bluuebunny/crossref_metadata_2025_split huggingface dataset:
Freezing stress damage and growth viability in Vaccinium macrocarpon Ait. bud structures
Authors: Villouta Camilo , Workmaster Beth Ann , Atucha Amaya 
Published: May 2021

AbstractAfter a freezing event, it can be challenging to extrapolate levels of freezing damage to plant growth viability based on the presence or absence of symptoms in specific bud tissues. This study investigated the relationship between freezing damage in terminal buds during ecodormancy and their viability during the subsequent growing season. We identified the bud structure that best explained this relationship, and developed a model to explain the changes in bud cold hardiness. Vertical shoots (uprights) of Vaccinium macrocarpon Ait. were sampled in central Wisconsin during Spring of 2018 and 2019. Sets of uprights with terminal buds were subjected to controlled freezing tests, followed by either visual freeze damage evaluation or assessment of shoot viability by growth assays. We determined the Browning Lethal‐Temperature50 (BLT50), as temperature for 50% damage (tissue browning) at each bud structure, and Growth Lethal‐Temperature50 (GLT50) temperature where 50% reduction in growth viability occurred. Two models were constructed to explain: (1) bud structure damage and growth viability, and (2) GLT50's seasonal changes, representing the cold hardiness variations, and environmental factors. The correlation between the BLT50 and GLT50 values was closest for the bud scales and bud axis, indicating the better correspondence between levels of freezing damage with the impact on the growth potential. In addition, the latter was also the most suitable candidate for modeling due to easier damage evaluation. The freezing stress damage of the bud axis explained comparatively best the resulting growth viability. Seasonal changes in GLT50 were best explained by temperature indices based on daily minimum and on maximum temperatures over 10‐day periods. However, among the model components, daily maximum temperatures had the greatest influence on V. macrocarpon cold hardiness changes during ecodormancy.
Role of highly sensitive nucleic acid amplification testing for plasma cytomegalovirus DNA load in diagnosis of cytomegalovirus gastrointestinal disease among kidney transplant recipients
Authors: Taksinwarajarn Touchapong , Sobhonslidsuk Abhasnee , Kantachuvesiri Surasak , Thongprayoon Charat , Cheungpasitporn Wisit , Bruminhent Jackrapong ,   the Ramathibodi Transplant Infectious Diseases (RTID) group
Published: May 2021

AbstractBackgroundHigh plasma cytomegalovirus (CMV) DNA load is generally associated with CMV tissue‐invasive disease in solid organ transplant recipients. However, some tissue‐invasive diseases, especially CMV gastrointestinal (GI) disease, have undetectable to very low plasma CMV DNA loads. Highly sensitive nucleic acid amplification testing (NAAT) has been increasingly used to quantify low‐level CMV DNA loads. Our primary objective was to investigate the epidemiology of CMV GI disease and evaluate the validity of plasma CMV NAAT for the diagnosis of CMV GI disease in kidney transplant (KT) recipients.MethodsWe conducted a retrospective study of all KT recipients who developed CMV GI disease from January 2016 to December 2018. Plasma CMV DNA load was measured using real‐time PCR. The cut‐off value of plasma CMV DNA load for diagnosing and risk factors of CMV GI disease were analyzed.ResultsA total 17 (3.4%) cases of CMV GI disease occurred in 494 KT recipients. Fifteen (88%) patients had CMV D + /R + serostatus. Fourteen (82%) patients developed CMV GI disease within 6 months after KT. Plasma CMV DNA loads were detectable in all (100%) patients with a median load 11,102 (IQR 2,935‐107,160) IU/ml. A plasma CMV DNA load of 4,063 IU/ml was established as al cut‐off for diagnosing CMV GI disease (AUC 0.74, sensitivity 76.5%, specificity 70%, PPV 68, NPV 78). In multivariate analysis, prolonged cold ischemic time (HR 1.14, 95% CI 1.05‐1.23, P = .002) and CMV D + /R ‐ serostatus (HR 9.31, 95% CI 2.12‐40.74, P = .003) were associated with CMV GI disease.ConclusionsUsing highly sensitive NAAT could potentially assist in the diagnosis of CMV GI disease in a CMV D + /R + serostatus setting. KT recipients with CMV seromismatch and prolonged cold ischemic time are at higher risk of CMV GI disease.
A prospective study on COVID‐19 convalescent plasma donor (CCP) recruitment strategies in a resource constrained blood centre
Authors: Biswas Durba , Maiti Chikam , Talukder Biplabendu , Azharuddin Md , Saha Sayantan , Pandey Sumita , Das Arijit , Adhikari Setu Das , Ray Yogiraj , Sarkar Biswanath S. , Paul Sekhar R. , Saha Bibhuti , Paul Sandip , Chatterjee Shilpak , Ganguly Dipyaman , Bhattacharya Prasun 
Published: May 2021

