bluuebunny/crossref_metadata_2025_split huggingface dataset:
A simple score to estimate the likelihood of pseudoprogression vs. recurrence following stereotactic radiosurgery for brain metastases: The Bergen Criteria
Authors: Skeie Bente Sandvei , Enger Per Øyvind , Knisely Jonathan , Pedersen Paal-Henning , Heggdal Jan Ingeman , Eide Geir Egil , Skeie Geir Olve 
Published: March 2020

Abstract

Background
A major challenge in the follow-up of patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) is to distinguish pseudoprogression (PP) from tumor recurrence (TR). The aim of the study was to develop a clinical risk assessment score.

Methods
Follow-up images of 87 of 97 consecutive patients treated with SRS for 348 BM were analyzed. Of these, 100 (28.7%) BM in 48 (53.9%) patients responded with either TR (n = 53, 15%) or PP (n = 47, 14%). Differences between the 2 groups were analyzed and used to develop a risk assessment score (the Bergen Criteria).

Results
Factors associated with a higher incidence of PP vs. TR were as follows: prior radiation with whole brain radiotherapy or SRS (P = .001), target cover ratio ≥98% (P = .048), BM volume ≤2 cm3 (P = .054), and primary lung cancer vs. other cancer types (P = .084). Based on the presence (0) or absence (1) of these 5 characteristics, the Bergen Criteria was established. A total score &lt;2 points was associated with 100% PP, 2 points with 57% PP and 43% TR, 3 points with 57% TR and 43% PP, whereas &gt;3 points were associated with 84% TR and 16% PP, P &lt; .001.

Conclusion
Based on 5 characteristics at the time of SRS the Bergen Criteria could robustly differentiate between PP vs. TR following SRS. The score is user-friendly and provides a useful tool to guide the decision making whether to retreat or observe at appropriate follow-up intervals.
A possible origin of kilohertz quasi-periodic oscillations in low-mass X-ray binaries
Authors: Kato Shoji , Machida Mami 
Published: March 2020

Abstract
A possible origin of kilohertz quasi-periodic oscillations (QPOs) in low-mass X-ray binaries is proposed. Recent numerical magnetohydrodynamic simulations of accretion disks with turbulent magnetic fields of magneto-rotational instability definitely show the presence of two-armed spiral structure in the quasi-steady state of accretion disks. In such deformed disks, two-armed ($m=2$) c-mode ($n=1$) oscillations are excited by wave–wave resonant instability. Among these excited oscillations, the fundamental in the radial direction ($n_{\rm r}=0$) will be the higher kHz QPO of twin QPOs, and the first overtone ($n_{\rm r}=1$) in the radial direction will be the lower kHz QPO of the twin. A possible cause of the twin high-frequency QPOs in black hole X-ray binaries is also discussed in the final section.
Therapeutic delivery from a solid formulation during breastfeeding: a feasibility study
Authors: Maier Theresa , Peirce Paula , Baird Laura , Whitehouse Sophie L. , Slater Nigel K. H. , Beardsall Kathryn 
Published: March 2020

ABSTRACTBackgroundEnteral drug and nutrient delivery to breastfed infants depends on the use of oral syringes and liquid formulations. This can pose both practical and emotional challenges to drug delivery.ObjectivesThe presented study aimed to explore the potential of using solid formulations for therapeutic delivery during breastfeeding.MethodsSingle centre feasibility study within a tertiary level neonatal unit in the UK, involving twenty-six breastfeeding mother-infant dyads. Vitamin B12 was delivered to infants during breastfeeding from a solid formulation within a commercial silicon nipple shield. Outcomes included the quantitative measurement of change in serum vitamin B12 and a mixed methods assessment of maternal expectations and experiences.ResultsParticipants described the surprising ease of ‘drug’ delivery, with no negative impact on breastfeeding behaviour or sensation reported. Vitamin B12 levels rose on average from a baseline of 533 pg/mL (236 - 925 pg/mL) to 1871 pg/mL (610 – 4981 pg/mL) at 6 - 8 hours post-delivery. All mothers expressed their support for this approach, 85% a preference over the use of oral syringes. Reasoning for support related to the reduced medicalisation of this procedure compared to the use of oral syringes, and a desire for choices in relation to their infants’ health.ConclusionsThis study demonstrated that therapeutic delivery from a solid formulation within a nipple shield was feasible and acceptable to mothers and infants.
Genetically encoded biosensors for branched-chain amino acid metabolism to monitor mitochondrial and cytosolic production of isobutanol and isopentanol in yeast
Authors: Zhang Yanfei , Hammer Sarah K. , Carrasco-Lopez Cesar , Garcia Echauri Sergio A. , Avalos José L. 
Published: March 2020

