Miracle-dz/UniFAR-FTUs huggingface dataset:
VYKDOMOSIOS FUNKCIJOS RAIDA

more “pure” in this group. We briefly describe the developmental trends of main executive functions, concluding that the development of these abilities starts as early as the first year of life, undergoes the biggest changes in preschool years and continues till late childhood and even adulthood. We finally outline the importance of studying psychosocial context of the development of executive function. There is evidence that early social interaction may affect the development of executive function (Bibok et al., 2009; Bernier et al., 2010), but much remains to be done to better understand the mechanisms of the development of these functions. The second part of the paper is devoted to the connection between the development of executive function and theory of mind. There are four main proofs of this connection: 1) positive correlation between the executive function and theory of mind test results; 2) matching developmental paths of these two psychic functions; 3) matching brain regions; 4) disorders of both psychic functions in case of psychopathology (autism disorder in particular). Although the connection between executive function and theory of mind development is well documented, little is known about the nature and direction of this connection. The most prominent hypothesis is that executive function development stimulates the emergence of executive function (Carlson et al., 2004; Hughes and Ensor, 2007), but alternative explanations exist. We suggest that the explanations taking into account the social context of the development of both psychic functions should be considered. adults, function However, research of
Tetraploidy‐linked sensitization to CENP‐E inhibition in human cells

Tetraploidy caused by whole-genome duplication is a hallmark of cancer cells, and tetraploidy-selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti-proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin CENP-E than diploids. CENP-E inhibitor preferentially diminished the tetraploid cell population in diploid-tetraploid co-culture at optimum conditions. Live imaging revealed that tetraploidy-linked increase in unsolvable polar chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP-E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy-selective cell growth suppression. In contrast, the microtubule-stabilizing compound paclitaxel caused tetraploidy-selective growth suppression through the aggravation of spindle multipolarization. We also found that CENP-E inhibitor had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP-E inhibitors in tetraploidy-selective suppression, giving us clues on the further development of tetraploidy-targeting interventions in cancer.
Biochemically validated structural model of the 15-subunit IFT-B complex

Cilia are ubiquitous eukaryotic organelles important to cellular motility, signalling and sensory reception. Cilium formation requires intraflagellar transport for trafficking of structural and signalling components. The large MDa IFT-B complex constitutes the backbone of polymeric IFT trains that carry ciliary cargo between the cilium and the cell body. Currently, high-resolution structures are only available for smaller IFT-B sub-complexes leaving >50% of the IFT-B complex structurally uncharacterized. We have used recent advances in protein structure prediction as implemented in Alphafold to assemble a structural model for the 15-subunit IFT-B complex. The model was validated using crosslinking/MS data on reconstituted IFT-B complexes, X-ray scattering in solution and diffraction from crystals as well as site-directed mutagenesis and protein binding assays. The IFT-B structural model reveals an elongated and highly flexible complex consistent with cryo-electron tomographic reconstructions of IFT trains. The >400Å long IFT-B complex can roughly be divided into IFT-B1 and IFT-B2 parts with binding sites for ciliary cargo and the inactive IFT dynein motor, respectively. Interestingly, our structural modelling and crosslinking/MS results are consistent with two different binding sites for IFT81/74 on IFT88/70/52/46 suggesting the possibility of two different structural architectures for the IFT-B1 complex. Our data present a structural framework to understand IFT-B complex assembly, function, and ciliopathy variants.
Active thermal control of power electronic modules in smart transformer applications

The Smart Transformer (ST) is a possible solution to obtain intelligent nodes in the electrical grid, which can be used for the grid management and increase the capacity for the integration of renewable energy sources. A problem for the application of the ST in the distribution grid is the expected lower reliability in comparison with the traditional transformer. To address this problem, the knowledge of power system, power electronics and reliability is combined in this work. Following the "Physics of failure" approach, the most frequently failing components are identified, their load profile in the electrical distribution grid is analyzed and finally solutions are developed to improve the reliability. The power semiconductors are found to be the most prone to fail components and most of their failure mechanisms are found to be affected by thermal cycling. For this reason, thermal stress analysis is performed for the three-stage ST. As an opportunity to increase the reliability, active thermal control is introduced, which is a software based solution for the reduction of the thermal stress during operation. The existing approaches from literature are reviewed and categorized into control of the power converter losses and the control of the device loading. For increasing the reliability by control of the power converter losses, one algorithm is introduced and validated for hard switching power converters and one algorithm is introduced for soft switching power semiconductors. Controlling the thermal stress of modular building blocks in a modular power converter, referring to power routing, is proposed. The capability of the algorithm is investigated analytically for series connected and parallel connected modular building blocks. For the validation, the influence of the power routing on the loading of the single cell is demonstrated experimentally for series connected, parallel connected and medium frequency transformer coupled cells in modular power converters.
Evidence for a travel direction signal in humans that is independent of head direction

