Miracle-dz/UniFAR-FTUs huggingface dataset:
A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.
Widefield laser doppler velocimeter: development and theory.

The widefield laser Doppler velocimeter is a new measurement technique that significantly expands the functionality of a traditional scanning system. This new technique allows full-field velocity measurements without scanning, a drawback of traditional measurement techniques. This is particularly important for tests in which the sample is destroyed or the motion of the sample is non-repetitive. The goal of creating ''velocity movies'' was accomplished during the research, and this report describes the current functionality and operation of the system. The mathematical underpinnings and system setup are thoroughly described. Two prototype experiments are then presented to show the practical use of the current system. Details of the corresponding hardware used to collect the data and the associated software to analyze the data are presented.
Fundamental Limits of Remote Estimation of Autoregressive Markov Processes Under Communication Constraints

The fundamental limits of remote estimation of autoregressive Markov processes under communication constraints are presented. The remote estimation system consists of a sensor and an estimator. The sensor observes a discrete-time autoregressive Markov process driven by a symmetric and unimodal innovations process. At each time, the sensor either transmits the current state of the Markov process or does not transmit at all. The estimator estimates the Markov process based on the transmitted observations. In such a system, there is a trade-off between communication cost and estimation accuracy. Two fundamental limits of this trade-off are characterized for infinite horizon discounted cost and average cost setups. First, when each transmission is costly, we characterize the minimum achievable cost of communication plus estimation error. Second, when there is a constraint on the average number of transmissions, we characterize the minimum achievable estimation error. Transmission and estimation strategies that achieve these fundamental limits are also identified.
Edinburgh Research Explorer A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10 −8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Data-Driven Gamification Design: An Enterprise Systems Perspective from the Front Line

The need for data-driven gamification in enterprise systems is essential for the design, development and implementation of robust management information systems capability. However, the gamification of enterprise systems need to look beyond the user interface as a key driver of the effectiveness of system design and implementation by taking a more holistic approach. A survey was undertaken of 25 global organisations that have implemented a gamification project which found that enterprises are reporting positive results from gamification projects, but are also claiming that there’s still room for improvement across many operational areas. In particular, there are effectiveness issues associated with technology and vendor maturity, and a need to improve the capabilities of organisations in the design and implementation of gamification projects. Design was considered to be a collaborative activity amongst stakeholders, and the process and inclusiveness of the design process was considered to be just as important as the specific design elements employed.
On the Emergent Constraints of Climate Sensitivity

AbstractDifferences among climate models in equilibrium climate sensitivity (ECS; the equilibrium surface temperature response to a doubling of atmospheric CO2) remain a significant barrier to the accurate assessment of societally important impacts of climate change. Relationships between ECS and observable metrics of the current climate in model ensembles, so-called emergent constraints, have been used to constrain ECS. Here a statistical method (including a backward selection process) is employed to achieve a better statistical understanding of the connections between four recently proposed emergent constraint metrics and individual feedbacks influencing ECS. The relationship between each metric and ECS is largely attributable to a statistical connection with shortwave low cloud feedback, the leading cause of intermodel ECS spread. This result bolsters confidence in some of the metrics, which had assumed such a connection in the first place. Additional analysis is conducted with a few thousand artificia.
Olivary subthreshold oscillations and burst activity revisited

The inferior olive (IO) forms one of the major gateways for information that travels to the cerebellar cortex. Olivary neurons process sensory and motor signals that are subsequently relayed to Purkinje cells. The intrinsic subthreshold membrane potential oscillations of the olivary neurons are thought to be important for gating this flow of information. In vitro studies have revealed that the phase of the subthreshold oscillation determines the size of the olivary burst and may gate the information flow or encode the temporal state of the olivary network. Here, we investigated whether the same phenomenon occurred in murine olivary cells in an intact olivocerebellar system using the in vivo whole-cell recording technique. Our in vivo findings revealed that the number of wavelets within the olivary burst did not encode the timing of the spike relative to the phase of the oscillation but was related to the amplitude of the oscillation. Manipulating the oscillation amplitude by applying Harmaline confirmed the inverse relationship between the amplitude of oscillation and the number of wavelets within the olivary burst. Furthermore, we demonstrated that electrotonic coupling between olivary neurons affect this modulation of the olivary burst size. Based on these results, we suggest that the olivary burst size might reflect the “expectancy” of a spike to occur rather than the spike timing, and that this process requires the presence of gap junction coupling.
Divide and conquer: A basis for augmenting a conventional query optimizer with multiple query-processing capabilities

