Miracle-dz/UniFAR-FTUs huggingface dataset:
The Development of LAT1 Efflux Agonists as Mechanistic Probes of Cellular Amino Acid Stress

Amino acid restriction induces cellular stress and cells often respond via the induction of autophagy. Autophagy or ‘self-eating’ enables the recycling of proteins and provides the essential amino acids needed for cell survival. Of the naturally occurring amino acids, methionine restriction has pleiotropic effects on cells because methionine also contributes to the intracellular methyl pools required for epigenetic controls as well as polyamine biosynthesis. In this report, we describe the chemical synthesis of four diastereomers of a methionine depletion agent and demonstrate how controlled methionine efflux from cells significantly reduces intracellular methionine, S-adenosylmethionine (SAM), S-adenosyl homocysteine (SAH), and polyamine levels. We also demonstrate that human pancreatic cancer cells respond via a lipid signaling pathway to induce autophagy. The methionine depletion agent causes the large amino acid transporter 1 (LAT1) to preferentially work in reverse and export the cell’s methionine (and leucine) stores. The four diastereomers of the lead methionine/leucine depletion agent were synthesized and evaluated for their ability to (a) efflux 3H-leucine from cells, (b) dock to LAT1 in silico, (c) modulate intracellular SAM, SAH, and phosphatidylethanolamine (PE) pools, and (d) induce the formation of the autophagy-associated LC3-II marker. The ability to modulate the intracellular concentration of methionine regardless of exogenous methionine supply provides new molecular tools to better understand cancer response pathways. This information can then be used to design improved therapeutics that target downstream methionine-dependent processes like polyamines.
Cytokine-Induced Apoptosis of Beta-Thalassemia/Hemoglobin E Erythroid Progenitor Cells via Nitric Oxide-Mediated Process in vitro

Background/Aim: β-Thalassemia/hemoglobin E (β-thal/HbE) is a common hereditary anemia in Thailand. Ineffective erythropoiesis due to apoptosis and decreased lifespan of circulating thalassemic red blood cells are the major causes of anemia. Changes to bone marrow microenvironment could contribute to apoptotic events. This study examined the effects of cytokines interleukin-1β, tumor necrosis factor-α and interferon-γ on apoptosis of β-thal/HbE erythroid progenitor cells in vitro, including nitric oxide-mediated apoptotic processes. Methods: Percent apoptosis of erythroid progenitor cells from 5 β-thal/HbE patients and 5 normal control subjects was examined using flow cytometry. In addition, the inducible nitric oxide synthase (iNOS) mRNA level and nitrite production were measured using quantitative PCR and the Griess method, respectively. Results: Upon cytokine treatment, a higher percent apoptosis was obtained with β-thal/HbE erythroid progenitor cells compared with control, and the maximum effect was observed using 20 ng/ml interferon-γ on day 14 of culture. There was an increase in iNOS mRNA level and a concomitant elevation of nitrite concentration in culture medium. Apoptosis and nitrite level were abrogated when β-thal/HbE and control cells were treated with S-methylisothiourea sulfate, an iNOS inhibitor. Conclusion: The marked sensitivity of erythroid progenitor cells from β-thal/HbE patients to cytokine-induced apoptosis via an NO-mediated process reflects a proapoptotic status of such thalassemic red blood cells.
A reconstruction filter for bone-conducted speech

Bone conduction is useful as a tool to accomplish speech enhancement in noisy environments. In this paper, we design a linear phase impulse response filter to reconstruct the quality of the bone-conducted speech signal obtained from a speaker. The bone-conducted speech observation as well as the normal speech information is effectively utilized to design the filter. From experimental results, the properties of the reconstruction filter are investigated.
Stressful life events are not associated with the development of dementia