We often assume that travel direction is redundant with head direction, but from first principles these two factors provide differing spatial information. Although head direction has been found to be a fundamental component of human navigation, it is unclear how self-motion signals for travel direction contribute to forming a travel trajectory. Employing a novel motion adaptation paradigm from visual neuroscience designed to preclude a contribution of head direction, we found high-level aftereffects of perceived travel direction, indicating that travel direction is a fundamental component of human navigation. Interestingly, we discovered a higher frequency of reporting perceived travel toward the adapted direction compared to a no-adapt control – an aftereffect that runs contrary to low-level motion aftereffects. This travel aftereffect was maintained after controlling for possible response biases and approaching effects, and it scaled with adaptation duration. These findings demonstrate the first evidence of how a pure travel direction signal might be represented in humans, independent of head direction.
Seasonal polyphenism underlies the origin of a sterile caste in aphids

The origin of a sterile caste among eusocial animals has been a fundamental but still unresolved problem in understanding the evolution of biological complexity. At the origin of a sterile caste, recruitment of pre-existing plasticity may lead to produce physiologically, morphologically and behaviorally distinct caste phenotypes. Here, we provide convincing evidence that preexisting seasonal polyphenism has been recruited to generate a sterile soldier caste in host-alternating social aphids. We demonstrate that sterile soldier nymphs of Colophina aphids resemble those of monomorphic defensive nymphs produced in a different host-plant generation. Notably, the two morphs in the basal species show the closest similarity in morphology and gene expression among all morph pairs. Moreover, their evolutionary phenotypic changes along the phylogeny of four Colophina species are significantly correlated positively. These results suggest that they may share the common regulatory mechanisms of development, which underpin the heterochronic expression of monomorphic defenders on the different host plant leading to the evolution of a novel soldier phenotype. We further demonstrate that the monomorphic defenders can increase their inclusive fitness by killing predator’s eggs on a seasonally different host plant. Taken together, our findings suggest that preexisting plasticity that can gain indirect fitness benefits facilitates the early evolution of a sterile caste.
3-D structure based prediction of SUMOylation sites

SUMOylation is a posttranslational modification that involves lysine residues from eukaryotic proteins. Misregulation of the modification has been linked to neuro-degenrative diseases and cancer. All the presently available tools to predict SUMOylation sites are sequence based. Here, we propose a novel structure based prediction tool to discriminate between SUMOylated and non-SUMOylated lysines. We demonstrate the method by carrying out a proof-of-concept study. The method achieved an accuracy of 81% and a Matthews’ Correlation Coefficient of 0.4.
Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models

Introduction The KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRASG12C protein have been developed and demonstrate clinical response rates of 37-43%. Importantly, these agents fail to generate durable therapeutic responses with median progression-free survival of ~6.5 months. Methods To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines. The co-occurring NRASQ61L mutation in KRASG12C-positive LLC cells was deleted and the KRASG12V allele in CMT167 cells was edited to KRASG12C with CRISPR/Cas9 methods. Also, a novel murine KRASG12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model. Results The three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to modest shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with combinations of MRTX-1257 and the SHP2/PTPN11 inhibitor, RMC-4550. Moreover, treatment with a MRTX-849/RMC-4550 combination yielded transient tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice and durable shrinkage of mKRC.1 tumors. Notably, single-agent MRTX-849 activity in mKRC.1 tumors and the combination response in LLC-NRAS KO tumors was lost when the experiments were performed in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. Discussion These new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.
Physiological and functional heterogeneity in the mouse locus coeruleus

Neurons in the locus coeruleus (LC) have been traditionally viewed as a homogenous population. Recent studies are beginning to uncover heterogeneous molecular phenotypes and projection targets in this nucleus, but how such heterogeneity is ultimately manifested in neuronal physiology and function is largely unknown. We took an orthogonal approach to directly assess the physiological and functional heterogeneity in the LC. By identifying noradrenergic neurons using a genetic-based tagging approach, our study revealed a subset of neurons exhibiting a distinctive narrow spike waveform and lacking the prolonged after-hyperpolarization. We further provided evidence establishing a link between the proximity of LC neurons and their response latency, where putatively proximal neurons tended to have a long latency to optogenetic activation. Finally, we found that response latency of LC neurons was correlated with their burst firing and distinct relationship with pupil diameter. Together, our study presents novel evidence to reveal and link LC heterogeneity at the physiological level to that at the functional level.
Beyond the average: An updated framework for understanding the relationship between cell growth, DNA replication, and division in a bacterial system

