Miracle-dz/UniFAR-FTUs huggingface dataset:
Pushing the boundaries of high content imaging

MICROSCOPY performance is routinely assessed based on three criteria (i) Speed, (ii) Resolution, and (iii) Sensitivity. Whilst we, the research community, have access to a spectacular array of advanced equipment, alas the perfect instrument does not exist—we cannot simultaneously have optimal performance in each criterion. For this reason, the ubiquitous triangle of compromise (Fig. 1) is drawn to demonstrate these limitations. Thankfully, the triangle is continuously shrinking with new technological improvements. There are additional important considerations, like the need keep cells healthy in live-cell imaging experiments; ensuring the phenomenon being observed is not simply a consequence of phototoxicity; or how effective a given technique is in terms of depth-penetration into a 3D sample. Great technological strides have been made in improving instrument performance, but when one criteria is improved it often comes at a cost to another. For example, super resolution microscopy (1) allows us to surpass the diffraction barrier that otherwise limits the resolution (to 250 nm in the lateral, xy, direction), however these techniques are generally slow and less cell-friendly relative to more conventional approaches. In the first part of this special issue (2) we highlight the continuous advancements improving performance for highcontent (HC) and high-throughput (HT) imaging for a variety of applications from basic to applied and clinical research (3), in terms of [i] Reagents and assay tools (4–6), [ii] Microscopy advancements (6,7), [iii] Automation and robotics (7) and [iv] Computational advancements (8,9). Whilst the performance in terms of speed is key for HT imaging, the image quality in terms of both resolution and signal:noise ratio (A.K.A. sensitivity) is critical for HC imaging. The ideal HC instrument requires all three criteria to be enhanced. We want it all and we want it now! As will be clear from Part 2 of the special issue on High Throughput and High Content Imaging and Cellular Informatics, newer demands on HC imaging for live-cells, 3D samples, and whole organisms are becoming increasingly prevalent. This will provide the impetus for continued technological Figure 1. The triangle of compromise of microscopy performance.
Structure and transforming function of transduced mutant alleles of the chicken c-myc gene

A small retroviral vector carrying an oncogenic myc allele was isolated as a spontaneous variant (MH2E21) of avian oncovirus MH2. The MH2E21 genome, measuring only 2.3 kilobases, can be replicated like larger retroviral genomes and hence contains all cis-acting sequence elements essential for encapsidation and reverse transcription of retroviral RNA or for integration and transcription of proviral DNA. The MH2E21 genome contains 5' and 3' noncoding retroviral vector elements and a coding region comprising the first six codons of the viral gag gene and 417 v-myc codons. The gag-myc junction corresponds precisely to the presumed splice junction on subgenomic MH2 v-myc mRNA, the possible origin of MH2E21. Among the v-myc codons, the first 5 are derived from the noncoding 5' terminus of the second c-myc exon, and 412 codons correspond to the c-myc coding region. The predicted sequence of the MH2E21 protein product differs from that of the chicken c-myc protein by 11 additional amino-terminal residues and by 25 amino acid substitutions and a deletion of 4 residues within the shared domains. To investigate the functional significance of these structural changes, the MH2E21 genome was modified in vitro. The gag translational initiation codon was inactivated by oligonucleotide-directed mutagenesis. Furthermore, all but two of the missense mutations were reverted, and the deleted sequences were restored by replacing most of the MH2E21 v-myc allele by the corresponding segment of the CMII v-myc allele which is isogenic to c-myc in that region. The remaining two mutations have not been found in the v-myc alleles of avian oncoviruses MC29, CMII, and OK10. Like MH2 and MH2E21, modified MH2E21 (MH2E21m1c1) transforms avian embryo cells. Like c-myc, it encodes a 416-amino-acid protein initiated at the myc translational initiation codon. We conclude that neither major structural changes, such as in-frame fusion with virion genes or internal deletions, nor specific, if any, missense mutations of the c-myc coding region are necessary for activation of the basic oncogenic function of transduced myc alleles.
Environmental effects on the detection of adaptation

