bluuebunny/crossref_metadata_2025_split huggingface dataset:
The potential of mini‐ridging for controlling intrarow weeds: estimating minimum lethal burial depth
Authors: Merfield Charles N. , Bennett Jacquelyn R. , Berry Nadine A. , Bluon Arthur , O’Connell Dean M. , Hodge Simon 
Published: August 2020

AbstractWeed management using synthetic herbicides is undergoing a global decline, necessitating a re‐evaluation of existing control measures and the development of novel weed management tools. ‘Mini‐ridging’ is a non‐discriminatory, physical weeding method that functions by burying weeds in the intrarow with a laterally shifted ridge of soil. In glasshouse trials using potted plants, we found that plant recovery after soil application was influenced by plant size, which in turn was influenced by plant species, developmental stage and/or age. The likelihood of plant recovery after soil application was negatively related to the depth of soil applied: very few plants survived total coverage by soil but, conversely, survival could be substantial if some parts of the plants were not covered. The results suggest that burial under a depth of 6 cm of soil would eliminate most plants regardless of species or growth stage. Larger plants would require the application of a greater total depth of soil to achieve this 6 cm of soil cover, and weed management would, therefore, tend to be more successful and more practical if weeds were targeted when still small. This research demonstrates the potential of plant burial as a simple and reliable means of non‐chemical weed management, and re‐emphasises that, for weed control to be effective, the applied soil layer must cover the whole plant.
Internet-scale Insecurity of Consumer Internet of Things
Authors: Mangino Antonio , Pour Morteza Safaei , Bou-Harb Elias 
Published: August 2020

The number of Internet-of-Things (IoT) devices actively communicating across the Internet is continually increasing, as these devices are deployed across a variety of sectors, constantly transferring private data across the Internet. Due to the extensive deployment of such devices, the continuous discovery and persistence of IoT-centric vulnerabilities in protocols, applications, hardware, and the improper management of such IoT devices has resulted in the rampant, uncontrolled spread of malware threatening consumer IoT devices.
To this end, this work adopts a novel, macroscopic methodology for fingerprinting Internet-scale compromised IoT devices, revealing crucial cyber threat intelligence on the insecurity of consumer IoT devices. By developing data-driven techniques rooted in machine learning methods and analyzing 3.6 TB of network traffic data, we discover 855,916 compromised IP addresses, with 310,164 fingerprinted as IoT. Further analysis reveals China and Brazil to be hosting the most significant population of compromised IoT devices (100,000 and 55,000, respectively). Additionally, we provide a longitudinal analysis on data from one year ago against this work, revealing the evolving trends of IoT exploitation, such as the increased number of vendors targeted by malware, rising from 50 to 131. Moreover, countries such as China (420% increased infected IoT count) and Indonesia (177% increased infected IoT count) have seen notably high increases in infection rates. Last, we compare our geographic results against Global Cybersecurity Index (GCI) ratings, verifying that countries with high GCI ratings, such as the Netherlands and Germany, had relatively low infection rates. However, upon further inspection, we find that the GCI rate does not accurately represent the consumer IoT market, with countries such as China and Russia being rated with “high” CGI scores, yet hosting a large population of infected consumer IoT devices.
Targeting TSLP-Induced Tyrosine Kinase Signaling Pathways in CRLF2-Rearranged Ph-like ALL
Authors: Sia Keith C.S. , Zhong Ling , Mayoh Chelsea , Norris Murray D. , Haber Michelle , Marshall Glenn M. , Raftery Mark J. , Lock Richard B. 
Published: August 2020

Abstract

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is characterized by aberrant activation of signaling pathways and high risk of relapse. Approximately 50% of Ph-like ALL cases overexpress cytokine receptor-like factor 2 (CRLF2) associated with gene rearrangement. Activated by its ligand thymic stromal lymphopoietin (TSLP), CRLF2 signaling is critical for the development, proliferation, and survival of normal lymphocytes. To examine activation of tyrosine kinases regulated by TSLP/CRLF2, phosphotyrosine (P-Tyr) profiling coupled with stable isotope labeling of amino acids in cell culture (SILAC) was conducted using two CRLF2-rearranged (CRLF2r) Ph-like ALL cell lines stimulated with TSLP. As a result, increased P-Tyr was detected in previously reported TSLP-activated tyrosine kinases and substrates, including JAK1, JAK2, STAT5, and ERK1/2. Interestingly, TSLP also increased P-Tyr of insulin growth factor 1 receptor (IGF1R) and fibroblast growth factor receptor 1 (FGFR1), both of which can be targeted with small-molecule inhibitors. Fixed-ratio combination cytotoxicity assays using the tyrosine kinase inhibitors BMS-754807 and ponatinib that target IGF1R and FGFR1, respectively, revealed strong synergy against both cell line and patient-derived xenograft (PDX) models of CRLF2r Ph-like ALL. Further analyses also indicated off-target effects of ponatinib in the synergy, and novel association of the Ras-associated protein-1 (Rap1) signaling pathway with TSLP signaling in CRLF2r Ph-like ALL. When tested in vivo, the BMS-754807/ponatinib combination exerted minimal efficacy against 2 Ph-like ALL PDXs, associated with low achievable plasma drug concentrations. Although this study identified potential new targets in CRLF2r Ph-like ALL, it also highlights that in vivo validation of synergistic drug interactions is essential.