AbstractBranched-chain amino acid (BCAA) metabolism can be harnessed to produce many valuable chemicals. Among these, isobutanol, which is derived from valine degradation, has received substantial attention due to its promise as an advanced biofuel. WhileSaccharomyces cerevisiaeis the preferred organism for isobutanol production, the lack of isobutanol biosensors in this organism has limited the ability to screen strains at high throughput. Here, we use a transcriptional regulator of BCAA biosynthesis, Leu3p, to develop the first genetically encoded biosensor for isobutanol production in yeast. Small modifications allowed us to redeploy Leu3p in a second biosensor for isopentanol, another BCAA-derived product of interest. Each biosensor is highly specific to isobutanol or isopentanol, respectively, and was used to engineer metabolic enzymes to increase titers. The isobutanol biosensor was additionally employed to isolate high-producing strains, and guide the construction and enhancement of mitochondrial and cytosolic isobutanol biosynthetic pathways, including in combination with optogenetic actuators to enhance metabolic flux. These biosensors promise to accelerate the development of enzymes and strains for branched-chain higher alcohol production, and offer a blueprint to develop biosensors for other products derived from BCAA metabolism.
Integrated analysis of gene correlation reveals disordered relationship between metabolism and immunity in tumor microenvironment
Authors: Chen Zixi , Wei Jinfen , Yuan Yuchen , Cui Ying , Zhang Yanyu , Hu Yumin , Du Hongli 
Published: March 2020

AbstractBackgroundMetabolism reprogramming and immune evasion are the most fundamental hallmarks for cancer survival. The complex interactions between metabolism and immune systems in tumors and their microenvironment is complicated. Researching on the correlation changes between metabolic and immune related-genes in normal and tumor tissues would help to reveal these complex interactions.MethodsIn this study, the mRNA profiles across 11 cancer types was obtained from The Cancer Genome Atlas (TCGA). Then, the spearman’s correlation coefficient was calculated between metabolic and immune related-genes for each sample group.ResultsOur results showed that the number of correlated gene pairs was reduced significantly in tumor tissues compared with those of normal tissue, especially in KIRC, KIRP and STAD. Functional enrichment analysis for the universal (the pairs appeared in more than 2 cancer types) and specific (the pairs only in one specific cancer type) gene pairs across cancer types revealed top pathways which appeared in tumor and normal samples, such as phosphatidylinositol signaling system and inositol phosphate metabolism. Thereinto, the pairs in normal tissues missing in tumors may indicate they are important factors affecting immune system, such as, DGKs and PIP4ks. The correlation analysis between immune checkpoint and metabolism genes also showed a reduced correlation in tumor and had the tissue specificity, such as,FUT8was strongly correlated withPDCD1in the HC of STAD and they had a weaker correlation in other normal tissues and tumor types.ConclusionsOur study provides a novel strategy for investigating interaction of tumor immune and metabolism in microenvironment and offers some key points for exploring new targets including metabolic targets and immunomodulator of immune checkpoints.
The birth of a bacterial tRNA gene by large-scale, tandem duplication events
Authors: Ayan Gökçe B. , Park Hye Jin , Gallie Jenna 
Published: March 2020

