the reaction rates is discovered and approximated by a simple analytic expression. The developed method of nuclear reaction rate calculations with account of plasma screening can be extended to ion mixtures and crystallized phases of stellar matter.
A general framework to test gravity using galaxy clusters – V. A self-consistent pipeline for unbiased constraints of f(R) gravity
Authors: Mitchell Myles A , Arnold Christian , Li Baojiu
Published: September 2021

We present a Markov chain Monte Carlo pipeline that can be used for robust and unbiased constraints of f(R) gravity using galaxy cluster number counts. This pipeline makes use of a detailed modelling of the halo mass function in f(R) gravity, which is based on the spherical collapse model and calibrated by simulations, and fully accounts for the effects of the fifth force on the dynamical mass, the halo concentration, and the observable–mass scaling relations. Using a set of mock cluster catalogues observed through the thermal Sunyaev–Zel’dovich effect, we demonstrate that this pipeline, which constrains the present-day background scalar field fR0, performs very well for both Lambda cold dark matter (ΛCDM) and f(R) fiducial cosmologies. We find that using an incomplete treatment of the scaling relation, which could deviate from the usual power-law behaviour in f(R) gravity, can lead to imprecise and biased constraints. We also find that various degeneracies between the modified gravity, cosmological, and scaling relation parameters can significantly affect the constraints, and show how this can be rectified by using tighter priors and better knowledge of the cosmological and scaling relation parameters. Our pipeline can be easily extended to other modified gravity models, to test gravity on large scales using galaxy cluster catalogues from ongoing and upcoming surveys.
In vitro and integrated in vivo strategies to reduce animal use in genotoxicity testing
Authors: Groff Katherine , Evans Stephen J , Doak Shareen H , Pfuhler Stefan , Corvi Raffaella , Saunders Samantha , Stoddart Gilly
Published: September 2021

Abstract

Scientific, financial, and ethical drivers have led to unprecedented interest in implementing human-relevant, mechanistic in vitro and in silico testing approaches. Further, as non-animal approaches are being developed and validated, researchers are interested in strategies that can immediately reduce the use of animals in toxicology testing. Here, we aim to outline a testing strategy for assessing genotoxicity beginning with standard in vitro methods, such as the bacterial reverse mutation test and the in vitro micronucleus test, followed by a second tier of in vitro assays including those using advanced 3D tissue models. Where regulatory agencies require in vivo testing, one demonstrated strategy is to combine genotoxicity studies traditionally conducted separately into a single test or to integrate genotoxicity studies into other toxicity studies. Standard setting organisations and regulatory agencies have encouraged such strategies, and examples of their use can be found in the scientific literature. Employing approaches outlined here will reduce animal use as well as study time and costs.
Coupling high-throughput mapping with proteomics analysis delineates cis-regulatory elements at high resolution
Authors: Wu Ting , Jiang Danli , Zou Meijuan , Sun Wei , Wu Di , Cui Jing , Huntress Ian , Peng Xinxia , Li Gang
Published: September 2021

Growing evidence suggests that functional cis-regulatory elements (cis-REs) not only exist in epigenetically marked but also in unmarked sites of the human genome. While it is already difficult to identify cis-REs in the epigenetically marked sites, interrogating cis-REs residing within the unmarked sites is even more challenging. Here, we report adapting Reel-seq, an in vitro high-throughput (HTP) technique, to fine-map cis-REs at high resolution over a large region of the human genome in a systematic and continuous manner. Using Reel-seq, as a proof-of-principle, we identified 408 candidate cis-REs by mapping a 58 kb core region on the aging-related CDKN2A/B locus that harbors p16INK4a. By coupling Reel-seq with FREP-MS, a proteomics analysis technique, we characterized two cis-REs, one in an epigenetically marked site and the other in an epigenetically unmarked site. These elements are shown to regulate the p16INK4a expression over an ∼100 kb distance by recruiting the poly(A) binding protein PABPC1 and the transcription factor FOXC2. Downregulation of either PABPC1 or FOXC2 in human endothelial cells (ECs) can induce the p16INK4a-dependent cellular senescence. Thus, we confirmed the utility of Reel-seq and FREP-MS analyses for the systematic identification of cis-REs at high resolution over a large region of the human genome.
ELTD1 as a multi-focal target for malignant gliomas: preclinical studies
Authors: Zalles Michelle , Smith Nataliya , Saunders Debra , Guzman Mayra , Lerner Megan , Fung Kar-Ming , Babu Anish , Battiste James , Chung Junho , Hwang Kyusang , Jin Junyeong , Towner Rheal A
Published: September 2021