Implication:
Quantitative phosphotyrosine profiling identified potential therapeutic targets for high-risk CRLF2-rearranged Ph-like ALL.
Diffuse Intrinsic Pontine Glioma Cells Are Vulnerable to Mitotic Abnormalities Associated with BMI-1 Modulation
Authors: Senthil Kumar Shiva , Sengupta Satarupa , Zhu Xiaoting , Mishra Deepak Kumar , Phoenix Timothy , Dyer Lisa , Fuller Christine , Stevenson Charles B. , DeWire Mariko , Fouladi Maryam , Drissi Rachid 
Published: August 2020

AbstractDiffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor with a median survival of less than 1 year. No effective therapy is currently available, and no therapeutic advances have been made in several decades. We have previously identified BMI-1 as a potential therapeutic target in DIPG and have shown that BMI-1 is highly expressed in DIPG tumors regardless of histone 3 subtype. In the present study, we show that the modulation of BMI-1 leads to DNA damage, M phase cell-cycle arrest, chromosome scattering, and cell death. Interestingly, EZH2 inhibition did not alter these effects. Furthermore, modulation of BMI-1 sensitizes DIPG patient-derived stem-like cells to ionizing radiation (IR). Treatment of DIPG stem-like cells with PTC596, a BMI-1 modulator, and IR impairs the kinetics of DNA damage response (DDR). Both DDR foci formation and resolution were delayed, resulting in further reduction in cell viability compared with either treatment alone. In vivo, treatment of mice bearing DIPG xenografts with PTC596 leads to decreased tumor volume and growth kinetics, increased intratumoral apoptosis, and sustained animal survival benefit. Gene expression analysis indicates that BMI-1 expression correlates positively with DIPG stemness and BMI-1 signature. At the single-cell level, the analysis reveals that BMI-1 pathway is upregulated in undifferentiated cells and positively correlates with stemness in DIPG tumors.Implications:Together, our findings indicate that BMI-1 modulation is associated with mitotic abnormalities, impaired DDR, and cell death, supporting the combination of BMI-1 modulation and radiation as a promising novel therapy for children with DIPG.
RICTOR Amplification Promotes NSCLC Cell Proliferation through Formation and Activation of mTORC2 at the Expense of mTORC1
Authors: Kim Laura C. , Rhee Christopher H. , Chen Jin 
Published: August 2020

Abstract

Non–small cell lung cancer (NSCLC) is characterized by genomic alterations, yet a targetable mutation has not been discovered in nearly half of all patients. Recent studies have identified amplification of RICTOR, an mTORC2-specific cofactor, as a novel actionable target in NSCLC. mTORC2 is one of two distinct mTOR complexes to sense environmental cues and regulate a variety of cellular processes, including cell growth, proliferation, and metabolism, all of which promote tumorigenesis when aberrantly regulated. Interestingly, other components of mTORC2 are not coamplified with RICTOR in human lung cancer, raising the question as to whether RICTOR amplification-induced changes are dependent on mTORC2 function. To model RICTOR amplification, we overexpressed Rictor using the Cas9 Synergistic Activation Mediator system. Overexpression of Rictor increased mTORC2 integrity and signaling, but at the expense of mTORC1, suggesting that overexpressed Rictor recruits common components away from mTORC1. Additionally, Rictor overexpression increases the proliferation and growth of NSCLC 3D cultures and tumors in vivo. Conversely, knockout of RICTOR leads to decreased mTORC2 formation and activity, but increased mTORC1 function. Because Rictor has mTOR-dependent and -independent functions, we also knocked out mLST8, a shared mTOR cofactor but is specifically required for mTORC2 function. Inducible loss of mLST8 in RICTOR-amplified NSCLC cells inhibited mTORC2 integrity and signaling, tumor cell proliferation, and tumor growth. Collectively, these data identify a mechanism for Rictor-driven tumor progression and provide further rationale for the development of an mTORC2-specific inhibitor.

