Miracle-dz/UniFAR-FTUs huggingface dataset:
The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration.
Multistep Navigation and the Combinatorial Control of Leukocyte Chemotaxis

Cells migrating within tissues may encounter multiple chemoattractant signals in complex spatial and temporal patterns. To understand leukocyte navigation in such settings, we have explored the migratory behavior of neutrophils in model scenarios where they are presented with two chemoattractant sources in various configurations. We show that, over a wide range of conditions, neutrophils can migrate “down” a local chemoattractant gradient in response to a distant gradient of a different chemoattractant. Furthermore, cells can chemotax effectively to a secondary distant agonist after migrating up a primary gradient into a saturating, nonorienting concentration of an initial attractant. Together, these observations suggest the potential for cells' step-by-step navigation from one gradient to another in complex chemoattractant fields. The importance of such sequential navigation is confirmed here in a model system in which neutrophil homing to a defined domain (a) requires serial responses to agonists presented in a defined spatial array, and (b) is a function of both the agonist combination and the sequence in which gradients are encountered. We propose a multistep model of chemoattractant-directed migration, which requires that leukocytes display multiple chemoattractant receptors for successful homing and provides for combinatorial determination of microenvironmental localization.
Energy Balance After Sodium–Glucose Cotransporter 2 Inhibition

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively. RESEARCH DESIGN AND METHODS Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min−1 ⋅ 1.73 m−2) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes. RESULTS At week 90, weight loss averaged −3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of –11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = −0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01). CONCLUSIONS Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.
On RD optimized progressive image coding using JPEG

Among the many different modes of operations allowed in the current JPEG standard, the sequential and progressive modes are the most widely used. While the sequential JPEG mode yields essentially the same level of compression performance for most encoder implementations, the performance of progressive JPEG depends highly upon the designed encoder structure. This is due to the flexibility the standard leaves open in designing progressive JPEG encoders. In this work, a rate-distortion (RD) optimized JPEG compliant progressive encoder is presented that produces a sequence of scans, ordered in terms of decreasing importance. Our encoder outperforms an optimized sequential JPEG encoder in terms of compression efficiency, substantially at low and high bit rates. Moreover, unlike existing JPEG compliant encoders, our encoder can achieve precise rate/distortion control. Substantially better compression performance and precise rate control, provided by our progressive JPEG compliant encoding algorithm, are two highly desired features currently sought for the emerging JPEG-2000 standard.
Women Legislators in Central America: Politics, Democracy and Policy . By Michelle A. Saint-Germain and Cynthia Chavez Metoyer. Austin, Texas: University of Texas Press. 2008. 338 pp. $65.00 cloth, $29.95 paper.

remain. Falk suggests, I think rightly so, that her research lends credence to the speculation that women are less likely to run because of the biased and negative treatment they receive from the press. Nonetheless, despite bad coverage, they still win when they run. But the media fail to report on women’s viability, increasing the likelihood that they stay away from bids for elective office. This book is suitable for courses in political science, women’s studies, and communications. The text is rich with examples that support Falk’s findings and rife with historical comparisons. It is accessible and clearly written, although it does suffer from a few minor problems. First, at times, it reads like a series of journal articles whereby the theory and conclusions are held off until the end of the chapters. Weaving the larger insights throughout the chapters would better showcase the implications and significance of her findings. In addition, there is too much literature review and a perplexing array of disparate bodies of work introduced here and there without enough cohesion. A more consistent pursuit of the central theoretical tensions referenced by the authors would strengthen the book and make it more appropriate for graduate-level classes. Women for President is timely and will continue to be so as women move their way through the 18 millions cracks in the glass ceiling created by Hillary Rodham Clinton in her bid for the White House. With Clinton and Sarah Palin in the running in 2008, scholars will have no dearth of data to build on Falk’s fine work.
The Role of Microbial Communities in Parturition: Is There Evidence of Association with Preterm Birth and Perinatal Morbidity and Mortality?

