Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic patterns of local adaptation under gene flow in Arabidopsis lyrata.

Short-scale local adaptation is a complex process involving selection, migration and drift. The expected effects on the genome are well grounded in theory but examining these on an empirical level has proven difficult, as it requires information about local selection, demographic history and recombination rate variation. Here, we use locally adapted and phenotypically differentiated Arabidopsis lyrata populations from two altitudinal gradients in Norway to test these expectations at the whole-genome level. Demography modelling indicates that populations within the gradients diverged less than 2 kya and that the sites are connected by gene flow. The gene flow estimates are, however, highly asymmetric with migration from high to low altitudes being several times more frequent than vice versa. To detect signatures of selection for local adaptation, we estimate patterns of lineage specific differentiation among these populations. Theory predicts that gene flow leads to concentration of adaptive loci in areas of low recombination; a pattern we observe in both lowland-alpine comparisons. Although most selected loci display patterns of conditional neutrality, we found indications of genetic trade-offs, with one locus particularly showing high differentiation and signs of selection in both populations. Our results further suggest that resistance to solar radiation is an important adaptation to alpine environments, while vegetative growth and bacterial defense are indicated as selected traits in the lowland habitats. These results provide insights into genetic architectures and evolutionary processes driving local adaptation under gene flow. We also contribute to understanding of traits and biological processes underlying alpine adaptation in northern latitudes.
Phenylalanine 4-monooxygenase: the “sulfoxidation polymorphism”

Abstract 1. Consistent differences in the proportion of an orally administered dose of S-carboxymethyl-l-cysteine subsequently excreted in the urine as S-oxide metabolites were reported 40 years ago. This observation suggested the existence of inter-individual variation in the ability to undertake the enzymatic S-oxygenation of this compound. Pedigree studies and investigations employing twin pairs indicated a genetically controlled phenomenon overlaid with environmental influences. It was reproducible and not related to gender or age. 2. Studies undertaken in several healthy volunteer cohorts always provided similar results that were not significantly different when statistically analysed. However, when compared to these healthy populations, a preponderance of subjects exhibiting the characteristic of poor sulfoxidation of S-carboxymethyl-l-cysteine was found within groups of patients suffering from various disease conditions. The most striking of these associations were witnessed amongst subjects diagnosed with neurodegenerative disorders; although, underlying mechanisms were unknown. 3. Exhaustive investigation has identified the enzyme responsible for this S-oxygenation reaction as the tetrahydrobiopterin-dependent aromatic amino acid hydroxylase, phenylalanine 4-monooxygenase classically assigned the sole function of converting phenylalanine to tyrosine. The underlying principle is discussed that enzymes traditionally associated solely with intermediary metabolism may have as yet unrecognised alternative roles in protecting the organism from potential toxic assault.
Scaling trajectories of cities

Urban scaling research finds that agglomeration effects—the higher-than-expected outputs of larger cities—follow robust “superlinear” scaling relations in cross-sectional data. But the paradigm has predictive ambitions involving the dynamic scaling of individual cities over many time points and expects parallel superlinear growth trajectories as cities’ populations grow. This prediction has not yet been rigorously tested. I use geocoded microdata to approximate the city-size effect on per capita wage in 73 Swedish labor market areas for 1990–2012. The data support a superlinear scaling regime for all Swedish agglomerations. Echoing the rich-get-richer process on the system level, however, trajectories of superlinear growth are highly robust only for cities assuming dominant positions in the urban hierarchy.
Tethering guides fusion-competent trans-SNARE assembly

Significance R-SNARE (soluble N-ethylmaleimide–sensitive factor receptor) and the set of 3Q-SNAREs, anchored in separate membranes, can associate in trans in a coiled-coil tetramer. Proteoliposomes bearing only these SNAREs form abundant trans-complexes but fuse very poorly, while membrane association through even a synthetic tether allows rapid and functional SNARE complex assembly without catalysis by Munc18 or Munc13 family proteins. Tethering guides trans-SNARE associations to active conformations instead of the inactive trans-SNARE complexes which form in the absence of tethers. R-SNAREs (soluble N-ethylmaleimide–sensitive factor receptor), Q-SNAREs, and Sec1/Munc18 (SM)-family proteins are essential for membrane fusion in exocytic and endocytic trafficking. The yeast vacuolar tethering/SM complex HOPS (homotypic fusion and vacuole protein sorting) increases the fusion of membranes bearing R-SNARE to those with 3Q-SNAREs far more than it enhances their trans-SNARE pairings. We now report that the fusion of these proteoliposomes is also supported by GST-PX or GST-FYVE, recombinant dimeric proteins which tether by binding the phosphoinositides in both membranes. GST-PX is purely a tether, as it supports fusion without SNARE recognition. GST-PX tethering supports the assembly of new, active SNARE complexes rather than enhancing the function of the fusion-inactive SNARE complexes which had spontaneously formed in the absence of a tether. When SNAREs are more disassembled, as by Sec17, Sec18, and ATP (adenosine triphosphate), HOPS is required, and GST-PX does not suffice. We propose a working model where tethering orients SNARE domains for parallel, active assembly.
Multi-level platform descriptions

