Miracle-dz/UniFAR-FTUs huggingface dataset:
The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin

Background: Proteins have adopted negative design to diminish aggregation. Results: The replacement of Lys-35 by Leu increases the amyloidogenicity of the 26–57 segment of TTR as well as the entire protein. Conclusion: Lys-35 is as a gatekeeper residue in TTR, and its protective effect is suppressed by heparin. Significance: The elucidation of the principles that govern protein aggregation is helpful for the design of strategies against amyloid diseases. Protein aggregation into β-sheet-enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies to diminish their intrinsic propensity to aggregate, including enrichment of gatekeeper charged residues at the flanks of hydrophobic aggregation-prone segments. Wild type transthyretin (TTR) is responsible for senile systemic amyloidosis, and more than 100 mutations in the TTR gene are involved in familial amyloid polyneuropathy. The TTR 26–57 segment bears many of these aggressive amyloidogenic mutations as well as the binding site for heparin. We demonstrate here that Lys-35 acts as a gatekeeper residue in TTR, strongly decreasing its amyloidogenic potential. This protective effect is sequence-specific because Lys-48 does not affect TTR aggregation. Lys-35 is part of the TTR basic heparin-binding motif. This glycosaminoglycan blocks the protective effect of Lys-35, probably by neutralization of its side chain positive charge. A K35L mutation emulates this effect and results in the rapid self-assembly of the TTR 26–57 region into amyloid fibrils. This mutation does not affect the tetrameric protein stability, but it strongly increases its aggregation propensity. Overall, we illustrate how TTR is yet another amyloidogenic protein exploiting negative design to prevent its massive aggregation, and we show how blockage of conserved protective features by endogenous factors or mutations might result in increased disease susceptibility.
Potential Uncertainty Reduction in Model‐Averaged Benchmark Dose Estimates Informed by an Additional Dose Study

A methodology is presented for assessing the information value of an additional dosage experiment in existing bioassay studies. The analysis demonstrates the potential reduction in the uncertainty of toxicity metrics derived from expanded studies, providing insights for future studies. Bayesian methods are used to fit alternative dose‐response models using Markov chain Monte Carlo (MCMC) simulation for parameter estimation and Bayesian model averaging (BMA) is used to compare and combine the alternative models. BMA predictions for benchmark dose (BMD) are developed, with uncertainty in these predictions used to derive the lower bound BMDL. The MCMC and BMA results provide a basis for a subsequent Monte Carlo analysis that backcasts the dosage where an additional test group would have been most beneficial in reducing the uncertainty in the BMD prediction, along with the magnitude of the expected uncertainty reduction. Uncertainty reductions are measured in terms of reduced interval widths of predicted BMD values and increases in BMDL values that occur as a result of this reduced uncertainty. The methodology is illustrated using two existing data sets for TCDD carcinogenicity, fitted with two alternative dose‐response models (logistic and quantal‐linear). The example shows that an additional dose at a relatively high value would have been most effective for reducing the uncertainty in BMA BMD estimates, with predicted reductions in the widths of uncertainty intervals of approximately 30%, and expected increases in BMDL values of 5–10%. The results demonstrate that dose selection for studies that subsequently inform dose‐response models can benefit from consideration of how these models will be fit, combined, and interpreted.
Working memory following improvements in articulation rate in children with cerebral palsy

Abstract It has been postulated that rehearsal rate is the primary determinant of working memory capacity for verbal material (Baddeley et al., 1975). A previous study of normal control children and children with spastic diplegic cerebral palsy (SDCP) suggested that covert rather than overt rehearsal rate determines working memory capacity (White et al., 1994). In the current study, a subset of SDCP children who received a surgical treatment to relieve spasticity were retested on measures of articulation rate and memory span. A subset of control children from the original study were also retested. The SDCP group showed improvements in articulation rate at follow-up, though memory span did not change and was again equivalent to that of controls. These findings indicate that increases in articulation rate are not necessarily accompanied by improvements in memory span, and provide additional evidence that working memory capacity may be determined by covert rather than overt articulatory rehearsal. (JINS, 1995, I, 49–55.)
Does the Clarity of Monetary Policy Reports Reduce Volatility in Financial Markets