Our current understanding of the bacterial cell cycle is framed largely by population-based experiments that focus on the behavior of idealized average cells. Most famously, the contributions of Cooper and Helmstetter help to contextualize the phenomenon of overlapping replication cycles observed in rapidly growing bacteria. Despite the undeniable value of these approaches, their necessary reliance on the behavior of idealized average cells washes out the stochasticity inherent in single cell growth and physiology limiting their mechanistic value. To bridge this gap, we propose an updated and agnostic framework, informed by extant single-cell data, that quantitatively accounts for stochastic variations in single-cell dynamics and the impact of medium composition on cell growth and cell cycle progression. In this framework, stochastic timers sensitive to medium composition impact the relationship between cell cycle events, accounting for observed differences in the relationship between cell cycle events in slow and fast growing cells. We conclude with a roadmap for potential application of this framework to longstanding open questions in the bacterial cell cycle field.
Sex, stress and UCP2: 1 mitochondria illuminate microglial identity beyond the dichotomy

14 Environmental cues influence microglial interaction with their neuronal landscape, often 15 causing changes in microglial functional identity. This process demands rapid energy 16 production, which is supported by an optimized mitochondrial network. Whether 17 mitochondrial adaptations define a microglial functional state is unknown due to limitations 18 in mitochondrial visualization and manipulation within their microenvironment. 19 Here, we investigate the mitochondrial network of individual microglia in physiological and 20 dysfunctional conditions during a naïve or injury-induced mouse retinal environment. After 21 optic nerve crush (ONC) injury, we identify mitochondrial and microglial phenotypic 22 remodeling that is distinct from the naïve environment. Remarkably, knockout of uncoupling 23 protein 2 (UCP2) causes transient, stress-induced mitochondrial hyperfusion only in males 24 after ONC, even though both sexes suffer from increased intrinsic stress levels. When we 25 compare key metabolic genes between sexes in physiological conditions, only males exhibit a 26 metabolic transition towards glycolysis in the injury-induced environment, which attenuates 27 in UCP2 knockout resulting in acutely accelerated retinal ganglion cell death. Our data shows 28 that the cell-extrinsic ONC environment and cell-intrinsic UCP2 KO manipulation triggers 29 several microglial states distinguishable by mitochondrial networks that are heavily 30 influenced by sex and injury-induced stress.
Neural processing of goal and non-goal-directed movements on the smartphone

The discrete behavioral events captured on the smartphone touchscreen may help unravel real-world neural processing. We find that neural signals (EEG) surrounding a touchscreen event show peculiarly contralateral motor preparation, visual processing, and the consolidation of information. We leveraged these events in conjunction with kinematic recordings of the thumb and an artificial neural network to separate highly similar movements according to whether they resulted in a smartphone touch (goal-directed) or not (non-goal-directed). Despite their kinematic similarity underscored by the model, the signatures of neural control of movement and the post-movement processing were substantially dampened for the non-goal-directed movements, and these movements uniquely evoked error-related signals. We speculate that these unnecessary movements are common in the real world and although inconsequential the brain still provides limited motor preparation and tracks the action outcome. Real-world behavior is composed of neural processes that are difficult to capture in conventional laboratory-based tasks.
The Drosophila AWP1 ortholog Doctor No regulates JAK/STAT signaling for left-right asymmetry in the gut by promoting receptor endocytosis

Many internal Drosophila organs show stereotypical left-right (LR) asymmetry, for which the underlying mechanisms remain elusive. Here, we identified an evolutionarily conserved ubiquitin-binding protein, AWP1/Doctor no (Drn), as a novel factor required for the LR asymmetry of the embryonic anterior gut in Drosophila. We showed that drn is essential in the circular visceral muscle cells of the midgut for JAK/STAT signaling, which contributes to the first known cue for anterior gut lateralization via LR-asymmetric nuclear rearrangement. Embryos homozygous for drn and lacking its maternal contribution showed phenotypes similar to that of depleted JAK/STAT signaling, suggesting that Drn is a general component of JAK/STAT signaling. The absence of Drn resulted in the specific accumulation of Domeless (Dome), the receptor of JAK/STAT signaling, in intracellular compartments. Thus, Drn is required for the endocytic trafficking of Dome, which is subsequently degraded in lysosomes. Our results suggest that the endocytosis of Dome is a critical step in activating JAK/STAT signaling. The roles of AWP1/Drn in activating JAK/STAT signaling and in LR-asymmetric development may be conserved in various organisms. Summary Statement Dr. No, a Drosophila ortholog of AWP1, activates JAK/STAT signaling via Dome receptor endocytosis in a crucial step for left-right asymmetry in the developing gut.
A Java middleware for High Performance Computing (HPC) and Internet of Things (IoT).

