Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca2+ transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autophagy. Moreover, and perhaps not surprisingly, it has become clear that signaling events regulated at the ER–mitochondria intersection regulate key processes in oncogenesis and in the response of cancer cells to therapeutics. ER–mitochondria appositions have been shown to dynamically recruit oncogenes and tumor suppressors, modulating their activity and protein complex formation, adapt the bioenergetic demand of cancer cells and to regulate cell death pathways and redox signaling in cancer cells. In this review, we discuss some emerging players of the ER–mitochondria contact sites in mammalian cells, the key processes they regulate and recent evidence highlighting the role of MAMs in shaping cell-autonomous and non-autonomous signals that regulate cancer growth.
Digital LC-2: from bits & gates to a little computer

This paper describes DigLC2, a gate-level simulator for the Little Computer 2 architecture (LC-2) [3] which serves to strengthen the bottom-up approach to teach computer architecture. DigLC2 is based on Chipmunk's digital circuit simulator [1]; the circuit is freely available on the web and ready to use.
RNA Modeling by Combining Stochastic Context-Free Grammars and n-Gram Models

The RNA sentences present structured regions caused by pairwise correlations, and nonstructured regions where any global relation can be found. In this paper, we present a combination of stochastic context-free grammars (SCFG) and bigram models. The SCFGs are used to represent the long-term relations of the structured part of RNA sequences, while the bigram models are used to capture the local relations of the nonstructured part. A stochastic version of Sakakibara's algorithm is used to study the SCFGs. Finally, experiments to evaluate the behavior of this proposal were carried out.
Global analyses of the dynamics of mammalian microRNA metabolism

Rates of production and degradation together specify microRNA (miRNA) abundance and dynamics. Here, we used approach-to-steady-state metabolic labeling to assess these rates for 176 miRNAs in contact-inhibited mouse embryonic fibroblasts (MEFs), 182 miRNAs in dividing MEFs, and 127 miRNAs in mouse embryonic stem cells (mESCs). MicroRNA duplexes, each comprising a mature miRNA and its passenger strand, are produced at rates as fast as 110 ± 50 copies/cell/min, which exceeds rates reported for any mRNAs. These duplexes are rapidly loaded into Argonaute, with <30 min typically required for duplex loading and silencing-complex maturation. Within Argonaute, guide strands have stabilities that vary by 100-fold. Half-lives also vary globally between cell lines, with median values ranging from 11 to 34 h in mESCs and contact-inhibited MEFs, respectively. Moreover, relative half-lives for individual miRNAs vary between cell types, implying the influence of cell-specific factors in dictating turnover rate. The apparent influence of miRNA regions most important for targeting, together with the effect of one target on miR-7 accumulation, suggest that targets fulfill this role. Analysis of the tailing and trimming of miRNA 3′ termini showed that the flux was typically greatest through the isoform tailed with a single uridine, although changes in this flux did not correspond to changes in stability, which suggested that the processes of tailing and trimming might be independent from that of decay. Together, these results establish a framework for describing the dynamics and regulation of miRNAs throughout their life cycle.
Assessment of pre-ejection period in ambulatory subjects using seismocardiogram in a wearable blood pressure monitor

The ability to monitor arterial blood pressure continuously with unobtrusive body worn sensors may provide a unique and potentially valuable assessment of a patient's cardiovascular health. Pulse wave velocity (PWV) offers an attractive method to continuously monitoring blood pressure. However, PWV technologies based on timing measurements between the ECG and a distal PPG suffer from inaccuracies on mobile patients due to the confounding influence of pre-ejection period (PEP). In this paper, we presented a wearable, continuous blood pressure monitor (ViSi Mobile) that can measure and track changes in PEP. PEP is determined from precordial vibrations captured by an accelerometer coupled to the patient's sternum. The performance of the PEP measurements was evaluated on test subjects with postural change and patient activity. Results showed potential to improve cNIBP accuracy in active patients.
Synergistic Effects of Targeting Survivin and CDK1 on Nasopharyngeal Carcinoma in Vitro and in Vivo