ABSTRACT Background: The impact of stressful life events as a risk factor of dementia diseases is inconclusive. We sought to determine whether stressful negative life events are associated with incidental dementia in a population-based study with long-term follow-up. We also tested the hypothesis that the occurrence of positive life events could mitigate or overcome the possible adverse effects of negative life events on dementia conversion. Methods: The study involved 2,462 dementia-free participants aged 55 years and older. Information on life events was ascertained at baseline from a comprehensive Life Event Inventory, which included 56 questions about specific life events. For each life event, the emotional impact (both positive and negative) and emotional adjustment were asked for. Results: During follow-up, 423 participants developed dementia; of these, 240 developed Alzheimer's disease (AD). Cox regression analysis showed no association between the total number of negative life events and the incidence of dementia when adjusted solely for age and gender (hazard ratio = 0.97, 95% CI = 0.92–1.02), or with multiple adjustments for a range of covariates (hazard ratio = 0.96, 95% CI = 0.91–1.01). Similarly, neither emotional impact nor emotional adjustment to these life events was associated with incident dementia. A separate analysis of AD did not alter the results. Conclusions: The result of this population-based study finds no association between negative or positive life events and dementia. Accordingly, our results reject the hypothesis that stressful life events trigger the onset of dementia diseases.
Adoption of precision management to improve efficiency of grassland-based livestock production

A number of case studies are used to demonstrate the financial viability of precision farming methods for intensively managed pastures. Precision farming has sometimes been criticized as being technology-led where the management goals and desired outcomes are sometimes poorly defined. Case studies presented in this paper demonstrate a strong management approach where appropriate technologies are selected to contribute to the financial success of the farm. The first case study farm has increased milk production by 70% in four years, increased pasture production by 43%, reduced fertilizer costs to 43% of previous levels and has successfully predicted annual production to within 2 to 3% of actual. A strong emphasis on performance measurement is used to support a four stage management approach which consists of Planning, Measurement, Management and Review. The measurement systems in place inform the management at both strategic and operational levels and include twice daily recording of individual milk production and cow weight. The electronic identification (EID) system has been in place since 1996. The second case study farm has demonstrated similar savings in base fertiliser utilisation but has utilised other additional precision agriculture technologies such as the use of crop sensors and variable rate application of nutrients. Again a strong management focus is given, this time expressed as measure, manage, mitigate. This farming partnership also has a very strong environmental sustainability focus and recently received national recognition as the Supreme Winner of the 2013 New Zealand Ballance Farm Environmental Awards, giving further validation to the idea that precision agriculture is profitable as well as environmentally sustainable. Craige Mackenzie has also invested in precision irrigation, and there is a growing body of evidence to suggest that this method can give significant economic and environmental benefits on intensively managed pastures. Further case studies presenting the advantage of variable rate irrigation are also presented.
Detection of Web Service substitutability and composability

Web services are used in software applications as a standard and convenient way of accessing remote applications over the Internet. Web service s can be thought of as remote procedure calls. This paper proposes an approach to determine web service substitutability and composability. Because web services may be unreliable, finding other services substitutable for an existing one can increase application uptime . Finding composable services enables applications to be programmed by composing several web services (using one service’s output as an input to another web service). We have imp lemented our technique and evaluated it on 14 freely available web services producing 92 outputs. Our approach correctly detects all composable and substitutable web ser vices from this set.
Finding Partners: Emerging Protein Interaction Technologies Applied to Signaling Networks

Signal transduction pathways play essential roles in cell differentiation, proliferation, and survival. Their precise regulation is achieved through specific protein-protein interactions that mediate the assembly of protein complexes in response to different signals. Disturbances of the normal protein-protein interactions within signaling pathways can lead to many diseases, including cancer. In this review, Stagljar aims to highlight the emerging protein interaction technologies that are advancing the field of signal transduction. These approaches include stable isotope labeling by amino acids in cell culture, SH2 profiling, target-assisted iterative screening, and the split-ubiquitin membrane yeast two-hybrid system. Although still at an early stage, these technologies show promise as useful methods for the characterization of novel components of various signal transduction pathways.
The Series Product and Its Application to Quantum Feedforward and Feedback Networks