ABSTRACTOrganisms differ in the types and numbers of tRNA genes that they carry. While the evolutionary mechanisms behind tRNA gene set evolution have been investigated theoretically and computationally, direct observations of tRNA gene set evolution remain rare. Here, we report the evolution of a tRNA gene set in laboratory populations of the bacteriumPseudomonas fluorescensSBW25. The growth defect caused by deleting the single-copy tRNA gene,serCGA, is rapidly compensated by large-scale (45-290 kb) duplications in the chromosome. Each duplication encompasses a second, compensatory tRNA gene (serTGA) and is associated with a rise in tRNA-Ser(UGA) in the mature tRNA pool. We postulate that tRNA-Ser(CGA) elimination increases the translational demand for tRNA-Ser(UGA), a pressure relieved by increasingserTGAcopy number. This work demonstrates that tRNA gene sets can evolve through duplication of existing tRNA genes, a phenomenon that may contribute to the presence of multiple, identical tRNA gene copies within genomes.
EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma
Authors: Roessner Philipp M. , Cid Laura Llaó , Lupar Ekaterina , Roider Tobias , Bordas Marie , Schifflers Christoph , Gaupel Ann-Christin , Kilpert Fabian , Krötschel Marit , Arnold Sebastian J. , Sellner Leopold , Stilgenbauer Stephan , Dietrich Sascha , Lichter Peter , Izcue Ana , Seiffert Martina 
Published: March 2020

AbstractThe transcription factor Eomesodermin (EOMES) promotes IL-10 production of CD4+T-cells, which has been linked to immunosuppressive and cytotoxic activities. We detected EOMES-expressing CD4+T-cells in lymph node samples of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. This was in line with an observed expansion of EOMES-positive CD4+T-cells in leukemic Eµ-TCL1 mice, a well-established model of CLL, and upon adoptive transfer of TCL1 leukemia in mice. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive the transcription of IL-10, but rather controls a unique differentiation program in CD4+T-cells. Moreover, EOMES was necessary for the accumulation of a specific CD4+T-cell subset that expresses IFNγ and IL-10, as well as inhibitory receptors, like PD-1 and LAG3. T-cell transfer studies in leukopenicRag2-/-mice showed that EOMES-deficient CD4+T-cells were inferior in controlling TCL1 leukemia development compared to wildtype T-cells, even though expansion ofEomes-/-CD4+T-cells was observed. We further showed that control of TCL1 leukemia was driven by IL-10 receptor-mediated signals, asIl10rb-deficient CD4+T-cells showed impaired anti-leukemia activity. Altogether, our data suggest that IL-10 producing PD-1+CD4+T-cells contribute to CLL control in an EOMES- and IL-10R-dependent manner.
A novel stimulus paradigm for simultaneous recording of monaural and binaural frequency following response for identification of binaural interaction component
Authors: Bhagavan Srividya Grama , Kalaiah Mohan Kumar 
Published: March 2020

AbstractThe objective of the study was to investigate whether monaural frequency following response (FFR) of right and left ear and binaural FFR could be obtained in the same recording using a novel stimulus presentation paradigm, for the purpose of identification the BIC. Twenty six young adults participated in the study. The FFR was recorded for 220 Hz pure-tone using a novel stimulus paradigm. The pure-tone was presented sequentially to two ears. Initially, the pure-tone was presented to the right ear, then to both ears, and finally to the left ear. The FFR could be elicited from all participants (all three responses: right ear, left ear, and both ears) in the same recording using the novel stimulus presentation paradigm used in the present study. The novel stimulus presentation paradigm used in the present study could be used for obtaining monaural and binaural FFRs in the same recording for identification of BIC.
The Drosophila Amyloid Precursor Protein homologue mediates neuronal survival and neuro-glial interactions
Authors: Kessissoglou Irini A. , Langui Dominique , Hasan Amr , Maral Maral , Dutta Suchetana Bias , Hiesinger P. Robin , Hassan Bassem A. 
Published: March 2020