The MDA approach to software development is based on the notion of automating the mapping of platform independent models into implementation-level platform specific models based on abstract models of platforms [OMG03]. The notions of “platform” and “platform model” are thus central to the whole MDA vision. However, most research on MDA to date has focused on the “transformation” problem [SPG03], and there are few explicit definitions of the notion of “platform” or “platform model” in the MDA literature. Moreover, those that do exist are rather vague and incomplete.
Architecture for Location Independent CORBA Environments

Declaration I, the undersigned, declare that this dissertation is entirely my own work, except where otherwise accredited, and that it has not been previously submitted for a degree at this or any other university or institution. I hereby declare that Trinity College may lend or copy this dissertation upon request. Abstract The construction of distributed applications is a complex and time consuming task, which has been addressed by the Object Management Group's Common Object Request Broker Architecture. However implementations of this standard are typically designed for stationary hosts connected to a fixed network and do not take into account the problems associated with mobile computing. These problems include limited processing resources on the mobile host and the use of unreliable and low-bandwidth wireless networks. A full CORBA implementation is unsuitable for use on mobile hosts, such as laptops and personal digital assistants, since it is too resource intensive. It is however desirable for mobile hosts to be able to interopate with existing CORBA applications while simultaneously taking advantage of mobility. This dissertation describes the design and implementation of a collection of components suitable for building applications, which are capable of interoperating with CORBA implementations and which are suitable for mobile hosts. The collection of components allows an application to act as a client or as a server in a CORBA context.
Nitrogen Fertilization of Host Plant Influenced the Nutritional Status and Life History of the Madeira Mealybug (Hemiptera: Pseudococcidae)

Abstract Insect herbivores, especially sap-feeders, are sensitive to host-plant nitrogen quantity. However, past studies present contradicting results on sap-feeder life history traits influenced by plant nitrogen supplementation. This study analyzed the bottom-up effects of below-recommended nitrogen fertilization rates (0, 0.021, 0.048, and 0.091 g N/liter) on life history and total protein and lipid contents of a significant pest species, Phenacoccus madeirensis Green (the Madeira mealybug) (Hemiptera: Pseudococcidae). Developmental durations and survivorship from egg to adulthood of male and female mealybugs were similar across nitrogen fertilization levels. Females reared on plants fertilized at 0.021, 0.048, and 0.091 g N/liter produced, respectively, 152, 142, and 67% more eggs than females reared on unfertilized plants. Finite and intrinsic rates of increase and net reproductive rates of females were similar among the nitrogen fertilization levels, whereas the generation times of females from fertilized plants were significantly shorter than those from the unfertilized plants. Lipid contents of adult females and eggs, and average adult female protein content were similar across the nitrogen treatments. Average egg protein content increased with increasing host-plant fertilization rate.These results suggest that the response of the female Madeira mealybug to nitrogen fertilization is complex and may involve trade-offs and nutrient re-allocation.
Sensorimotor Coding of Vermal Granule Neurons in the Developing Mammalian Cerebellum

The vermal cerebellum is a hub of sensorimotor integration critical for postural control and locomotion, but the nature and developmental organization of afferent information to this region have remained poorly understood in vivo. Here, we use in vivo two-photon calcium imaging of the vermal cerebellum in awake behaving male and female mice to record granule neuron responses to diverse sensorimotor cues targeting visual, auditory, somatosensory, and motor domains. Use of an activity-independent marker revealed that approximately half (54%) of vermal granule neurons were activated during these recordings. A multikernel linear model distinguished the relative influences of external stimuli and co-occurring movements on neural responses, indicating that, among the subset of activated granule neurons, locomotion (44%–56%) and facial air puffs (50%) were more commonly and reliably encoded than visual (31%–32%) and auditory (19%–28%) stimuli. Strikingly, we also uncover populations of granule neurons that respond differentially to voluntary and forced locomotion, whereas other granule neurons in the same region respond similarly to locomotion in both conditions. Finally, by combining two-photon calcium imaging with birth date labeling of granule neurons via in vivo electroporation, we find that early- and late-born granule neurons convey similarly diverse sensorimotor information to spatially distinct regions of the molecular layer. Collectively, our findings elucidate the nature and developmental organization of sensorimotor information in vermal granule neurons of the developing mammalian brain. SIGNIFICANCE STATEMENT Cerebellar granule neurons comprise over half the neurons in the brain, and their coding properties have been the subject of theoretical and experimental interest for over a half-century. In this study, we directly test long-held theories about encoding of sensorimotor stimuli in the cerebellum and compare the in vivo coding properties of early- and late-born granule neurons. Strikingly, we identify populations of granule neurons that differentially encode voluntary and forced locomotion and find that, although the birth order of granule neurons specifies the positioning of their parallel fiber axons, both early- and late-born granule neurons convey a functionally diverse sensorimotor code. These findings constitute important conceptual advances in understanding the principles underlying cerebellar circuit development and function.
Ferritin in Kidney and Vascular Related Diseases: Novel Roles for an Old Player