Background and ObjectivesThe COVID‐19 pandemic has spread across 87 million people with more than 1·8 million deaths in the world. As there is no definite treatment modality, the use of convalescent plasma has become increasingly popular worldwide. This study aimed to identify an appropriate strategy of donor recruitment and to evaluate the appropriateness of pre‐set plasma donation guidelines.Material and MethodsIn this prospective study conducted from May to September 2020, the donors were recruited under the following two circumstances: Group I, patients in the post–COVID‐19 follow‐up in the clinic, and Group II, patients recovered from COVID‐19 recruited through mass and electronic media. A pre‐set donor selection criteria and laboratory investigation was designed according to national and international guidelines. Approximately 500 ml of COVID‐19 convalescent plasma (CCP) was collected from recovered individuals in each group by two different cell separators. The overall donor’s attendance rate, deferral rate, adverse events and donor compliance was analysed and compared between the two groups.ResultsThere was a significant difference in attendance in relation to registration between the groups (P < 0·0001). Donor deferral was significantly higher in group II compared with group I. The single most frequent cause of donor deferral was low antibody index (P = 0·0001). The total donor adverse event rate in CCP donation was significantly lower compared with routine plateletpheresis procedures. The donor’s compliance to blood centre’s protocol was satisfactory in both the groups.ConclusionRecruitment of patients in the post–COVID‐19 follow‐up in the clinic was more effective than the general recruitment through mass and electronic media for convalescence plasma donation in a resource‐constrained blood centre.
The gender and geography of publishing: a review of sex/gender reporting and author representation in leading general medical and global health journals
Authors: Merriman Rebekah , Galizia Ilaria , Tanaka Sonja , Sheffel Ashley , Buse Kent , Hawkes Sarah 
Published: May 2021

IntroductionDiverse gender and geographical representation matters in research. We aimed to review medical and global health journals’ sex/gender reporting, and the gender and geography of authorship.Methods542 research and non-research articles from 14 selected journals were reviewed using a retrospective survey design. Paper screening and systematic data extraction was conducted with descriptive statistics and regression analyses calculated from the coded data. Outcome measures were journal characteristics, the extent to which published articles met sex/gender reporting guidelines, plus author gender and location of their affiliated institution.ResultsFive of the fourteen journals explicitly encourage sex/gender analysis in their author instructions, but this did not lead to increased sex/gender reporting beyond the gender of study participants (OR=3.69; p=0.000 (CI 1.79 to 7.60)). Just over half of research articles presented some level of sex/gender analysis, while 40% mentioned sex/gender in their discussion. Articles with women first and last authors were 2.4 times more likely to discuss sex/gender than articles with men in those positions (p=0.035 (CI 1.062 to 5.348)). First and last authors from high-income countries (HICs) were 19 times as prevalent as authors from low-income countries; and women from low-income and middle-income countries were at a disadvantage in terms of the impact factor of the journals they published in.ConclusionGlobal health and medical research fails to consistently apply a sex/gender lens and remains largely the preserve of authors in HIC. Collaborative partnerships and funding support are needed to promote gender-sensitive research and dismantle historical power dynamics in authorship.
Bifunctional iRGD-anti-CD3 enhances antitumor potency of T cells by facilitating tumor infiltration and T-cell activation
Authors: Zhou Shujuan , Meng Fanyan , Du Shiyao , Qian Hanqing , Ding Naiqing , Sha Huizi , Zhu Mei , Yu Xiaoxiao , Wang Lifeng , Liu Baorui , Wei Jia 
Published: May 2021