Background

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults. These high-grade gliomas undergo unregulated vascular angiogenesis, migration and cell proliferation allowing the tumor cells to evade cell-cycle checkpoints and apoptotic pathways. The Epidermal growth factor, latrophilin, and seven transmembrane domain-containing 1 on chromosome 1 (ELTD1) is an angiogenic biomarker that is highly expressed in malignant gliomas. Novel treatments targeting ELTD1 with monovalent monoclonal (mmAb) and single chain variable fragment (scFv) antibodies were effective in increasing animal survival, decreasing tumor volume and normalizing the vasculature. Due to the success of our antibody treatments on angiogenesis, this study sought to determine if our anti-ELTD1 treatments affected other aspects of tumorigenesis (cell proliferation, migration, and apoptosis) in a G55 glioma xenograft preclinical mouse model.

Methods

Tumor tissue from untreated, mmAb and scFv anti-ELTD1 treated animals was used to quantify the positivity levels of human mitochondrial antibody, c-MET and Ki-67 for cellular proliferation, migratory markers CD44v6, TRPM8, and BMP2, and cleaved caspase 3 to assess apoptotic activity.

Results

This approach demonstrated that our anti-ELTD1 treatments directly affected and decreased the human tumor cells within the tumor region. Additionally, there was a significant decrease in both cellular proliferation and migration due to anti-ETLD1 therapy. Lastly, anti-ELTD1 treatments successfully increased apoptotic activity within the tumor region.

Conclusion

Our data suggest that anti-ELTD1 therapies would be effective against malignant gliomas by having a multi-focal effect and targeting all four aspects of tumorigenesis.
Adolescents’ Use of Nicotine-Free and Nicotine E-Cigarettes: A Longitudinal Study of Vaping Transitions and Vaper Characteristics
Authors: Tokle Rikke , Brunborg Geir Scott , Vedøy Tord Finne
Published: September 2021

Introduction

Although adolescents’ nicotine addiction from e-cigarettes is a concern, few studies differentiate between vaping with and without nicotine. This study examines the prevalence of nicotine and nicotine-free vaping, maps transitions between vaping behaviors, and assesses differences in the personal characteristics of vapers in a sample of Norwegian adolescents.

Aims and Methods

Data came from a nationwide longitudinal study of adolescents (n = 2018) conducted in 2017 (T1), 2018 (T2), and 2019 (T3) (mean age: 14.2, 15.0, and 16.2). Using an online questionnaire, we measured vaping with and without nicotine, snus use, smoking, sensation-seeking, conduct problems, and levels of depression.

Results

Past 12-month vaping prevalence was stable (12%, 13%, and 15%). Among adolescents reporting vaping at T1, 66% had used e-cigarettes without nicotine, 22% with nicotine, and 12% were unsure of nicotine content. Individual vaping trajectories were unstable: of nicotine-free vapers, 54% became non-users, while 14% became nicotine vapers from T1 to T2. From T2 to T3, 50% became non-users, while 17% became nicotine vapers. Of nicotine vapers, 39% became non-users from T1 to T2, while 46% became non-users from T2 to T3. Compared to nicotine-free vapers, nicotine vapers had more conduct problems (mean = 3.67 vs 2.17), had more symptoms of depression (mean = 11.38 vs 6.95), and comprised more past 30-day snus users (33% vs 14%) and cigarette users (33% vs 9%).

Conclusions

Adolescent vapers most commonly used e-cigarettes without nicotine, few of these transitioned into nicotine vaping, and a majority became non-users. Nicotine vapers were more likely to use other tobacco products and have more conduct problems and symptoms of depression compared to nicotine-free vapers.