AbstractThe amyloid precursor protein (APP) is a structurally and functionally conserved transmembrane protein whose physiological role in adult brain function and health is still unclear. Because mutations in APP cause familial Alzheimer’s disease, most research focuses on this aspect of APP biology. We investigated the physiological function of APP in the adult brain using the fruit flyDrosophila melanogaster, which harbors a single APP homologue called APP Like (APPL). Previous studies have provided evidence for the implication of APPL in neuronal wiring and axonal growth through the Wnt signaling pathway. However, like APP, APPL continues to be expressed in all neurons of the adult brain where its functions and their molecular and cellular underpinnings are unknown. We report that APPL loss of function results in the dysregulation of endolysosomal function, in both neurons and glia, with a notable enlargement of early endosomal compartment in neurons followed by neuronal cell death, the accumulation of dead neurons in the brain during a critical period at a young age and subsequent reduction in lifespan. These defects can be rescued by reduction in the levels of the early endosomal regulator Rab5, indicating a causal role of endosomal function for cell death. Finally, we show that the secreted extracellular domain of APPL is taken up by glia, regulates their endosomal morphology and this is necessary and sufficient for the clearance of neuronal debris in an axotomy model. We propose that the APP proteins represent a novel family of neuro-glial signaling proteins required for adult brain homeostasis.
An investigation ofBurkholderiacepacia complex methylomesviaSMRT sequencing and mutant analysis
Authors: Mannweiler Olga , Pinto-Carbó Marta , Lardi Martina , Agnoli Kirsty , Eberl Leo 
Published: March 2020

AbstractTheBurkholderia cepaciacomplex (Bcc) is a group of 22 closely related opportunistic pathogens which produce a wide range of bioactive secondary metabolites with great biotechnological potential, for example in biocontrol and bioremediation.This study aimed to investigate methylation in the Bcc by SMRT sequencing, and to determine the impact of restriction-methylation (RM) systems on genome protection and stability and on phenotypic traits. We constructed and analysed a mutant lacking all RM components in the clinical isolateB. cenocepaciaH111. We show that a previously identified essential gene of strain H111,gp51, encoding a methylase within a prophage region, is required for maintaining the bacteriophage in a lysogenic state. We speculate that epigenetic modification of a phage promoter provides a mechanism for a constant, low level of phage production within the bacterial population. We also found that, in addition to bacteriophage induction, methylation was important in biofilm formation, cell shape, motility, siderophore production and membrane vesicle production. Moreover, we found that DNA methylation had a massive effect on the maintenance of the smallest replicon present in this bacterium, which is essential for its virulence.In silicoinvestigation revealed the presence of two core RM systems, present throughout the Bcc and beyond, suggesting that the acquisition of these RM systems occurred prior to the phylogenetic separation of the Bcc. We used SMRT sequencing of single mutants to experimentally assign theB. cenocepaciaH111 methylases to their cognate motifs. Analysis of the distribution of methylation patterns suggested roles for m6A methylation in replication, since motifs recognised by the core Type III RM system were more abundant at the replication origins of the three H111 replicons, and in regions encoding functions related to cell motility and iron uptake.Author summaryWhile nucleotide sequence determines an organism’s proteins, methylation of the nucleotides themselves can confer additional properties. In bacteria, methyltransferases methylate specific motifs to allow discrimination of ‘self’ from ‘non-self’ DNA, e.g. from bacteriophages. Restriction enzymes detect ‘non-self’ methylation patterns and cut foreign DNA. Furthermore, methylation of promoter regions can influence gene expression and hence affect phenotype. In this study, we determined the methylated motifs of four strains from theBurkholderia cepaciacomplex of opportunistic pathogens. Three novel motifs were found, and two that were previously identified in a related species. We deleted the genes encoding the restriction and modification components in a representative strain from among the four sequenced. In this study, methylation is shown to affect various phenotypes, among which maintenance of the lysogenic state of a phage and segregational stability of the smallest megareplicon are most remarkable.
Dual Energy X-ray Absorptiometry (DEXA) as a Longitudinal Outcome Measure of Cancer-Related Muscle Wasting in Mice
Authors: Cole Calvin L. , Robinson Deja , Ye Jian , Mills Bradley , Gerber Scott A. , Beck Christopher A. , Schwarz Edward M. , Linehan David 
Published: March 2020