Implications:
RICTOR amplification drives NSCLC proliferation through formation of mTORC2, suggesting mTORC2-specific inhibition could be a beneficial therapeutic option.
Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade
Authors: Zhang Qu , Luo Jia , Wu Song , Si Han , Gao Chen , Xu Wenjing , Abdullah Shaad E. , Higgs Brandon W. , Dennis Phillip A. , van der Heijden Michiel S. , Segal Neil H. , Chaft Jamie E. , Hembrough Todd , Barrett J. Carl , Hellmann Matthew D. 
Published: August 2020

AbstractThe utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n = 978) and on-treatment (n = 171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (± the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of “molecular response” using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease.Significance:In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A “molecular response” metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.This article is highlighted in the In This Issue feature, p. 1775
Anti‐Inflammatory HDL Function, Incident Cardiovascular Events, and Mortality: A Secondary Analysis of the JUPITER Randomized Clinical Trial
Authors: Ajala Oluremi N. , Demler Olga V. , Liu Yanyan , Farukhi Zareen , Adelman Steven J. , Collins Heidi L. , Ridker Paul M , Rader Daniel J. , Glynn Robert J. , Mora Samia 
Published: August 2020

Background
High‐density lipoprotein (HDL) cholesterol has inverse association with cardiovascular disease. HDL possesses anti‐inflammatory properties in vitro, but it is unknown whether this may be protective in individuals with inflammation.

Methods and Results

The functional capacity of HDL to inhibit oxidation of oxidized low‐density lipoprotein (ie, the HDL inflammatory index; HII) was measured at baseline and 12 months after random allocation to rosuvastatin or placebo in a nested case‐control study of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Evaluating Rosuvastatin) trial. There were 517 incident cases of cardiovascular disease and all‐cause mortality compared to 517 age‐ and sex‐matched controls. Multivariable conditional logistic regression was used to examine associations of HII with events. Median baseline HII was 0.54 (interquartile range, 0.50–0.59). Twelve months of rosuvastatin decreased HII by a mean of 5.3% (95% CI, −8.9% to −1.7%;
P
=0.005) versus 1.3% (95% CI, −6.5% to 4.0%;
P
=0.63) with placebo (
P
=0.22 for between‐group difference). HII had a nonlinear relationship with incident events. Compared with the reference group (HII 0.5–1.0) with the lowest event rates, participants with baseline HII ≤0.5 had significantly increased risk of cardiovascular disease/mortality (adjusted hazard ratio, 1.53; 95% CI, 1.06–2.21;
P
=0.02). Furthermore, there was significant (
P
=0.002) interaction for HDL particle number with HII, such that having more HDL particles was associated with decreased risk only when HDL was anti‐inflammatory.

Conclusions
In JUPITER participants recruited on the basis of chronic inflammation, HII was associated with incident cardiovascular disease/mortality, with an optimal anti‐inflammatory HII range between 0.5 and 1.0. This nonlinear relationship of anti‐inflammatory HDL function with risk may account in part for the HDL paradox.

Registration

URL:
https://www.clini​caltr​ials.gov
; Unique identifier: NCT00239681.
Legumain in Acute Coronary Syndromes: A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial
Authors: Gregersen Ida , Michelsen Annika E. , Lunde Ngoc Nguyen , Åkerblom Axel , Lakic Tatevik G. , Skjelland Mona , Ryeng Skagen Karolina , Becker Richard C. , Lindbäck Johan , Himmelmann Anders , Solberg Rigmor , Johansen Harald T. , James Stefan K. , Siegbahn Agneta , Storey Robert F. , Kontny Frederic , Aukrust Pål , Ueland Thor , Wallentin Lars , Halvorsen Bente 
Published: August 2020

Background
The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome.

Methods and Results

Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow‐up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04–1.21),
P
=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02–1.19;
P
=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44–0.88;
P
=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37–0.88;
P
=0.0114).

Conclusions
Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome.

Registration

URL:
https://www.clini​caltr​ials.gov
; Unique identifier: NCT00391872.
Impact of Interatrial Shunts on Invasive Hemodynamics and Exercise Tolerance in Patients With Heart Failure
Authors: Griffin Jan M. , Borlaug Barry A. , Komtebedde Jan , Litwin Sheldon E. , Shah Sanjiv J. , Kaye David M. , Hoendermis Elke , Hasenfuß Gerd , Gustafsson Finn , Wolsk Emil , Uriel Nir , Burkhoff Daniel 
Published: August 2020

