Miracle-dz/UniFAR-FTUs huggingface dataset:
miR-221-3p promotes hepatocellular carcinogenesis by downregulating O6-methylguanine-DNA methyltransferase

ABSTRACT This study aimed to investigate the influence of miR-221-3p and O6-methylguanine-DNA methyltransferase (MGMT) interaction in human hepatocellular carcinoma (HCC), thereby revealing a novel molecular mechanism of hepatic carcinogenesis involving miR-221-3p and MGMT. Fluorescence qPCR and immunoblot assays were performed to determine the expression of RNA and protein in HCC tissues and cell lines. We also employed the firefly and Renilla luciferase assay to verify the target relationship between miR-221-3p and MGMT mRNA. Assessments including the MTT assay, wound-healing assay, transwell assay, colony foci formation experiment, and flow cytometric experiment were carried out to determine the viability, migration, invasion, proliferation, cell cycle progression, and apoptosis of SMMC-7721 and BEL-7404 cell lines with the modulated expression of miR-221-3p and MGMT. Compared to healthy tissues and cell line HL7702, miR-221-3p was significantly upregulated but MGMT was significantly downregulated in carcinomas and cancerous cell lines. Forced miR-221-3p overexpression was found to enhance the proliferation, migration, invasion, and clonogenicity of cell lines, but it suppressed cell apoptosis. Findings also revealed that forced miR-221-3p overexpression had little effect on cell cycle progression. After MGMT was confirmed to be atarget gene of miR-221-3p, it was found that the forced upregulation of miR-221-3p downregulated MGMT mRNA and protein levels significantly. MiR-221-3p was identified as an HCC promoting factor, and it specifically inhibited the expression of the MGMT. Besides, the upregulation of miR-221-3p had apositive influence on HCC pathogenesis by inhibiting MGMT expression.
Integrated Strength and Fundamental Movement Skill Training in Children: A Pilot Study

Competence in fundamental movement skills is essential to enable children to be physically active. We investigated the effect of an integrated fundamental movement skill with a strength training intervention on children’s fundamental movement skills. Seventy-two (53% female) 10- to 11-year-old children from three primary schools assented to take part in this study (87% compliance). Schools were randomly allocated to a control (no intervention; n = 21), fundamental movement skill (FMS) (n = 18) or FMS and strength (FMS+; n = 20) group. Interventions were delivered twice weekly for four weeks, in addition to normal physical education. FMS competence was measured through the Canadian agility and movement skills assessment (CAMSA) (product-process) and through countermovement jump (CMJ) and 40-m sprint tests (product). Improvements were observed in the CAMSA in both FMS (4.6, 95% confidence intervals 2.9 to 6.4 Arbitrary Units (AUs), second-generation p-value (pδ) = 0.03) and FMS+ (3.9, 2.1 to 5.3 AU, pδ = 0.28) with no difference beyond our minimum threshold of 3 AU observed between these intervention groups (pδ = 1). Clear improvements in CMJ were observed in FMS+ relative to the control (25, 18 to 32%, pδ = 0) and FMS groups (15, 6.1 to 24%, pδ = 0). These preliminary data suggest combined FMS and strength training warrants further investigation as a tool to develop fundamental movement skills in children.
An animal model of Huntington’s disease : behavioral, pharmacological and morphological changes following intrastriatal injections of kainic acid

Compared with saline injected controls, rats with b i la t era l injections of kainic acid (KA) in the dorsal striatum showed temporary aphagia and adipsia, long-lasting body weight decreases, increased locomotor response to d-amphetamine, increased spontaneous nocturnal locomotor act iv i ty , increased resistance to extinction, impaired acquisition and retention of avoidance behavior and increased latencies to leave start boxes in various mazes. The KA injections resulted in loss of loca l neurons in the dorsal striatum, with no appreciable damage either to dopaminergic terminals or to extr inis ic myelinated axons, thus supporting both the selective neurotoxic action of KA on neuronal perikarya and the proposed s imilari ty of KA-induced s t r i a t a l lesions with those found in the caudate-putamen of patients with Huntington's disease (HD). The present results demonstrate that KA s t r ia ta l lesioned rats also show behavioral and pharmacological s i m i l a r i ties with HD patients. In addition, they support the view that HD is characterized by a "subcortical dementia syndrome". A review of HD is also presented. Dr. H. C. Fibiger Research Supervisor
Reproductive Potential of Yeast Cells Depends on Overall Action of Interconnected Changes in Central Carbon Metabolism, Cellular Biosynthetic Capacity, and Proteostasis