We study whether increased clarity of central bank reports on monetary policy can reduce volatility of returns in financial markets. We measure clarity of reports by the Czech National Bank, the European Central Bank, the Bank of England, and Sveriges Riksbank using the Flesch-Kincaid grade level. In contrast to much of the recent literature, we find only limited evidence of a negative relationship between clarity of monetary policy reports and market volatility. We conclude that reducing volatility using clearer reports is not straightforward, especially in times of crisis.
The host environment determines strain‐specific differences in the timing of skeletal muscle regeneration: cross‐transplantation studies between SJL/J and BALB/c mice

The difference in the timing of the regeneration process of skeletal muscle between SJL/J and BALB/c mice was investigated using grafts of whole skeletal muscle (both autografts and allografts). Histological, autoradiographic and immunohistochemical techniques were used in the investigation. Infiltration of leucocytes into autografts, numbers of desmin‐positive myogenic cells and myotube formation were all more advanced in the SJL/J compared with BALB/c mice. Furthermore, autoradiographic evidence showed that myoblasts in the SJL/J autografts were synthesising DNA 12 h earlier than myoblasts in BALB/c autografts. In allografts, where SJL/J host mice received BALB/c grafts, and vice versa, leucocyte infiltration and myotube formation occurred earlier in the BALB/c muscles grafted into SJL/J hosts, than in the reverse situation with BALB/c hosts. The results show that, at least for whole muscle grafts, it is the host environment which determines the speed and outcome of the regenerative process.
Transcriptome‐wide gene expression in a rat model of attention deficit hyperactivity disorder symptoms: Rats developmentally exposed to polychlorinated biphenyls

Polychlorinated biphenyls (PCB) exposure in rodents provides a useful model for the symptoms of Attention deficit hyperactivity disorder (ADHD). The goal of this study is to identify genes whose expression levels are altered in response to PCB exposure. The brains from 48 rats separated into two age groups of 24 animals each (4 males and 4 females for each PCB exposure level (control, PCB utero, and PCB lactational)) were harvested at postnatal days 23 and 35, respectively. The RNA was isolated from three brain regions of interest and was analyzed for differences in expression of a set of 27,342 transcripts. Two hundred seventy‐nine transcripts showed significant differential expression due to PCB exposure mostly due to the difference between PCB lactational and control groups. The cluster analysis applied to these transcripts revealed that significant changes in gene expression levels in PFC area due to PCB lactational exposure. Our pathway analyses implicated 27 significant canonical pathways and 38 significant functional pathways. Our transcriptome‐wide analysis of the effects of PCB exposure shows that the expression of many genes is dysregulated by lactational PCB exposure, but not gestational exposure and has highlighted biological pathways that might mediate the effects of PCB exposure on ADHD‐like behaviors seen in exposed animals. Our work should further motivate studies of fatty acids in ADHD, and further suggests that another potentially druggable pathway, oxidative stress, may play a role in PCB induced ADHD behaviors. © 2011 Wiley Periodicals, Inc.
Incidence of Smith‐Lemli‐Opitz syndrome in Ontario, Canada

