Miracle-dz/UniFAR-FTUs huggingface dataset:
Golgi localized Arl15 regulates cargo transport, cell adhesion and motility

Arf-like GTPases (Arls) regulate membrane trafficking and cytoskeletal organization. Genetic studies predicted a role for Arl15 in type-2 diabetes, insulin resistance, adiposity, and rheumatoid arthritis. Recent studies indicate a possible role for Arl15 in multiple physiological processes, including magnesium homeostasis. However, the molecular function of Arl15 is poorly defined. We evaluated the role of Arl15 in vesicular transport using techniques to quantify cargo trafficking, to mechanobiology. Fluorescence microscopy of stably expressing Arl15-GFP HeLa cells showed its localization to the Golgi and cell surface, including filopodia, and a cohort to recycling endosomes. The dissociation of Golgi, using small molecular inhibitors or the expression of Arf1 dominant-negative mutant, completely mislocalized Arl15 to the cytosol. Interestingly, site-directed mutagenesis analysis identified a novel V80A mutation in the GTP-binding domain that turns Arl15 into a dominant-negative form with reduced number of filopodia. Depletion of Arl15 in HeLa cells caused mislocalization of cargo, such as caveolin-2 and STX6, from the Golgi. Arl15 knockdown cells displayed reduced filopodial number, altered focal adhesion kinase organization, and enhanced soluble and receptor-mediated cargo uptake without affecting the TfR recycling. Arl15 knockdown decreased cell migration and enhanced cell spreading and adhesion strength. Traction force microscopy experiments revealed that Arl15 depleted cells exert higher tractions and generate multiple focal adhesion points during the initial phase of cell adhesion as compared to control cells. Collectively, these studies demonstrated a functional role for Arl15 in the Golgi, which includes regulating cargo transport to organize membrane domains at the cell surface. Key points Arl15 primarily localizes to Golgi and plasma membrane, including filopodia Membrane localization of Arl15 is dependent on Golgi integrity or Arf1 activation Arl15 knockdown mislocalizes STX6-dependent Golgi localized cargo required for cell surface organization and reduces the filopodial number Arl15 is involved in cell spreading, adhesion, and migration
Transcriptome-wide gene-gene interaction associations elucidate pathways and functional enrichment of complex traits

It remains unknown to what extent gene-gene interactions contribute to complex traits. Here, we introduce a new approach using predicted gene expression to perform exhaustive transcriptome-wide interaction studies (TWISs) for multiple traits across all pairs of genes expressed in several tissue types. Using imputed transcriptomes, we simultaneously reduce the computational challenge and improve interpretability and statistical power. We discover and replicate several interaction associations, and find several hub genes with numerous interactions. We also demonstrate that TWIS can identify novel associated genes because genes with many or strong interactions have smaller single-locus model effect sizes. Finally, we develop a method to test gene set enrichment of TWIS associations (E-TWIS), finding numerous pathways and networks enriched in interaction associations. Epistasis is likely widespread, and our procedure represents a tractable framework for beginning to explore gene interactions and identify novel genomic targets.
Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in Caenorhabditis elegans

The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food almost everywhere, from the baking industry to our everyday life. However, the Maillard reaction also takes place in all cells, from prokaryotes to eukaryotes, leading to the formation of Advanced Glycation End-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNA-seq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGEs (MG-H1) induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream factor for increased feeding upon accumulation of AGEs by partially regulating the expression of tdc-1 and tyra-2 genes. Further, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MGO and associated AGEs. Understanding this signaling pathway is essential to modulate hedonistic overfeeding behavior observed in modern AGEs rich diets.
Transcriptional and translational profiling in yeast reveals the use of diverse genome decoding mechanisms to generate functionally distinct proteoforms

The coding potential of the eukaryotic genome can be greatly expanded by the regulated use of mechanisms that generate more than one protein product from a gene. We combined techniques for mapping 5’ and 3’ ends of RNA transcripts with ribosome profiling to study the organisation of protein coding gene expression in the yeast Kluyveromyces marxianus. We uncovered over 1000 cases of novel proteoforms due to use of alternative transcription or translation start sites, identified 800 translated upstream open reading frames, observed surprising translation of antisense RNAs, and discovered a novel case of programmed ribosomal frameshifting. In some cases, features are conserved across yeast species, whereas others are species-specific. This offers new possibilities to explore the evolution of genomes and gene regulation in budding yeasts. Our analysis also enabled us to improve the genome annotation of K. marxianus by adding or correcting annotations of over 300 protein coding genes. The processed data has been made available on the GWIPS-viz and Trips-Viz browsers, thus providing an accurate data-driven annotation of transcripts and their protein coding regions along with quantitative information on their transcription and translation.
Independent synaptic inputs to motor neurons driving antagonist muscles

