Miracle-dz/UniFAR-FTUs huggingface dataset:
Yeast and Mammalian Epsins Use Different Determinants for Localization and Function: Role of Clathrin/AP2/Ubiquitin Binding Motifs and Poly-Glutamine Stretches

Epsins are endocytic adaptor proteins involved in the internalization of important membrane proteins such as EGFR and Notch ligands. Therefore, this protein family impacts critical signaling pathways and processes such as cell migration and cytokinesis and is ultimately required for embryo development in mammals and cell viability in yeast. Intriguingly, although Epsins are conserved and display similar binding determinants, the process of endocytosis in yeast and mammals exhibit some dramatic mechanistic differences. Therefore, we wondered if the function of Epsins in these organisms are similar and are similarly regulated or they also differ. Since proper and timely localization is needed for function, we determined what elements target Epsins to endocytic sites in yeast vs mammals. Specifically, using a systematic/combinatorial mutagenesis approach we produced a collection of yeast and human Epsin mutated variants that was tested for localization at endocytic sites and for function. Our results showed that the intrinsically disordered carboxy-terminus holds the major determinants (involved in binding of ubiquitin, AP2, clathrin and EH domain-containing proteins) for proper intracellular localization of different Epsin paralogs and homologs in yeast and mammals, while also having a major impact on function. Importantly, we established hierarchies of carboxy-terminal binding determinants for sustaining Epsin localization which turned to be different for human vs. yeast cells; favoring clathrin and AP2 binding in the former and recognition of cargo and EH domain-containing proteins for the latter. Further, we found evidence in both systems that yeast Epsins also use for localization regions of the protein that were until now of unknown functional relevance, i.e., glutamine-rich sequences. Interestingly, some molecular determinants within the Epsin molecule seem to have functional importance beyond its contribution to localization to endocytic sites. Based on these findings, we propose working models for Epsin function and recruitment to membranes/endocytic sites at different maturation stages.
Low photosynthetic rate under low light stress inhibited sucrose distribution and transportation to grain

Under the condition of low light, the yield of summer maize decreased significantly, but the decrease of yield under low light stress was not only caused by the lack of photosynthetic assimilates in leaves, but also the transportation and utilization of assimilates by stems and grains. In this study, we investigated the effects of low light stress on leaves, stems and grains of summer maize and the relationship between them. The results showed that the synthesis ability of sucrose and export sucrose to grains ability in leaves decreased under low light. Due to dry matter transfer, the number and area of small vascular bundles in spike node and shank decreased, which restricted the translocation of photoassimilates to grains at filling stage. The activities of SUS and AGPase was decreased in grains under low light stress, which limited the availability of sucrose. The process of leaf synthesis, sucrose loading and sucrose utilization in grains was affected under low light, resulting in relatively higher sucrose concentration in grains than in leaves, forming a “leaf low” - “grain high” sugar concentration gradient, resulting in the opposite hydrostatic pressure, and then feedback inhibition of sucrose output in leaves, reducing sucrose loading and transportation rate. Hightlight The key factor of low light stress reducing summer maize yield was the decrease of leaf photosynthetic rate, resulting in insufficient grain dry matter supply. The sugar concentration gradient between leaves and grains further restricted the sucrose transport from leaves to grains.
Energy dissipation in early detection of cellular responses to metabolic challenges

Metabolic alterations have been recognized to underly the etiology of many diseases. Herein, cellular energy dissipation was evaluated as a novel non-specific global biomarker of metabolic alterations. Energy dissipation, measured as heat by microcalorimetry, was maximal during Saccharomyces cerevisiae adaptation to growth conditions before fast proliferation took place. This response was further augmented by 95 % in media where nutrient assimilation was more difficult, and by 133 % under sub-optimal non-carbon nutrient levels. In this last case, the increase in energy dissipation (1) reflected changes in amino acid and glycolytic metabolism and (2) anticipated changes in the growth curve significantly later observed by traditional microbiological measurements. It was, therefore, an early marker of adaptive responses that compensated for sub-optimal nutrient levels and maintained phenotypic stability. Compensatory responses buffer systems against perturbations and delay the onset of diseases. Microcalorimetry can, therefore, provide a biomarker development platform for early disease-diagnosis. HIGHLIGHTS Energy dissipation measurements detect cell responses to metabolic challenges. The detection by microcalorimetry occurs considerably earlier than by traditional microbiological measurements. Sub-optimal non-carbon nutrient levels impact energy dissipation long before cell proliferation. Energy dissipation is highly sensitive to increased nutrient assimilation difficulty.
Decomposing Neural Circuit Function into Information Processing Primitives

