Miracle-dz/UniFAR-FTUs huggingface dataset:
Production of 3-Hydroxypropionic Acid via the Propionyl-CoA Pathway Using Recombinant Escherichia coli Strains

Our study aimed to produce the commercially promising platform chemical 3-hydroxypropionic acid (3-HP) via the propionyl-CoA pathway in genetically engineered Escherichia coli. Recombinant E. coli Ec-P overexpressing propionyl-CoA dehydrogenase (PACD, encoded by the pacd gene from Candida rugosa) under the T7 promoter produced 1.33 mM of 3-HP in a shake flask culture supplemented with 0.5% propionate. When propionate CoA-transferase (PCT, encoded by the pct gene from Megasphaera elsdenii) and 3-hydroxypropionyl-CoA dehydratase (HPCD, encoded by the hpcd gene from Chloroflexus aurantiacus) were expressed along with PACD, the 3-HP titer of the resulting E. coli Ec-PPH strain was improved by 6-fold. The effect of the cultivation conditions on the 3-HP yield from propionate in the Ec-PPH strain was also investigated. When cultured at 30°C with 1% glucose in addition to propionate, 3-HP production by Ec-PPH increased 2-fold and 12-fold compared to the cultivation at 37°C (4.23 mM) or without glucose (0.68 mM). Deletion of the ygfH gene encoding propionyl-CoA: succinate CoA-transferase from Ec-PPH (resulting in the strain Ec-△Y-PPH) led to increase of 3-HP production in shake flask experiments (15.04 mM), whereas the strain Ec-△Y-PPH with deletion of the prpC gene (encoding methylcitrate synthase in the methylcitrate cycle) produced 17.76 mM of 3-HP. The strain Ec-△Y-△P-PPH with both ygfH and prpC genes deleted produced 24.14 mM of 3-HP, thus showing an 18-fold increase in the 3-HP titer in compare to the strain Ec-P.
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Central Nervous System Metastases from Non-Small Cell Lung Cancer.

Central nervous system (CNS) metastases are a common complication in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), resulting in a poor prognosis and limited treatment options. Treatment of CNS metastases requires a multidisciplinary approach, and the optimal treatment options and sequence of therapies are yet to be established. Many systemic therapies have poor efficacy in the CNS due to the challenges of crossing the blood-brain barrier (BBB), creating a major unmet need for the development of agents with good BBB-penetrating biopharmaceutical properties. Although the CNS penetration of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) is generally low, EGFR-TKI treatment has been shown to delay time to CNS progression in patients with CNS metastases from EGFR-mutated disease. However, a major challenge with EGFR-TKI treatment for patients with NSCLC is the development of acquired resistance, which occurs in most patients treated with a first-line EGFR-TKI. Novel EGFR-TKIs, such as osimertinib, have been specifically designed to address the challenges of acquired resistance and poor BBB permeability and have demonstrated efficacy in the CNS. A rational, iterative drug development process to design agents that could penetrate the BBB could prevent morbidity and mortality associated with CNS disease progression. To ensure a consistent approach to evaluating CNS efficacy, special consideration also needs to be given to clinical trial endpoints. IMPLICATIONS FOR PRACTICE Historically, treatment options for patients who develop central nervous system (CNS) metastases have been limited and associated with poor outcomes. The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved outcomes for patients with EGFR-mutated disease, and emerging data have demonstrated the ability of these drugs to cross the blood-brain barrier and elicit significant intracranial responses. Recent studies have indicated a role for next-generation EGFR-TKIs, such as osimertinib, in the treatment of CNS metastases. In the context of an evolving treatment paradigm, treatment should be individualized to the patient and requires a multidisciplinary approach.
Zero-Delay Gaussian Joint Source–Channel Coding for the Interference Channel