Background: To explore the impact of pU6-based tandem survivin and CDK1-specific short hairpin RNA on the biological behaviors of CNE-2 nasopharyngeal carcinoma cells in vitro and in vivo. Patients and Methods: The vectors of pU6-survivinshRNA, pU6-CDK1shRNA and pU6-survivinshRNA-CDK1shRNA were constructed and transfected into CNE-2 cells with Lipofectamine TM 2000, respectively. The mRNAs and proteins of CDK1 and survivin were determined by RT-PCR and Western blotting, accordingly. MTT assay was employed to evaluate the proliferation of CNE-2 cells, and flow cytometry was performed to determine the apoptosis of CNE-2 cells. The effects of interfering survivin and CDK1 on tumorigenesis were evaluated by tumor xenografts experiments. Results: Effective plasmids were successfully constructed knocking down survivin and/or CDK1. The proliferation inhibition of CNE-2 cells by pU6-survivinshRNA-CDK1shRNA (32.5%) was higher than that of by pU6-survivinshRNA (25.6%) and pU6-CDK1shRNA (15.6%), and apoptosis in CNE-2 cells simultaneously interfering survivin and CDK1 (15.2%) dramatically increased when compared to those of interfering survivin (5.4%) or CDK1 (4.7%) alone. Furthermore, simultaneously interfering survivin and CDK1 is more effective than interfering alone component in inhibiting tumor growth of fBalb/C nude mice xenografted with CNE-2 cells. Conclusion: The results altogether indicate that interfering survivin and CDK1simutaneously can produce synergistic effects of anti-nasopharyngeal carcinoma, which could be a potential therapeutic method.
Genome-wide association and pathway analysis of feed efficiency in pigs reveal candidate genes and pathways for residual feed intake

Residual feed intake (RFI) is a complex trait that is economically important for livestock production; however, the genetic and biological mechanisms regulating RFI are largely unknown in pigs. Therefore, the study aimed to identify single nucleotide polymorphisms (SNPs), candidate genes and biological pathways involved in regulating RFI using Genome-wide association (GWA) and pathway analyses. A total of 596 Yorkshire boars with phenotypes for two different measures of RFI (RFI1 and 2) and 60k genotypic data was used. GWA analysis was performed using a univariate mixed model and 12 and 7 SNPs were found to be significantly associated with RFI1 and RFI2, respectively. Several genes such as xin actin-binding repeat-containing protein 2 (XIRP2),tetratricopeptide repeat domain 29 (TTC29),suppressor of glucose, autophagy associated 1 (SOGA1),MAS1,G-protein-coupled receptor (GPCR) kinase 5 (GRK5),prospero-homeobox protein 1 (PROX1),GPCR 155 (GPR155), and FYVE domain containing the 26 (ZFYVE26) were identified as putative candidates for RFI based on their genomic location in the vicinity of these SNPs. Genes located within 50 kbp of SNPs significantly associated with RFI and RFI2 (q-value ≤ 0.2) were subsequently used for pathway analyses. These analyses were performed by assigning genes to biological pathways and then testing the association of individual pathways with RFI using a Fisher’s exact test. Metabolic pathway was significantly associated with both RFIs. Other biological pathways regulating phagosome, tight junctions, olfactory transduction, and insulin secretion were significantly associated with both RFI traits when relaxed threshold for cut-off p-value was used (p ≤ 0.05). These results implied porcine RFI is regulated by multiple biological mechanisms, although the metabolic processes might be the most important. Olfactory transduction pathway controlling the perception of feed via smell, insulin pathway controlling food intake might be important pathways for RFI. Furthermore, our study revealed key genes and genetic variants that control feed efficiency that could potentially be useful for genetic selection of more feed efficient pigs.
Activation of endothelin-1 receptor signaling pathways is associated with neointima formation, neoangiogenesis and irreversible pulmonary artery hypertension in patients with congenital heart disease.

BACKGROUND It is unclear why some patients, who undergo complete repair or palliative surgery for congenital heart disease (CHD), still develop irreversible pulmonary artery hypertension (PAH). There is no consensus to preoperationally assess the reversible and irreversible pulmonary vasculopathy seen in PAH. METHODS AND RESULTS The peri-operative pulmonary hemodynamic data of 16 CHD patients (reversible PAH, n = 6; irreversible PAH, n = 10) were analyzed. The lung biopsies were also performed during surgery for defining histopathological characteristics as well as immunohistochemical expression of endothelin-1 (ET-1), endothelin-1 receptors (ETR), and its downstream signaling markers in the small pulmonary arteries and arterioles. Neointimal formation and neoangiogenesis was characterized by increased intimal layer immunoreactivity for α-SMA, Factor VIII, CD34, and VEGF. Neointimal formation was found in 90% of patients and neoangiogenesis was found in 80% of patients with irreversible PAH. Neither was present in the reversible PAH group and the control group. Expression of ET-1 and ETR in the neointimal layer of the pulmonary arterioles was upregulated in irreversible PAH, and immunoreactivity of phospho-Akt, phospho-ERK1/2, and phospho-mTOR was also increased in irreversible PAH. CONCLUSIONS Increased expression of ET-1, ETR, and activation of signaling pathways were observed in the pulmonary arteries and arterioles of irreversible PAH patients associated with CHD. Activation of these pathways might in turn lead to neointimal formation and neoangiogenesis and thus might contribute to irreversible pulmonary vascular abnormalities.
Monitoring of Antiretroviral Therapy and Mortality in HIV Programmes in Malawi, South Africa and Zambia: Mathematical Modelling Study

