Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence for a stromal-epithelial “lactate shuttle” in human tumors

Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to “feed” adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. These data are consistent with the “reverse Warburg effect,” which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, “energy transfer” or “metabolic-coupling” between the tumor stroma and epithelial cancer cells “fuels” tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors.
Traditional Korean medicine theory based-therapeutic potential of Gung-Gwi-Tang on postpartum obesity: psychosocial aspects of postpartum obesity

Obesity is psychological and socioeconomic problems as well as health problems related to physical disease and disorder. The obesity epidemic, including a marked increase in the prevalence of obesity among pregnant women, represents a critical public health problem throughout the world. Gung-Gui-Tang (GGT), a prescription of traditional Korean medicine, has been used to treat dizziness due to loss of blood as well as static blood after childbirth. However, the therapeutic potential of GGT on postpartum obesity has not been fully elucidated in an experimental model. In our research, GGT inhibited the increases of body weight and adipose tissues in postpartum mice fed a high-fat diet. GGT also inhibited the elevations of plasma lipid profiles such as triglyceride, low-density lipoprotein cholesterol, total cholesterol, and glutamate pyruvate transaminase. Overall, these results provide evidence that GGT can help to inhibit postpartum obesity and open new perspective to recover the shape of mother into the moment of conception.
Visual field progression in glaucoma

Editor,—We read with interest the article by Viswanathan et al . 1 We were surprised by the authors’ progression criteria for theprogressor method; their criteria are extremely sensitive and very non-specific: only one point needs to show significantly negative slope when tested on the 5% level, together with an observed slope of <−1 dB/year and <−2 dB/year for inner and outer points, respectively. With 74 test points, it goes without saying that one here faces a problem with mass significance testing, which explains the very low specificity. It is obvious that almost any stable glaucoma patient would be detected as progressing with the reported method. To illustrate the effect, we studied 10 patients with manifest glaucoma which, after at least 5 year follow up studies and at least eight visual fields, did not show visual field progression on the same clinical grounds as those used by Viswanathan et al . We had used same type of visual field test as the authors—that is, Humphrey 30-2 full threshold. In order to eliminate the possibility of any significant subclinical progression, the order of field tests were randomised before tests were analysed by the progressormethod. This randomisation secures that all significant progression would be the results of pure chance. Using the progression criteria of Viswanathan et al , stated above, five visual fields showed progression at the fourth visit, and already at the sixth visit eight eyes (80%) had shown false progression at one or more visits. Further, we performed a Monte Carlo simulation study with the same criteria: 10 000 fields were simulated and tested 10 times and the regression slope was tested at each point starting at the third test occasion. The field was divided into two regions with 50 inner points and …
G LUE M INI S AT 2 . 2 . 10 & 2 . 2 . 10-5

GLUEM INI SAT 2.2. 10 is a SAT solver based on M INI SAT 2.2 and the LBD evaluation criteria of learned clauses. A new feature of 2.2. 10 is an adaptive restart strategy based on literal block size. The default restart strategy is same as GLUCOSE, that is, the solver restarts when the average of LBDs for recent learned clauses becomes worse. When the average size of literal block is small, the solver uses other strategies: the conflict generation speed based restart strategy for slow restart instances, and Luby restart strategy for fast restart instances.
The Reliability and Cross-Cultured Adaptation of the Boston Questionnaire; in Turkish Illiterate Patients

Objective: In Turkey, the illiterate patients may not be able to complete many self-administered questionnaires. The aim of this study was to adapt the self-administered Boston questionnaire (BQ) for the assessment of the severity of symptoms and functional status (BQ-SS, BQ-F) in carpal tunnel syndrome to the illiterate Turkish population and investigate the reliability of the cross cultured adaptation. Material and Methods: A total of 120 outpatients with carpal tunnel syndrome (60 literate, 60 illiterate) were assessed using this Turkish version of BQ. Translation/back-translation of the English version BQ was done by using blinded method and independently by four different individuals, and adapted by a team. For illiterate people, the term “writing” was changed as “crocheting” and the statement “holding a book while reading” was modified as “holding the Holy Quran while reading”. Reliability was investigated by the reproducibility and internal consistency. Results: Cronbach’s alpha was calculated at 0.914 for BQ-SS scale, 0.94 for BQ-F scale in the illiterate group and at 0.971 for BQ-SS scale, 0.96 for BQ-F scale in the literate group, respectively. The intraclass correlation coefficients were excellent and range between 0.89 and 0.96 for BQ-SS and BQ-F in the illiterate and the literate patients. Conclusion: This adapted version of BQ provides a reliable tool in iliterate Turkish patients with carpal tunnel syndrome. For application of self-administered questionnaire, some conceptual modifications should be required for accommodation of the different educational levels. (Turk J Rheumatol 2009; 24: 10-6)
Angiotensin receptor blockers regulate the synchronization of circadian rhythms in heart rate and blood pressure