This letter studies zero-delay joint source–channel coding for transmission of correlated Gaussian sources over a Gaussian interference channel. We propose to adopt a delay-free hybrid digital and analog scheme, which is transmitting the superposition of scaled source and its quantized version after applying scalar quantization to the source at each transmitter. At the corresponding receiver, two kinds of estimators are presented. It is shown that both the schemes, when optimized, beat the uncoded transmission if the channel signal-to-noise ratio is higher than a threshold value for different correlation coefficients and interference values.
Treatment of Vitamin D Deficiency Increases Lower Limb Muscle Strength in Institutionalized Older People Independently of Regular Physical Activity: A Randomized Double-Blind Controlled Trial

Aims: To investigate the effects of a 6-month supplementation with calcium and cholecalciferol on biochemical parameters and muscle strength of institutionalized elderly. Methods: This prospective, double-blind, placebo-controlled, randomized trial included Brazilian institutionalized people ≥60 years of age receiving a 6-month supplementation (December to May) of daily calcium plus monthly placebo (calcium/placebo group) or daily calcium plus oral cholecalciferol (150,000 IU once a month during the first 2 months, followed by 90,000 IU once a month for the last 4 months; calcium/vitamin D group). Fasting blood samples for 25(OH)D, PTH and calcium determination were collected (n = 56) and muscle tests were performed (n = 46) to measure the strength of hip flexors (SHF) and knee extensors (SKE) before (baseline) and after the 6-month intervention (6 months). Results: Due to seasonal variations, serum 25(OH)D significantly enhanced in both groups after treatment, but the calcium/vitamin D group had significantly higher 25 (OH)D levels than the calcium/placebo group (84 vs. 33%, respectively; p < 0.0001). No cases of hypercalcemia were observed. While the calcium/placebo group showed no improvement in SHF and SKE at 6 months (p = 0.93 and p = 0.61, respectively), SHF was increased in the calcium/vitamin D group by 16.4% (p = 0.0001) and SKE by 24.6% (p = 0.0007). Conclusions: The suggested cholecalciferol supplementation was safe and efficient in enhancing 25(OH)D levels and lower limb muscle strength in the elderly, in the absence of any regular physical exercise practice.
Classification of simulated radio signals using Wide Residual Networks for use in the search for extra-terrestrial intelligence

We describe a new approach and algorithm for the detection of artificial signals and their classification in the search for extraterrestrial intelligence (SETI). The characteristics of radio signals observed during SETI research are often most apparent when those signals are represented as spectrograms. Additionally, many observed signals tend to share the same characteristics, allowing for sorting of the signals into different classes. For this work, complex-valued time-series data were simulated to produce a corpus of 140,000 signals from seven different signal classes. A wide residual neural network was then trained to classify these signal types using the gray-scale 2D spectrogram representation of those signals. An average $F_1$ score of 95.11\% was attained when tested on previously unobserved simulated signals. We also report on the performance of the model across a range of signal amplitudes.
Estimating Simple and Complex Cell Receptive Fields from Natural Image Stimuli and 2-Photon Imaging Recordings of the V 1 in Ferrets

The visual cortex in many species displays a columnar organisation into topographic domains, which was for a long time fundamentally associated with cortical computation. More recently experiments have shown that most rodent species do not display this topographic organisation of neurons into maps, calling unifying theories of cortical computation into question. The characteristics of individual neurons are defined by so called receptive fields, which can be visualised using a variety of estimation techniques. The receptive field properties of V1 neurons in have generally been assumed to vary little across species although no detailed comparison of entire neuronal populations have so far been performed. By extending two-photon calcium imaging protocols previously applied in mice at Tom Mrsic-Flogel’s lab entire populations of neurons in the primary visual cortex can be imaged at single cell resolution and their responses to visual stimuli be recorded. This project develops the necessary procedures and protocols to perform receptive field estimation in ferrets, including the stimuli, pre-processing procedures and receptive field estimation techniques. Two novel stimuli are implemented in the laboratory software toolbox used by various labs including Stephen van Hooser’s at Brandeis University. In addition, the development of pre-processing tools to convert the raw luminance signal from two-photon calcium imaging into the appropriate formats for further analysis is demonstrated. To complete the toolchain a variety of receptive field estimation techniques are tested on simulated and real datasets, including electrophysiology recordings from ferret and macaque and a single twophoton calcium imaging dataset from mouse recordings at Tom Mrsic-Flogel’s lab. The ferret dataset was recorded as part of the visit to Stephen van Hooser’s lab using the stimulus protocol that is part of this project. Moving forward this work provides the foundation to collect detailed datasets of V1 volumes in ferrets, which can be compared to already existing datasets of mice. The ultimate aim will be to provide clear data about the differences in functional organisation, development and information processing in species with and without topographic maps.
The Basic Helix–Loop–Helix Transcription Factor GubHLH3 Positively Regulates Soyasaponin Biosynthetic Genes in Glycyrrhiza uralensis

