bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIF-1α switches the functionality of TGF-β signaling via changing the partners of smads to drive glucose metabolic reprogramming in non-small cell lung cancer
Authors: Huang Yiwei , Chen Zhencong , Lu Tao , Bi Guoshu , Li Ming , Liang Jiaqi , Hu Zhengyang , Zheng Yuansheng , Yin Jiacheng , Xi Junjie , Lin Zongwu , Zhan Cheng , Jiang Wei , Wang Qun , Tan Lijie 
Published: December 2021

Abstract
Background
Most cancer cells have fundamentally different metabolic characteristics, particularly much higher glycolysis rates than normal tissues, which support the increased demand for biosynthesis and promote tumor progression. We found that transforming growth factor (TGF)-β plays a dual function in regulating glycolysis and cell proliferation in non-small cell lung cancer.

Methods
We used the PET/MRI imaging system to observe the glucose metabolism of subcutaneous tumors in nude mice. Energy metabolism of non-small cell lung cancer cell lines detected by the Seahorse XFe96 cell outflow analyzer. Co-immunoprecipitation assays were used to detect the binding of Smads and HIF-1α. Western blotting and qRT-PCR were used to detect the regulatory effects of TGF-β and HIF-1α on c-MYC, PKM1/2, and cell cycle-related genes.

Results
We discovered that TGF-β could inhibit glycolysis under normoxia while significantly promoting tumor cells’ glycolysis under hypoxia in vitro and in vivo. The binding of hypoxia-inducible factor (HIF)-1α to the MH2 domain of phosphorylated Smad3 switched TGF-β function to glycolysis by changing Smad partners under hypoxia. The Smad-p107-E2F4/5 complex that initially inhibited c-Myc expression was transformed into a Smad-HIF-1α complex that promoted the expression of c-Myc. The increased expression of c-Myc promoted alternative splicing of PKM to PKM2, resulting in the metabolic reprogramming of tumor cells. In addition, the TGF-β/Smad signal lost its effect on cell cycle regulatory protein p15/p21. Furthermore, high expression of c-Myc inhibited p15/p21 and promoted the proliferation of tumor cells under hypoxia.

Conclusions
Our results indicated that HIF-1α functions as a critical factor in the dual role of TGF-β in tumor cells, and may be used as a biomarker or therapeutic target for TGF-β mediated cancer progression.
New anatomical reference systems for the bones of the foot and ankle complex: definitions and exploitation on clinical conditions
Authors: Conconi Michele , Pompili Alessandro , Sancisi Nicola , Leardini Alberto , Durante Stefano , Belvedere Claudio 
Published: December 2021

AbstractBackgroundA complete definition of anatomical reference systems (ARS) for all bones of the foot and ankle complex is lacking. Using a morphological approach, we propose new ARS for these bones with the aim of being highly repeatable, consistent among individuals, clinically interpretable, and also suited for a sound kinematic description.MethodsThree specimens from healthy donors and three patients with flat feet were scanned in weight‐bearing CT. The foot bones were segmented and ARS defined according to the proposed approach.To assess repeatability, intra class coefficients (ICC) were computed both intra‐ and inter‐operator.Consistency was evaluated as the mean of the standard deviations of the ARS position and orientation, both within normal and flat feet.Clinical interpretability was evaluated by providing a quantification of the curvature variation in the medial‐longitudinal and transverse arches and computing the Djiann‐Annonier angle for normal and flat feet from these new ARS axes.To test the capability to also provide a sound description of the foot kinematics, the alignment between mean helical axes (MHA) and ARS axes was quantified.ResultsICC was 0.99 both inter‐ and intra‐operator.Rotational consistency was 4.7 ± 3.5 ° and 6.2 ± 4.4° for the normal and flat feet, respectively; translational consistency was 4.4 ± 4.0 mm and 5.4 ± 2.9 mm for the normal and flat feet, respectively. In both these cases, the consistency was better than what was achieved by using principal axes of inertia.Curvature variation in the arches were well described and the measurements of the Djiann‐Annoier angles from both normal and flat feet matched corresponding clinical observations.The angle between tibio‐talar MHA and ARS mediolateral axis in the talus was 12.3 ± 6.0, while the angle between talo‐calcaneal MHA and ARS anteroposterior axis in the calcaneus was 17.2 ± 5.6, suggesting good capability to represent joint kinematics.ConclusionsThe proposed ARS definitions are robust and provide a solid base for the 3‐dimensional description of posture and motion of the foot and ankle complex from medical imaging.
Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF)
Authors: Kirwan Marcus , Munshi Reema , O’Keeffe Hannah , Judge Conor , Coyle Mary , Deasy Evelyn , Kelly Yvelynne P. , Lavin Peter J. , Donnelly Maria , D’Arcy Deirdre M. 
Published: December 2021

Abstract
Background
Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates.

Methods
This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations.

Results
A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L.