Implications

Reporting the prevalence of nicotine-free vaping is critical for assessing nicotine exposure and subsequent risks of nicotine addiction. This multi-cohort longitudinal study showed that use of nicotine-free e-cigarettes is common among young vapers in Norway. Adolescents’ vaping patterns—both with and without nicotine—are generally temporal and experimental. Despite the majority of nicotine vapers becoming non-users, they are characterized by having more conduct problems and poorer mental health, and they more often used other tobacco products.
A New Philosophy for the Margin of Appreciation and European Consensus
Authors: Tripkovic Bosko
Published: September 2021

The article advances an anti-foundationalist account of the key doctrines of the European Court of Human Rights (ECtHR): the margin of appreciation (MoA) and European consensus (EuC). The first part of the article argues that anti-foundationalism, which understands the existence of human rights as ultimately dependent on social practices and their justification as based on a plurality of values, is a credible conception of human rights grounds. The second part contends that anti-foundationalism offers the best explanation of the MoA and EuC, without making the ECtHR’s practice less normatively appealing. These arguments challenge the dominant critiques of the MoA and EuC, which often assume, but rarely explicitly defend, a foundationalist understanding of human rights. While the ECtHR’s use of the MoA and EuC can be inadequate, this is not because it is mistaken about the grounds of human rights.
Dynastic Scenario Thinking in the Holy Roman Empire
Authors: van der Steen Jasper
Published: September 2021

Owing to the prevailing definition of ‘dynasty’ as a line of succession, historians have long neglected the fundamental tensions that underlie succession, and have undervalued both the active attempts of princes to control these tensions as well as their ability to anticipate the need to adjust to changing circumstances. Yet premodern dynasties were well equipped to anticipate and develop coping mechanisms for a wide range of future challenges regarding succession, religion, marital alliances and extinction. They did so by considering alternative scenarios for the future in house regulations. Using as an example the seventeenth-century house of Nassau in the Holy Roman Empire, this article argues that even though conflict remained endemic to dynastic power, future-orientated regulations constituted a basic consensus within princely families on how to deal with conflict, which both reflected and contributed to the associative political practices that held the Holy Roman Empire together.
Assessment, diagnosis, and management of developmental coordination disorder
Authors: Ip Angie , Mickelson Elizabeth C R , Zwicker Jill G
Published: September 2021

Developmental coordination disorder (DCD) is a neurodevelopmental condition that affects 5% to 6% of school-aged children. DCD can significantly impact early development and life-long functioning. Evidence supports promising interventions for DCD, but the disorder continues to be under-recognized and under-diagnosed. Paediatricians play an important role in the identification and management of DCD. This practice point, with accompanying tables, assists and supports paediatricians in diagnosing and managing uncomplicated cases of DCD.
Purification of MAP–kinase protein complexes and identification of candidate components by XL–TAP–MS
Authors: Leissing Franz , Misch Nicola V , Wang Xiaorong , Werner Linda , Huang Lan , Conrath Uwe , Beckers Gerold J M
Published: September 2021

The purification of low-abundance protein complexes and detection of in vivo protein–protein interactions in complex biological samples remains a challenging task. Here, we devised crosslinking and tandem affinity purification coupled to mass spectrometry (XL–TAP–MS), a quantitative proteomics approach for analyzing tandem affinity-purified, crosslinked protein complexes from plant tissues. We exemplarily applied XL–TAP–MS to study the MKK2–Mitogen-activated protein kinase (MPK4) signaling module in Arabidopsis thaliana. A tandem affinity tag consisting of an in vivo-biotinylated protein domain flanked by two hexahistidine sequences was adopted to allow for the affinity-based isolation of formaldehyde–crosslinked protein complexes under fully denaturing conditions. Combined with 15N stable isotopic labeling and tandem MS we captured and identified a total of 107 MKK2–MPK4 module-interacting proteins. Consistent with the role of the MPK signaling module in plant immunity, many of the module-interacting proteins are involved in the biotic and abiotic stress response of Arabidopsis. Validation of binary protein–protein interactions by in planta split-luciferase assays and in vitro kinase assays disclosed several direct phosphorylation targets of MPK4. Together, the XL–TAP–MS approach purifies low abundance protein complexes from biological samples and discovers previously unknown protein–protein interactions.
Spatiotemporal cytokinin response imaging and ISOPENTENYLTRANSFERASE 3 function in Medicago nodule development
Authors: Triozzi Paolo M , Irving Thomas B , Schmidt Henry W , Keyser Zachary P , Chakraborty Sanhita , Balmant Kelly , Pereira Wendell J , Dervinis Christopher , Mysore Kirankumar S , Wen Jiangqi , Ané Jean-Michel , Kirst Matias , Conde Daniel
Published: September 2021