Objectives Mortality in patients starting antiretroviral therapy (ART) is higher in Malawi and Zambia than in South Africa. We examined whether different monitoring of ART (viral load [VL] in South Africa and CD4 count in Malawi and Zambia) could explain this mortality difference. Design: Mathematical modelling study based on data from ART programmes. Methods We used a stochastic simulation model to study the effect of VL monitoring on mortality over 5 years. In baseline scenario A all parameters were identical between strategies except for more timely and complete detection of treatment failure with VL monitoring. Additional scenarios introduced delays in switching to second-line ART (scenario B) or higher virologic failure rates (due to worse adherence) when monitoring was based on CD4 counts only (scenario C). Results are presented as relative risks (RR) with 95% prediction intervals and percent of observed mortality difference explained. Results RRs comparing VL with CD4 cell count monitoring were 0.94 (0.74–1.03) in scenario A, 0.94 (0.77–1.02) with delayed switching (scenario B) and 0.80 (0.44–1.07) when assuming a 3-times higher rate of failure (scenario C). The observed mortality at 3 years was 10.9% in Malawi and Zambia and 8.6% in South Africa (absolute difference 2.3%). The percentage of the mortality difference explained by VL monitoring ranged from 4% (scenario A) to 32% (scenarios B and C combined, assuming a 3-times higher failure rate). Eleven percent was explained by non-HIV related mortality. Conclusions VL monitoring reduces mortality moderately when assuming improved adherence and decreased failure rates.
Geodetic network optimization for geophysical parameters

The first order design problem in geodesy is generalized here, to seek the network configuration that optimizes the precision of geophysical parameters. An optimal network design that satisfies intuitively appropriate criteria corresponds to minimizing the sum of logarithmic variances of eigenparameters. This is equivalent to maximizing the determinant of the design matrix, allowing for closed‐form analysis. An equivalent expression is also given specifically for square root information filtering, to facilitate numerical solution. Appropriate seeding of numerical solutions can be provided by exact analytical solutions to idealized models. For example, for an ideal transform fault, simultaneous resolution of both the locking depth Dand location of the fault is optimized by placing stations at ±D/√3 (∼9 km) from the a priori fault plane. In a two‐fault system, the resolution of slip partitioning is optimized by including a station midway between faults; however resolution is fundamentally limited for fault separation <2D(∼30 km).
Common Cancer Stem Cell Gene Variants Predict Colon Cancer Recurrence

Purpose: Recent evidence suggests that cancer stem cells (CSC) are responsible for key elements of colon cancer progression and recurrence. Germline variants in CSC genes may result in altered gene function and/or activity, thereby causing interindividual differences in a patient's tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer. Experimental Design: A total of 234 patients treated with 5-fluorouracil–based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for germline polymorphisms in genes that have been previously associated with colon CSC (CD44, Prominin-1, DPP4, EpCAM, ALCAM, Msi-1, ITGB1, CD24, LGR5, and ALDH1A1) by PCR-RFLP or direct DNA-sequencing. Results: The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35–0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33–0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12–0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71–16.63, P < 0.001). Conclusion: This is the first study identifying common germline variants in colon CSC genes as independent prognostic markers for stage III and high-risk stage II colon cancer patients. Clin Cancer Res; 17(21); 6934–43. ©2011 AACR.
Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension

Combination therapy has been recommended for the treatment of pulmonary arterial hypertension (PAH). However, there is scant information on combination therapy after failure of monotherapy, particularly in patients with scleroderma-associated PAH (PAH-SSD). From a group of 82 consecutive patients with PAH who received initial bosentan monotherapy, a total of 13 idiopathic PAH (IPAH) and 12 PAH-SSD patients requiring additional therapy with sildenafil were studied. Sildenafil was added for clinical deterioration based upon symptoms, New York Heart Association (NYHA) classification or 6-min walk distance (6MWD). Clinical data and haemodynamics were collected at baseline. Assessments were made at 1–3-month intervals. At baseline, there were no differences in demographics, NYHA classification, haemodynamics or 6MWD between the two groups. After initiation of bosentan, both groups experienced clinical improvement but ultimately deteriorated (median time to monotherapy failure 792 versus 458 days for IPAH and PAH-SSD patients, respectively). After addition of sildenafil, more IPAH patients tended to improve in NYHA class (five out of 13 versus two out of 12) and walked further (mean difference in 6MWD 47±77 m versus -7±40 m) compared with PAH-SSD patients. In conclusion, addition of sildenafil after bosentan monotherapy failure improved New York Heart Association class and 6-min walk distance in idiopathic pulmonary arterial hypertension patients but failed to improve either parameter in scleroderma-associated pulmonary arterial hypertension patients. Additional studies are needed to assess the tolerability and efficacy of this combination in patients with scleroderma-associated pulmonary arterial hypertension.
Cortical waves and post‐stroke brain stimulation