An approach for adding a new component without radically changing an existing single-query optimizer (SQO) is proposed. A new way of organizing the strategy space of a set of queries being optimized is proposed for developing a multiple-query optimizer (MQO) architecture. The architecture relies on the generation of two strategy spaces using subsumption and equivalence of subexpressions at the logical level. Heuristics for pruning the space of multistrategies are also presented. It is shown that the partitioned organisation of the strategy space not only reduces the size of the strategy space but also lends itself to division of labor, thereby leading to a simpler MQO design. Clear separation of the module specific to multistrategy generation provides an easy migration path from SQOs to MQOs. In the decomposition algorithm, selections are propagated down the operator tree (counterintuitively) enabling the detection and creation of larger common subexpressions. <<ETX>>
Oral carbohydrate sensing and exercise performance

Purpose of reviewCarbohydrate during exercise has been demonstrated to improve exercise performance even when the exercise is of high intensity (>75% VO2max) and relatively short duration (∼1 h). It has become clear that the underlying mechanisms for the ergogenic effect during this type of activity are not metabolic but may reside in the central nervous system. Recent findingsCarbohydrate mouth rinses have been shown to result in similar performance improvements. This would suggest that the beneficial effects of carbohydrate feeding during exercise are not confined to its conventional metabolic advantage but may also serve as a positive afferent signal capable of modifying motor output. These effects are specific to carbohydrate and are independent of taste. The receptors in the oral cavity have not (yet) been identified and the exact role of various brain areas is not clearly understood. Further research is warranted to fully understand the separate taste transduction pathways for simple and complex carbohydrates and how these differ between mammalian species, particularly in humans. SummaryCarbohydrate is detected in oral cavity by unidentified receptors and this can be linked to improvements in exercise performance.
Motion planning using adaptive random walks

We propose a novel single-shot motion-planning algorithm based on adaptive random walks. The proposed algorithm turns out to be simple to implement, and the solution it produces can be easily and efficiently optimized. Furthermore, the algorithm can incorporate adaptive components, so the developer is not required to specify all the parameters of the random distributions involved, and the algorithm itself can adapt to the environment it is moving in. Proofs of the theoretical soundness of the algorithm are provided, as well as implementation details. Numerical comparisons with well-known algorithms illustrate its effectiveness.
Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with splice-switching antisense oligonucleotides

Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific tyrosine kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused by a deletion polymorphism in Intron 2 of the BIM gene, whose product is required for TKI-induced apoptosis. The deletion biases BIM splicing from exon 4 to exon 3, generating splice isoforms lacking the exon 4-encoded pro-apoptotic BH3 domain, which impairs the ability of TKIs to induce apoptosis. We sought to identify splice-switching antisense oligonucleotides (ASOs) that block exon 3 but enhance exon 4 splicing, and thereby resensitize BIM deletion-containing cancers to imatinib. First, we mapped multiple cis-acting splicing elements around BIM exon 3 by minigene mutations, and found an exonic splicing enhancer acting via SRSF1. Second, by a systematic ASO walk, we isolated ASOs that corrected the aberrant BIM splicing. Eight of 67 ASOs increased exon 4 levels in BIM deletion-containing cells, and restored imatinib-induced apoptosis and TKI sensitivity. This proof-of-principle study proves that resistant CML cells by BIM deletion polymorphism can be resensitized to imatinib via splice-switching BIM ASOs. Future optimizations might yield a therapeutic ASO as precision-medicine adjuvant treatment for BIM-polymorphism-associated TKI-resistant CML and other cancers.
Cancer Patients: Their Desire for Information and Participation in Treatment Decisions

The relationship between cancer patients’ desire for information and their preference for participation in decision making has been examined. Approximately 77% of the 52 patients reported that they had participated in decision making to the extent that they wished, while most of the remaining 23% would have preferred an opportunity to have greater input. Although many of the patients actively sought information, a majority preferred the physician to assume the role of the primary decision maker. Ethically, the disclosure of information has been assumed to be necessary for autonomous decision making. Nevertheless, the results of this study indicate that patients may actively seek information to satisfy an as yet unidentified aspect of psychological autonomy that does not necessarily include participation in decision making.
Intervening with Everyday Memory Problems in Dementia of Alzheimer Type: An Errorless Learning Approach

Dementia of Alzheimer Type (DAT) is increasingly detected at an earlier stage of the disorder, when interventions to assist with everyday memory difficulties might be most valuable. Some learning is possible in DAT and a number of factors have been identified which may facilitate performance, although applications to everyday memory problems have been limited. The concept of errorless learning has not previously been directly examined in relation to DAT, but might provide a useful additional strategy. In the present study, 6 participants with early stage DAT (MMSE scores 21 – 26) received individually tailored interventions, based on errorless learning principles and targeted at a specific everyday memory problem. Five of the participants showed significant improvement on the target measures, and maintained this improvement up to 6 months later. The results suggest that it is feasible to intervene with everyday memory problems in the early stages
Revenue Sharing and Information Leakage in a Supply Chain