Most legumes can establish a symbiotic association with soil rhizobia that trigger the development of root nodules. These nodules host the rhizobia and allow them to fix nitrogen efficiently. The perception of bacterial lipo-chitooligosaccharides (LCOs) in the epidermis initiates a signaling cascade that allows rhizobial intracellular infection in the root and de-differentiation and activation of cell division that gives rise to the nodule. Thus, nodule organogenesis and rhizobial infection need to be coupled in space and time for successful nodulation. The plant hormone cytokinin (CK) contributes to the coordination of this process, acting as an essential positive regulator of nodule organogenesis. However, the temporal regulation of tissue-specific CK signaling and biosynthesis in response to LCOs or Sinorhizobium meliloti inoculation in Medicago truncatula remains poorly understood. In this study, using a fluorescence-based CK sensor (pTCSn::nls:tGFP), we performed a high-resolution tissue-specific temporal characterization of the sequential activation of CK response during root infection and nodule development in M. truncatula after inoculation with S. meliloti. Loss-of-function mutants of the CK-biosynthetic gene ISOPENTENYLTRANSFERASE 3 (IPT3) showed impairment of nodulation, suggesting that IPT3 is required for nodule development in M. truncatula. Simultaneous live imaging of pIPT3::nls:tdTOMATO and the CK sensor showed that IPT3 induction in the pericycle at the base of nodule primordium contributes to CK biosynthesis, which in turn promotes expression of positive regulators of nodule organogenesis in M. truncatula.
Two TOBAMOVIRUS MULTIPLICATION 2A homologs in tobacco control asymptomatic response to tobacco mosaic virus
Authors: Hu Qun , Zhang Hui , Zhang Lei , Liu Yong , Huang Changjun , Yuan Cheng , Chen Zefan , Li Kunpeng , Larkin Robert M , Chen Jiongjiong , Kuang Hanhui
Published: September 2021

The most common response of a host to pathogens is arguably the asymptomatic response. However, the genetic and molecular mechanisms responsible for asymptomatic responses to pathogens are poorly understood. Here we report on the genetic cloning of two genes controlling the asymptomatic response to tobacco mosaic virus (TMV) in cultivated tobacco (Nicotiana tabacum). These two genes are homologous to tobamovirus multiplication 2A (TOM2A) from Arabidopsis, which was shown to be critical for the accumulation of TMV. Expression analysis indicates that the TOM2A genes might play fundamental roles in plant development or in responses to stresses. Consistent with this hypothesis, a null allele of the TOM2A ortholog in tomato (Solanum lycopersicum) led to the development of bent branches and a high tolerance to both TMV and tomato mosaic virus (ToMV). However, the TOM2A ortholog in Nicotiana glauca did not account for the asymptomatic response to TMV in N. glauca. We showed that TOM2A family is plant-specific and originated from Chlorophyte, and the biological functions of TOM2A orthologs to promote TMV accumulation are highly conserved in the plant kingdom—in both TMV host and nonhost species. In addition, we showed that the interaction between tobacco TOM1 and TOM2A orthologs in plant species is conserved, suggesting a conserved nature of TOM1–TOM2A module in promoting TMV multiplication in plants. The tradeoff between host development, the resistance of hosts to pathogens, and their influence on gene evolution are discussed. Our results shed light on mechanisms that contribute to asymptomatic responses to viruses in plants and provide approaches for developing TMV/ToMV-resistant crops.
Social Proximity to Capital: Implications for Investors and Firms
Authors: Kuchler Theresa , Li Yan , Peng Lin , Stroebel Johannes , Zhou Dexin
Published: September 2021

We show that institutional investors are more likely to invest in firms from regions to which they have stronger social ties but find no evidence that these investments earn a differential return. Firms in regions with stronger social ties to locations with many institutional investors have higher valuations and liquidity. These effects are largest for small firms with little analyst coverage, suggesting that the investors’ behavior is explained by their increased awareness of firms in socially proximate locations. Our results highlight that the social structure of regions affects firms’ access to capital and contributes to geographic differences in economic outcomes.