Detecting adaptation involves comparing the performance of populations evolving in different environments. This detection may be confounded by effects due to the environment experienced by organisms prior to the test. We tested whether such confounding effects occur, using spider‐mite selection lines on two novel hosts and one ancestral host, after 15 generations of selection. Mites were either sampled directly from the selection lines or subjected to a common juvenile or to a common maternal environment, mimicking the most frequent environmental manipulations. These environments strongly affected all life‐history traits. Moreover, the detection of adaptation and correlated responses on the ancestral host was inconsistent among environments in almost 20% of the cases. Indeed, we did not detect responses unambiguously for any life‐history trait. This inconsistency was due to differential environmental effects on lines from different selection regimes. Therefore, the detection of adaptation requires a careful control of these environmental effects.
Apoptosis in resolution of inflammation

The last few years have seen the accumulation of compelling evidence that apoptosis (programmed cell death) plays a major role in promoting resolution of the acute inflammatory response. Neutrophils are constitutively programmed to undergo apoptosis, which limits their pro‐inflammatory potential and leads to rapid, specific, and non‐phlogistic recognition by macrophages and semi‐professional phagocytes. Similar mechanisms have been implicated in clearance of eosinophils, lymphocytes, and monocytes and apoptosis also plays a role in remodeling the inflamed site by deletion of myofibroblasts. A growing understanding of the mechanisms regulating leukocyte apoptosis and of the molecules mediating safe phagocytic clearance of dying cells may yield new insights into the pathogenesis and therapy of inflammatory diseases. J. Leukoc. Biol. 61: 375–380; 1997.
Department of Economics Working Paper Series the Effect of Classmate Characteristics on Individual Outcomes: Evidence from the Add Health

We use data from the National Longitudinal Study of Adolescent Health (Add Health) to examine the effects of classmate characteristics on economic and social outcomes of students. The unique structure of the Add Health allows us to estimate these effects using comparisons across cohorts within schools, and to examine a wider range of outcomes than other studies that have used this identification strategy. This strategy yields variation in cohort composition that is uncorrelated with student observables suggesting that our estimates are not biased by the selection of students into schools or grades based on classmate characteristics. We find that increases in the percent of classmates whose mother is college educated has significant, desirable effects on educational attainment and substance use. We find no evidence that in-school achievement, student attitudes, or behaviors serve as mechanisms for this effect. The percent of students from disadvantaged minority groups does not show any negative effects on the post-secondary outcomes we examine, but is associated with students reporting less caring student-teacher relationships and increased prevalence of some undesirable student behaviors during high school. Jonah Rockoff who provided comments on the work presented here, as well as participants at the Syracuse University education policy seminar, the Tufts economics department seminar, the Yale labor economics lunch and Center for Research on Inequalities and the Life Course (CIQLE) seminar, the Georgia State University labor/health economics seminar, and the New York Federal Reserve Education Seminar. This research uses data from Add Health, a program project designed by J.
Mechanical fabrication of graphene devices using focused-ion beam

Graphene, due to its material stability, mechanical strength, unique band structure and excellent electrical properties, holds great promise for future nanoscale electronic devices. Here, we report a novel mechanical fastprototyping method to fabricate graphene-based electronic structures on few-layer graphene (FLG) using focused-ion beam (FIB). FIB is a versatile tool and FIB-assisted deposition and milling processes feature mask-free patterning, quick turnaround time as well as high precision. Specifically, in this study, the parameters of FIB are well controlled. The platinum wire, which is induced from the gaseous precursors by the fine focused gallium ions of low energy, is conveniently deposited on the substrate to connect FLG. The measured channel resistance of around 50 k indicates good electrical contact between platinum wire and FLG. With the computer controlled alignment and patterning, the accuracy of deposition and milling can be as high as 15-20 nm. For the milling process, 2-D ribbon structures can be easily produced by milling the patterned area, followed by an annealing process. Raman spectra are used to examine the quality of graphene after the FIB and annealing processes.
Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience.