Approximately 50% of patients with heart failure have preserved ejection fraction. Although a wide variety of conditions cause or contribute to heart failure with preserved ejection fraction, elevated left ventricular filling pressures, particularly during exercise, are common to all causes. Acute elevation in left‐sided filling pressures promotes lung congestion and symptoms of dyspnea, while chronic elevations often lead to pulmonary vascular remodeling, right heart failure, and increased risk of mortality. Pharmacologic therapies, including neurohormonal modulation and drugs that modify the nitric oxide/cyclic GMP‐protein kinase G pathway have thus far been limited in reducing symptoms or improving outcomes in patients with heart failure with preserved ejection fraction. Hence, alternative means of reducing the detrimental rise in left‐sided heart pressures are being explored. One proposed method of achieving this is to create an interatrial shunt, thus unloading the left heart at rest and during exercise. Currently available studies have shown 3‐ to 5‐mm Hg decreases of pulmonary capillary wedge pressure during exercise despite increased workload. The mechanisms underlying the hemodynamic changes are just starting to be understood. In this review we summarize results of recent studies aimed at elucidating the potential mechanisms of improved hemodynamics during exercise tolerance following interatrial shunt implantation and the current interatrial shunt devices under investigation.
Trigeminal activation patterns evoked by chemical stimulation of the dura mater in rats
Authors: Laborc Klaudia Flóra , Spekker Eleonóra , Bohár Zsuzsanna , Szűcs Mónika , Nagy-Grócz Gábor , Fejes-Szabó Annamária , Vécsei László , Párdutz Árpád 
Published: August 2020

AbstractBackgroundAlthough migraine is one of the most common primary headaches, its therapy is still limited in many cases. The use of animal models is crucial in the development of novel therapeutic strategies, but unfortunately, none of them show all aspects of the disease, therefore, there is a constant need for further improvement in this field. The application of inflammatory agents on the dura mater is a widely accepted method to mimic neurogenic inflammation in rodents, which plays a key role in the pathomechanism of migraine. Complete Freund’s Adjuvant (CFA), and a mixture of inflammatory mediators, called inflammatory soup (IS) are often used for this purpose.MethodsTo examine the activation pattern that is caused by chemical stimulation of dura mater, we applied CFA or IS over the right parietal lobe. After 2 h and 4 h (CFA groups), or 2.5 h and 4 h (IS groups), animals were perfused, and c-Fos immunoreactive cells were counted in the caudal trigeminal nucleus. To explore every pitfall, we examined whether our surgical procedure (anesthetic drug, stereotaxic apparatus, local lidocaine) can alter the results under the same experimental settings. c-Fos labeled cells were counted in the second-order neuron area based on the somatotopic organization of the trigeminal nerve branches.ResultsWe could not find any difference between the CFA and physiological saline group neither 2 h, nor 4 h after dural stimulation. IS caused significant difference after both time points between IS treated and control group, and between treated (right) and control (left) side. Stereotaxic frame usage had a substantial effect on the obtained results.ConclusionsCounting c-Fos immunoreactive cells based on somatotopic organization of the trigeminal nerve helped to examine the effect of chemical stimulation of dura in a more specific way. As a result, the use of IS over the parietal lobe caused activation in the area of the ophthalmic nerve. To see this effect, the use of lidocaine anesthesia is indispensable.In conclusion, application of IS on the dura mater induces short-term, more robust c-Fos activation than CFA, therefore it might offer a better approach to model acute migraine headache in rodents.
Genome-wide characterization and expression analysis of geranylgeranyl diphosphate synthase genes in cotton (Gossypium spp.) in plant development and abiotic stresses
Authors: Ali Faiza , Qanmber Ghulam , Wei Zhenzhen , Yu Daoqian , Li Yong hui , Gan Lei , Li Fuguang , Wang Zhi 
Published: August 2020

AbstractBackgroundGGPP (geranylgeranyl diphosphate) is produced in the isoprenoid pathway and mediates the function of various plant metabolites, which is synthesized by GGPPS (GGPP synthases) in plants.GGPPScharacterization has not been performed in any plant species exceptArabidopsis thaliana. Here, we performed a complete computational and bioinformatics analysis ofGGPPSand detected their transcription expression pattern inGossypium hirsutumfor the first time so that to explore their evolutionary relationship and potential functions. Finally, we unravelled evolutionary relationship, conserved sequence logos, gene duplication and potential involvement in plant development and abiotic stresses tolerance ofGGPPSgenes inG. hirsutumand other plant species.ResultsA total of 159GGPPSgenes from 18 plant species were identified and evolutionary analysis divided theseGGPPSgenes into five groups to indicate their divergence from a common ancestor. Further,GGPPSfamily genes were conserved during evolution and underwent segmental duplication. The identified 25GhGGPPSgenes showed diverse expression pattern particularly in ovule and fiber development indicating their vital and divers roles in the fiber development. Additionally,GhGGPPSgenes exhibited wide range of responses when subjected to abiotic (heat, cold, NaCl and PEG) stresses and hormonal (BL, GA, IAA, SA and MeJA) treatments, indicating their potential roles in various biotic and abiotic stresses tolerance.ConclusionsTheGGPPSgenes are evolutionary conserved and might be involve in different developmental stages and stress response. Some potential key genes (e.g.GhGGPP4, GhGGPP9,andGhGGPP15) were suggested for further study and provided valuable source for cotton breeding to improve fiber quality and resistant to various stresses.