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.
Improved Whole-Genome Sequence of Fusarium meridionale, the Fungal Pathogen Causing Fusarium Head Blight in Rice
Authors: Liu Xin , Fang Xin , Yu Fangwei , Wang Shuang , Zhang Zhichao , Li Kainan , Ye Wenwu , Lee Yin-Won , Mohamed Sherif Ramzy , Dong Fei , Xu Jianhong , Shi Jianrong
Published: September 2021

Members of the Fusarium graminearum species complex (FGSC) cause extensive yield losses in cereal production worldwide, and food safety concerns due to the accumulation of Fusarium toxins in infected grains. Among these pathogens, F. meridionale is responsible for Fusarium head blight of wheat and rice, ear and stalk rot of maize, and pod blight of soybean. Here, we present an improved genome assembly of F. meridionale strain SR5 isolated from rice in China based on PacBio long-read sequencing and Illumina short-read sequencing technology. The assembled genome of SR5 has a total size of 36.82 Mb, an N50 scaffold length of 7.82 Mb, nine scaffolds, and encodes 12,409 predicted genes. These high-quality data expand FGSC genomic resources and provide a valuable resource for better understanding their genetic diversity and the molecular basis of pathogenesis, which will facilitate the development of an effective control strategy.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
A SYBR Green qPCR Method for Detecting and Quantifying Spores of Colletotrichum acutatum and C. gloeosporioides Species Complexes Causing Ripe Rot of Grape
Authors: Cosseboom Scott D. , Hu Mengjun
Published: September 2021

Four species belonging to Colletotrichum acutatum and Colletotrichum gloeosporioides species complexes, including C. aenigma, C. fioriniae, C. fructicola, and C. nymphaeae, were identified from ripe rot symptomatic fruit from Mid-Atlantic vineyards. A quantitative real-time PCR (qPCR) SYBR Green method was developed to detect and quantify conidia of the two Colletotrichum complexes to better understand the distribution and the extent of Colletotrichum inoculum. Primers were designed to specifically target the β-tubulin gene of the C. acutatum complex or the C. gloeosporioides complex and were found to be specific to the desired complex, not amplifying DNA of other prevalent fungi from vineyards. The sensitivity of the primers was also assessed, and the C. acutatum complex-specific and C. gloeosporioides complex-specific primers were able to quantify as little as 50 C. fioriniae conidia and 100 C. aenigma conidia, respectively. Therefore, this would be a cost-effective, specific, and sensitive detection and quantification method for these two destructive species complexes in vineyards and many other crops through spore trapping applications.
A Retrospective Study of Hearing Loss in Patients Diagnosed with Peroxisome Biogenesis Disorders in the Zellweger Spectrum
Authors: Lee John , Yergeau Christine , Kawai Kosuke , Braverman Nancy , Géléoc Gwenaëlle S.G.
Published: September 2021

Objectives:

Peroxisome Biogenesis Disorders in the Zellweger Spectrum (PBD-ZSD) are autosomal recessive disorders characterized by defects in peroxisome function, biosynthesis, and/or assembly. Despite its frequent documentation, hearing loss associated with PBD-ZSD has not been extensively characterized. The purpose of this retrospective natural history study was to better characterize the hearing loss associated with PBD-ZSD and to provide additional insight into the evaluation and management of PBD-ZSD patients with hearing loss.

Design:

Audiological data from medical records of 42 patients with PBD-ZSD or D-bifunctional protein deficiency were collected from an ongoing longitudinal retrospective natural history study. An initial dataset of 300 audiograms and/or audiometric test results from the 42 patients were used to characterize the degree of hearing loss, type of hearing loss, relationships between air and bone conduction thresholds, age-related changes in hearing loss, and benefit with amplification.

Results:

The majority of PBD-ZSD patients in this study presented with moderately-severe to severe hearing loss and relatively slow rates of longitudinal changes in hearing sensitivity. Improvements in hearing thresholds were observed with use of hearing aid amplification. Though bone conduction data were limited, air-bone gaps and air conduction threshold fluctuations observed in several patients suggest there may be an increased occurrence of mixed hearing losses in PBD-ZSD populations.

Conclusion:

The results of this retrospective study provide insight into the hearing loss associated with PBD-ZSD, but also emphasize the need for more complete assessments of hearing loss type and middle ear function in these patients. The addition of more comprehensive datasets to the ongoing natural history study will enhance our understanding of the pathophysiology underlying PBD-ZSD and guide the development of targeted evaluation and management recommendations for patients with PBD-ZSD.
Adipose tissue and adipose secretome in systemic sclerosis
Authors: Brezovec Neža , Burja Blaž , Lakota Katja
Published: September 2021

Purpose of review

Adipose tissue is closely associated with systemic sclerosis (SSc)-pathology, both anatomically and functionally. This review focuses on local effects of adipocytes in the context of adipose to mesenchymal transdifferentiation (AMT), effects of the adipose stromal vascular fraction on SSc pathogenesis and systemic effects of adipose tissue secretome.