1. The authors stated that their study is ‘‘the first prospective determination of incidence of SLOS using the biochemical diagnosis test in North America’’. However, to perform a prospective study aimed to calculate the frequency (better than incidence) of SLOS in a population, based on biochemical data, it is necessary to perform the biochemical diagnostic test in all the newborn infants,during a pre-determined period of time. Then, those infants presenting the anomaly should be followed up for clinical diagnosis. This does not seem to be the methodology followed by these authors, although it is not clearly explained in the paper. It appears that they studied all those infants clinically diagnosed and referred to their laboratory for biochemical test. Thus, we believe that this study is not ‘‘prospective’’. 2. Why did Nowaczyk et al. consider that they have estimated the ‘‘incidence’’ of SLOS? The real incidence of SLOS (as for the majority of congenital defects) is always unknown due to the spontaneous abortions of fetuses with the syndrome. In our opinion, they only obtained aminimal estimation of the prevalence in their population. This is so because many cases died soon after birth and, as also stated by these authors, the clinical diagnosis of mild and atypical cases of SLOS are often not clinically identified before the first birthday, and many cases of females with less severe phenotypes are not diagnosed. Nevertheless, it is possible to estimate the frequency of SLOS in newborn infants (that could be considered as the ‘‘incidence in newborns’’). But to do this, it is necessary to examine in the same manner all the newborn infants in the way we stated above.
The challenges for solid waste management in accordance with Agenda 21: A Brazilian case review

This paper aims to evaluate the suitability of the Brazilian solid waste policy (BSWP) with global Agenda 21 and the challenges of implementing the BSWP in municipalities. For this, a review of the principles that guided the creation of this policy was performed to demonstrate that international pressures were important in determining its effectiveness. The contradictory relationship between the satisfactory legal framework that established the Brazilian waste management policy and its weakened implementation in the municipalities is also examined . To illustrate the difficulties faced at the local level, a case study involving municipalities that compose the state of Espírito Santowe was undertaken. In this state, the municipalities signed terms of environmental commitment with supervisory agencies who undertook, within a pre-established schedule, to implement a set of actions to shape the proper management of solid waste, adapted to the requirements of national policy and the guidelines of Agenda 21. Finally, the various difficulties in meeting the requirements are discussed. It is necessary and urgent that Brazil finds a way to coordinate the mechanisms of an innovative and well formulated legal instrument to ensure the successful implementation of solid waste management at the local level to achieve the environmental, economic and social objectives
Design of 3-dB Hybrid Coupler Based on RGW Technology

Hybrid couplers are essential devices in various microwave circuits and systems, such as radar systems and beam forming networks. The development of this device is necessary along with the development of the new communication standards for the most modern guiding structures. One of the most recent and promising guiding technologies is the ridge gap waveguides, which is expected to play an essential role in the millimeter wave and submillimeter wave applications, not only the 5G communications but also other future communication. Therefore, standards are recommended to make use of the high-frequency guiding structures. In this paper, a design procedure for the hybrid couplers is presented. The frequency band of interest is centered at the 15 GHz, which can be deployed for both the 5G mobile communication and the airborne radar applications. The proposed design is fabricated and measured. The measured and simulated results are in excellent agreement.
Multi-channel features fitted 3D CNNs and LSTMs for human activity recognition

Human activity recognition has been widely used in many fields, especially in video surveillance and virtual reality, etc. The paper investigates a general feature combination method for a relatively new 3D CNNs and LSTMs fusion model in human activity recognition. All the features used in this combination method are from human activity videos without manually extracting features or any prior knowledge, and the model has good generalization performance. Through extracting multi-channel features of the motion optical flow vector, grayscale and body edge, putting them to 3D convolutional neural network, and processing time characteristics within Long-Short Term Memory neural network, the recognition rate of the model rises greatly. The experiment selects KTH dataset as the data source. The model based on RGB is used to compare with the model based on multi-channel features. It shows that multi-channel features can improve recognition accuracy rate obviously, and have great robustness in different scenes, which proves that it is an efficient feature combination method fitted 3D CNNs and LSTMs.
Conference on ‘ Carbohydrates in health : friends or foes ’ Symposium 3 : Non-digestible carbohydrates , gut microbiota and obesity The multifactorial interplay of diet , the microbiome and appetite control : current knowledge and future challenges

Bernard M. Corfe*, Charlotte J. Harden, Matthew Bull and Iveta Garaiova Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK Organisms and Environment Division, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK Cultech Ltd, Research Department, Port Talbot SA12 7BZ, UK
Subthalamotomy improves MPTP-induced parkinsonism in monkeys.