A neural field model with different activation and inhibition connectivity and response functions is considered. Stability analysis of a homogeneous in space solution determines the conditions of the emergence of stationary periodic solutions and of periodic travelling waves. Various regimes of wave propagation are illustrated in numerical simulations. The influence of external stimulation on the wave properties is investigated.
Pilot-based ML estimation in Amplify-and-Forward cooperative networks

Cooperative communication is a promising technique that achieves spatial diversity without requiring multi-antenna receivers. In this paper we consider the cooperative Amplify-and-Forward protocol and assume the channel realizations to be unknown. We study several pilot-based channel estimation strategies at the relay and the destination. The obtained maximum-likelihood estimators are evaluated for transmission over Rice-fading channels, in terms of channel estimation accuracy and error performance.
How to Understand Connections Based on Big Data : From Crisp Granules ( e . g . , Cliques ) to Flexible Granules

One of the main objectives of science and engineering is to predict the future state of the world – and to come up with actions which will lead to the most favorable outcome. To be able to do that, we need to have a quantitative model describing how the values of the desired quantities change – and for that, we need to know which factors influence this change. Usually, these factors are selected by using traditional statistical techniques, but with the current drastic increase in the amount of available data – known as the advent of big data – the traditional techniques are no longer feasible. A successful semi-heuristic method has been proposed to detect true connections in the presence of big data. However, this method has its limitations. The first limitation is that this method is heuristic – its main justifications are common sense and the fact that in several practical problems, this method was reasonably successful. The second limitation is that this heuristic method is based on using “crisp” granules (clusters), while in reality, the corresponding granules are flexible (“fuzzy”). In this paper, we explain how the known semi-heuristic method can be justified in statistical terms, and we also show how the ideas behind this justification enable us to improve the known method by taking granule flexibility into account. 1 Understanding Connections Based on Big Data – An Important Practical Problem What are our main objectives? The role of science and engineering. We have preferences: we want tasty food, we want a comfortable environment,
Effects of Plasma Kallikrein Specific Inhibitor and Active-site Blocked Factor VIIa on the Pulmonary Vascular Injury Induced by Endotoxin in Rats

Summary The acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. To evaluate the role of the coagulation system in the pathogenesis of ARDS in sepsis, we examined the effects of the administration of a synthetic plasma kallikrein specific inhibitor (PKSI) and of active-site blocked factor VIIa (DEGR-VIIa) on the pulmonary vascular injury induced by E. coli endotoxin (ET) in rats. Administration of PKSI prevented the pulmonary vascular injury induced by ET as well as pulmonary histological changes in animals administered ET, but it did not affect the intravascular coagulation. The opposite effect was seen with DEGR-VIIa, which prevented the intravascular coagulation but not the pulmonary vascular injury. PKSI did not inhibit the activation of the complement system induced by ET leading to the activation of neutrophils. Findings suggest that PKSI may prevent the pulmonary vascular injury induced by ET by inhibiting kallikrein, which activates the neutrophils. The intrinsic pathway of coagulation may be more important than the extrinsic pathway in the pulmonary vascular injury produced byET.
Real-time upper limb motion prediction from noninvasive biosignals for physical human-machine interactions

Human motion and its intention sensing from noninvasive biosignals is one of the significant issues in the field of physical human-machine interactions (pHMI). This paper presents a real-time upper limb motion prediction method using surface electromyography (sEMG) signals for pHMI. The sEMG signals from 5 channels were collected and used to predict the motion by an artificial neural network (ANN) algorithm. We designed a human-machine interaction system to verify the proposed method. Interaction experiments were performed with or without physical contact, and the effects of instances of contact were investigated. The experimental results were compared with controlled experiments using a customized goniometer, which is able to measure upper limb flexion-extension. The results showed that the proposed method was not superior to the use of direct angle measurements; however, it provides sufficient accuracy and a fast response speed for interactions. SEMG-based interactions will become more natural with further studies of human-machine combination models.