Glycyrrhiza uralensis (licorice) is a widely used medicinal plant belonging to the Fabaceae. Its main active component, glycyrrhizin, is an oleanane-type triterpenoid saponin widely used as a medicine and as a natural sweetener. Licorice also produces other triterpenoids, including soyasaponins. Recent studies have revealed various oxidosqualene cyclases and cytochrome P450 monooxygenases (P450s) required for the biosynthesis of triterpenoids in licorice. Of these enzymes, β-amyrin synthase (bAS) and β-amyrin C-24 hydroxylase (CYP93E3) are involved in the biosynthesis of soyasapogenol B (an aglycone of soyasaponins) from 2,3-oxidosqualene. Although these biosynthetic enzyme genes are known to be temporally and spatially expressed in licorice, the regulatory mechanisms underlying their expression remain unknown. Here, we identified a basic helix-loop-helix (bHLH) transcription factor, GubHLH3, that positively regulates the expression of soyasaponin biosynthetic genes. GubHLH3 preferentially activates transcription from promoters of CYP93E3 and CYP72A566, the second P450 gene newly identified and shown to be responsible for C-22β hydroxylation in soyasapogenol B biosynthesis, in transient co-transfection assays of promoter-reporter constructs and transcription factors. Overexpression of GubHLH3 in transgenic hairy roots of G. uralensis enhanced the expression levels of bAS, CYP93E3 and CYP72A566. Moreover, soyasapogenol B and sophoradiol (22β-hydroxy-β-amyrin), an intermediate between β-amyrin and soyasapogenol B, were increased in transgenic hairy root lines overexpressing GubHLH3. We found that soyasaponin biosynthetic genes and GubHLH3 were co-ordinately up-regulated by methyl jasmonate (MeJA). These results suggest that GubHLH3 regulates MeJA-responsive expression of soyasaponin biosynthetic genes in G. uralensis. The regulatory mechanisms of triterpenoid biosynthesis in legumes are compared and discussed.
Finding the Needle in a Haystack: Entropy Guided Exploration of Very Large Graph Cubes

Graphs provide an elegant and versatile solution for modeling complex datasets, especially when the focus of the analysis is on highlighting interesting associations between data entities. Graph cubes permit analysis of the resulting data graphs at various levels of granularity based on their node and edge attributes. In this work, we utilize information entropy measures in order to help the analyst navigate within the rich information contained in a graph cube. Our metrics suggest navigations (drill-downs) towards more detailed data descriptions, conditioned on what has been observed at a coarser resolution. We propose a graph analysis workflow that first suggests interesting cuboids from the exponential collection of aggregations that exist in the graph cube. At a latter step, this workflow handpicks sub-graphs out of these aggregations that deviate significantly from the rest of the data. We experimentally validate our techniques using real datasets and demonstrate that the proposed entropy-based exploration can help eliminate large portions of the respective graph cubes from consideration. Our techniques help locate the "needle in the haystack" and steer the user towards data skew hidden within vast valleys of near-uniform interactions.
Protocol for the residents in action pilot cluster randomised controlled trial (RiAT): evaluating a behaviour change intervention to promote walking, reduce sitting and improve mental health in physically inactive older adults in retirement villages