Carbon metabolism is a crucial aspect of cell life. Glucose, as the primary source of energy and carbon skeleton, determines the type of cell metabolism and biosynthetic capabilities, which, through the regulation of cell size, may affect the reproductive capacity of the yeast cell. Calorie restriction is considered as the most effective way to improve cellular physiological capacity, and its molecular mechanisms are complex and include several nutrient signaling pathways. It is widely assumed that the metabolic shift from fermentation to respiration is treated as a substantial driving force for the mechanism of calorie restriction and its influence on reproductive capabilities of cells. In this paper, we propose another approach to this issue based on analysis the connection between energy-producing and biomass formation pathways which are closed in the metabolic triangle, i.e., the respiration-glycolysis-pentose phosphate pathway. The analyses were based on the use of cells lacking hexokinase 2 (∆hxk2) and conditions of different glucose concentration corresponding to the calorie restriction and the calorie excess. Hexokinase 2 is the key enzyme involved in central carbon metabolism and is also treated as a calorie restriction mimetic. The experimental model used allows us to explain both the role of increased respiration as an effect of calorie restriction but also other aspects of carbon metabolism and the related metabolic flux in regulation of reproductive potential of the cells. The obtained results reveal that increased respiration is not a prerequisite for reproductive potential extension but rather an accompanying effect of the positive role of calorie restriction. More important seems to be the changes connected with fluxes in central carbon metabolic pathways resulting in low biosynthetic capabilities and improved proteostasis.
Mps1 controls spindle assembly, SAC, and DNA repair in the first cleavage of mouse early embryos

Monopolar spindle‐1 (Mps1) is a critical interphase regulator that also involves into the spindle assembly checkpoint for the cell cycle control in both mitosis and meiosis. However, the functions of Mps1 during mouse early embryo development is still unclear. In this study, we reported the important roles of Mps1 in the first cleavage of mouse embryos. Our data indicated that the loss of Mps1 activity caused precocious cleavage of zygotes to 2‐cell embryos; however, prolonged culture disturbed the early embryo development to the blastocyst. We found that the spindle organization was disrupted after Mps1 inhibition, and the chromosomes were misaligned in the first cleavage. Moreover, the kinetochore–microtubule attachment was lost and Aurora B failed to accumulate to the kinetochores, indicating that the spindle assembly checkpoint (SAC) was activated. Furthermore, the inhibition of Mps1 activity resulted in an increase of DNA damage, which further induced oxidative stress, showing with positive γ‐H2A.X signal and increased reactive oxygen species level. Ultimately, irreparable DNA damage and oxidative stress‐activated apoptosis and autophagy, which was confirmed by the positive Annexin‐V signal and increased autophagosomes. Taken together, our data indicated that Mps1 played important roles in the control of SAC and DNA repair during mouse early embryo development.
Diagnostic Ability of Radiofrequency Ultrasound in Parkinson’s Disease Compared to Conventional Transcranial Sonography and Magnetic Resonance Imaging

We aimed to estimate tissue displacements’ parameters in midbrain using ultrasound radiofrequency (RF) signals and to compare diagnostic ability of this RF transcranial sonography (TCS)-based dynamic features of disease affected tissues with conventional TCS (cTCS) and magnetic resonance imaging (MRI) while differentiating patients with Parkinson’s disease (PD) from healthy controls (HC). US tissue displacement waveform parametrization by RF TCS for endogenous brain tissue motion, standard neurological examination, cTCS and MRI data collection were performed for 20 PD patients and for 20 age- and sex-matched HC in a prospective manner. Three logistic regression models were constructed, and receiver operating characteristic (ROC) curve analyses were applied. The model constructed of RF TCS-based brain tissue displacement parameters—frequency of high-end spectra peak and root mean square—revealed presumably increased anisotropy in the midbrain and demonstrated rather good diagnostic ability in the PD evaluation, although it was not superior to that of the cTCS or MRI. Future studies are needed in order to establish the true place of RF TCS detected tissue displacement parameters for the evaluation of pathologically affected brain tissue.
A practical method of drug provocation testing to prove tolerance to alternative drugs in drug hypersensitivity

Background/aim Drug provocation tests (DPTs) are the gold standard method performed at the end of a stepwise approach in a drug allergy workup. Drug provocation tests are administered as a single drug on a test day. Testing more than one drug in a day is a feasible option and could be a safe and time- and manpower-saving procedure in well-selected patients. The aim of the present study was to investigate the efficacy and safety of performing a DPT with two or three alternative drugs in one test day (Hacettepe method). Materials and methods Adult patients who were admitted with drug hypersensitivity between August 2010 and December 2016 and underwent DPTs with the described method were included. The method was based on performing DPTs with two or three different, alternative drugs on the same test day. Data was obtained from standard drug provocation test forms and from patient files. Results A total of 1448 DPTs were performed by the Hacettepe method in 1131 patients. The reaction rate was 5.45% (n = 79), and none of the reactions were severe. The Hacettepe method saved 19.95 DPTs per month which was a considerable time savings. Conclusion In cases of proven drug hypersensitivity reactions, performing a drug provocation test with a combination of two or three different, alternative drugs instead of one saved time and manpower and was a safe procedure. We recommend implementing this method in drug allergy workups.
Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice.

Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control for food intake and energy expenditure. Here we reported that, contrary to females, male mice lacking circadian nuclear receptors REV-ERB alpha and beta in the tuberal hypothalamus (HDKO) gained excessive weight on an obesogenic high fat diet due to both decreased energy expenditure and increased food intake during the light phase. Moreover, rebound food intake after fasting was markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior was due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity was impaired in HDKO mice on an obesogenic diet in a diurnal manner. Thus, REV-ERBs play a crucial role in hypothalamic control of food intake and diurnal leptin sensitivity in diet-induced obesity.
Structural Antibiotic Surveillance and Stewardship via Indication-Linked Quality Indicators: Pilot in Dutch Primary Care

Insight into antibiotic prescribing quality is key to general practitioners (GPs) to improve their prescribing behavior and to national antibiotic surveillance and stewardship programs. Additionally to numbers of prescribed antibiotics, quality indicators (QIs) linked to the clinical indication for prescribing are urgently needed. The aim of this proof of concept study was to define indication-linked QIs which can be easily implemented in Dutch primary care by collaborating with data-extraction/processing companies that routinely process patient data for GP practices. An expert group of academic and practicing GPs defined indication-linked QIs for which outcomes can be derived from routine care data. QI outcomes were calculated and fed back to GPs from 44 practices, associations between QI outcomes were determined, and GPs’ opinions and suggestions with respect to the new set were captured using an online questionnaire. The new set comprises: (1) total number of prescribed antibiotics per 1000 registered patients and percentages of generally non-1st choice antibiotics; (2) prescribing percentages for episodes of upper and lower respiratory tract infection; (3) 1st choice prescribing for episodes of tonsillitis, pneumonia and cystitis in women. Large inter-practice variation in QI outcomes was found. The validity of the QI outcomes was confirmed by associations that were expected. The new set was highly appreciated by GPs and additional QIs were suggested. We conclude that it proved feasible to provide GPs with informative, indication-linked feedback of their antibiotic prescribing quality by collaborating with established data extraction/processing companies. Based on GPs’ suggestions the set will be refined and extended and used in the near future as yearly feedback with benchmarking for GPs and for national surveillance and stewardship purposes.
Image Compressive Sensing via Hybrid Nonlocal Sparsity Regularization

This paper focuses on image compressive sensing (CS). As the intrinsic properties of natural images, nonlocal self-similarity and sparse representation have been widely used in various image processing tasks. Most existing image CS methods apply either self-adaptive dictionary (e.g., principle component analysis (PCA) dictionary and singular value decomposition (SVD) dictionary) or fixed dictionary (e.g., discrete cosine transform (DCT), discrete wavelet transform (DWT), and Curvelet) as the sparse basis, while single dictionary could not fully explore the sparsity of images. In this paper, a Hybrid NonLocal Sparsity Regularization (HNLSR) is developed and applied to image compressive sensing. The proposed HNLSR measures nonlocal sparsity in 2D and 3D transform domain simultaneously, and both self-adaptive singular value decomposition (SVD) dictionary and fixed 3D transform are utilized. We use an efficient alternating minimization method to solve the optimization problem. Experimental results demonstrate that the proposed method outperforms existing methods in both objective evaluation and visual quality.
Clarifying assumptions in age-period-cohort analyses and validating results

Background Age-period-cohort (APC) models are often used to decompose health trends into period- and cohort-based sources, but their use in epidemiology and population sciences remains contentious. Central to the contention are researchers’ failures to 1) clearly state their analytic assumptions and/or 2) thoroughly evaluate model results. These failures often produce varying conclusions across APC studies and generate confusion about APC methods. Consequently, scholarly exchanges about APC methods usually result in strong disagreements that rarely offer practical advice to users or readers of APC methods. Methods We use research guidelines to help practitioners of APC methods articulate their analytic assumptions and validate their results. To demonstrate the usefulness of the guidelines, we apply them to a 2015 American Journal of Epidemiology study about trends in black-white differences in U.S. heart disease mortality. Results The application of the guidelines highlights two important findings. On the one hand, some APC methods produce inconsistent results that are highly sensitive to researcher manipulation. On the other hand, other APC methods estimate results that are robust to researcher manipulation and consistent across APC models. Conclusions The exercise shows the simplicity and effectiveness of the guidelines in resolving disagreements over APC results. The cautious use of APC models can generate results that are consistent across methods and robust to researcher manipulation. If followed, the guidelines can likely reduce the chance of publishing variable and conflicting results across APC studies.
A Real-Time Thermal Monitoring System Intended for Embedded Sensors Interfaces