BackgroundPoor infiltration and limited activation of transferred T cells are fundamental factors impeding the development of adoptive cell immunotherapy in solid tumors. A tumor-penetrating peptide iRGD has been widely used to deliver drugs deep into tumor tissues. CD3-targeting bispecific antibodies represent a promising immunotherapy which recruits and activates T cells.MethodsT-cell penetration was demonstrated in tumor spheroids using confocal microscope, and in xenografted tumors by histology and in vivo real-time fluorescence imaging. Activation and cytotoxicity of T cells were assessed by flow cytometry and confocal microscope. Bioluminescence imaging was used to evaluate in vivo antitumor effects, and transmission electron microscopy was used for mechanistic studies.ResultsWe generated a novel bifunctional agent iRGD-anti-CD3 which could immobilize iRGD on the surface of T cells through CD3 engaging. We found that iRGD-anti-CD3 modification not only facilitated T-cell infiltration in 3D tumor spheroids and xenografted tumor nodules but also induced T-cell activation and cytotoxicity against target cancer cells. T cells modified with iRGD-anti-CD3 significantly inhibited tumor growth and prolonged survival in several xenograft mouse models, which was further enhanced by the combination of programmed cell death protein 1 (PD-1) blockade. Mechanistic studies revealed that iRGD-anti-CD3 initiated a transport pathway called vesiculovacuolar organelles in the endothelial cytoplasm to promote T-cell extravasation.ConclusionAltogether, we show that iRGD-anti-CD3 modification is an innovative and bifunctional strategy to overcome major bottlenecks in adoptive cell therapy. Moreover, we demonstrate that combination with PD-1 blockade can further improve antitumor efficacy of iRGD-anti-CD3-modified T cells.
The Hamiltonian of f(R) gravity
Authors: Abdelmohssin Faisal A.Y. , El Mekki Osman M.H. 
Published: May 2021

We derive conjugate momenta variable tensors and the Hamiltonian equation of the source-free f(R) gravity from first principles using the Legendre transformation of these conjugate momenta variable tensors, conjugate coordinates variables — fundamental metric tensor and its first ordinary partial derivatives with respect to space–time coordinates and second ordinary partial derivatives with respect to space–time coordinates — and the Lagrangian of the f(R) gravity. Interpreting the derived Hamiltonian as the energy of the f(R) gravity we have shown that it vanishes for linear Lagrangians in Ricci scalar curvature without source (e.g., Einstein–Hilbert Lagrangian without matter fields), which is the same result obtained using the stress–energy tensor equation derived from variation of the matter field Lagrangian density. The resulting Hamiltonian equation forbids any negative power law model in the dependence of the f(R) gravity on Ricci scalar curvature: f(R) = αR–r, where r and α are positive real numbers; it also forbids any polynomial equation that contains terms with negative powers of the Ricci scalar curvature including a constant term, in which cases the Hamiltonian function in the Ricci scalar and therefore the energy of the f(R) gravity would attain a negative value and would not be bounded from below. The restrictions imposed by the non-negative Hamiltonian have far-reaching consequences as a result of applying f(R) gravity to the study of black holes and the Friedmann–Lemaître–Robertson–Walker model in cosmology.
Optimal collection of radiation emitted by a trapped atomic ensemble
Authors: Kurkó Árpád , Domokos Peter , Vukics András , Bækkegaard Thomas , Zinner Nikolaj Thomas , Fortágh József , Petrosyan David 
Published: May 2021

AbstractTrapped atomic ensembles are convenient systems for quantum information storage in the long-lived sublevels of the electronic ground state and its conversion to propagating optical photons via stimulated Raman processes. Here we investigate a phase-matched emission of photons from a coherently prepared atomic ensemble. We consider an ensemble of cold atoms in an elongated harmonic trap with normal density distribution, and determine the parameters of paraxial optics to match the mode geometry of the emitted radiation and optimally collect it into an optical waveguide.
Event-B Hybridation
Authors: Dupont Guillaume , Ait-Ameur Yamine , Singh Neeraj Kumar , Pantel Marc 
Published: May 2021

Hybrid systems are complex systems where a software controller interacts with a physical environment, usually named a plant, through sensors and actuators. The specification and design of such systems usually rely on the description of both continuous and discrete behaviours. From complex embedded systems to autonomous vehicles, these systems became quite common, including in safety critical domains. However, their formal verification and validation as a whole is still a challenge.
To address this challenge, this article contributes to the definition of a reusable and tool supported formal framework handling the design and verification of hybrid system models that integrate both discrete (the controller part) and continuous (the plant part) behaviours. This framework includes the development of a process for defining a class of basic theories and developing domain theories and then the use of these theories to develop a generic model and system-specific models. To realise this framework, we present a formal proof tool chain, based on the Event-B correct-by-construction method and its integrated development environment Rodin, to develop a set of theories, a generic model, proof processes, and the required properties for designing hybrid systems in Event-B.
Our approach relies on hybrid automata as basic models for such systems. Discrete and continuous variables model system states and behaviours are given using discrete state changes and continuous evolution following a differential equation. The proposed approach is based on refinement and proof using the Event-B method and the Rodin toolset. Two case studies borrowed from the literature are used to illustrate our approach. An assessment of the proposed approach is provided for evaluating its extensibility, effectiveness, scalability, and usability.
Alteration of MDM2 by the Small Molecule YF438 Exerts Antitumor Effects in Triple-Negative Breast Cancer
Authors: Shan Peipei , Yang Feifei , Qi Hongzhao , Hu Yunjie , Zhu Sujie , Sun Zhenqing , Zhang Zhe , Wang Chuanxiao , Hou Caixia , Yu Jie , Wang Lirong , Zhou Zhixia , Li Peifeng , Zhang Hua , Wang Kun 
Published: May 2021

