Miracle-dz/UniFAR-FTUs huggingface dataset:
Physiological comparison of intensity-controlled, isocaloric intermittent and continuous exercise†

Abstract VO2 fluctuations are argued to be an important mechanism underpinning chronic adaptations following interval training. We compared the effect of exercise modality, continuous vs. intermittent realized at a same intensity, on electrical muscular activity, muscular oxygenation and on whole body oxygen uptake. Twelve participants (24 ± 5 years; VO2peak: 43 ± 6 mL· min−1·kg−1) performed (i) an incremental test to exhaustion to determine peak work rate (WRpeak); two randomized isocaloric exercises at 70%WRpeak; (ii) 1 bout of 30 min; (iii) 30 bouts of 1 min work intercepted with 1 min passive recovery. For electromyography, only the CON exercise showed change for the vastus lateralis root-mean-square (+6.4 ± 5.1%, P < .01, 95%CI 3.2, 8.3) and mean power frequency (−5.2 ± 4.8, P < .01, 95%CI −8.2, −3.5). Metabolic fluctuations (i.e. Oxygen Fluctuation Index and HHb Fluctuation Index) were higher in the intermittent modality, while post-exercise blood lactate concentrations (4.80 ± 1.50 vs. 2.32 ± 1.21 mM, respectively, for the CON and INT, P < .01, 95%CI 1.72, 3.12) and the time spent over 90% of VO2 target (1644 ± 152 vs. 356 ± 301 sec, respectively, for the CON and INT, P < .01, 95%CI 1130, 1446) were higher in the continuous modality. In conclusion, despite a similar energy expenditure and intensity, intermittent and continuous exercises showed two very different physiological responses. The intermittent modality would lead to a larger recruitment of fast twitch fibres that are less mitochondria-equipped and therefore may be more likely respondent to mitochondrial adaptations. In addition, this modality induces greater metabolic variations, a stimulus who could lead to mitochondrial development.
131‐Oxophorbine protopheophorbide A from Ziziphus lotus as a novel mesenchymal‐epithelial transition factor receptor inhibitory lead for the control of breast tumor growth in vitro and in vivo

The failure of chemotherapy especially in triple negative breast cancer (TNBC) patients has been correlated with the overexpression of the mesenchymal‐epithelial transition factor (c‐Met) receptor. Thus, the hepatocyte growth factor (HGF)/c‐Met signaling axis has gained considerable attention as a valid molecular target for breast cancer therapy. This study reports for the first time the discovery of the 131‐oxophorbines pheophorbide A and protopheophorbide A along with chlorophyllide A from Ziziphus lotus, an edible typical Tunisian plant, as the potent antiproliferative compounds against the human breast cancer cells MDA‐MB‐231 and MCF‐7. Compared to other compounds, protopheophorbide A exerted the highest light‐independent antiproliferative effect against the metastatic TNBC MDA‐MB‐231 cells (IC50 = 6.5 μM). In silico, this compound targeted the kinase domain of multiple c‐Met crystal structures. It potently inhibited the kinase domain phosphorylation of wild and mutant c‐Met in Z‐LYTE kinase assay. Protopheophorbide A inhibited HGF‐induced downstream c‐Met‐dependent cell proliferation, survival, adhesion and migration through RAF/MEK/ERK and PI3K/PTEN/AKT signaling pathways modulation, ROS generation and activation of JNK and p38 pathways. Interestingly, this compound impaired the ability of the MDA‐MB‐231 cells to adhere at different extracellular matrix proteins by reducing the HGF‐induced expression of integrins αv, β3, α2, and β1. Moreover, protopheophorbide A exhibited anti‐migratory properties (IC50 = 2.2 μM) through impacting the expression levels of E‐cadherin, vimentin, β‐catenin, FAK, Brk, Rac, and Src proteins. Importantly, treatment with protopheophorbide A significantly inhibited the MDA‐MB‐231 tumor growth in vivo. Our results suggest that protopheophorbide A could be a novel c‐Met inhibitory lead with promise to control c‐Met/HGF‐dependent breast malignancies.
Hodgkin lymphoma of the elderly patients: a retrospective multicenter analysis from the Polish Lymphoma Research Group*