Objective: The sympathetic nervous system plays an important role in blood pressure regulation even in the early stages of chronic kidney disease (CKD). Methods: To understand the role of the sympathetic system, we examined the relationship between day/night ratios of both heart rate (HR) and mean arterial pressure (MAP) as well as HR variability (HRV, SD) before and during an 8-week treatment with the angiotensin II receptor blocker (ARB), olmesartan, in 45 patients with CKD. Results: The day/night HR ratio strongly correlated with the day/night MAP ratio before and during ARB treatment. The ratio of [day/night HR ratio] over [day/night MAP ratio] was increased as renal function deteriorated at baseline (r = −0.31, P = 0.04), and it was attenuated (1.10 ± 0.10 to 1.06 ± 0.10; P = 0.04) and became independent of renal function during ARB treatment (r = −0.04, P = 0.8). ARB increased both the day/night HR ratio (1.17 ± 0.09 to 1.21 ± 0.13; P = 0.04) and HRV (10.6 ± 2.9 to 11.7 ± 4.2; P = 0.04), which were lower when baseline renal function deteriorated. Conclusion: The present study indicates that there exists a close correlation in circadian rhythms between HR and MAP in CKD. Synchronization between the two rhythms was progressively lost as renal function deteriorated, and ARB partly restored the synchronization. These findings suggest that the sympathetic nervous system is activated as renal function deteriorates, and ARB may suppress its activation.
A framework for comparison of methods for solving complemetarity problems that arise in multibody dynamics

The simulation of multibody dynamics with physical constraints has been significant in the areas of science, engineering, computer graphics and robotics. There is a growing need for fast, accurate simulation tools in robotics applications such as manipulation planning and model-predictive control. However, the underlying dynamics model of multibody systems with contacts and friction is fundamentally nonsmooth and nonlinear, due to the intermittent unilateral contact and the stickslip transitions. The model is most commonly written as a differential complementarity problem, for which there is no closed-form solution. Therefore, one must use numerical methods to approximate the solution. This is commonly done by time discretization of the differential complementarity problem, which results in a sequence of algebraic complementarity problems. These problems also have no closed-form solution and are difficult to solve. This thesis contributes to the field of simulation of multibody dynamics systems in three primary areas: the development of new parallel solution algorithms, the development of methods to compare physical system behavior to that of simulated systems, and the development of a benchmark framework for the fair comparision of simulation algorithms. Among the simulation software packages in popular use today, there is no entirely satisfactory algorithm to compute the contact impacts with friction, and unbiased comparison and physical validation remain rare. Users with different application purposes are confused about which method to use based on the trade-off between accuracy and efficiency. Thus, we present the benchmark problems for multibody dynamics (BPMD) framework, with novel error metrics that evaluate not only the numerical error, but also the physical constraint violations to facilitate a fair comparison of common simulation models and solvers. The statistics and analytical metrics provide the robotics community, and others with a comprehensive tool to review the accuracy of possible simulation methods. To further validate the applicability of simulation methods, we conduct simulations of physical experiments and develop two analysis tools to tune model parameters and quantify errors.
Taking the Escherichia coli TonB Transmembrane Domain “Offline”? Nonprotonatable Asn Substitutes Fully for TonB His20

ABSTRACT The TonB system of Gram-negative bacteria uses the proton motive force (PMF) of the cytoplasmic membrane to energize active transport of nutrients across the outer membrane. The single transmembrane domain (TMD) anchor of TonB, the energy transducer, is essential. Within that TMD, His20 is the only TMD residue that is unable to withstand alanine replacement without a loss of activity. H20 is required for a PMF-dependent conformational change, suggesting that the importance of H20 lies in its ability to be reversibly protonated and deprotonated. Here all possible residues were substituted at position 20 (H20X substitutions). The His residue was also relocated throughout the TonB TMD. Surprisingly, Asn, a structurally similar but nonprotonatable residue, supported full activity at position 20; H20S was very weakly active. All the remaining substitutions, including H20K, H20R, H20E, and H20D, the obvious candidates to mimic a protonated state or support proton translocation, were inactive. A second-site suppressor, ExbB(A39E), indiscriminately reactivated the majority of H20 substitutions and relocations, including H20V, which cannot be made protonatable. These results suggested that the TonB TMD was not on a proton conductance pathway and thus only indirectly responds to PMF, probably via ExbD.
Die size reduction by optimizing the dimensions of the vertical feedthrough pitch and sealing area in the advanced MEMS (aMEMS) process