Abstract In 2005, the World Health Organization estimated that 9.6% or 12.9 million births worldwide were born preterm at <37 weeks of gestation and were accompanied by a mortality rate as high as 42% (http://www.who.int/bulletin/volumes/88/1/08-062554). Significant data suggesting that intrauterine infection is an important modifier for the risk of preterm birth have emerged over the past four decades. However, causative microbial culprits have yet to be identified, and interventional trials with antimicrobials have uniformly failed to demonstrate a significant benefit. To the contrary, treatment for clinically asymptomatic, commonly associated polymicrobial communities (i.e., bacterial vaginosis) has resulted in an increase in the rate of preterm birth. This article discusses the importance of vaginal microbiome and the variance in its composition during normal pregnancy. We will expand this discussion to include possible mechanisms that might trigger preterm birth in at-risk subjects. Finally, we will review why preterm birth may be an ideal forum with which to apply our rapidly expanding metagenomic sequencing and analytic pipelines to discern the role of host and microbe in the relative continuum of health and disease.
Typography in children’s reading schemes may be suboptimal: Evidence from measures of reading rate

We investigated whether the layout of type in two popular children’s reading schemes was suitable for the intended reading age. 120 children read four passages of text that adopted the typography of four reading stages in each of the two schemes. The size and spacing of the texts decreased with successive stages as the intended reading age increased. The reading speed of children aged 5 to 7 years decreased as the text size decreased: in particular, these children read fastest the text designed for 5 and 6 year olds. Older children aged 8 to 11 years were neither assisted nor disadvantaged by text size. Children of all ages, particularly those susceptible to visual stress, were found to make more errors on the smaller than on the larger text. We conclude that the reading development of some children might benefit from a larger text size and spacing than is currently the norm, and that no children would be disadvantaged by such a change.
Analysis of Adult Neurogenesis: Evidence for a Prominent “Non-Neurogenic” DCX-Protein Pool in Rodent Brain

Here, we have developed a highly sensitive immunoassay for Dcx to characterize expression in brain and cerebrospinal fluid (CSF) of rodents. We demonstrate that Dcx is widely expressed during development in various brain regions and as well can be detected in cerebrospinal fluid of rats (up to 30 days postnatal). While Dcx protein level decline in adulthood and were detectable in neurogenic regions of the adult rodent brain, similar levels were also detectable in brain regions expected to bear no neurogenesis including the cerebral cortex and CA1/CA3 enriched hippocampus. We monitored DCX protein levels after paradigms to increase or severely decrease adult hippocampal neurogenesis, namely physical activity and cranial radiation, respectively. In both paradigms, Dcx protein- and mRNA-levels clearly reflected changes in neurogenesis in the hippocampus. However, basal Dcx-levels are unaffected in non-neurogenic regions (e.g. CA1/CA3 enriched hippocampus, cortex). These data suggest that there is a substantial “non-neurogenic” pool of Dcx- protein, whose regulation can be uncoupled from adult neurogenesis suggesting caution for the interpretation of such studies.
Cis proline mutants of ribonuclease A. II. Elimination of the slow‐folding forms by mutation

Ribonuclease A is known to form an equilibrium mixture of fast‐folding (UF) and slow‐folding (US) species. Rapid unfolding to UF is then followed by a reaction in the unfolded state, which produces a mixture of UF, USII, USI, and possibly also minor populations of other US species. The two cis proline residues, P93 and P114, are logical candidates for producing the major US species after unfolding, by slow cis → trans isomerization. Much work has been done in the past on testing this proposal, but the results have been controversial. Site‐directed mutagenesis is used here. Four single mutants, P93A, P93S, P114A, and P114G, and also the double mutant P93A, P114G have been made and tested for the formation of US species after unfolding. The single mutants P114G and P114A still show slow isomerization reactions after unfolding that produce US species; thus, Pro 114 is not required for the formation of at least one of the major US species of ribonuclease A. Both the refolding kinetics and the isomerization kinetics after unfolding of the Pro 93 single mutants are unexpectedly complex, possibly because the substituted amino acid forms a cis peptide bond, which should undergo cis → trans isomerization after unfolding. The kinetics of peptide bond isomerization are not understood at present and the Pro 93 single mutants cannot be used yet to investigate the role of Pro 93 in forming the US species of ribonuclease A.
Electrode Positioning and Montage in Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a non-invasive and safe alternative to change cortical excitability2. The effects of one session of tDCS can last for several minutes, and its effects depend on polarity of stimulation, such as that cathodal stimulation induces a decrease in cortical excitability, and anodal stimulation induces an increase in cortical excitability that may last beyond the duration of stimulation6. These effects have been explored in cognitive neuroscience and also clinically in a variety of neuropsychiatric disorders – especially when applied over several consecutive sessions4. One area that has been attracting attention of neuroscientists and clinicians is the use of tDCS for modulation of pain-related neural networks3,5. Modulation of two main cortical areas in pain research has been explored: primary motor cortex and dorsolateral prefrontal cortex7. Due to the critical role of electrode montage, in this article, we show different alternatives for electrode placement for tDCS clinical trials on pain; discussing advantages and disadvantages of each method of stimulation.
Spaces and scales of innovation