BACKGROUND We present our single center experience of 27 patients of hyperadrenergic postural orthostatic tachycardia syndrome (POTS). METHODS In a retrospective analysis, we reviewed the charts of 300 POTS patients being followed at our autonomic center from 2003 to 2010, and found 27 patients eligible for inclusion in this study. POTS was defined as symptoms of orthostatic intolerance (of greater than six months' duration) accompanied by a heart rate increase of at least 30 bpm (or a rate that exceeds 120 bpm) that occurs in the first 10 min of upright posture or head up tilt test (HUTT) occurring in the absence of other chronic debilitating disorders. Patients were diagnosed as having the hyperadrenergic form based on an increase in their systolic blood pressure of ≥ 10 mm Hg during the HUTT (2) with concomitant tachycardia or their serum catecholamine levels (serum norepinephnrine level ≥ 600 pg/mL) upon standing. RESULTS Twenty seven patients, aged 39 ± 11 years, 24, (89%) of them female and 22 (82%) Caucasian were included in this study. Most of these patients were refractory to most of the first and second line treatments, and all were on multiple combinations of medications. CONCLUSIONS Hyperadrenergic POTS should be identified and differentiated from neuropathic POTS. These patients are usually difficult to treat and there are no standardized treatment protocols known at this time for patients with hyperadrenergic POTS.
Selection on Coding and Regulatory Variation Maintains Individuality in Major Urinary Protein Scent Marks in Wild Mice

Recognition of individuals by scent is widespread across animal taxa. Though animals can often discriminate chemical blends based on many compounds, recent work shows that specific protein pheromones are necessary and sufficient for individual recognition via scent marks in mice. The genetic nature of individuality in scent marks (e.g. coding versus regulatory variation) and the evolutionary processes that maintain diversity are poorly understood. The individual signatures in scent marks of house mice are the protein products of a group of highly similar paralogs in the major urinary protein (Mup) gene family. Using the offspring of wild-caught mice, we examine individuality in the major urinary protein (MUP) scent marks at the DNA, RNA and protein levels. We show that individuality arises through a combination of variation at amino acid coding sites and differential transcription of central Mup genes across individuals, and we identify eSNPs in promoters. There is no evidence of post-transcriptional processes influencing phenotypic diversity as transcripts accurately predict the relative abundance of proteins in urine samples. The match between transcripts and urine samples taken six months earlier also emphasizes that the proportional relationships across central MUP isoforms in urine is stable. Balancing selection maintains coding variants at moderate frequencies, though pheromone diversity appears limited by interactions with vomeronasal receptors. We find that differential transcription of the central Mup paralogs within and between individuals significantly increases the individuality of pheromone blends. Balancing selection on gene regulation allows for increased individuality via combinatorial diversity in a limited number of pheromones.
Contrasting Effects of Propranolol on Sympathetic Nerve Activity and Vascular Resistance During Orthostatic Stress

BackgroundPrevious studies in humans advanced the concept that cardiac filling pressure and contractility, the primary determinants of ventricular mechanoreceptor discharge, are important determinants of sympathetic outflow during orthostatic stress. Thus, intravenous propranolol greatly attenuated forearm vasoconstrictor response to venous pooling with lower body negative pressure (LBNP). The aim of this study was to reevaluate the experimental support for this concept by using direct measurements of sympathetic nerve activity. Methods and ResultsIn 11 healthy humans, we recorded muscle sympathetic nerve activity (MSNA) with microelectrodes (peroneal nerve), as well as blood flow in the forearm and calf (venous occlusion plethysmography) at baseline and during graded LBNP. The same experiments were repeated after administration of propranolol (0.15 mg/kg i.v.), which is thought to decrease ventricular mechanoreceptor discharge. The major new findings are that propranolol neither increased baseline MSNA nor attenuated the increases in MSNA during graded orthostatic stress even though in the same subjects, propranolol simultaneously increased the baseline level of vascular resistance in both the forearm and calf and substantially attenuated the increases in regional vascular resistance during orthostatic stress. ConclusionsSystemic β-blockade causes a marked dissociation between sympathetic outflow and vascular resistance that invalidates the use of intravenous propranolol as an experimental model to examine the reflex effects of ventricular mechanoreceptors on peripheral vascular resistance in humans.
Altered Differential Control of Sympathetic Outflow Following Sedentary Conditions: Role of Subregional Neuroplasticity in the RVLM