Recent findings

Novel populations of fibroblasts evolving from adipose tissue were identified– for example COL11+ cancer-associated fibroblasts differentiated from adipose-derived stromal cells. Lipofibroblasts in human lungs were described using nonconventional markers that allow more effective population identification. These findings could make an important contribution to further clarification of adipocyte involvement in SSc.

Recent studies confirmed that lipolysis contributes to fibrogenesis through AMT differentiation and release of fatty acids (FA). Unbalanced metabolism of FA has been reported in several studies in SSc. Other adipose tissue secretome molecules (e.g. lysophosphatidic acid), novel adipokines and extracellular vesicles from adipose mesenchymal stem cells make important contributions to the pro-/antifibrotic balance.

There is a growing evidence of important contribution of adipose tissue and its secretome to SSc pathogenesis. Novel techniques such as single-cell RNA sequencing (scRNAseq) and metabolomics, albeit challenging to use in adipose tissue, will provide further evidence.
Managing Bone Defects in the Femur With a Motorized Intramedullary Bone Transport Nail: Case Review With Follow-Up
Authors: Kern Thomas
Published: September 2021

Bone transport is an effective treatment for segmental bone defects. Until now, the need for external fixation, at least during the transport phase, has been a major disadvantage. New developments such as the bone transport nail allow an all-internal bone transport. A segment transport nail and the therapy regimen are described, and first cases are presented.
What Are the Rate and Risk Factors for Developing a Complication With the Pavlik Method for the Treatment of Hip Dysplasia?
Authors: Masrouha Karim , Gibon Emmanuel , Roof Mackenzie A. , Castañeda Pablo
Published: September 2021

Background:

The Pavlik method for the treatment of developmental dysplasia of the hip (DDH) has been proven successful for over 85 years. The high success rate and reproducibility have made it the mainstay of treatment.

Methods:

We performed a retrospective cohort study of patients with DDH treated with the Pavlik method between September 2016 and August 2018 with at least 24 months of follow up in a single academic center. We excluded patients with neuromuscular conditions, teratologic dislocations, and arthrogryposis. We identified and included a total of 307 patients in the analysis. There were 66 patients with dysplasia, 97 with instability, and 144 with a dislocation. Data collected included age at initiation of the Pavlik method, diagnosis (isolated dysplasia, subluxation, or dislocation), duration of treatment, follow up duration and any complication. At final follow up, anteroposterior radiographs of the pelvis were used to determine the Severin classification.

Results:

Major complications were proximal femoral growth disturbance (5.8%) and femoral nerve palsy (0.98%). Multivariate analysis showed that an initial diagnosis of a dislocated hip (odds ratio, 2.20; P<0.01), was significantly associated with developing a complication. At final follow up, we found Severin type I or II radiographic findings in 100% of patients with dysplasia, 95% of patients with instability and 54% of patients with dislocation (P=0.001).

Conclusions:

Complications are not entirely uncommon when the Pavlik method is used for the treatment of DDH. The overall rate of major complications was 7%. The Pavlik method is safe, and independent risk factors for complications were being over 5 months of age and having a dislocated hip at initial presentation.

Level of Evidence:

Level IV—cohort study.
Effective Implementation of Ventilator Care Bundles in Improves Outcomes: A Multicenter Randomized Controlled Clinical Trial
Authors: Rahimi-Bashar Farshid , Gohari-Moghadam Keivan , Vahedian-Azimi Amir
Published: September 2021

OBJECTIVES:

To evaluate the effect of 17-ventilator care bundles and different training strategies for critical care nurses on clinical outcomes.

DESIGN:

A randomized controlled triple-blinded clinical trial.

SETTING:

The multicenter study was conducted in four academic teaching hospitals in Tehran, Iran, from October 2011 to June 2015.

PATIENTS:

A total of 1,600 adult patients (age ≥ 18 yr) who were admitted to mixed medical-surgical ICUs (> 72 hr) and received invasive ventilation (> 48 hr) were included in this study. In addition, 160 critical care nurses were recruited through letters and telephone and face-to-face invitations.