Contemporary research on innovative processes makes use of a range of scales, from the global to the regional/local. In addition, network-based approaches have introduced a nonterritorially bounded dimension to studies of innovation. While much of the latter has, to date, been concerned with local networks, recent work has pointed to the importance of non-local interconnections. This paper seeks to build upon such insights suggesting that greater attention be given to extra-local connections in studies of innovation. We explore ways in which extra-local interconnection may be extended beyond the globalization of formalized R&D by, and between, transnational corporations (TNCs), which is the overwhelming preoccupation of existing research. The paper is divided into two main parts. The first consists of a review of work on the three key scales of innovation. The second considers the role of firms and individuals as key actors in systems of innovation, and suggests how network-based approaches may offer the best way for analysing how these actors operate through and across spatial scales. In conclusion, we emphasize the need to further investigate non-TNC-based dimensions of extra-local interconnection.
iDetective: A Location Based Game to Persuade Users Unconsciously

Persuasive applications that change user behaviors and attitudes have been used for dietary support and healthcare and so on. When we use persuasive application to solve the social problems such as global warming and health issues, it is necessary that we extend the range of target users to people who are not interested in a problematic behavior. In this paper, we suggested an unconscious persuasive technique to design a persuasive application that is able to encourage people unconsciously. We have developed iDetective as a prototype application that persuades users unconsciously using agent persuasion and consciousness sensing. At the same time, we have evaluated the effectiveness of unconscious persuasion and influence on users through a user study using iDetective. As the result, although the unconscious persuasion on iDetective has yielded desirable effect, we could not find whether our application was able to attract people who are no interested in the target behavior. In addition, we have found that participants were not offended by the fact of unconscious persuasion and obtained possibilities and problems of unconscious persuasion.
Legislative Bargaining with Heterogeneous Disagreement Values: Theory and Experiments

We study a legislative bargaining game in which failure to agree in a given round may result in a breakdown of negotiations. In that case, each player receives an exogenous `disagreement value'. We characterize the set of stationary subgame perfect equilibria under all q-majority rules. Under unanimity rule, equilibrium payoffs are strictly increasing in disagreement values. Under all less-than-unanimity rules, expected payoffs are either decreasing or first increasing and then decreasing in disagreement values. We conduct experiments involving three players using majority and unanimity rule finding support for these predictions.
Volume guarantee ventilation, interrupted expiration, and expiratory braking

Background: In volume guarantee ventilation with the Dräger Babylog 8000 ventilator, inspiratory and expiratory flows are monitored and the expiratory tidal volume calculated following each inflation. The pressure for the next inflation is modified to ensure the expired tidal volume is close to the set value. Aim: To investigate interrupted expiration observed during volume guarantee ventilation of spontaneously breathing, ventilated infants. Methods: Spontaneously breathing infants, ventilated with volume guarantee, had recordings of gas flow, ventilator pressures, tidal volume waveforms, oximetry, heart rate, and transcutaneous oxygen and carbon dioxide during 10 minute recordings. Results: A total of 6540 inflations were analysed from 10 infants; 62% were triggered. Two different patterns were found: (1) Normal volume guarantee pattern with 97% of triggered and 91% untriggered inflations. It had a normal expiratory curve and a mean expired tidal volume within 3% of the set volume, but a large variation due to the babies’ breathing. (2) A pattern of interrupted expiratory flow after ∼3% of inflations due to a small inspiration (∼1.3 ml/kg) during expiration. This led the ventilator to calculate an inappropriate total expired tidal volume for that inflation and an increase in the pressure for the next inflation. Conclusions: After about 3% of inflations, with volume guarantee ventilation, interruption of the expiration causes an increased pressure for the next inflation of ∼4.9 cm H2O, compared with normal volume guarantee inflation. The interrupted expiration is most likely to be due to diaphragmatic braking.
Fabrication of Micropatterned Hydrogels for Neural Culture Systems using Dynamic Mask Projection Photolithography