Abstract We retrospectively analyzed long-term disease outcome of 350 elderly Hodgkin Lymphoma (eHL) patients treated with ABVD/ABVD-like regimen enrolled in the PLRG-R9 study between 2001 and 2013 in Poland. Complete remission was reported for 73% of early (ES) and 61% advanced stage (AS) patients. Nine (10%) ES and 56 (20%) AS patients have died. With the median follow-up of 36 (1–190) months, 3-year EFS and OS was 0.74 (95%CI: 0.63–0.85) and 0.90 (95%CI: 0.82–0.98) for ES; 0.51 (95%CI: 0.44–0.57), and 0.81 (95%CI: 0.75–0.86) for AS patients, respectively. For ES patients, Cox regression revealed ECOG <2 and age >70 as predictive for inferior OS and EFS. For AS patients, the most predictive for OS was the presence of cardiovascular disorders (CVD) (p = .00044), while for EFS four factors were significantly associated with a poor outcome: ECOG< 2, age >70 years, CVD and extranodal disease. In conclusion, CVD significantly impacts outcomes of ABVD-treated advanced eHL patients.
Cross-Cultural Adaptation, Validity, and Reliability Study of the Turkish Version of Back Performance Scale

Study Design. Validation of a performance scale. Objective. The purpose of this study is to investigate adaptation, validity, and reliability of the Turkish version of the Back Performance Scale (BPS). Summary of Background Data. Low back pain affects people of all ages and causes pain, disability, and psychosocial problems. BPS is a condition-specific performance measure of activity limitation in patients with low back pain. The purpose of this study is to investigate the cross-cultural adaptation, validity, and reliability of the Turkish version of the BPS. Methods. The study included 180 patients with low back pain. For the reliability assessment of the scale, test-retest, and internal consistency analyses were performed. The results of the test-retest analysis were analyzed by Intraclass Correlation Coefficient (ICC) method. For the internal consistency, Cronbach Alpha value was calculated and to construct validity, total points of the BPS were compared with the total points of Roland Morris Disability Questionnaire (RMDQ) and Oswestry Disability Index (ODI) using Pearson correlation coefficient analysis. Results. BPS was found to have high internal consistency (Cronbach alpha value 0.827). Test-retest results were found highly correlated (range from 0.723 to 0.899). Factor analysis indicated that the scale had one factor. BPS is well correlated with RMDQ and ODI (Pearson correlation coefficient with RMDQ 0.576 and with ODI 0.603). Conclusion. The Turkish version of BPS is valid and reliable. Level of Evidence: 3
The ‘TranSeq’ 3′‐end sequencing method for high‐throughput transcriptomics and gene space refinement in plant genomes

High-throughput RNA sequencing has proven invaluable not only to explore gene expression but also for both gene prediction and genome annotation. However, RNA sequencing, carried out on tens or even hundreds of samples, requires easy and cost-effective sample preparation methods using minute RNA amounts. Here, we present TranSeq, a high-throughput 3'-end sequencing procedure that requires 10- to 20-fold fewer sequence reads than the current transcriptomics procedures. TranSeq significantly reduces costs and allows a greater increase in size of sample sets analyzed in a single experiment. Moreover, in comparison with other 3'-end sequencing methods reported to date, we demonstrate here the reliability and immediate applicability of TranSeq and show that it not only provides accurate transcriptome profiles but also produces precise expression measurements of specific gene family members possessing high sequence similarity. This is difficult to achieve in standard RNA-seq methods, in which sequence reads cover the entire transcript. Furthermore, mapping TranSeq reads to the reference tomato genome facilitated the annotation of new transcripts improving >45% of the existing gene models. Hence, we anticipate that using TranSeq will boost large-scale transcriptome assays and increase the spatial and temporal resolution of gene expression data, in both model and non-model plant species. Moreover, as already performed for tomato (ITAG3.0; www.solgenomics.net), we strongly advocate its integration into current and future genome annotations.
Fruit and vegetable consumption and breast cancer incidence: Repeated measures over 30 years of follow‐up