Introduction Ageing is accompanied by increased risks of chronic disease, declined functioning and increased dependency. Physical activity is critical to retaining health and independence, but the majority of older people are insufficiently physically active to achieve these benefits and have high levels of sedentary (sitting) time. Activity programmes are often offered in retirement villages; however, their uptake is limited. Furthermore, although the physical environment in and around these villages can play an important role in decisions to be physically active, its role is often overlooked by research in these settings. We aim to develop, implement and evaluate a proof-of-concept motivationally embellished intervention designed to increase walking, reduce sitting and improve mental health in residents in retirement villages. Methods and analysis This will be a 16-week pilot intervention using a cluster randomised design with retirement villages as the unit of randomisation and residents as the unit of assessment. Fourteen retirement villages around Perth, Western Australia, will be recruited for the intervention. Objective audits of neighbourhood environments around each village will be completed using the Pathway Environmental Audit Tool. Seven villages will be randomised to the experimental arm and seven to the control arm. Only participants in the experimental arm will receive motivational training. All outcomes will be assessed at baseline, end of intervention and 6-month follow-up. Changes in physical activity levels, sitting time and mental health will be examined. Multilevel modelling will be used to analyse the data. A mixed methods process evaluation will also be conducted. Ethics and dissemination Ethics approval was granted by Curtin University’s Human Research Ethics Committee (HREC2016-0187). The results of the study will be disseminated via peer-reviewed publications, conference presentations and reports to, and seminars with, stakeholders. Trial registration The trial is registered with the Australian New Zealand Clinical Trials Registry: ACTRN12616001177448.
Cultural transmission and the diffusion of innovations : adoption dynamics indicate that biased cultural transmission is the predominate force in behavioral change and much of sociocultural evolution

In challenging the pervasive model of individual actors as cost-benefit analysts who adapt their behavior by learning from the environment, this article analyzes the temporal dynamics of both environmental (individual) learning and biased cultural transmission processes by comparing these dynamics with the robust “5-shaped” curves that emerge from the diffusion of innovations literature. The analysis shows three things: (1) that environmental learning alone never produces the 5-shaped adoption dynamics typically observed in the spread of novel practices, ideas, and technologies; (2) that biased cultural transmission always produces the S-shaped temporal dynamics; and (3) that a combination of environmental learning and biased cultural transmission can generate 5-dynamics but only when biased cultural transmission is the predominate force in the spread of new behaviors. These findings suggest that biased cultural transmission processes are much more important to understanding the diffusion of innovations and sociocultural evolution than is often assumed by most theorists. [diffusion of innovations, cultural transmission, learning, cultural evolution]
The knock‐down of the expression of MdMLO19 reduces susceptibility to powdery mildew (Podosphaera leucotricha) in apple (Malus domestica)

Summary Varieties resistant to powdery mildew (PM; caused by Podosphaera leucotricha) are a major component of sustainable apple production. Resistance can be achieved by knocking‐out susceptibility S‐genes to be singled out among members of the MLO (Mildew Locus O) gene family. Candidates are MLO S‐genes of phylogenetic clade V up‐regulated upon PM inoculation, such as MdMLO11 and 19 (clade V) and MdMLO18 (clade VII). We report the knock‐down through RNA interference of MdMLO11 and 19, as well as the complementation of resistance with MdMLO18 in the Arabidopsis thaliana triple mlo mutant Atmlo2/6/12. The knock‐down of MdMLO19 reduced PM disease severity by 75%, whereas the knock‐down of MdMLO11, alone or in combination with MdMLO19, did not result in any reduction or additional reduction of susceptibility compared with MdMLO19 alone. The test in A. thaliana excluded a role for MdMLO18 in PM susceptibility. Cell wall appositions (papillae) were present in both PM‐resistant and PM‐susceptible plants, but were larger in resistant lines. No obvious negative phenotype was observed in plants with mlo genes knocked down. Apparently, MdMLO19 plays the pivotal role in apple PM susceptibility and its knock‐down induces a very significant level of resistance.
Samter’s Triad: State of the Art