Middleware systems are everywhere and most likely will remain everywhere for a long time to help reduce the complexity of application development. There are real user-applications (UAs) that need the integration between Internet of Things (IoT) and High Performance Computing (HPC), however there is no middleware alternative that addresses issues of both IoT and HPC technologies at the same time. In terms of HPC, the presented middleware solutions did not address solutions for sensing, actuating and context awareness services. In terms of IoT, the presented middleware solutions did not address solutions to simplify general-purpose parallel/distributed processing and storage services. To reduce the gap between HPC and IoT technologies, we first present a review about IoT and HPC integration. After that, we describe an IoT/HPC middleware solution, called JavaCá&Lá (JCL), with an API capable of programming different device categories and supporting three programming models. JCL is an already existing middleware solution originally designed for HPC. In this work, we made many improvements to turn it a middleware that supports the development of IoT/HPC integrated applications. The main contributions of this work are: i) a literature review and comparative analysis of the main IoT and HPC middleware solutions; ii) the definition of a list of requirements based on the literature that an integrated IoT/HPC middleware solution should support; iii) a middleware that attends most of the requirements that an integrated solution should have, attenuating the existing gap in the middleware literature. The results demonstrated that JCL scales well, has a simple deployment, addresses most of the fundamental IoT/HPC requirements and it is very simple to develop portable and
Dynamic Regulation of Phosphoinositide 3-Kinase- (cid:1) Activity and (cid:2) -Adrenergic Receptor Trafficking in End-Stage Human Heart Failure Heart Failure

Background —Downregulation of (cid:1) -adrenergic receptors ( (cid:1) ARs) under conditions of heart failure requires receptor targeting of phosphoinositide 3-kinase (PI3K)– (cid:2) and redistribution of (cid:1) ARs into endosomal compartments. Because support with a left ventricular assist device (LVAD) results in significant improvement of cardiac function in humans, we investigated the effects of mechanical unloading on regulation of PI3K (cid:2) activity and intracellular distribution of (cid:1) ARs. Additionally, we tested whether displacement of PI3K (cid:2) from activated (cid:1) ARs would restore agonist responsiveness in failing human cardiomyocytes. Methods and Results —To test the role of PI3K on (cid:1) AR endocytosis in failing human hearts, we assayed for PI3K activity in human left ventricular samples before and after mechanical unloading (LVAD). Before LVAD, failing human hearts displayed a marked increase in (cid:1) AR kinase 1 ( (cid:1) ARK1)–associated PI3K activity that was attributed exclusively to enhanced activity of the PI3K (cid:2) isoform. Increased (cid:1) ARK1-coupled PI3K activity in the failing hearts was associated with downregulation of (cid:1) ARs from the plasma membrane and enhanced sequestration into early and late endosomes compared with unmatched nonfailing controls. Importantly, LVAD support reversed PI3K (cid:2) activation, normalized the levels of agonist-responsive (cid:1) ARs at the plasma membrane, and depleted the (cid:1) ARs from the endosomal compartments without changing the total number of receptors (sum of plasma membrane and early and late endosome receptors). To test whether the competitive displacement of PI3K from the (cid:1) AR complex restored receptor responsiveness, we overexpressed the phosphoinositide kinase domain of PI3K (which disrupts (cid:1) ARK1/PI3K interaction) in primary cultures of failing human cardiomyocytes. Adenoviral-mediated phosphoinositide kinase overexpression significantly increased basal contractility and rapidly reconstituted responsiveness to (cid:1) -agonist. Conclusions —These results suggest a novel paradigm in which human (cid:1) ARs undergo a process of intracellular sequestration that is dynamically reversed after LVAD support. Importantly, mechanical unloading leads to complete reversal in PI3K (cid:2) and (cid:1) ARK1-associated PI3K activation. Furthermore, displacement of active PI3K from (cid:1) ARK1 restores (cid:1) AR responsiveness in failing myocytes. ( Circulation . 2007;116:2571-2579.) previously 17 (cid:1) AR ligand [ 125 I]-cyanopindolol (250 pmol/L). assays were performed in triplicate, and receptor density (in femto- moles) was normalized to milligrams of membrane protein. Adenylyl cyclase assays as 17 20 (cid:3) g of the membrane fraction under basal conditions and after stimulation with isoproterenol (10 (cid:1) 4 cAMP quantified with a liquid scintillation counter Co/PerkinElmer,