This paper presents the recent reduction of the die size by 44% in the Advanced MEMS (aMEMS) process, now being compatible in size with most of the available through-wafer packaging processes while offering the unique simplicity of the aMEMS process. Size reduction is achieved by reducing the pitch of vertical feedthroughs from 700 μm down to 350 μm and the bonding area width from 300 μm down to 100 μm, approaching to the process limits and still preserving the hermeticity of the package. Both small and large dies, containing the identical resonance sensors inside for benchmarking, are produced together on the same wafer. The cavity pressures of the both dies are measured to be around 1 mTorr even after thermal cycling tests.
Distinct gelation mechanism between linear and branched (1 → 3)‐β‐D‐glucans as revealed by high‐resolution solid‐state 13C NMR

We have recorded high‐resolution 13C‐NMR spectra of linear (curdlan) and branched (lentinan, HA‐β‐glucan and its polyol and aldehyde derivatives) (1 → 3)‐β‐D‐glucans in hydrate and gel states, in order to gain insight into their gelation mechanism. Network structure of curdlan turned out to be highly heterogeneous from its motional state, from liquid‐like, through intermediate, to solid‐like domains. They are studied by a variety of experiments, conventional high‐resolution NMR by broad‐band decoupling, high‐power decoupling with magic angle spinning (MAS), and cross‐polarization‐magic‐angle‐spinning (CP‐MAS). Nevertheless, we found that conformations of these distinct liquid‐like and solid‐like do‐ mains exhibit an identical single helix conformation with a small proportion of a triple helix form, supporting our previous view as to the gelation mechanism. In contrast, the network structure of branched (1 → 3)‐β‐D‐glucans in the gel state arises mainly from the triple helix conformation. This means that gelation of branched (1 → 3)‐β‐D‐glucan proceeds from partial association of the triple helical chains, previously proposed for gelation of a linear glucan. Furthermore, we found that conversion from the single chain to the single helix was not achieved readily by hydration of over 8h at 96% R. H. for branched glucan but the triple helix form is obtained when these samples are hydrated fully as in gel state.
Reconfigurable ground plane membranes for analog/digital microstrip phase shifters and frequency agile antenna

A new type of RF MEMS device is presented for microstrip transmission line phase shifters and frequency agile patch antenna. Ground plane membranes are implemented to control local substrate effective dielectric constant and so microstrip device capacitance. Continuous control of transmission line phase shift or antenna resonant frequency is demonstrated. In phase shifter implementation, a figure of merit of over 700/spl deg/ phase shift/dB signal power loss has been achieved. In MPA implementation, a MPA was continuously swept from 16.8 GHz to 17.82 GHz (6% variation). Additionally, while MEM switch devices are limited in power handling capability, the presented device is not so limited.
Comparing robotic control using a spiking model of cerebellar network and a gain adapting forward-inverse model

Internal models inspired from the functioning of cerebellum are being increasingly used to predict and control movements of anthropomorphic manipulators. A major function of cerebellum is to fine tune the body movements with precision and are comparative to capabilities of artificial neural network. Several studies have focused on encoding the real-world information to neuronal responses but temporal information was not given due importance. Spiking neural network accounts to conversion of temporal information into the adaptive learning process. In this study, cerebellum like network was reconstructed which encodes spatial information to kinematic parameters, self-optimized by learning patterns as seen in rat cerebellum. Learning rules were incorporated into our model. Performance of the model was compared to an optimal control model and have evaluated the role of bioinspired models in representing inverse kinematics through applications to a low cost robotic arm developed at the lab. Artificial neural network of Kawato was used to compare with our existing model because of their similarity to biological circuit as seen in a real brain. Kawato's paired forward inverse model has used to train for fast movement based tasks which resembles human based motor tasks. Result suggest kinematics of a 6 DOF robotic arm was internally represented and this may have potential application in neuroprosthesis.
Inverse relationship between FST and microsatellite polymorphism in the marine fish, walleye pollock (Theragra chalcogramma): implications for resolving weak population structure