Increasingly, patterned cell culture environments are becoming a relevant technique to study cellular characteristics, and many researchers believe in the need for 3D environments to represent in vitro experiments which better mimic in vivo qualities 1-3. Studies in fields such as cancer research 4, neural engineering 5, cardiac physiology 6, and cell-matrix interaction7,8have shown cell behavior differs substantially between traditional monolayer cultures and 3D constructs. Hydrogels are used as 3D environments because of their variety, versatility and ability to tailor molecular composition through functionalization 9-12. Numerous techniques exist for creation of constructs as cell-supportive matrices, including electrospinning13, elastomer stamps14, inkjet printing15, additive photopatterning16, static photomask projection-lithography17, and dynamic mask microstereolithography18. Unfortunately, these methods involve multiple production steps and/or equipment not readily adaptable to conventional cell and tissue culture methods. The technique employed in this protocol adapts the latter two methods, using a digital micromirror device (DMD) to create dynamic photomasks for crosslinking geometrically specific poly-(ethylene glycol) (PEG) hydrogels, induced through UV initiated free radical polymerization. The resulting "2.5D" structures provide a constrained 3D environment for neural growth. We employ a dual-hydrogel approach, where PEG serves as a cell-restrictive region supplying structure to an otherwise shapeless but cell-permissive self-assembling gel made from either Puramatrix or agarose. The process is a quick simple one step fabrication which is highly reproducible and easily adapted for use with conventional cell culture methods and substrates. Whole tissue explants, such as embryonic dorsal root ganglia (DRG), can be incorporated into the dual hydrogel constructs for experimental assays such as neurite outgrowth. Additionally, dissociated cells can be encapsulated in the photocrosslinkable or self polymerizing hydrogel, or selectively adhered to the permeable support membrane using cell-restrictive photopatterning. Using the DMD, we created hydrogel constructs up to ~1mm thick, but thin film (<200 μm) PEG structures were limited by oxygen quenching of the free radical polymerization reaction. We subsequently developed a technique utilizing a layer of oil above the polymerization liquid which allowed thin PEG structure polymerization. In this protocol, we describe the expeditious creation of 3D hydrogel systems for production of microfabricated neural cell and tissue cultures. The dual hydrogel constructs demonstrated herein represent versatile in vitro models that may prove useful for studies in neuroscience involving cell survival, migration, and/or neurite growth and guidance. Moreover, as the protocol can work for many types of hydrogels and cells, the potential applications are both varied and vast.
High-performance computing for systems of spiking neurons

We propose a bottom-up computer engineering approach to the Grand Challenge of understanding the Architecture of Brain and Mind as a viable complement to top-down modelling and alternative approaches informed by the skills and philosophies of other disciplines. Our approach starts from the observation that brains are built from spiking neurons and then progresses by looking for a systematic way to deploy spiking neurons as components from which useful information processing functions can be constructed, at all stages being informed (but not constrained) by the neural structures and microarchitectures observed by neuroscientists as playing a role in biological systems. In order to explore the behaviours of large-scale complex systems of spiking neuron components we require high-performance computing equipment, and we propose the construction of a machine specifically for this task – a massively parallel computer designed to be a universal spiking neural network simulation engine.
Axiomatisation and decidability of multi-dimensional duration calculus

We investigate properties of a spatio-temporal logic based on an n-dimensional duration calculus tailored for the specification and verification of mobile real-time systems. After showing non-axiomatisability, we give a complete embedding in n-dimensional interval temporal logic and present two different decidable subsets, which are important for tool support and practical use.