The CNS may produce the same endpoint trajectory or torque profile with different muscle activation patterns. What differentiates these patterns is the presence of co-contraction, which does not contribute to joint torque generation but allows to modulate mechanical impedance. Whether co-contraction is controlled through the same synaptic input to motor neurons involved in generating joint torque is still unclear. We hypothesized that co-contraction is controlled through a specific synaptic input, independent from that underlying the control of torque. To test this hypothesis, we asked participants to concurrently generate multi-directional isometric forces at the hand and to modulate the co-contraction of arm muscles to displace and stabilize a virtual end-effector. The firings of motor units were identified through decomposition of High-Density EMGs collected from two antagonist muscles, Biceps Brachii and Triceps Brachii. We found significant peaks in the coherence between the neural drive to the two muscles, suggesting the existence of a common input modulating co-contraction across different exerted forces. Moreover, the within-muscle coherence computed after removing the component synchronized with the drive to the antagonist muscle or with the exerted force revealed two subsets of motor neurons that were selectively recruited to generate joint torque or modulate co-contraction. This study is the first to directly investigate the extent of shared versus independent control of antagonist muscles at the motor neuron level in a task involving concurrent force generation and modulation of co-contraction. Significance Statement How the CNS coordinates the activity of antagonist muscles to modulate limb mechanical impedance is still unclear. We hypothesized that a common synaptic input, shared by the motor neurons pools of antagonist muscles, and independent from the inputs underlying force generation, regulates co-contraction. We then analyzed the coherence between the firing trains of motor neurons to assess whether a common input drives antagonist muscles only during tasks requiring co-activation for impedance but not for force generation. Results highlighted the existence of separate neural pathways underlying the control of joint torque or impedance. Scientifically, this study addressed an important gap in understanding how neural drive is delivered to antagonist muscles, disentangling the control of muscles for joint torque or impedance modulation.
Fifty years of reduction in sulphur deposition drives recovery in soil pH and plant communities

Sulphur deposition through rainfall has led to species loss and ecosystem degradation globally, and across Europe huge reductions in sulphur emissions since the 1970s were expected to promote the recovery of acidified ecosystem. However, the rate and ecological impact of recovery from acidification in terrestrial ecosystems is still unclear as is the influence of management and climate, as to date there has been no long-term spatially extensive evaluation of these changes. Here we present data from thousands of sites across Great Britain surveyed repeatedly from 1978-2019 and assess change in soil pH and plant acidity preference (Ellenberg R) in response to atmospheric deposition of sulphur and nitrogen. We analyse change in grasslands managed for pasture, referred to as high-intensity habitats, and compare to semi-natural habitats comprising rough grassland, broadleaved woodland, bog and heathland, referred to as low-intensity habitats. Soil pH increased from 1978 to 2007 but then decreased between 2007 and 2019, resulting in a net increase of ~0.2 pH units in low-intensity habitats but no change in high-intensity habitats. The community average Ellenberg R increased in semi-natural habitats by ~0.2 units but remained stable in intensive grasslands. In semi-natural habitats, but not intensive grasslands, these changes in plant community composition were associated with the soil pH changes which were in turn linked to decreasing sulphur deposition and differences in rainfall. Nitrogen deposition, which was relatively stable over the survey period, showed no additional effect upon soil acidity once sulphur deposition was accounted for. Synthesis: Our results provide conclusive evidence that reductions in acid emissions are stimulating the gradual recovery of chronically acidified terrestrial ecosystems at a whole-country scale, while also suggesting this recovery is being compromised by changing climate and land management.
Neural sequences in primate prefrontal cortex encode working memory in naturalistic environments

Working memory is the ability to briefly remember and manipulate information after it becomes unavailable to the senses. The mechanisms supporting working memory coding in the primate brain remain controversial. Here we demonstrate that microcircuits in layers 2/3 of the primate lateral prefrontal cortex dynamically represent memory content in a naturalistic task through sequential activation of single neurons. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of macaque monkeys during a naturalistic visuospatial working memory task set in a virtual environment. We found that the sequential activation of single neurons encoded trajectories to target locations held in working memory. Neural sequences were not a mere successive activation of cells with memory fields at specific spatial locations, but an abstract representation of the subject’s trajectory to the target. Neural sequences were less correlated to target trajectories during perception and were not found during working memory tasks lacking the spatiotemporal structure of the naturalistic task. Finally, ketamine administration distorted neural sequences, selectively decreasing working memory performance. Our results indicate that neurons in the lateral prefrontal cortex causally encode working memory in naturalistic conditions via complex and temporally precise activation patterns.
Zyxin contributes to coupling between cell junctions and contractile actomyosin networks during apical constriction