Conclusions
PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.
Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects
Authors: Dempster Joshua M. , Boyle Isabella , Vazquez Francisca , Root David E. , Boehm Jesse S. , Hahn William C. , Tsherniak Aviad , McFarland James M. 
Published: December 2021

AbstractCRISPR loss of function screens are powerful tools to interrogate biology but exhibit a number of biases and artifacts that can confound the results. Here, we introduce Chronos, an algorithm for inferring gene knockout fitness effects based on an explicit model of cell proliferation dynamics after CRISPR gene knockout. We test Chronos on two pan-cancer CRISPR datasets and one longitudinal CRISPR screen. Chronos generally outperforms competitors in separation of controls and strength of biomarker associations, particularly when longitudinal data is available. Additionally, Chronos exhibits the lowest copy number and screen quality bias of evaluated methods. Chronos is available at https://github.com/broadinstitute/chronos.
The economics of organellar gene loss and endosymbiotic gene transfer
Authors: Kelly Steven 
Published: December 2021

Abstract
Background
The endosymbiosis of the bacterial progenitors of the mitochondrion and the chloroplast are landmark events in the evolution of life on Earth. While both organelles have retained substantial proteomic and biochemical complexity, this complexity is not reflected in the content of their genomes. Instead, the organellar genomes encode fewer than 5% of the genes found in living relatives of their ancestors. While many of the 95% of missing organellar genes have been discarded, others have been transferred to the host nuclear genome through a process known as endosymbiotic gene transfer.

Results
Here, we demonstrate that the difference in the per-cell copy number of the organellar and nuclear genomes presents an energetic incentive to the cell to either delete organellar genes or transfer them to the nuclear genome. We show that, for the majority of transferred organellar genes, the energy saved by nuclear transfer exceeds the costs incurred from importing the encoded protein into the organelle where it can provide its function. Finally, we show that the net energy saved by endosymbiotic gene transfer can constitute an appreciable proportion of total cellular energy budgets and is therefore sufficient to impart a selectable advantage to the cell.

Conclusion
Thus, reduced cellular cost and improved energy efficiency likely played a role in the reductive evolution of mitochondrial and chloroplast genomes and the transfer of organellar genes to the nuclear genome.
Quantitative-enhancer-FACS-seq (QeFS) reveals epistatic interactions among motifs within transcriptional enhancers in developing Drosophila tissue
Authors: Waters Colin T. , Gisselbrecht Stephen S. , Sytnikova Yuliya A. , Cafarelli Tiziana M. , Hill David E. , Bulyk Martha L. 
Published: December 2021

AbstractUnderstanding the contributions of transcription factor DNA binding sites to transcriptional enhancers is a significant challenge. We developed Quantitative enhancer-FACS-Seq for highly parallel quantification of enhancer activities from a genomically integrated reporter inDrosophila melanogasterembryos. We investigate the contributions of the DNA binding motifs of four poorly characterized TFs to the activities of twelve embryonic mesodermal enhancers. We measure quantitative changes in enhancer activity and discover a range of epistatic interactions among the motifs, both synergistic and alleviating. We find that understanding the regulatory consequences of TF binding motifs requires that they be investigated in combination across enhancer contexts.
INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial
Authors: Song Lili , Hu Xin , Ma Lu , Chen Xiaoying , Ouyang Menglu , Billot Laurent , Li Qiang , Muñoz-Venturelli Paula , Abanto Carlos , Pontes-Neto Octavio Marques , Antonio Arauz , Wasay Mohammad , Silva Asita de , Thang Nguyen Huy , Pandian Jeyaraj Durai , Wahab Kolawole Wasiu , You Chao , Anderson Craig S. ,   for the INTERACT3 investigators
Published: December 2021

Abstract
Background
Early intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH.

Methods
INTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), cluster-randomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (< 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic < 140 mmHg; glucose control, target 6.1–7.8 mmol/L and 7.8–10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio < 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7-day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions.

Discussion
As the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established.

Trial registration
ClinicalTrials.gov NCT03209258. Registered on 1 July 2017. Chinese Trial Registry ChiCTR-IOC-17011787. Registered on 28 June 2017
Eccentric-only versus concentric-only resistance training effects on biochemical and physiological parameters in patients with type 2 diabetes
Authors: Kudiarasu Christine , Rohadhia Wafina , Katsura Yoshihiro , Koeda Tomoko , Singh Favil , Nosaka Kazunori 
Published: December 2021

Abstract
Background
The benefits of resistance training for patients with type 2 diabetes (T2D) are well documented; however, the effects of exercise with different muscle contraction types such as eccentric versus concentric contractions on physiological outcomes for this population are not clear. This study compared eccentric-only (ECC) and concentric-only resistance training (CON) to test the hypothesis that ECC would be superior to CON to improve insulin sensitivity, lipid profile, body composition, muscle strength and physical function of patients with T2D.

Methods
Adults with T2D (50–79 years) were allocated to the ECC (n = 9) or CON group (n = 9). Resistance exercises (chest press, lateral pulldown, bicep curl, triceps extension, leg extension, leg curl, calf raise, abdominal crunch) consisting of 2–3 sets of 10 eccentric-only (5 s) or concentric-only contractions (1–2 s) was performed twice a week for 12 weeks. Changes in blood biomarkers, body composition, muscle strength and physical function from pre- to post-intervention were compared between groups.