Despite the classically held belief of an “all-or-none” activation of the sympathetic nervous system, differential responses in sympathetic nerve activity (SNA) can occur acutely at varying magnitudes and in opposing directions. Sympathetic nerves also appear to contribute differentially to various disease states including hypertension and heart failure. Previously we have reported that sedentary conditions enhanced responses of splanchnic SNA (SSNA) but not lumbar SNA (LSNA) to activation of the rostral ventrolateral medulla (RVLM) in rats. Bulbospinal RVLM neurons from sedentary rats also exhibit increased dendritic branching in rostral regions of the RVLM. We hypothesized that regionally specific structural neuroplasticity would manifest as enhanced SSNA but not LSNA following activation of the rostral RVLM. To test this hypothesis, groups of physically active (10–12 weeks on running wheels) or sedentary, male Sprague-Dawley rats were instrumented to record mean arterial pressure, LSNA and SSNA under Inactin anesthesia and during microinjections of glutamate (30 nl, 10 mM) into multiple sites within the RVLM. Sedentary conditions enhanced SSNA but not LSNA responses and SSNA responses were enhanced at more central and rostral sites. Results suggest that enhanced SSNA responses in rostral RVLM coincide with enhanced dendritic branching in rostral RVLM observed previously. Identifying structural and functional neuroplasticity in specific populations of RVLM neurons may help identify new treatments for cardiovascular diseases, known to be more prevalent in sedentary individuals.
Long‐term results of an ultra low‐dose cytarabine‐based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome

Children with acute megakaryoblastic leukaemia (AMKL) and Down syndrome (DS) show a favourable response to chemotherapy, probably due to increased sensitivity of the leukaemic blasts to cytarabine. In contrast, dose‐intensive approaches have resulted in disproportionate treatment‐related mortality in this group. The survival of children with AMKL and DS was retrospectively compared following treatment with a low‐dose chemotherapy protocol, consisting of cytarabine (10 mg/m2/dose), retinylpalmitate and vincristine or standard chemotherapy. Event‐free (67 ± 11%) and overall survival (77 ± 10%) at 5 years were not significantly different in both groups. Further reduction of treatment intensity in AMKL of children with DS, therefore, appears feasible.
Determination of the effect of fabric properties on the coupled heat and moisture transport of underwear–shirt fabric combinations

In this study, the heat transfer and moisture management properties of fabric combinations for office wear consisting of underwear and shirt fabrics, including three different fiber types and three kinds of weave types, were investigated. A sweating torso methodology was applied in order to characterize fabric combinations in terms of thermophysiological comfort for office occupants. This study showed that the cooling effect due to perspiration, accumulated moisture, and drying time of the combinations with cotton underwear were unaffected by both weave type and fiber type of shirt layer. However, initial cooling and drying time values of the combinations with underwear consisting of hydrophobic fibers were affected statistically significant by the fiber of the shirt layer. The percentage of moisture accumulation in the fabric layers was directly related to the fiber type of the underwear fabrics. Based on an extended data analysis, it was concluded that the combination of polyester underwear and cotton polyester twill shirt fabrics was the most recommendable of all the combinations used in this study with regard to the thermophysiological comfort of office occupants.
PHENOTYPIC EVOLUTION BY NEUTRAL MUTATION