Iron is at the forefront of a number of pivotal biological processes due to its ability to readily accept and donate electrons. However, this property may also catalyze the generation of free radicals with ensuing cellular and tissue toxicity. Accordingly, throughout evolution numerous pathways and proteins have evolved to minimize the potential hazardous effects of iron cations and yet allow for readily available iron cations in a wide variety of fundamental metabolic processes. One of the extensively studied proteins in the context of systemic and cellular iron metabolisms is ferritin. While clinicians utilize serum ferritin to monitor body iron stores and inflammation, it is important to note that the vast majority of ferritin is located intracellularly. Intracellular ferritin is made of two different subunits (heavy and light chain) and plays an imperative role as a safe iron depot. In the past couple of decades our understanding of ferritin biology has remarkably improved. Additionally, a significant body of evidence has emerged describing the significance of the kidney in iron trafficking and homeostasis. Here, we briefly discuss some of the most important findings that relate to the role of iron and ferritin heavy chain in the context of kidney-related diseases and, in particular, vascular calcification, which is a frequent complication of chronic kidney disease.
Development and Testing of a M-Learning System for the Professional Development of Academics Through Design-Based Action Research

In the present study, a mobile learning system for the professional development of academics was developed by design based action research, and the perceptions and experiences of the academics using this system were examined. In the first phase of this design-based action research, the research question was defined. In the second phase, a m-learning system called “Mobile Academic Research Support” (MARS) was designed as a solution to the problem, and the IOS mobile application for this design was developed. In the third phase of the study, the MARS application was regularly tested and evaluated by the academics over eight weeks. At the end of the research process, the results were reflected upon. It was found that the primary and important professional development needs of the academics were at the scientific research level. It was also observed that the m-learning system developed for the professional development of the academics regarding scientific research was appropriate to the overall purpose, accessible, adaptable and appealing; that it served both as a m-learning and as an academic support system; that its content was satisfactory; and that the tools used in the system were useful. In addition, it was observed that the academics were able to use mobile technologies for learning. Also, it was stated that such a system could provide positive contributions to the professional development of academics.
Gait Abnormalities and the Risk of Falls in CKD.

BACKGROUND AND OBJECTIVES Older adults with CKD are at high risk of falls and disability. It is not known whether gait abnormalities contribute to this risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Quantitative and clinical gait assessments were performed in 330 nondisabled community-dwelling adults aged ≥65 years. CKD was defined as an eGFR <60 ml/min per 1.73 m2. Cox proportional hazards models were created to examine fall risk. RESULTS A total of 41% (n=134) of participants had CKD. In addition to slower gait speed, participants with CKD had gait cycle abnormalities including shorter stride length and greater time in the stance and double-support phases. Among people with CKD, lower eGFR was independently associated with the severity of gait cycle abnormalities (per 10 ml/min per 1.73 m2 lower eGFR: 3.6 cm [95% confidence interval (95% CI), 1.4 to 5.8] shorter stride length; 0.7% [95% CI, 0.3 to 1.0] less time in swing phase; 1.1% [95% CI, 0.5 to 1.7] greater time in double-support phase); these abnormalities mediated the association of lower eGFR with slower gait speed. On clinical gait exam, consistent with the quantitative abnormalities, short steps and marked swaying or loss of balance were more common among participants with CKD, yet most had no identifiable gait phenotype. A gait phenotype defined by any of these abnormal signs was associated with higher risk of falls among participants with CKD: compared with people without CKD and without the gait phenotype, the adjusted hazard ratio was 1.72 (95% CI, 1.06 to 2.81) for those with CKD and the phenotype; in comparison, the adjusted hazard ratio was 0.71 (95% CI, 0.40 to 1.25) for people with CKD but without the phenotype (P value for interaction of CKD status and gait phenotype =0.01). CONCLUSIONS CKD in older adults is associated with quantitative gait abnormalities, which clinically manifest in a gait phenotype that is associated with fall risk.
Arylacetamide Deacetylase Enzyme: Presence and Interindividual Variability in Human Lungs