This work explores the potential of revenue-sharing contracts to facilitate information sharing in a supply chain and mitigate the negative effects of information leakage. We consider a supplier who offers a revenue-sharing contract to two competing retailers, one of whom has private information about uncertain market potential and orders first. This order information may be leaked to the uninformed retailer by the supplier to realize higher profits. We show that the incentives of the supplier and retailers are better aligned under a revenue-sharing contract, as opposed to under a wholesale-price contract, reducing the supplier's incentive to leak. This is true for a wide range of wholesale prices and revenue-share percentages and is more likely when the revenue-share percentage is higher and when variation in demand is greater. Preventing information leakage may result in higher profits not only for the informed retailer and supplier but surprisingly even for the uninformed retailer. Our results are robust when the model is generalized along various dimensions. This paper was accepted by Yossi Aviv, operations management.
Differential spatiotemporal expression of K+ channel polypeptides in rat hippocampal neurons developing in situ and in vitro

Hippocampal neurons are highly plastic in their excitable properties, both during development and in the adult brain. As voltage-sensitive K+ channels are major determinants of membrane excitability, one mechanism for generating plasticity is through regulation of K+ channel activity. To gain insights into the regulation of K+ channels in the hippocampus, we have analyzed the spatiotemporal expression patterns of five K+ channel polypeptides in rat hippocampal neurons developing in situ and in vitro. Delayed rectifier-type channels (Kv1.5, Kv2.1, and Kv2.2) are expressed on all neuronal somata and proximal dendrites, while A-type channels (Kv1.4 and Kv4.2) are present distally on distinct subpopulations of neurons. The development of these patterns in situ is monotonic; that is, while the time and spatial development varies among the channels, each K+ channel subtype initially appears in its adult pattern, suggesting that the mechanisms underlying spatial patterning operate through development. Immunoblots confirm the differential temporal expression of K+ channels in the developing hippocampus, and demonstrate developmentally regulated changes in the microheterogeneity of some K+ channel polypeptide species. Temporal expression patterns of all five K+ channels observed in situ are retained in vitro, while certain aspects of cellular and subcellular localization are altered for some of the K+ channel polypeptides studied. Similarities in K+ channel polypeptide expression in situ and in vitro indicate that the same regulatory mechanisms are controlling spatiotemporal patterning in both situations. However, differences between levels of expression for all subtypes studied except Kv2.1 indicate additional mechanisms operating in situ but absent in vitro that are important in determining polypeptide abundance.
Using Web-Search Results to Measure Word-Group Similarity

Semantic relatedness between words is important to many NLP tasks, and numerous measures exist which use a variety of resources. Thus far, such work is confined to measuring similarity between two words (or two texts), and only a handful utilize the web as a corpus. This paper introduces a distributional similarity measure which uses internet search counts and also extends to calculating the similarity within word-groups. The evaluation results are encouraging: for word-pairs, the correlations with human judgments are comparable with state-of-the-art web-search page-count heuristics. When used to measure similarities within sets of 10 words, the results correlate highly (up to 0.8) with those expected. Relatively little comparison has been made between the results of different search-engines. Here, we compare experimental results from Google, Windows Live Search and Yahoo and find noticeable differences.
Cdc42 and Par proteins stabilize dynamic adherens junctions in the Drosophila neuroectoderm through regulation of apical endocytosis

Cell rearrangements require dynamic changes in cell–cell contacts to maintain tissue integrity. We investigated the function of Cdc42 in maintaining adherens junctions (AJs) and apical polarity in the Drosophila melanogaster neuroectodermal epithelium. About one third of cells exit the epithelium through ingression and become neuroblasts. Cdc42-compromised embryos lost AJs in the neuroectoderm during neuroblast ingression. In contrast, when neuroblast formation was suppressed, AJs were maintained despite the loss of Cdc42 function. Loss of Cdc42 function caused an increase in the endocytotic uptake of apical proteins, including apical polarity factors such as Crumbs, which are required for AJ stability. In addition, Cdc42 has a second function in regulating endocytotic trafficking, as it is required for the progression of apical cargo from the early to the late endosome. The Par complex acts as an effector for Cdc42 in controlling the endocytosis of apical proteins. This study reveals functional interactions between apical polarity proteins and endocytosis that are critical for stabilizing dynamic basolateral AJs.
Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats.

We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle (n = 12), eplerenone (50 mg x kg(-1) x day(-1), p.o. , n = 12), amlodipine (3 mg x kg(-1) x day(-1), p.o. , n = 12), or eplerenone plus amlodipine (n = 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects.
Digital High Order Multiplier-free Delta Sigma Modulator for Multistandard Fractional-N Frequency Synthesizer

This paper proposes a new stable design strategy for 1-bit high order digital DS modulator for multistandard fractional-N frequency synthesizer. The proposed digital DS modulator presents simplicity, low power consumption and controls a dual-modulus divider instead of multi-modulus one as in existing DS fractional-N frequency synthesizer. Simulation results illustrate the DS modulator good performances in terms of spectrum purity and accuracy. Using this stable 1-bit digital DS modulator output to a fractional-N frequency synthesizer Simulink model verifies the multistandard frequency synthesizer specifications.