INTERVENTIONS:

Seventeen-ventilator care bundles applied by four different groups of nurses.

MEASUREMENTS AND MAIN RESULTS:

Clinical outcomes were compared between four groups of study which include three intervention groups (who received 17-ventilator care bundles by trained nurses) and one control group (who received routine care). According to the results, ICU length of stay, non-ICU length of stay, ventilator-associated pneumonia occurrence date, ventilator-associated pneumonia, and mortality rates were significantly higher in control group compared with other groups.

CONCLUSIONS:

Critical care nurses training program to accurately implement 17-ventilator care bundles improves outcomes.
Geriatric assessments and frailty scores in multiple myeloma patients: a needed tool for individualized treatment?
Authors: Möller Mandy-Deborah , Gengenbach Laura , Graziani Giulia , Greil Christine , Wäsch Ralph , Engelhardt Monika
Published: September 2021

Purpose of review

Multiple myeloma is a disease of elderly adults. Improvement in survival has occurred because of biological insights and novel agents. Therapeutic options involve choices today, thus have become more complex. Demographics have led to an increased number of elderly patients and age may be associated with a poorer outcome but is not the only prognostic predictor today.

Recent findings

To evaluate patients’ health status rather than their chronological age alone, frailty scores and functional geriatric assessments are used to identify prognostic groups, avoid adverse events, compare clinical trials and tailor treatment. As most clinical trials exclude frail elderly patients, those enrolled therein are often younger and healthier than the typical multiple myeloma patient. This represents a challenge for frail cohorts because of their increased risk of adverse events, overtreatment and undertreatment and/or therapy discontinuation, which may lead to poorer survival and quality of life (QoL). Reassessing patients’ status via geriatric assessments is also relevant during treatment to adjust interventions appropriately.

Integrating geriatric assessments may lead to individual treatment decisions, dose adjustments, better clinical outcome and QoL. Prospective clinical trials that enroll elderly multiple myeloma patients with comorbidities, incorporate frailty scores/geriatric assessments and help with prognostication, adverse event avoidance and QoL maintenance, remain warranted.
Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome
Authors: Nummela Aleksi J. , Laaksonen Lauri T. , Laitio Timo T. , Kallionpää Roosa E. , Långsjö Jaakko W. , Scheinin Joonas M. , Vahlberg Tero J. , Koskela Harri T. , Aittomäki Viljami , Valli Katja J. , Revonsuo Antti , Niemi Mikko , Perola Markus , Scheinin Harry
Published: September 2021

BACKGROUND

Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown.

OBJECTIVE

We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile.

DESIGN

Randomised, open-label, controlled, parallel group, phase IV clinical drug trial.

SETTING

The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017.

PARTICIPANTS

One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable.

INTERVENTIONS

Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml−1; n 
= 40), propofol (1.7 μg ml−1; n 
= 40), sevoflurane (0.9% end-tidal; n 
= 39), S-ketamine (0.75 μg ml−1; n 
= 20) or placebo (n = 20).

MAIN OUTCOME MEASURES

Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min post-anaesthesia.

RESULTS

All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereasbranched chain amino acids and tyrosine decreased.

CONCLUSION

A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror a2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT02624401
Ischemic mitral regurgitation: when should one intervene?
Authors: Rahmouni Kenza , Shahinian Jasmin H. , Deng Mimi , Qureshi Saqib , Chikwe Joanna , Chan Vincent
Published: September 2021

Purpose of review

Optimal timing of intervention for ischemic mitral regurgitation remains to be elucidated. This review summarizes the data on the management of ischemic mitral regurgitation, and their implications on current practice and future research.

Recent findings

Mechanistically, ischemic mitral regurgitation can present as Type I, Type IIIb or mixed Type I and IIIb disease. Severity of mitral regurgitation is typically quantified with echocardiography, either transthoracic or transesophageal echocardiography, but may also be assessed via cardiac MRI. In patients with moderate ischemic mitral regurgitation, revascularization can lead to left ventricular reverse remodeling in some. In patients with severe ischemic mitral regurgitation, mitral valve replacement may be associated with fewer adverse events related to heart failure and cardiovascular readmissions, compared with valve repair, although reverse remodeling may be better in patients following successful mitral repair. Transcatheter edge-to-edge repair also further complements the treatment of ischemic mitral regurgitation.

A tailored approach to patients should be considered for each patient presenting with ischemic mitral regurgitation.