It is challenging to measure how specific aspects of coordinated neural dynamics translate into operations of information processing and, ultimately, cognitive functions. An obstacle is that simple circuit mechanisms—such as self-sustained or propagating activity and nonlinear summation of inputs—do not directly give rise to high-level functions. Nevertheless, they already implement simple the information carried by neural activity. Here, we propose that distinct functions, such as stimulus representation, working memory, or selective attention, stem from different combinations and types of low-level manipulations of information or information processing primitives. To test this hypothesis, we combine approaches from information theory with simulations of multi-scale neural circuits involving interacting brain regions that emulate well-defined cognitive functions. Specifically, we track the information dynamics emergent from patterns of neural dynamics, using quantitative metrics to detect where and when information is actively buffered, transferred or nonlinearly merged, as possible modes of low-level processing (storage, transfer and modification). We find that neuronal subsets maintaining representations in working memory or performing attentional gain modulation are signaled by their boosted involvement in operations of information storage or modification, respectively. Thus, information dynamic metrics, beyond detecting which network units participate in cognitive processing, also promise to specify how and when they do it, that is, through which type of primitive computation, a capability that may be exploited for the analysis of experimental recordings.
Fiber Diameter and Architecture Direct Three-Dimensional Assembly of Pericytes into Spheroids

Due to their physiological relevance, multicellular 3D spheroids are actively replacing standard 2D monolayer cultures. How spheroids are formed through the assembly of individual cells in natural fibrous environments that include a mix of diameters and architectures in vivo remains unknown. Here, we demonstrate that the spontaneous assembly of human vasa vasorum-derived pericytes in 3D spheroids depends on the fiber diameter and network architecture. A parallel arrangement of suspended fibers of all tested diameters (200, 500, and 800 nm) leads to the formation of spheroids, while on crosshatch networks, spheroid assembly on larger diameters is absent. The design of fibrous networks of a mix of diameters and architectures leads to the patterning of spheroids in desired locations. Fiber remodeling in parallel arrangements serves as force sensors providing mechanical insights into the assembly dynamics of spheroids and subsequent cell sprouting from spheroids. Translocation and merger of spheroids occur predominantly on parallel fiber networks, while on crosshatch networks, a cellular exchange is observed between spheroids connected with remodeled fibers. Rho kinase inhibition by Y27632 and subsequent wash-off leads to spheroid disintegration and reassembly, thus, highlighting the role of cell contractility in the assembly and integrity of 3D spheroids. Overall, using extracellular mimicking fiber networks of varying diameters and architectures, we report new insights into the 3D dynamics of spheroids which may inform pericyte’s role in vasculogenesis, and (patho)physiological angiogenesis
Production of brain-derived neurotrophic factor gates plasticity in developing visual cortex

We have previously shown that recovery of visual responses to a deprived eye during the critical period in mouse primary visual cortex (V1) requires both export of mRNA encoding brain derived neurotrophic factor (BDNF) to the dendrites of cortical cells (Kaneko et al., 2012) and phosphorylation of the TrkB receptor for BDNF (Kaneko et al., 2008a). TrkB phosphorylation is not required for the loss of response during monocular deprivation (MD). Studies in vitro show that formation of new connections requires BDNF (Meyer-Franke et al., 1995, 1998; Gottmann et al., 2009). We have now studied the temporal relationship between the production of mature BDNF and the recovery of visual responses. Visual cortical responses to an eye whose vision has been occluded for several days during the critical period and is then re-opened recovers rapidly during binocular vision or more slowly following reverse occlusion, when the previously intact fellow eye is occluded in a model of “patch therapy” for amblyopia. The time to recovery of visual responses differed by 18 hours between these two procedures, but in each the production of mature BDNF preceded the recovery by 6 hours. These findings suggest that a spurt of BDNF secretion stimulates the growth of connections serving the deprived eye to restore visual responses. Significance Statement By demonstrating that BDNF production precedes rather than merely accompanies the increase in cortical responses, we provide further evidence that BDNF production plays a causal role, thereby gating the plasticity that underlies the recovery of visual cortex from monocular deprivation.
Peningkatan Profesionalisme Guru Melalui Pengawas Madrasah