The purpose of this paper is to present simple and general algebraic methods for describing series connections in quantum networks. These methods build on and generalize existing methods for series (or cascade) connections by allowing for more general interfaces, and by introducing an efficient algebraic tool, the series product. We also introduce another product, which we call the concatenation product, that is useful for assembling and representing systems without necessarily having connections. We show how the concatenation and series products can be used to describe feedforward and feedback networks. A selection of examples from the quantum control literature are analyzed to illustrate the utility of our network modeling methodology.
Genetic Programming Artificial Features with Applications to Epileptic Seizure Prediction

In this paper, we propose a general-purpose, systematic algorithm, consisting of a genetic programming module and a k-nearest neighbor classifier to automatically create artificial features (i.e., features that are computer crafted and may not have a known physical meaning) directly from the reconstructed state-space trajectory of the EEG signals that reveal patterns predictive of epileptic seizures. The algorithm was evaluated in three different patients, with prediction defined over a horizon of 5 minutes before unequivocal electrographic onset. Experiments are carried out using 20 baseline epochs (non-seizures) and 18 preictal epochs (pre-seizures). Results show that just two seizures were missed while a perfect classification on the baseline epochs was achieved, yielding a 0.0 false positive per hour
Antimasking effects of the olivocochlear reflex. II. Enhancement of auditory-nerve response to masked tones.

1. The antimasking effects of olivocochlear (OC) efferent feedback were studied in anesthetized or decerebrate cats by comparing responses of single auditory-nerve fibers (ANFs) to tone bursts in continuous masking noise seen with and without addition of a moderate-level contralateral noise known to activate the OC reflex. Responses were measured as a function of tone-burst intensity, tone-burst frequency, and masker intensity and were analyzed so as to allow quantitative estimates of the detectability of the tone bursts against the noise background. 2. Addition of the contralateral OC elicitor both increased the maximum discharge rates to the masked tone bursts and decreased the rates to the ipsilateral masker. The rate increases to the tone bursts could be explained on the basis of a decrease in adaptation caused by decreasing the steady response to the masker. The result is a steepening of the rate-versus-level function for masked tone bursts and a concomitant increase in the estimated discriminability of small increments of tone-burst intensity. 3. For tone bursts at the fiber's characteristic frequency (CF), the OC effects on detection threshold for the masked tone bursts depended on masker level, with small increases in threshold for low masker levels and somewhat larger decreases in threshold for higher masker levels. For tone bursts below CF, OC effects, when present, always decreased the detection threshold. 4. The largest antimasking effects were seen for fibers with CFs between 6 and 12 kHz and for masker levels within 20 dB of the fiber's threshold to the masker. These trends appeared to hold for fibers of all spontaneous rates (SRs). 5. Enhancement of the response to unmasked tone bursts and concomitant decrease in the "spontaneous rate" was elicited by OC activation in fibers if threshold sensitivity approached -10 dB SPL. This "enhancement-in-quiet" appears to arise when an animal-generated noise produces a continuous response (in the absence of purposely applied sound) that is suppressed by OC activity. This finding raises questions as to the range of "true" spontaneous rates in the cat. 6. The results highlight two important distinctions between the effects of OC feedback in quiet versus those in noise. In quiet, the effects are predominately suppressive and are restricted to stimuli at frequencies near a fiber's CF and at intensities within its dynamic range. In continuous background noise, the OC reflex can enhance the responses to transient stimuli. Such effects are seen throughout the fiber's response area. (ABSTRACT TRUNCATED AT 400 WORDS)
Issues with Meta-Knowledge

At the SEKE'99 conference, knowledge engineering researchers held a panel on the merits of meta-knowledge (i.e. problem solving methods and ontologies) for the development of knowledge-based systems. The original panel was framed as a debate on the merits of meta-knowledge for knowledge maintenance [21]. However, the debate quickly expanded. In the end, we were really discussing the merits of different technologies for the specification of reusable components for KBS. In this brief article we record some of the lively debate from that panel and the email exchanges it generated.
A Hypoxia-Related miRNA-mRNA Signature for Predicting the Response and Prognosis of Transcatheter Arterial Chemoembolization in Hepatocellular Carcinoma