AbstractIntroductionPancreatic ductal adenocarcinoma (PDAC) is notorious for its associated skeletal muscle wasting (SMW) and mortality. Currently, the relationships between PDAC, SMW, and survival are poorly understood. Thus, there is a great need for a faithful small animal model with a quantitative longitudinal outcome measure that recapitulates clinical PDAC, to define SMW onset and assess progression. Therefore, we aimed to validate dual energy X-ray absorptiometry (DEXA) as a longitudinal outcome of lean body mass, and demonstrate its utility to quantify SMW in the KCKO murine model of PDAC.MethodsIn vivo body composition of: 1) untreated mice at 5, 8, 12, 18, and 22 weeks of age (n=4), and 2) a cohort of mice with (n=20) and without PDAC (n=10), was determined via DEXA, and lean mass of the lower hind limbs was predicted via a region of interest analysis by two independent observers. Total body weight was determined. Tibialis anterior (TA) muscles were weighed and processed for histomorphometry immediately post-mortem. Statistical differences between groups were assessed using t-tests and ANOVA. Linear regression models and correlation analysis were used to measure the association between TA and DEXA mass, and reproducibility of DEXA was quantified via the intraclass correlation coefficient (ICC).ResultsLean mass in growing untreated mice determined by DEXA correlated with TA mass (r2= 0.94; p <0.0001) and body weight (r2= 0.89; p <0.0001). DEXA measurements were highly reproducible between observers (ICC = 0.95; 95% CI: 0.89-0.98). DEXA and TA mass also correlated in the PDAC cohort (r2= 0.76; p <0.0001). Significant SMW in tumor-bearing mice was detected within 38 days of implantation by DEXA, TA mass, and histomorphometry.ConclusionsDEXA is a longitudinal outcome measure of lower limb lean mass in mice. The KCKO syngeneic model is abona fidemodel of PDAC-associated SMW that can be quantified with longitudinal DEXA.
Envelope Simulation: A New Adaptive Method for Dose Optimization
Authors: Piantadosi Steven , Zhou Guohai 
Published: March 2020

AbstractWe present a flexible and general adaptive experimental design for dose finding clinical trials. This method can be applied in sterotypical settings such as determining a maximum tolerated dose, when the dose response relationship is complex, or when the response is an arbitrary quantitative measure. Our design generalizes dose finding methods such as the continual reassessment method (CRM), modified CRM, and estimation with overdose control (EWOC). Similar to those, our design requires a working mathematical model, which assures efficiency, low bias, and a higher fraction of dose selected near the optimum compared to purely operational designs. Unlike typical model based designs that always employ the same model, our method allows individual dose response models tailored to the circumstance. Simulations are also integral to our design allowing it to account for both known and unknown effects of dose on outcome. This method is applicable to general dose finding problems such as those encountered with modern targeted anti-cancer agents, immunotherapies, and titrations against biomarker outcome measures. The method can also support improvements in the design of the experiment being conducted by providing a platform for concurrent simulations to assess the influence of projected design points. Although we present the design in the context of clinical trials, it is equally applicable to experiments with non-human subjects.
What happens to oak growth and survival when there is both competitionandbrowsing?
Authors: Jensen Anna M. , Petersson Linda K. , Felton Annika , Löf Magnus , Persson Maria 
Published: March 2020

AbstractCompetition from neighboring vegetation and browsing by large herbivores are two of the most important factors affecting the structure and dynamics of temperate forests. While the previous literature has been able to identify individual negative effects from competition or browsing, no one has yet identified and quantified both the individual and the joint effects. Still, when plants face both competition and browsing, it is possible that the combined effect is not simply a sum of the individual negative effects, but perhaps a more complicated situation, where plants perform either better (in case there is also a facilitative effect from the neighboring vegetation) or worse (if the effects amplify each other) than they would if experiencing only one of the two factors. In this paper, we focus on regeneration of oak (Quercus roburL) to study these questions. We analyze a rich data set from a large long-term field experiment conducted at multiple sites in mixed temperate forests in southern Sweden over almost a decade. By the use of four separate treatments on each site – (i) neither competition, nor browsing, (ii) only competition, (iii) only browsing, and (iv) both competition and browsing – we can identify and quantify both the individual and combined effects of competition and browsing on oak growth and survival. We find that both competition and browsing individually affect growth and survival negatively. For growth, browsing has the largest effect, while competition is the larger problem from a survival point of view. When the plant experiences both competition and browsing, the combined, negative, effect is larger than either individual effect for survival, but for growth, the relationship is more complicated, and the surrounding woody vegetation offers at least some protection for the oak, reducing the negative effects from browsing.