The aims ofthis studyare; 1) to describe process of planning to increase the professionalism of teachersled by the madrasah supervisors, 2) implementation, and3) Evaluation of improving the professionalism teachers supervised by madrasah supervisors. The results of this study showed that; 1) the planning process started by the coordinating and meeting team work of supervisor, the determination of the object and the review of the instruments of supervision, 2) the improving of teachers proffessionalism implemented with visiting to the madrasah, lesson planning supervision, learning administration, assessment and supervision for guidance and counseling, workshop and technical guidance, 3) professionalism of teachers evaluated with supervision instruments and Performance Evaluation of Teachers (PKG) instruments.
Perceptual stability reflected in neuronal pattern similarities in human visual cortex

The magnitude of neuronal activation is commonly considered a critical factor for conscious perception of visual content. However, this dogma contrasts with the phenomenon of rapid adaptation, in which the magnitude of neuronal activation drops dramatically in a rapid manner, while the visual stimulus and the conscious experience it elicits remain stable. Here we report that the profiles of multi-site activation patterns and their relational geometry –i.e. the similarity distances between activation patterns, as revealed using iEEG recordings, are sustained during extended stimulation despite the major magnitude decrease. These results are compatible with the hypothesis that conscious perceptual content is associated with the neuronal pattern profiles and their similarity distances, rather than by the overall activation magnitude, in human visual cortex.
CRHR1-mediated Akt activation involves endocytosis and soluble adenylyl cyclase activity

Corticotropin-releasing hormone receptor 1 (CRHR1) signaling initiates at the cell membrane and continues after receptor internalization. A sustained cAMP generation after ligand-activated CRHR1 endocytosis supported by the soluble adenylyl cyclase (sAC) is required for the G protein-independent phase of ERK1/2 phosphorylation in neuronal cells. Here, we report that Akt is activated by CRHR1 stimulation in a mechanism dependent on the endosomal cAMP production by sAC activity. Moreover, AktS473 phosphorylation profile was distinct to that of phospho-ERK1/2 revealing a crosstalk between these pathways. We found that the CRHR1 activation of PI3K/Akt pathway is required for a full ERK1/2 activation but negatively regulates the cAMP response and CREB phosphorylation downstream CRHR1 stimulation. Immunofluorescence colocalization analysis revealed that activated CRHR1 transits to early (Rab5) and recycling (Rab11) endosomes. Additionally, CRHR1 colocalized with two Rab5 effectors, APPL1 and EEA1. shRNA mediated knockdown uncovered a role of these proteins in CRHR1 signaling. APPL1 silencing led to a decrease in pAktS473 levels without affecting ERK1/2 activation, whereas EEA1 depletion had the opposite effect, suggesting that CRHR1 intracellular signaling diversity may be achieved through different signaling platforms.
A novel beta-adrenergic like octopamine receptor modulates the audition of malaria mosquitoes and serves as insecticide target

Hearing is an essential sense in the life cycle of malaria mosquitoes. Within large swarms formed transiently at dusk, mosquitoes acoustically recognize their mating partners by their wingbeats. Indeed, malaria mosquitoes only respond to the flight tones of mating partners during swarm time. This phenomenon implies a sophisticated context- and time-dependent modulation of mosquito audition, the mechanisms of which are still largely unknown. Using transcriptomics, we identify a complex network of candidate neuromodulators regulating mosquito hearing. Among them, octopamine stands out as regulator of the auditory performance during swarm time. To explore octopamine’s roles in mosquito hearing, we carried out an in-depth analysis of octopamine-mediated effects on auditory function. We found that octopamine affects the properties of the mosquito ear on multiple levels: it modulates the tuning and stiffness of the flagellar sound receiver and it controls the erection of antennal fibrillae in males. We found that two different receptors are driving octopamine’s auditory roles, including a novel beta octopamine receptor. We also demonstrate that the octopaminergic auditory control system can be targeted by insecticides. Our findings identify octopamine signalling as a key component of hearing and mating partner detection in malaria mosquitoes, and as a potential novel target for mosquito control.
Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis

Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNF-TNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its anti-depressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases.
CAMSAP-driven microtubule release from γ-TuRC and its regulation by nucleation-promoting factors