Microsatellites have proved to be useful for the detection of weak population structure in marine fishes and other species characterized by large populations and high gene flow. None the less, uncertainty remains about the net effects of the particular mutational properties of these markers, and the wide range of locus polymorphism they exhibit, on estimates of differentiation. We examined the effect of varying microsatellite polymorphism on the magnitude of observed differentiation in a population survey of walleye pollock, Theragra chalcogramma. Genetic differentiation at 14 microsatellite loci among six putative populations from across the North Pacific Ocean and Bering Sea was weak but significant on large geographical scales and conformed to an isolation‐by‐distance pattern. A negative relationship was found between locus variability and the magnitude of estimated population subdivision. Estimates of FST declined with locus polymorphism, resulting in diminished power to discriminate among samples, and we attribute this loss to the effects of size homoplasy. This empirical result suggests that mutation rates of some microsatellite loci are sufficiently high to limit resolution of weak genetic structure typical of many marine fishes.
Response to Comment on Zhu et al. Fasting Plasma Glucose at 24–28 Weeks to Screen for Gestational Diabetes Mellitus: New Evidence From China. Diabetes Care 2013;36:2038–2040

We thank Drs. Agarwal and Dhatt for their letter (1). To avoid overburdening the health system with carrying out oral glucose tolerance tests (OGTTs) in all pregnant women, theMinistry of Health of China (MOH) recommends using the two-step approach of screening with fasting plasma glucose (FPG) followed by a 75-g OGTT only in low-resourced rural areas (2). To avoid missed and delayed diagnosis, the MOH recommends that all well-resourced medical institutions use the one-step 75-g OGTT to screen all pregnant women. Also the FPG screening test done in low-resourced centers is administered as a stand-alone test and pregnant women do not wait for the result after the sample is collected. Only women with FPG values between 4.4–5.0 mmol/L come back for the 75-g OGTT on another day. Thus, the FPG is regarded as an independent screening test. With the high patient load, most hospitals in China cannot have the turnaround time of less than 1 h as mentioned by Drs. Agarwal and Dhatt. If fasting capillary glucose (FCG) can beused for screening, millions of women who need the full OGTT can avoid a second trip and can immediately proceed to the full 75-g OGTT. However, we believe that using FCG for screening should be considered extremely carefully given its variability and lack of precision (3).
Ecology Predicts Large‐Scale Patterns of Phylogenetic Diversification in Birds

One of the most striking patterns in evolutionary biology is that clades may differ greatly in the number of species they contain. Numerous hypotheses have been put forward to explain this phenomenon, and several have been tested using phylogenetic methods. Remarkably, however, all such tests performed to date have been characterized by modest explanatory power, which has generated an interest in explanations stressing the importance of random processes. Here we make use of phylogenetic methods to test whether ecological variables, typically ignored in previous models, may explain phylogenetic tree imbalance in birds. We show that diversification rate possesses an intermediate phylogenetic signal across families. Using phylogenetic comparative methods, we then build a multipredictor model that explains more than 50% of the variation in diversification rate among clades. High annual dispersal is identified as the strongest predictor of high rates of diversification. In addition, high diversification rate is strongly associated with feeding generalization. In all but one instance, these key findings remain qualitatively unchanged when we use an alternative phylogeny and methodology and when small clades, containing five species or less, are excluded. Taken together, these results suggest that large‐scale patterns in avian diversification can be explained by variation in intrinsic biology.
Predicting the Risk of Recurrent Venous Thromboembolism: Current Challenges and Future Opportunities

Acute venous thromboembolism (VTE) is a commonly diagnosed condition and requires treatment with anticoagulation to reduce the risk of embolisation as well as recurrent venous thrombotic events. In many cases, cessation of anticoagulation is associated with an unacceptably high risk of recurrent VTE, precipitating the use of indefinite anticoagulation. In contrast, however, continuing anticoagulation is associated with increased major bleeding events. As a consequence, it is essential to accurately predict the subgroup of patients who have the highest probability of experiencing recurrent VTE, so that treatment can be appropriately tailored to each individual. To this end, the development of clinical prediction models has aided in calculating the risk of recurrent thrombotic events; however, there are several limitations with regards to routine use for all patients with acute VTE. More recently, focus has shifted towards the utility of novel biomarkers in the understanding of disease pathogenesis as well as their application in predicting recurrent VTE. Below, we review the current strategies used to predict the development of recurrent VTE, with emphasis on the application of several promising novel biomarkers in this field.