Samter’s triad (ST) is a well-known disease characterized by the triad of bronchial asthma, nasal polyps, and aspirin intolerance. Over the past few years, a rapid development in the knowledge of the pathogenesis and clinical characteristics of ST has happened. The aim of this paper is to review the recent investigations on the pathophysiological mechanisms and genetic background, diagnosis, and different therapeutic options of ST to advance our understanding of the mechanism and the therapeutic control of ST. As concern for ST increase, more application of aspirin desensitization will be required to manage this disease successfully. There is also a need for continued research efforts in pathophysiology, treatment, and possible prevention.
Modeling constraints improves software architecture design reasoning

Requirements and project-related factors influence architectural design in intricate and multivariate ways. We are only beginning to understand some of the tacit but fundamental mechanisms involved in reasoning about design decisions, and one of them concerns the role of design constraints. This paper examines design constraints and how they shape design solutions. We introduce a design constraint model and an architectural design reasoning process for specifying design constraints and checking for design conflicts. We experiment with using logic for constraint verification with the Alloy tool.
Emerging drugs for primary progressive multiple sclerosis

ABSTRACT Introduction: The identification of effective therapies for progressive forms of multiple sclerosis (MS) has remains a priority and challenge for the global MS community. Despite a few proposed mechanisms, a more complete understanding of the mechanisms involved in the pathogenesis of these MS phenotypes, animal models that incorporate these pathogenic characteristics, novel trial designs, drug repurposing strategies, and new models of collaboration between clinical and basic science personnel may be required in identifying effective therapies. Areas covered: Here, we review the current knowledge on putative pathogenic mechanisms in primary progressive MS (PPMS). Also, the rationale and outcomes of key phase II or III trial initiatives in PPMS are summarized. Future perspectives are outlined. Expert opinion: The recent approval of ocrelizumab is a major milestone forward in the therapy of PPMS. One reason for success of this drug is appropriate patient selection. The ultimate goal in PPMS therapy should be the reversal of disability, and the arrest of disease progression. Our current understanding of PPMS suggests that a combination of immune-modulatory, myelin-restorative, and neuro-regenerative therapies particularly early in the disease course would be a reasonable strategy. Finally, selection of appropriate patients, selection of appropriate outcomes and monitoring therapy is again crucial for success of therapeutic strategies.
A Complex Network of Interactions between Mitotic Kinases, Phosphatases and ESCRT Proteins Regulates Septation and Membrane Trafficking in S. pombe

Cytokinesis and cell separation are critical events in the cell cycle. We show that Endosomal Sorting Complex Required for Transport (ESCRT) genes are required for cell separation in Schizosaccharomyces pombe. We identify genetic interactions between ESCRT proteins and polo and aurora kinases and Cdc14 phosphatase that manifest as impaired growth and exacerbated defects in septation, suggesting that the encoded proteins function together to control these processes. Furthermore, we observed defective endosomal sorting in mutants of plo1, ark1 and clp1, as has been reported for ESCRT mutants, consistent with a role for these kinases in the control of ESCRT function in membrane traffic. Multiple observations indicate functional interplay between polo and ESCRT components: firstly, two-hybrid in vivo interactions are reported between Plo1p and Sst4p, Vps28p, Vps25p, Vps20p and Vps32p; secondly, co-immunoprecipitation of human homologues of Vps20p, Vps32p, Vps24p and Vps2p by human Plk1; and thirdly, in vitro phosphorylation of budding yeast Vps32p and Vps20p by polo kinase. Two-hybrid analyses also identified interactions between Ark1p and Vps20p and Vps32p, and Clp1p and Vps28p. These experiments indicate a network of interactions between ESCRT proteins, plo1, ark1 and clp1 that coordinate membrane trafficking and cell separation in fission yeast.
Mining Vessel Trajectory Data for Patterns of Search and Rescue

The overall aim of this work is to explore the possibility of automatically detecting Search And Rescue (SAR) activity, even when a distress call has on yet been received. For this, we exploit a large volume of historical Automatic Identification System (AIS) data so as to detect SAR activity from vessel trajectories, in a scalable, data-driven supervised way, with no reliance on external sources of information (e.g. coast guard reports). Specifically, we present our approach which is based on a parallelised, nonparametric statistical method (Random Forests), which has proved capable of achieving prediction accuracy rates higher than 77%.