This paper proposes a real-time thermal monitoring method using embedded integrated sensor interfaces dedicated to industrial integrated system applications. Industrial sensor interfaces are complex systems that involve analog and mixed signals, where several parameters can influence their performance. These include the presence of heat sources near sensitive integrated circuits, and various heat transfer phenomena need to be considered. This creates a need for real-time thermal monitoring and management. Indeed, the control of transient temperature gradients or temperature differential variations as well as the prediction of possible induced thermal shocks and stress at early design phases of advanced integrated circuits and systems are essential. This paper addresses the growing requirements of microelectronics applications in several areas that experience fast variations in high-power density and thermal gradient differences caused by the implementation of different systems on the same chip, such as the new-generation 5G circuits. To mitigate adverse thermal effects, a real-time prediction algorithm is proposed and validated using the MCUXpresso tool applied to a Freescale embedded sensor board to monitor and predict its temperature profile in real time by programming the embedded sensor into the FRDM-KL26Z board. Based on discrete temperature measurements, the embedded system is used to predict, in advance, overheating situations in the embedded integrated circuit (IC). These results confirm the peak detection capability of the proposed algorithm that satisfactorily predicts thermal peaks in the FRDM-KL26Z board as modeled with a finite element thermal analysis tool (the Numerical Integrated elements for System Analysis (NISA) tool), to gauge the level of local thermomechanical stresses that may be induced. In this paper, the FPGA implementation and comparison measurements are also presented. This work provides a solution to the thermal stresses and local system overheating that have been a major concern for integrated sensor interface designers when designing integrated circuits in various high-performance technologies or harsh environments.
Phantom material testing indicates that the mechanical properties, geometrical dimensions, and tensional state of tendons affect oscillation-based measurements

Objective: There is an increasing interest in the application of oscillation-based measurement techniques to evaluate the mechanical stiffness of healthy and diseased tendons. These techniques measure the stiffness of a tendon indirectly by registering the oscillation response of a tendon to an external mechanical impulse. Although these measurement techniques seem to be comparatively easy and time-saving, their applicability is implicitly limited by their indirect measurement principle. Approach: In this study, we aim to find evidence that the oscillation response of a tendon to an external mechanical impulse is not only affected by the stiffness of a tendon but also by the tendons’ cross-sectional area (CSA), length, and tension. Therefore, we reviewed the current literature on oscillation-based techniques that measure in vivo tendon properties. Further, a phantom material was used to mimic the nature of tendons and to test the impact of four factors on oscillation-based measurements. Main results: Our results indicate that the mechanical properties, geometrical dimensions (length and CSA), and tensional state affect oscillation-based measures. Surprisingly, most studies on tendon behavior often exclusively associate their oscillation-based measurements with the mechanical stiffness of a tendon. Significance: While this narrow perspective bears the risk of misinterpretation or false implications, a broader understanding of oscillation-based measurements has the potential to shed new light on the interaction of muscles and tendons in vivo.
Characterisation of articular manifestations in primary Sjögren's syndrome: clinical and imaging features.

OBJECTIVES Articular manifestations (AMs) are observed in a large proportion of patients with primary Sjögren's syndrome (pSS) and can occur at the time of pSS diagnosis or during the disease course. Although in the majority of cases AMs are mild and self-limiting, some patients may experience chronic polyarthritis requiring treatment with DMARDs. Ultrasonography (US) and magnetic resonance imaging (MRI) can help assessing the extent of articular involvement and guide the treatment. The aim of this study was to describing clinical, serological, and histological picture of a cohort of pSS patients with AMs. METHODS Clinical and serological records were retrospectively evaluated and either US or MRI were performed to evaluate AMs and their features were described according to the OMERACT scoring systems. RESULTS One hundred and thirty-three pSS patients were enrolled, of which 115 (86%) with articular involvement. In particular, 91 patients (68%) displayed AMs at the time of pSS diagnosis while 24 patients (32%) during the course of the disease. Patients with AMs during the disease course were diagnosed with pSS at a younger age and reported a higher VAS dryness compared to patients displaying AMs at pSS onset. Hands and wrists were the most frequently involved sites followed by knees, shoulders and ankles. Overall, a consistent number of abnormalities were detected, more by MRI than US. Hands and wrists were the most frequently evaluated sites and the prevalence of all MRI abnormalities was similar between the different sites and comparable between the groups. CONCLUSIONS pSS AMs encompass a wide disease spectrum ranging from arthralgia to erosive arthritis resembling RA and therefore represent an important determinant of patients' quality of life. Imaging techniques such as US and MRI may be useful in the follow-up of pSS patients for prompt identification of AMs, for the quantification of their extent and ultimately for providing guidance on treatment and improving patient care.