Purpose Transcatheter arterial chemoembolization (TACE) is commonly used in the treatment of hepatocellular carcinoma (HCC). However, not all patients respond to this treatment. TACE typically leads to hypoxia in the tumor microenvironment. Therefore, we aimed to construct a prognostic model based on hypoxia-related differentially expressed microRNA (miRNAs) in hepatocellular carcinoma (HCC) and to investigate the potential target mRNAs for predicting TACE response. Methods The hypoxia-related miRNAs (HRMs) were identified in liver cancer cells, then global test was performed to further select the miRNAs which were associated with recurrence and vascular invasion. A prognostic model was constructed based on multivariate Cox regression analysis; qRT-PCR analysis was used to validate the differentially expressed miRNAs in HCC cell lines under hypoxic condition. We further identified the putative target genes of the miRNAs and investigate the relationship between the target genes and TACE response, immune cells infiltration. Results We established a HRMs prognostic model for HCC patients, containing two miRNAs (miR-638, miR-501-5p), the patients with high-HRMs score showed worse survival in discovery and validation cohort; qRT-PCR analysis confirmed that these two miRNAs are up-regulated in hepatoma cells under hypoxic condition. Furthermore, four putative target genes of these two miRNAs were identified (ADH1B, CTH, FTCD, RCL1), which were significantly associated with TACE response, immune score, immunosuppressive immune cells infiltration, PDCD1 and CTLA4. Conclusion The HCC-HRMs signature may be utilized as a promising prognostic factor and may have implications for guiding TACE and immune therapy.
Myelin Activates FAK/Akt/NF-κB Pathways and Provokes CR3-Dependent Inflammatory Response in Murine System

Inflammatory response following central nervous system (CNS) injury contributes to progressive neuropathology and reduction in functional recovery. Axons are sensitive to mechanical injury and toxic inflammatory mediators, which may lead to demyelination. Although it is well documented that degenerated myelin triggers undesirable inflammatory responses in autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), there has been very little study of the direct inflammatory consequences of damaged myelin in spinal cord injury (SCI), i.e., there is no direct evidence to show that myelin debris from injured spinal cord can trigger undesirable inflammation in vitro and in vivo. Our data showed that myelin can initiate inflammatory responses in vivo, which is complement receptor 3 (CR3)-dependent via stimulating macrophages to express pro-inflammatory molecules and down-regulates expression of anti-inflammatory cytokines. Mechanism study revealed that myelin-increased cytokine expression is through activation of FAK/PI3K/Akt/NF-κB signaling pathways and CR3 contributes to myelin-induced PI3K/Akt/NF-κB activation and cytokine production. The myelin induced inflammatory response is myelin specific as sphingomyelin (the major lipid of myelin) and myelin basic protein (MBP, one of the major proteins of myelin) are not able to activate NF-κB signaling pathway. In conclusion, our results demonstrate a crucial role of myelin as an endogenous inflammatory stimulus that induces pro-inflammatory responses and suggest that blocking myelin-CR3 interaction and enhancing myelin debris clearance may be effective interventions for treating SCI.
ModelGen: model independent schema translation

A customizable and extensible tool is proposed to implement ModelGen, the model management operator that translates a schema from one model to another. A wide family of models is handled, by using a metamodel in which models can be succinctly and precisely described. The approach is novel because the tool exposes the dictionary that stores models, schemas, and the rules used to implement translations. In this way, the transformations can be customized and the tool can be easily extended.
Delivery of Telomerase Reverse Transcriptase Small Interfering RNA in Complex with Positively Charged Single-Walled Carbon Nanotubes Suppresses Tumor Growth