One of the most common cell shape changes driving morphogenesis in diverse animals is the constriction of the apical cell surface. Apical constriction depends on contraction of an actomyosin network in the apical cell cortex, but such actomyosin networks have been shown to undergo continual, conveyor belt-like contractions before the shrinking of an apical surface begins. This finding suggests that apical constriction is not necessarily triggered by the contraction of actomyosin networks, but rather can be triggered by unidentified, temporally-regulated mechanical links between actomyosin and junctions. Here, we used C. elegans gastrulation as a model to seek genes that contribute to such dynamic linkage. We found that α-catenin and β-catenin initially failed to move centripetally with contracting cortical actomyosin networks, suggesting that linkage is regulated between intact cadherin-catenin complexes and actomyosin. We used proteomic and transcriptomic approaches to identify new players, including the candidate linkers AFD-1/afadin and ZYX-1/zyxin, as contributing to C. elegans gastrulation. We found that ZYX-1/zyxin is among a family of LIM domain proteins that have transcripts that become enriched in multiple cells just before they undergo apical constriction. We developed a semi-automated image analysis tool to describe rates of myosin and membrane movement, which we then used to discover that ZYX-1/zyxin contributes to cell-cell junctions’ centripetal movement in concert with contracting actomyosin networks. These results identify several new genes that contribute to C. elegans gastrulation, and they identify zyxin as a key protein important for actomyosin networks to effectively pull cell-cell junctions inward during apical constriction. The transcriptional upregulation of ZYX-1/zyxin in specific cells in C. elegans points to one way that developmental patterning spatiotemporally regulates cell biological mechanisms in vivo. Because zyxin and related proteins contribute to membrane-cytoskeleton linkage in other systems, we anticipate that its roles in regulating apical constriction in this manner may be conserved.
Reaction Time Sensitivity to Spectrotemporal Modulations of Sound

We tested whether sensitivity to acoustic spectrotemporal modulations can be observed from reaction times for normal-hearing and impaired-hearing conditions. In a manual reaction-time task, normal-hearing listeners had to detect the onset of a ripple (with density between 0–8 cycles/octave and a fixed modulation depth of 50%), that moved up or down the log-frequency axis at constant velocity (between 0–64 Hz), in an otherwise-unmodulated broadband white-noise. Spectral and temporal modulations elicited band-pass filtered sensitivity characteristics, with fastest detection rates around 1 cycle/oct and 32 Hz for normal-hearing conditions. These results closely resemble data from other studies that typically used the modulation-depth threshold as a sensitivity criterion. To simulate hearing-impairment, stimuli were processed with a 6-channel cochlear-implant vocoder, and a hearing-aid simulation that introduced separate spectral smearing and low-pass filtering. Reaction times were always much slower compared to normal hearing, especially for the highest spectral densities. Binaural performance was predicted well by the benchmark race model of binaural independence, which models statistical facilitation of independent monaural channels. For the impaired-hearing simulations this implied a “best-of-both-worlds” principle in which the listeners relied on the hearing-aid ear to detect spectral modulations, and on the cochlear-implant ear for temporal-modulation detection. Although singular-value decomposition indicated that the joint spectrotemporal sensitivity matrix could be largely reconstructed from independent temporal and spectral sensitivity functions, in line with time-spectrum separability, a substantial inseparable spectral-temporal interaction was present in all hearing conditions. These results suggest that the reaction-time task yields a valid and effective objective measure of acoustic spectrotemporal-modulation sensitivity.
Phase Controlled 2.6-3.5 GHz Fractional-N PLL IC

This paper describes a fractional-N PLL IC with absolute phase control utilizing an on-chip loop-filter. The frequency range is 2.6 to 3.5 GHz, which covers one of the bands for future low-band 5G telecommunication systems. For phased-array operation a compact form-factor is needed as the space available for the complete front-end is limited by the wave-length. The on-chip loop-filter allows to obtain the compact form factor required. The absolute phase-control allows for phased-array operation. The chip has been implemented in a $\mathbf{0.25}\mu\mathbf{m}$ BiCMOS process.
Design, fabrication, and preclinical testing of a miniaturized, multispectral, chip-on-tip, imaging probe for intraluminal fluorescence imaging of the gastrointestinal tract