We evaluated the relation of fruit and vegetable consumption, including specific fruits and vegetables, with incident breast cancer characterized by menopausal status, hormone receptor status and molecular subtypes. Fruit and vegetable consumption, cumulatively averaged across repeated, validated questionnaires, was examined in relation to risk of invasive breast cancer among 182,145 women initially aged 27–59 years in the Nurses’ Health Study (NHS, 1980–2012) and NHSII (1991–2013). Cox proportional hazards regression, adjusted for known risk factors, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and assessed tumors by hormone receptor status and molecular subtypes. We prospectively documented 10,911 invasive breast cancer cases. Greater intake of total fruits and vegetables, especially cruciferous and yellow/orange vegetables, was associated with significantly lower breast cancer risk (>5.5 vs. ≤2.5 servings/day HR = 0.89, 95% CI = 0.83–0.96; ptrend = 0.006). Intake of total vegetables was especially associated with lower risk of estrogen receptor negative tumors (HR per 2 additional servings/day as a continuous variable = 0.84, 95%CI = 0.77–0.93; pheterogeneity = 0.02). Among molecular subtypes, higher intake of total fruits and vegetables (HR per 2 additional servings/day as a continuous variable) was most strongly associated with lower risk of human epidermal growth factor receptor 2 (HER2)‐enriched (HR = 0.79, 95%CI = 0.67–0.93), basal‐like (HR = 0.84, 95%CI = 0.72–0.97) and luminal A (HR = 0.94, 95%CI = 0.89–0.99), but not with luminal B tumors (pheterogeneity = 0.03). In conclusion, our findings support that higher intake of fruits and vegetables, and specifically cruciferous and yellow/orange vegetables, may reduce the risk of breast cancer, especially those that are more likely to be aggressive tumors.
Grid-Cell Activity on Linear Tracks Indicates Purely Translational Remapping of 2D Firing Patterns at Movement Turning Points

Grid cells in rodent medial entorhinal cortex are thought to play a critical role for spatial navigation. When the animal is freely moving in an open arena the firing fields of each grid cell tend to form a hexagonal lattice spanning the environment. For movements along a linear track the cells seem to respond differently. They show multiple firing fields that are not periodically arranged and whose shape and position change when the running direction is reversed. In addition, peak firing rates vary widely from field to field. Measured along one running direction only, firing fields are, however, compatible with a slice through a two-dimensional (2D) hexagonal pattern. It is an open question, whether this is also true if leftward and rightward runs are jointly considered. By analyzing data from 15 male Long–Evans rats, we show that a single hexagonal firing pattern explains the linear-track data if translational shifts of the pattern are allowed at the movement turning points. A rotation or scaling of the grid is not required. The agreement is further improved if the peak firing rates of the underlying 2D grid fields can vary from field to field, as suggested by recent studies. These findings have direct consequences for experiments using linear tracks in virtual reality. SIGNIFICANCE STATEMENT Various types of neurons support spatial navigation. Their response properties are often studied in reduced settings and might change when the animal can freely explore its environment. Grid cells in rodents, for example, exhibit seemingly irregular firing fields when animal movement is restricted to a linear track but highly regular patterns in two-dimensional (2D) arenas. We show that linear-track responses of a cell for both leftward and rightward running directions can be explained as cuts through a single hexagonal pattern if translational remapping is allowed at movement turning points; neither rotations nor scale transformations are needed. These results provide a basis to quantify grid-cell activity in 1D virtual reality and could help to detect and categorize grid cells without experiments in 2D environments.
Computer simulation analysis of source‐detector position for percutaneously measured O2‐gas signal in a three‐dimensional preterm infant lung

Further improvements in the clinical care of our most vulnerable patients—preterm infants—are needed. Novel diagnostic and surveillance tools facilitate such advances. The GASMAS technique has shown potential to become a tool to, noninvasively, monitor gas in the lungs of preterm infants, by placing a laser source and a detector on the chest wall skin. It is believed that this technology will become a valuable clinical diagnostic tool for monitoring the lung function of these patients. Today, the technology is, for this application, in an early stage and further investigations are needed. In the present study, a three‐dimensional computer model of the thorax of an infant is constructed, from a set of CT images. Light transport simulations are performed to provide information about the position dependence of the laser‐ and detector probe on the thorax of the infant. The result of the simulations, based on the study method and the specified model used in this work, indicates that measurement geometries in front and on the side of the lung are favorable in order to obtain a good gas absorption signal.
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway

A series of novel matrinic thiadiazole derivatives were designed, synthesized and evaluated for their inhibitory effect on COL1A1 promotor. The SAR indicated that: (i) the introduction of a thiadiazole on the 11-side chain was beneficial for activity; (ii) a 12-N-benzyl moiety was favorable for activity. Among them, compound 6n displayed a high activity with an inhibitory rate of 39.7% at a concentration of 40 μM. It also effectively inhibited the expression of two representative collagen proteins (COL1A1 and α-SMA) on both the mRNA and protein levels and showed a high safety profile in vivo, indicating its great promise as an anti-liver fibrosis agent. Further study indicated that it might repress hepatic fibrogenesis via the TGFβ/Smad pathway. This study provided powerful information for further strategic optimization and the top compound 6n was selected for further study as an ideal liver fibrosis lead for next investigation.
Circulating microRNA expression profiling and bioinformatics analysis of dysregulated microRNAs of patients with coronary artery disease

Abstract MicroRNs (miRNAs) are small non-coding RNAs that modulate the expression of protein-coding genes at the post-transcription level and their dysregulated expression has been implicated in cardiovascular diseases. Circulating miRNAs have been widely recommended as potential biomarkers for many diseases including coronary artery disease. In this study, the miRNA expression profiles of 6 normal coronary artery (NCA), 12 patients with coronary artery disease including 6 unstable angina (UA) patients and 6 ST-segment elevation myocardial infarction (STEMI) patients were determined by small RNA sequencing. The differential expression of miRNAs was verified via using quantitative reverse transcription polymerase chain reaction (qRT-PCR). We further performed bioinformatics analysis for the differentially expressed miRNAs. The results showed that 60 miRNAs were up-regulated and 26 miRNAs were down-regulated in the UA group and 49 miRNAs were up-regulated and 62 miRNAs were down-regulated in the UA group when compared with the NCA group. Among them, both of UA group and STEMI group shared 38 dysregulated miRNAs (28 up-regulated and 10 down-regulated) versus NCA group. ROC curves analysis showed that miR-142-3p and miR-17-5p might server as potential biomarkers for the detection and diagnosis of UA and STEMI. Bioinformatics functional predictions showed that the differential expressed miRNAs were closely related with the pathological process of coronary artery disease. We comprehensively analyzed profile expression of circulating miRNAs of patients with coronary artery disease. Our study suggested that miR-142-3p and miR-17-5p might be potential targets for follow-up research in evaluating biomarkers of coronary artery disease.
Interaction via the N terminus of the type IV secretion system (T4SS) protein VirB6 with VirB10 is required for VirB2 and VirB5 incorporation into T-pili and for T4SS function

Many bacterial pathogens employ multicomponent protein complexes such as type IV secretion systems (T4SSs) to transfer virulence factors into host cells. Here we studied the interaction between two essential T4SS components: the very hydrophobic inner membrane protein VirB6, which may be a component of the translocation channel, and VirB10, which links the inner and outer bacterial membranes. To map the interaction site between these two T4SS components, we conducted alanine scanning and deleted six-amino acid stretches from the N-terminal periplasmic domain of VirB6 from Brucella suis. Using the bacterial two-hybrid system to analyze the effects of these alterations on the VirB6–VirB10 interaction, we identified the amino acid regions 16–21 and 28–33 and Leu-18 in VirB6 as being required for this interaction. SDS-PAGE coupled with Western blotting of cell lysates and native PAGE of detergent-extracted membrane proteins revealed that the corresponding VirB6 residues in Agrobacterium tumefaciens (Phe-20 and amino acids 18–23 and 30–35) modulate the stability of both VirB6 and VirB5. However, the results from immuno-EM and super-resolution microscopy suggested that these regions and residues are not required for membrane association or for polar localization of VirB6. The six-amino acid deletions in the N terminus of VirB6 abolished pilus formation and virulence of A. tumefaciens, and the corresponding deletions in the VirB6 homolog TraD from the plasmid pKM101-T4SS abrogated plasmid transfer. Our results indicate that specific residues of the VirB6 N-terminal domain are required for VirB6 stabilization, its interaction with VirB10, and the incorporation of VirB2 and VirB5 into T-pili.
Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction

ABSTRACT Introduction: Heart failure with preserved ejection fraction (HFpEF) continues to be a major challenge for clinicians. Many crucial aspects of the syndrome remain unclear, including the exact pathophysiology, early diagnosis, and treatment. Patients with HFpEF are often asymptomatic late into the disease process, and treatment with medications commonly used in heart failure with reduced ejection fraction (HFrEF) has not been proven to be beneficial. In addition, the confusion of similar terms with HFpEF, such as diastolic heart failure, and diastolic dysfunction (DD), has led to a misunderstanding of the true scope of HFpEF. Areas covered: In this review, authors highlight the differences in terminology and critically review the current knowledge on the underlying mechanisms, diagnosis, and latest treatment strategies of HFpEF. Expert commentary: While significant advances have been made in the understanding of HFpEF, the definitive diagnosis of HFpEF continues to be difficult. The development of improved and standardized methods for detecting DD has shown promise in identifying early HFpEF. However, even with early detection, there are few treatment options shown to provide mortality benefit warranting further investigation.
Nonalcoholic Fatty Liver Disease and Risk of Diabetes: A Prospective Study in China.

OBJECTIVE We aimed to investigate whether liver steatosis severity affects the risk of developing diabetes in a large cohort study. METHODS We prospectively examined the association in 41,650 Chinese adults with negative hepatitis-B surface antigen who were free of alcohol consumption, diabetes, and liver cirrhosis at baseline. Cox proportional models were used to estimate the risk of diabetes after a mean of 3.6 years of follow-up. Nonalcoholic fatty liver disease (NAFLD) was assessed with hepatic ultrasonography. Elevated alanine transaminase (ALT) was defined as ALT concentrations >19 and >30 U/L in females and males, respectively. Diabetes was defined as a fasting glucose 37.0 mmol/L or treatment with hypoglycemic medication. RESULTS Liver steatosis severity was significantly associated with higher risks of developing diabetes (adjusted hazard ratio [HR] for severe vs. without NAFLD = 2.66, 95% confidence interval [CI]: 2.17-3.25, P-trend<.001) and impaired fasting glucose (fasting glucose between 5.6 and 6.9 mmol/L, adjusted HR = 1.36, 95% CI: 1.16-1.59, P-trend<.001), as well as a faster increase rate of fasting glucose concentrations ( P-trend<.001), during 3.6 years of follow-up. Elevated ALT was also associated with incident diabetes (HR = 1.12, 95% CI: 1.02-1.22), adjusting for NAFLD and other covariates. CONCLUSION We observed a dose-response relationship between liver steatosis severity and increased diabetes risk, and ALT may predict incident diabetes independently of NAFLD. ABBREVIATIONS ALT = alanine transaminase; BP = blood pressure; CI = confidence interval; HCV = hepatitis C virus; HR = hazard ratio; IFG = impaired fasting glucose; NAFLD = nonalcoholic fatty liver disease; ULN = upper limit of normal.
Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations

PIK3CA is a frequently mutated gene in cancer, including about ~15 to 20% of colorectal cancers (CRC). PIK3CA mutations lead to activation of the PI3K/AKT/mTOR signaling pathway, which plays pivotal roles in tumorigenesis. Here, we investigated the mechanism of resistance of PIK3CA‐mutant CRC cell lines to gedatolisib, a dual PI3K/mTOR inhibitor. Out of a panel of 29 CRC cell lines, we identified 7 harboring one or more PIK3CA mutations; of these, 5 and 2 were found to be sensitive and resistant to gedatolisib, respectively. Both of the gedatolisib‐resistant cell lines expressed high levels of active glycogen synthase kinase 3‐beta (GSK3β) and harbored the same frameshift mutation (c.465_466insC; H155fs*) in TCF7, which encodes a positive transcriptional regulator of the WNT/β‐catenin signaling pathway. Inhibition of GSK3β activity in gedatolisib‐resistant cells by siRNA‐mediated knockdown or treatment with a GSK3β‐specific inhibitor effectively reduced the activity of molecules downstream of mTOR and also decreased signaling through the WNT/β‐catenin pathway. Notably, GSK3β inhibition rendered the resistant cell lines sensitive to gedatolisib cytotoxicity, both in vitro and in a mouse xenograft model. Taken together, these data demonstrate that aberrant regulation of WNT/β‐catenin signaling and active GSK3β induced by the TCF7 frameshift mutation cause resistance to the dual PI3K/mTOR inhibitor gedatolisib. Cotreatment with GSK3β inhibitors may be a strategy to overcome the resistance of PIK3CA‐ and TCF7‐mutant CRC to PI3K/mTOR‐targeted therapies.