Purpose: To determine whether -CONH-(CH2)6-NH3+Cl− functionalized single-walled carbon nanotubes (SWNT) carrying complexed small interfering RNA (siRNA) can enter into tumor cells, wherein they release the siRNA to silence the targeted gene. Experimental Design: -CONH-(CH2)6-NH3+Cl− was used to mediate the conjugation of telomerase reverse transcriptase (TERT) siRNA to SWNTs. The ability of TERT siRNA delivered via SWNT complexes to silence the expression of TERT was assessed by their effects on the proliferation and growth of tumor cells both in vitro and in mouse models. Results: The functionalized SWNTs -CONH-(CH2)6-NH3+Cl− could facilitate the coupling of siRNAs that specifically target murine TERT expression to form the mTERT siRNA:SWNT+ complex. These functionalized SWNTs rapidly entered three cultured murine tumor cell lines, suppressed mTERT expression, and produced growth arrest. Injection of mTERT siRNA:SWNT+ complexes into s.c. Lewis lung tumors reduced tumor growth. Furthermore, human TERT siRNA:SWNT+ complexes also suppressed the growth of human HeLa cells both in vitro and when injected into tumors in nude mice. Conclusions: -CONH-(CH2)6-NH3+Cl− functionalized SWNTs carry complexed siRNA into tumor cells, wherein they release the siRNA from the nanotube sidewalls to silence the targeted gene. The -CONH-(CH2)6-NH3+Cl− functionalized SWNTs may represent a new class of molecular transporters applicable for siRNA therapeutics.
Combining Clinical Treatment and Peer Support: A Unique Approach to Overcoming Stigma and Delivering Care

Abstract : Operational Stress Injury (OSI) is the term used in the Canadian military to describe psychological illnesses resulting from traumatic events experienced by soldiers during operational duties. These include post-traumatic stress disorder, depression and substance abuse. The Canadian Forces and Veterans Affairs Canada have established mental health clinics, called Operational Trauma and Stress Support Centres (OTSSC's), and Operational Stress Injury (OSI) Clinics across Canada to facilitate early diagnosis and treatment of members and veterans suffering from OSI's. Yet it often takes years for traumatized soldiers to present for care. There are many reasons for this. Shame, isolation, and institutional stigmatizing of mental illness are compelling counter-forces to the urge to seek help. Recent research has shown that the fear of stigma is one of the principal reasons why soldiers do not seek treatment, even when they recognize that they are suffering from psychological problems. In contrast to this, the literature tells us that early intervention is a critical factor in decreasing the sequelae of PTSD and other mental disorders.
Body composition and physical activity in New Zealand Maori, Pacific and European children aged 5–14 years

Body fatness and the components of energy expenditure in children aged 5–14 years were investigated. In a group of seventy-nine healthy children (thirty-nine female, forty male), mean age 10·0 (sd 2·8) years, comprising twenty-seven Maori, twenty-six Pacific Island and twenty-six European, total energy expenditure (TEE) was determined over 10 d using the doubly-labelled water method. Resting metabolic rate (RMR) was measured by indirect calorimetry and physical activity level (PAL) was calculated as TEE:RMR. Fat-free mass (FFM), and hence fat mass, was derived from the 18O-dilution space using appropriate values for FFM hydration in children. Qualitative information on physical activity patterns was obtained by questionnaire. Maori and Pacific children had a higher BMI than European children (P<0·003), but % body fat was similar for the three ethnic groups. The % body fat increased with age for girls (r 0·42, P=0·008), but not for boys. Ethnicity was not a significant predictor of RMR adjusted for FFM and fat mass. TEE and PAL, adjusted for body weight and age, were higher in Maori than European children (P<0·02), with Pacific children having intermediate values. PAL was inversely correlated with % body fat in boys (r −0·43, P=0·006), but was not significantly associated in girls. The % body fat was not correlated with reported time spent inactive or outdoors. Ethnic-related differences in total and activity-related energy expenditure that might account for higher obesity rates in Maori and Pacific children were not seen. Low levels of physical activity were associated with increased body fat in boys but not in girls.