A general model is developed for predicting the genetic variance within populations and the rate of divergence of population mean phenotypes for quantitative traits under the joint operation of random sampling drift and mutation in the absence of selection. In addition to incorporating the dominance effects of mutant alleles, the model yields some insight into the effects of linkage and the mating system on the mutational production of quantitative‐genetic variation. Despite these additional and potentially serious complications, it is found that, for small populations, the simple predictions obtained by previous investigators using additive‐genetic models hold reasonably well. Even after accounting for dominance and linkage, the equilibrium level of genetic variance is unlikely to be much less than 2NVm or to be more than 4NVm, where N is the effective population size and Vm is the new variance from mutation appearing each generation. The rate of increase of the between‐line variance per generation ultimately equals 2Vm regardless of population size, although the time to attain the asymptotic rate is proportional to N. Expressions are presented for the rate of approach to the equilibrium level of genetic variance and for the expected variance of the within‐population and between‐population genetic variances. The relevance of the derived model, which amounts to a generalization of the neutral theory to the phenotypic level, is discussed in the context of the detection of natural selection, the maintenance of pure lines for biomedical and agricultural purposes, the development of genetic conservation programs, and the design of indices of morphological distance between species.
On a micro-macro system arising in diffusion-reaction problems in porous media

In this note we describe a model of a reaction-diffusion process in a heterogeneous medium. The model resolves processes on the macro-scale as well as on the micro-scale by imposing a continuous family of local cell problems at each point of the medium. We list the model equations and derive a variational formulation in terms of special Sobolev spaces, constructed as direct integrals of Hilbert spaces. This construction modifies the concept of distributed-microstructure models of singlephase flow in fissured media, presented by Showalter et al. [1, 2]. The basic results on existence and uniqueness of weak solutions are given, and their proofs are sketched.
The impact of a school-based nutrition education intervention on dietary intake and cognitive and attitudinal variables relating to fruits and vegetables

Abstract Objective To assess the impact of a school-based nutrition education intervention aimed at increasing the consumption of fruits and vegetables. Design The intervention programme increased the provision of fruits and vegetables in schools and provided a range of point-of-purchase marketing materials, newsletters for children and parents, and teacher information. Curriculum materials at age 6–7 and 10–11 years were also developed and utilised. Evaluation was undertaken with groups of younger (aged 6–7 years) and older (aged 10–11 years) children. Methods included 3-day dietary records with interview and cognitive and attitudinal measures at baseline, with follow-up at 9 months, in intervention and control schools. Setting The work was undertaken in primary schools in Dundee, Scotland. Subjects Subjects comprised 511 children in two intervention schools with a further 464 children from two schools acting as controls. Results Children (n = 64) in the intervention schools had an average increase in fruit intake (133±1.9 to 183±17.0 g day-1) that was significantly (P < 0.05) greater than the increase (100±11.7 to 107±14.2 g day-1) estimated in children (n = 65) in control schools. No other changes in food or nutrient intake were detected. Increases in scores for variables relating to knowledge about fruits and vegetables and subjective norms were also greater in the intervention than in the control group, although taste preferences for fruits and vegetables were unchanged. Conclusions It is concluded that a whole school approach to increasing intakes of fruits and vegetables has a modest but significant effect on cognitive and attitudinal variables and on fruit intake.
A single OpAmp 2nd-Order ΔΣ ADC with a double integrating quantizer

Time-to-digital converters are an attractive topology for quantization because they rely on mostly digital blocks that benefit from scaling of transistors. Time-to-digital converters inherently need a time-domain input, but the input to analog-to-digital converters is primarily in the voltage-domain. Therefore, a voltage-to-time converter is necessary to use time-to-digital converters in analog-to-digital converters. Previously, circuit modifications have allowed voltage-to-time converters to provide an extra order of quantization noise shaping when used within a delta-sigma analog-to-digital converter. This work proposes another method that allows the voltage-to-time converter to function as an integrator. When combined with previous methods, this allows for an extra two orders of noise shaping to result from the quantizer.