Hyperactivity of the subthalamic nucleus (STN) is major characteristic of parkinsonism secondary to substantia nigra lesions. Interruption of the STN-internal pallidum (GPi) pathway is a new stereotactic target for Parkinson's disease. We have studied the antiparkinsonian efficacy of STN lesions in MPTP-treated monkeys. Four rhesus monkeys were made parkinsonian by MPTP (i.v. 0.15 +/- 1 mg/kg) administration over 3 months. Unilateral subthalamotomy (kainic acid) was performed by a standard stereotactic method. Severity was rated from 0 (normal) to V by fine manual motor tests. Three monkeys (severity state III/IV) showed marked improvement in spontaneous activity, facial expression and manual dexterity bilaterally but significantly greater in the limb contralateral to the lesion. Mild hemichorea was present in 2 and hemiballism in one. L-Dopa treatment (50 mg b.i.d.) enhanced the hemidyskinesias moderately. The therapeutic effect has persisted for over 8 months postsurgery. Monkey No.4 (severity stage V) showed chorea in the lower limb contralateral to the lesion but no improvement and died a few days later. Subthalamotomy improves parkinsonism in moderately severe parkinsonian monkeys. Dyskinesia might be a persistent complication.
The role of sex hormones in induced-systemic inflammation in female albino rats.

UNLABELLED Estrogen (E(2)) and progesterone (P) hormones have a pro-inflammatory and an anti-inflammatory role under different conditions. The current study explored this phenomenon in the context of septic inflammation. MATERIALS AND METHODS This study involved 48 female albino rats. E(2) (4 mg/100 g body weight (b.w.) and P (5 mg/kg b.w.) were administered to ovariectomized (OVX) rats after systemic inflammation (SI) induced by puncturing the caecum I cm from its end with a single hole by using a 21-gauge needle. Key indices of inflammation and apoptosis were evaluated. RESULTS OVX animals subjected to SI showed significantly increased levels of serum tumor necrosis factor-alpha (TNF-u), C reactive protein (CRP) and alanine aminotransferase (ALT). They also showed higher levels of expression of the enzyme inducible nitric oxide synthase (iN OS); 312 ± 43 mg/ml; in the liver, and the activity of both cyclooxygenase 2 (COX-2); 59.4 ± 3.2 U/ml; and caspase 3 enzymes; 6.3 ± 0.54 ng/ml; when compared to non-OVX animals subjected to (SI), (180 ± 3 mg/ml, 16.4 ± 1.69 U/ml, 0.98 ± 0.23 ng/ml respectively). Administration of E(2) resulted in a significant reduction of all serum and liver tissue parameters of inflammation (e.g.decreased iNOS; 193 ± 28 mg/ml and COX-2; 27.6 ± 3.91 U/ml) and decreased apoptosis (Caspase 3; 1.18 ± 0.21 ng/ml). In contrast, OVX animals injected with P before induction of SI showed a significant rise of all measured parameters. CONCLUSIONS E(2) and Pin physiological levels have contrasting though complementary roles in regulation of the immune system possibly allowing a limited inflammatory response while preventing excessive damage to the tissues.
New insight into the TDDB and breakdown reliability of novel high-к gate dielectric stacks