γ-tubulin ring complex (γ-TuRC) is the major microtubule-nucleating factor. After nucleation, microtubules can be released from γ-TuRC and stabilized by other proteins, such as CAMSAPs, but the biochemical cross-talk between minus-end regulation pathways is poorly understood. Here, we reconstituted this process in vitro using purified components. We found that all CAMSAP proteins could bind to the minus-ends of γ-TuRC-attached microtubules. CAMSAP2 and CAMSAP3, which decorate and stabilize growing minus ends, but not the minus-end tracking protein CAMSAP1 induced microtubule release from γ-TuRC. CDK5RAP2, a γ-TuRC-interactor, and CLASP2, a regulator of microtubule growth, stimulated γ-TuRC-dependent microtubule nucleation, but only CDK5RAP2 inhibited CAMSAP-driven microtubule detachment by suppressing CAMSAP binding to γ-TuRC-anchored minus ends. CDK5RAP2 also improved γ-TuRC selectivity for 13-rather than 14-protofilament microtubules in microtubule-capping assays. Our results support a model whereby CAMSAPs exploit an imperfect attachment between γ-TuRC and the nucleated microtubule to promote minus-end elongation and release, whereas CDK5RAP2 improves the fit between γ-TuRC and 13-protofilament microtubules and enhances nucleation.
Comparative genomics of tarakihi (Nemadactylus macropterus) and five New Zealand fish species: assembly contiguity affects the identification of genic features but not transposable elements

Comparative analysis of whole-genome sequences can provide valuable insights into the evolutionary patterns of diversification and adaptation of species, including the genome contents and the regions under selection. However, such studies are lacking for fishes in New Zealand. To supplement the recently sequenced genome of tarakihi (Nemadactylus macropterus), the genomes of five additional percomorph species native to New Zealand (king tarakihi (Nemadactylus n.sp.), blue moki (Latridopsis ciliaris), butterfish (Odax pullus), barracouta (Thyrsites atun), and kahawai (Arripis trutta)) were determined and assembled using Illumina sequencing. While the proportion of repeat elements was highly correlated with the genome size (R2 = 0.97, P < 0.01), most of the metrics for the genic features (e.g. number of exons or intron length) were significantly correlated with assembly contiguity (| R2| = 0.79–0.97). A phylogenomic tree including eight additional high-quality fish genomes was reconstructed from sequences of shared gene families. The radiation of Percomorpha was estimated to have occurred c. 112 mya (mid-Cretaceous), while the Latridae have diverged from true Perciformes c. 83 mya (late Cretaceous). Evidence of positive selection was found in 65 genes in tarakihi and 209 genes in Latridae: the largest portion of these are involved in the ATP binding pathway and the integral structure of membranes. These results and the de novo genome sequences can be used to (1) inform future studies on both the strength and shortcomings of scaffold-level assemblies for comparative genomics and (2) provide insights into the evolutionary patterns and processes of genome evolution in bony fishes.
Sensory Target Detection at Local and Global Timescales Reveals a Hierarchy of Supramodal Dynamics in the Human Cortex

To ensure survival in a dynamic environment, the human neocortex monitors input streams from different sensory organs for important sensory events. Which principles govern whether different senses share common or modality-specific brain networks for sensory target detection? We examined whether complex targets evoke sustained supramodal activity while simple targets rely on modality-specific networks with short-lived supramodal contributions. In a series of hierarchical multisensory target detection studies (n = 77, of either sex) using EEG, we applied a temporal cross-decoding approach to dissociate supramodal and modality-specific cortical dynamics elicited by rule-based global and feature-based local sensory deviations within and between the visual, somatosensory, and auditory modality. Our data show that each sense implements a cortical hierarchy orchestrating supramodal target detection responses, which operate at local and global timescales in successive processing stages. Across different sensory modalities, simple feature-based sensory deviations presented in temporal vicinity to a monotonous input stream triggered a mismatch negativity-like local signal which decayed quickly and early, whereas complex rule-based targets tracked across time evoked a P3b-like global neural response which generalized across a late time window. Converging results from temporal cross-modality decoding analyses across different datasets, we reveal that global neural responses are sustained in a supramodal higher-order network, whereas local neural responses canonically thought to rely on modality-specific regions evolve into short-lived supramodal activity. Together, our findings demonstrate that cortical organization largely follows a gradient in which short-lived modality-specific as well as supramodal processes dominate local responses, whereas higher-order processes encode temporally extended abstract supramodal information fed forward from modality-specific cortices. SIGNIFICANCE STATEMENT Each sense supports a cortical hierarchy of processes tracking deviant sensory events at multiple timescales. Conflicting evidence produced a lively debate around which of these processes are supramodal. Here, we manipulated the temporal complexity of auditory, tactile, and visual targets to determine whether cortical local and global ERP responses to sensory targets share cortical dynamics between the senses. Using temporal cross-decoding, we found that temporally complex targets elicit a supramodal sustained response. Conversely, local responses to temporally confined targets typically considered modality-specific rely on early short-lived supramodal activation. Our finding provides evidence for a supramodal gradient supporting sensory target detection in the cortex, with implications for multiple fields in which these responses are studied (e.g., predictive coding, consciousness, and attention).