Gastrointestinal cancers continue to account for a disproportionately large percentage of annual cancer deaths in the US. Advancements in miniature imaging technology combined with a need for precise and thorough tumor detection in gastrointestinal cancer screenings fuel the demand for new, small-scale, and low-cost methods of localization and margin identification with improved accuracy. Here, we report the development of a miniaturized, chip-on-tip, multispectral, fluorescence imaging probe designed to port through a gastroscope working channel with the aim of detecting cancerous lesions in point-of-care endoscopy of the gastrointestinal lumen. Preclinical testing has confirmed fluorescence sensitivity and supports that this miniature probe can locate structures of interest via detection of fluorescence emission from exogenous contrast agents. This work demonstrates the design and preliminary performance evaluation of a miniaturized, single-use, chip-on-tip fluorescence imaging system, capable of detecting multiple fluorochromes, and devised for deployment via the accessory channel of a standard gastroscope.
A Multi-port High Step-up DC/DC Converter for Hybrid Renewable Energy Application

This paper presents a novel multi-port DC/DC converter which is suitable to be used as the interface of hybrid renewable energy systems. The converter contains three unidirectional power flow ports which two of them are input ports and are connected to two independent energy sources while the third one is the output port that feeds a standalone load. Furthermore, the proposed converter contains a bidirectional power flow port to charge/discharge an energy storage system (battery). In addition to multi-port structure, high boost value of voltage gain is the other merit of the converter. Hybrid system is composed of fuel cell (FC), photovoltaic (PV) panels and a battery pack. Different operating states are discussed, and a control system based on decoupling networks is presented. The control system is able to seek and extract maximum power of PV panel, adjust generated power of FC, and handle charging and discharging modes of battery. In order to control operating modes of the proposed converter, a power management method is also presented. By the way, small signal model is presented for the converter.The bode diagram has been plotted from the small signal model. Then the controller it was designed from the bode diagram. The results of simulation by the PI controller are presented. Also, the simulation results by P&O algorithm for the converter has been evaluated. Several Simulation and experimental tests have been carried out to evaluate the analysis and feasibility of the aforementioned system. The results verify well performance of the converter and confirm the simulations and theoretical results.
Graphene Devices for Tabletop and High-Current Quantized Hall Resistance Standards

We report the performance of a quantum Hall resistance standard based on epitaxial graphene maintained in a 5-T tabletop cryocooler system. This quantum resistance standard requires no liquid helium and can operate continuously, allowing year-round accessibility to quantized Hall resistance measurements. The <inline-formula> <tex-math notation="LaTeX">$\nu = 2$ </tex-math></inline-formula> plateau, with a value of <inline-formula> <tex-math notation="LaTeX">$R_{\mathrm {K}}$ </tex-math></inline-formula>/2, also seen as <inline-formula> <tex-math notation="LaTeX">$R_{\mathrm {H}}$ </tex-math></inline-formula>, is used to scale to 1 <inline-formula> <tex-math notation="LaTeX">$\text{k}\Omega $ </tex-math></inline-formula> using a binary cryogenic current comparator (BCCC) bridge and a direct current comparator (DCC) bridge. The uncertainties achieved with the BCCC are such as those obtained in the state-of-the-art measurements using GaAs-based devices. BCCC scaling methods can achieve large resistance ratios of 100 or more, and while room temperature DCC bridges have smaller ratios and lower current sensitivity, they can still provide alternate resistance scaling paths without the need for cryogens and superconducting electronics. Estimates of the relative uncertainties of the possible scaling methods are provided in this report, along with a discussion of the advantages of several scaling paths. The tabletop system limits are addressed as are potential solutions for using graphene standards at higher currents.
The use of satellite and ground based measurements for estimating and reducing uncertainties in the spatial distribution of emissions of nitrogen oxides

We explore possibilities of improving the spatial structure of NOx emissions employed in a continental scale chemistry transport model (CTM) by using satellite measurements of nitrogen dioxide and ground-based observations of near surface ozone. In this study, we combine the tropospheric NO2 columns derived from SCIAMACHY measurements, the data from the EMEP ozone-monitoring network and the calculations performed with the CHIMERE CTM in the framework of an advanced inverse modelling scheme. All data used in the study correspond to the period of June-August 2003. The main distinctive feature of our inversion scheme is that, in contrast to more common inverse modelling approaches, the magnitudes of uncertainties in the input data are not explicitly predefined but rather estimated consistently with the a posteriori emissions as a result of the inversion. While the tropospheric NO2 columns are used for fitting the spatial distribution of the emission parameters of the model, the ozone observations are only used to estimate the averaged levels of uncertainties in a priori emissions. We use our method in order to estimate and to reduce uncertainties in the gridded (with the resolution of 1 degree) NOx emission data for Europe, Middle East and Northern Africa. It is found that the a priori emission estimates used in the standard version of CHIMERE are probably biased in several regions. On average, the uncertainties in total NOx emissions are estimated to be about 1.7 in terms of the geometric standard deviation in Europe and about 2.1 outside of Europe. The corrected emission estimates provide better agreement of the modelled results with observations for both NO2 columns and near surface concentrations of ozone.