Abstract

Triple-negative breast cancer (TNBC) exhibits a high mortality rate and is the most aggressive subtype of breast cancer. As previous studies have shown that histone deacetylases (HDAC) may represent molecular targets for TNBC treatment, we screened a small library of synthetic molecules and identified a potent HDAC inhibitor (HDACi), YF438, which exerts effective anti-TNBC activity both in vitro and in vivo. Proteomic and biochemical studies revealed that YF438 significantly downregulated mouse double minute 2 homolog (MDM2) expression. In parallel, loss of MDM2 expression or blocking MDM2 E3 ligase activity rendered TNBC cells less sensitive to YF438 treatment, revealing an essential role of MDM2 E3 ligase activity in YF438-induced inhibition of TNBC. Mechanistically, YF438 disturbed the interaction between HDAC1 and MDM2, induced the dissociation of MDM2-MDMX, and subsequently increased MDM2 self-ubiquitination to accelerate its degradation, which ultimately inhibited growth and metastasis of TNBC cells. In addition, analysis of clinical tissue samples demonstrated high expression levels of MDM2 in TNBC, and MDM2 protein levels closely correlated with TNBC progression and metastasis. Collectively, these findings show that MDM2 plays an essential role in TNBC progression and targeting the HDAC1–MDM2–MDMX signaling axis with YF438 may provide a promising therapeutic option for TNBC. Furthermore, this novel underlying mechanism of a hydroxamate-based HDACi in altering MDM2 highlights the need for further development of HDACi for TNBC treatment.

Significance:
This study uncovers the essential role of MDM2 in TNBC progression and suggests that targeting the HDAC1–MDM2–MDMX axis with a hydroxamate-based HDACi could be a promising therapeutic strategy for TNBC.
Putting the Microenvironment into the Immunotherapy Companion Diagnostic
Authors: Moutafi Myrto , Rimm David L. 
Published: May 2021

Abstract
A post hoc analysis in advanced gastric cancer showed stronger association of programmed cell death-ligand 1 (PD-L1) with immunotherapy efficacy measured by combined positive score (CPS) compared with tumor cells (TC%). This finding suggests expression in immune cells in the tumor microenvironment increases the value of the companion diagnostic test.
See related article by Lei et al., p. 3926
Did Everolimus Break the Rules?
Authors: Kato Shumei , Cohen Ezra E.W. 
Published: May 2021

Abstract
A phase II study with everolimus (mTORC1 inhibitor) among advanced solid tumors patients with TSC1/TSC2 or MTOR alterations was recently published. Although efficacy was limited, the study provided the future groundwork to advance the targeted therapy approach.
See related article by Adib et al., p. 3845
Mastermind Like Transcriptional Coactivator 3 (MAML3) Drives Neuroendocrine Tumor Progression
Authors: Alzofon Nathaniel , Koc Katrina , Panwell Kristin , Pozdeyev Nikita , Marshall Carrie B. , Albuja-Cruz Maria , Raeburn Christopher D. , Nathanson Katherine L. , Cohen Debbie L. , Wierman Margaret E. , Kiseljak-Vassiliades Katja , Fishbein Lauren 
Published: May 2021