Human arylacetamide deacetylase (AADAC) is a single microsomal serine esterase involved in the hydrolysis of many acetyl-containing drugs. To date, the presence and activity of the AADAC enzyme in human lungs has been scarcely examined. We investigated its gene and protein expression as well as interindividual variations in AADAC activities in a large number of human lungs (n = 25) using phenacetin as a selective substrate. The kinetic parameters Km and Vmax were determined. Our findings highlighted a high interindividual variability in both AADAC mRNA levels and hydrolysis activities. Furthermore, for the first time we demonstrated the presence of the AADAC protein in various lung samples by means of immunoblot analysis. As a comparison, phenacetin hydrolysis was detected in pooled human liver microsomes. Lung activities were much lower than those found in the liver. However, similar Km values were found, which suggests that this hydrolysis could be due to the same enzyme. Pulmonary phenacetin hydrolysis proved to be positively correlated with AADAC mRNA (*P < 0.05) and protein (*P < 0.05) levels. Moreover, the average values of AADAC activity in smokers was significantly higher than in nonsmoker subjects (*P < 0.05), and this might have an important role in the administration of some drugs. These findings add more information to our knowledge of pulmonary enzymes and could be particularly useful in the design and preclinical development of inhaled drugs. SIGNIFICANCE STATEMENT This study investigated the presence and activity of the AADAC enzyme in several human lungs. Our results highlight high interindividual variability in both AADAC gene and protein expression as well as in phenacetin hydrolysis activity. These findings add more information to our knowledge of pulmonary enzymes and could be particularly useful in the design and preclinical development of inhaled drugs.
Number of Circulating CD73‐Expressing Lymphocytes Correlates With Survival After Cardiac Arrest

Background Patients resuscitated from cardiac arrest (CA) have highly variable neurological, circulatory, and systemic ischemia‐reperfusion injuries. After the initial hypoxic‐ischemic insult, a cascade of immune and inflammatory responses develops and is often fatal. The role of the immune response in pathophysiological characteristics and recovery is not well understood. We studied immune cell activity and its association with outcomes in a cohort of CA survivors. Methods and Results After informed consent, we collected blood samples at intervals over a week after resuscitation from CA. We examined the expression of CD39 and CD73 (alias 5′‐nucleotidase), production of tumor necrosis factor‐α, generation of reactive oxygen species, and secretion of vascular endothelial growth factor by circulating myeloid and lymphoid cells, in comparison to cells obtained from control subjects before coronary artery bypass grafting surgery. The number of circulating total and CD73‐expressing lymphocytes correlated with survival after CA. Incubation of immune cells, obtained from post‐CA subjects, with AMP, a substrate for CD73, resulted in inhibition of tumor necrosis factor‐α production and generation of reactive oxygen species. This effect was blocked by adenosine 5′‐(α, β‐methylene) diphosphate, a specific inhibitor of CD73 and ZM 241385, an A2 adenosine receptor antagonist. We also found that AMP‐dependent activation of CD73 induces production of vascular endothelial growth factor. Conclusions CD73‐expressing lymphocytes mediate cellular protection from inflammation after CA through inhibition of proinflammatory activation of myeloid cells and promotion of vascular endothelial growth factor secretion. The contribution of CD73 lymphocytes in the regulation of acute inflammation and tissue injury after CA warrants further study.
A new generation of predictive models: The added value of hybrid models for manufacturing processes of therapeutic proteins

Due to the lack of complete understanding of metabolic networks and reaction pathways, establishing a universal mechanistic model for mammalian cell culture processes remains a challenge. Contrarily, data‐driven approaches for modeling these processes lack extrapolation capabilities. Hybrid modeling is a technique that exploits the synergy between the two modeling methods. Although mammalian cell cultures are among the most relevant processes in biotechnology and indeed looks ideal for hybrid modeling, their application has only been proposed but never developed in the literature. This study provides a quantitative assessment of the improvement brought by hybrid models with respect to the state‐of‐the‐art statistical predictive models in the context of therapeutic protein production. This is illustrated using a dataset obtained from a 3.5 L fed‐batch experiment. With the goal to robustly define the process design space, hybrid models reveal a superior capability to predict the time evolution of different process variables using only the initial and process conditions in comparison to the statistical models. Hybrid models not only feature more accurate prediction results but also demonstrate better robustness and extrapolation capabilities. For the future application, this study highlights the added value of hybrid modeling for model‐based process optimization and design of experiments.