In order to achieve aggressive scaling of the equivalent oxide thickness (EOT) and simultaneously reduce leakage currents in logic devices, silicon-based oxides (SiON / SiO2) have been replaced by physically thicker high-к transition metal oxide thin films by many manufacturers starting from the 45nm technology node. CMOS process compatibility, integration and reliability are the key issues to address while introducing high-к at the front end. In this study, we analyze in-depth the reliability aspect of high-к dielectrics focusing on both the time-dependent-dielectric breakdown (TDDB) and the post breakdown evolution stage. Electrical characterization, physical failure analysis, statistical reliability modeling as well as atomistic simulations have all been used to achieve a comprehensive understanding of the physics of failure in HK and the associated microstructural defects and failure mechanisms. The role played by different gate materials ranging from poly-Si → FUSI → metal gate and different HK materials (HfO2, HfSiON, HfZrO4) is also investigated. Based on the results obtained, we emphasize the need and propose a few approaches of design for reliability (DFR) in high-к gate stacks.
Teleological approaches from complexity sciences in services

To describe and apply teleological approaches from complexity sciences in services. The performance of service encounters and the outcome of service quality are dependent upon complex and dynamic interactions between service providers and service receivers. A set of teleological approaches from complexity sciences is incorporated and applied in the context of service settings. A teleological application from complexity sciences in relation to the interactive nature of the performance of service encounters and the outcome of service quality is likely to trigger and encourage innovative research designs and alternative methodological approaches to new research problems in services. A suggestion of further research is to address where and how we can learn from other research disciplines that have explored the addressed aspects of teleological approaches from complexity sciences in a more advanced way, and how we can transfer and incorporate these aspects and knowledge into services. The research opportunities into service quality and service encounters by applying teleological approaches from complexity sciences are extensive. They might also stimulate innovative analytical techniques that could produce groundbreaking research findings, in extension, with important implications for practice. A continued emphasis on multi-disciplinary research may contribute to improve current research and practice of services.
The Political Economy of Geoengineering as Plan B: Technological Rationality, Moral Hazard, and New Technology

ABSTRACT Geoengineering would mask and reproduce capital’s contradictory needs to self-expand, on the one hand, and maintain a stable climate system, on the other. The Plan B frame, which presents geoengineering as a back-up plan to address climate change in case there is a failure to sufficiently reduce emissions (Plan A), is one means to depict this condition to the public and is a product of, and appeals to, a prevalent ‘technological rationality’. Despite its misleading simplicity, logical flaws, and irrational rationality, the Plan B frame is a relatively valid representation of geoengineering in current political-economic conditions. Although the Plan B frame will gain traction because Plan A is too expensive in the short term and does not serve powerful interests, there are alternative social futures in which technology could be used to address climate change in ways that preserve the environment and reduce social risks.
Comparision of doxorubicin-induced cardiotoxicity in the ICR mice of different sources

Doxorubicin is a widely used chemotherapeutic agents and is now part of standard therapeutic regimens for a variety of cancers (eg, hematopoietic malignancies and advanced solid tumors of the breast, ovary, thyroid, and bone). However, a potentially lethal and dose-dependent cardiotoxicity that appears within a short time after treatment limits the usage of doxorubicin in cancer patients. Although the mechanism of doxorubicin-induced cardiotoxicity is not completely understood, it is thought that free radical-induced oxidative stress and excessive production of reactive oxygen species are primary drivers of its toxicity. In this study, we compared the doxorubicin-induced cardiotoxicity of ICR mice obtained from three different sources and evaluated the utility of Korl:ICR stock established by the Korean FDA. Because doxorubicin-induced cardiotoxicity is thought to involve the excessive generation of ROS followed by oxidative stress, we determined the representative tissue index of oxidation, lipid peroxidation, and antioxidant, glutathione (GSH), as well as the parameters of heart injury. Doxorubicin treatment successfully induced cardiotoxicity as evidenced by histological examination and serum parameters (eg, levels of LDH and CK activities) in ICR mice. It was accompanied by increased lipid peroxidation and a decrease in both cysteine and GSH, further supporting previous reports that oxidative stress is a potential mechanism of doxorubicin-induced cardiotoxicity. Of interest, we did not observe a significant difference in doxorubicin-induced cardiotoxicity among mice of different origins. Collectively, our results suggest that Korl:ICR strain may be useful in the research of doxorubicin-induced cardiotoxicity.