Abstract

Metastatic disease in pheochromocytomas and paragangliomas (PCC/PGL) is not well-understood. The Cancer Genome Atlas discovered recurrent MAML3 fusion genes in a subset of tumors that lacked known germline or somatic driver mutations and were associated with aggressive disease. Here, we aimed to investigate the role of MAML3 in tumorigenesis. Human PCC/PGLs were used for IHC and genetic analysis. Three neuroendocrine tumor cell lines, SK-N-SH, QGP-1, and BON-1, were transiently transfected with MAML3 (FL) or exon 1 deleted MAML3 (dEx1; mimicking the fusion), and biologic effects of overexpression were examined in vitro. We found 7% (4/55) of human PCC/PGL have UBTF∼MAML3 fusions and all were sporadic cases with metastatic disease. Fusion-positive tumors had intense MAML3 nuclear staining and increased β-catenin by IHC and showed increased WNT4 expression. In vitro, overexpression of FL and dEx1 MAML3 increased invasion in SK-N-SH, QGP-1, and BON-1 (all P &lt; 0.05) and increased soft-agar colony formation in QGP-1 and BON-1 (all P &lt; 0.05). Cotransfection with FL or dEx1 MAML3 and β-catenin increased TCF/LEF promoter activation by luciferase activity and coimmunoprecipitation confirmed interaction between MAML3 and β-catenin. These data suggest MAML3 is involved in WNT signaling pathway activation. In summary, UBTF∼MAML3 fusions are present in a subset of PCC/PGL and associated with metastatic disease without other known drivers. MAML3 overexpression led to increased tumorigenicity in neuroendocrine tumor cells and the mechanism of action may involve WNT signaling pathways.

Implications:
MAML3 increases tumorigenicity and invasion in neuroendocrine tumor cells and may be a prognostic marker for aggressive disease.
Blocking FcγRIIB in Smooth Muscle Cells Reduces Hypertension
Authors: Song Xiaomin , Zou Xuan , Ge Weipeng , Hou Cuiliu , Cao Zhujie , Zhao Hongmei , Zhang Tiantian , Jin Ling , Fu Yi , Kong Wei , Yan Chen , Cai Jun , Wang Jing 
Published: May 2021

Rationale:
Hypertension is a common chronic disease, and its prevalence is increasing. Immunoglobulins play crucial roles in adaptive immune response and have been implicated in the pathogenesis of hypertension. However, which immunoglobulins and receptors as well as underlying mechanisms participating in hypertension remains unknown. We found that IgG is significantly increased in hypertensive patients, suggesting a potential association between IgG signaling and hypertension.

Objective:
This study is aimed to investigate the role and underlying mechanism of IgG and its receptor in hypertension.

Methods and Results:
We showed that serum IgG and the expression of IgG receptor FcγR (Fcγ receptor) IIB in vessel were significantly increased in hypertensive mice. Blockade of FcγRIIB function significantly reduced Ang II (angiotensin II)–induced vascular remodeling and hypertension in mice with genetic ablation of FcγRIIB or with systemic anti-FcγRIIB antibody treatment in mice. The studies with bone marrow transplantation approach or smooth muscle cell (SMC)–specific FcγRIIB ablation revealed that the role of FcγRIIB in vascular remodeling and hypertension is largely dependent on SMCs but not bone marrow–derived cells. Interestingly, we found that FcγRIIB expressed in SMCs is important in SMC-dependent vascular contraction ex vivo, as well as Ang II–induced SMC hypertrophy and matrix protein expression in vitro. Mechanistic studies further revealed that IgG stimulates FcγRIIB association with AT1R (Ang II type 1 receptor) in SMCs and inhibits AT1R internalization, thus increasing the cell membrane AT1R level. Furthermore, FcγRIIB-mediated regulation of AT1R internalization is critical for Ang II–induced SMC ERK (extracellular signal-regulated kinase) 1/2 activation and hypertrophy, as well as for Ang II–induced arterial contraction.

Conclusions:
Taken together, our findings indicate that IgG/FcγRIIB contributes to vascular remodeling and hypertension, at least partially through suppressing AT1R internalization in SMCs. Our findings also suggest that FcγRIIB may represent an innovative therapeutic target for hypertension, especially for patients with autoimmune diseases.
Audiovisual Simultaneity Judgements in Synaesthesia
Authors: Borgolte Anna , Bransi Ahmad , Seifert Johanna , Toto Sermin , Szycik Gregor R. , Sinke Christopher 
Published: May 2021

Abstract
Synaesthesia is a multimodal phenomenon in which the activation of one sensory modality leads to an involuntary additional experience in another sensory modality. To date, normal multisensory processing has hardly been investigated in synaesthetes. In the present study we examine processes of audiovisual separation in synaesthesia by using a simultaneity judgement task. Subjects were asked to indicate whether an acoustic and a visual stimulus occurred simultaneously or not. Stimulus onset asynchronies (SOA) as well as the temporal order of the stimuli were systematically varied. Our results demonstrate that synaesthetes are better in separating auditory and visual events than control subjects, but only when vision leads.