Results
Overall rating of perceived exertion (RPE, 1–10 Borg scale) was lower (p < 0.05) for ECC (2.9 ± 1.2) than CON (5.4 ± 1.1). No significant changes in blood biomarkers were found for both groups. Lean mass increased [effect size (ES) = 0.148, ECC 3.2 ± 6.9%; CON 3.6 ± 2.3%], and fat mass decreased (ES = 0.545, ECC − 6.1 ± 12.4%; CON − 7.1 ± 16.4%) (p < 0.05) similarly. One-repetition maximal strength of each exercise increased (p < 0.05) for both ECC (12–37%) and CON (27–68%). Both groups improved (p < 0.05) 6-min walk distance (ES = 0.083, ECC 12.2 ± 2.3%; CON 12.5 ± 15.3%) and chair rise time (ES = 0.463, ECC − 13.4 ± 25.4%; CON − 20.0 ± 53.3%) but only ECC improved (p < 0.05) the timed up-and-go test (− 11.3 ± 13.6%, ES 0.014). No significant changes in balance tests were found for both groups.

Conclusion
These results did not fully support the hypothesis but showed that ECC was as effective as CON to improve body composition, muscle strength, and physical function with lesser RPE. Future studies should investigate whether larger differences between ECC and CON are evident when increasing the exercise frequency and matching the intensities of the two-exercise protocols.
Trial registration ACTRN12621001026819 (retrospectively registered on 5th Aug 2021).
Data on the Facebook marketing strategies used by fast-food chains in four Latin American countries during the COVID-19 lockdowns
Authors: Rozas Lucila , Castronuovo Luciana , Busse Peter , Mus Sophia , Barnoya Joaquín , Garrón Alejandra , Tiscornia María Victoria , Guanieri Leila 
Published: December 2021

Abstract
Objectives
During the COVID-19 pandemic, most countries implemented lockdowns that motivated changes in the dietary patterns, physical activity, and body mass index (BMI) of consumers worldwide, as well as the emergence of new food marketing strategies in social media. We sought to design and validate a methodology for monitoring and evaluating the Facebook marketing strategies of multinational fast-food chains in response to the COVID-19 pandemic.

Data description
We developed three datasets. First, a dataset with the Uniform Resource Locators (URLs) of 1015 Facebook posts of five fast-food chains present in Argentina, Bolivia, Guatemala, and Peru. Second, a dataset of 106 content-analyzed posts we used in a pilot to determine intercoder reliability using statistical tests. Third, a dataset of a final sample of the 1015 content-analyzed posts that we used to determine the variables most frequently used. Following a mixed-methods approach, we developed 29 variables that recorded general information, as well as the marketing strategies we identified in the posts, including 14 COVID-19 specific variables. These data should help to monitor the social media marketing strategies that fast-food chains have introduced during the COVID-19 lockdowns, thus providing initial evidence about how they could be contributing to an unhealthy food environment.
Impact of potential modifications to Alzheimer’s disease clinical trials in response to disruption by COVID-19: a simulation study
Authors: Schneider Lon S. , Qiu Yuqi , Thomas Ronald G. , Evans Carol , Jacobs Diane M. , Jin Shelia , Kaye Jeffrey A. , LaCroix Andrea Z. , Messer Karen , Salmon David P. , Sano Mary , Schafer Kimberly , Feldman Howard H. 
Published: December 2021

Abstract
Background
The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made.

Methods
We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.

Results
Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.

Discussion
These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials’ validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.
Deep learning approach for automatic segmentation of ulna and radius in dual-energy X-ray imaging
Authors: Yang Fan , Weng Xin , Miao Yuehong , Wu Yuhui , Xie Hong , Lei Pinggui 
Published: December 2021

Abstract
Background
Segmentation of the ulna and radius is a crucial step for the measurement of bone mineral density (BMD) in dual-energy X-ray imaging in patients suspected of having osteoporosis.

Purpose
This work aimed to propose a deep learning approach for the accurate automatic segmentation of the ulna and radius in dual-energy X-ray imaging.

Methods and materials
We developed a deep learning model with residual block (Resblock) for the segmentation of the ulna and radius. Three hundred and sixty subjects were included in the study, and five-fold cross-validation was used to evaluate the performance of the proposed network. The Dice coefficient and Jaccard index were calculated to evaluate the results of segmentation in this study.

Results
The proposed network model had a better segmentation performance than the previous deep learning-based methods with respect to the automatic segmentation of the ulna and radius. The evaluation results suggested that the average Dice coefficients of the ulna and radius were 0.9835 and 0.9874, with average Jaccard indexes of 0.9680 and 0.9751, respectively.

Conclusion
The deep learning-based method developed in this study improved the segmentation performance of the ulna and radius in dual-energy X-ray imaging.