Miracle-dz/UniFAR-FTUs huggingface dataset:
Deciphering the conformations and dynamics of FG-nucleoporins in situ

The ∼120 MDa nuclear pore complex (NPC) acts as a gatekeeper for the molecular traffic between the nucleus and the cytosol. Small cargo readily passes through the transport channel, yet large cargo requires specialized nuclear transport receptors. While the scaffold structure that anchors the NPC in the double-layered nuclear envelope has been resolved to remarkable details, the spatial organization of intrinsically disordered nucleoporins (NUPs) within the central channel remains enigmatic. These so-called FG-NUPs account for about one-third of the total mass of the NPC and form the actual transport barrier. Here we combined site-specific fluorescent labeling in non-fixed cells and fluorescent lifetime imaging microscopy (FLIM) to directly decipher the conformations of an essential constituent of the permeability barrier, NUP98, inside the functioning NPCs using Fluorescence resonance energy transfer (FRET). With detailed measurements of the distance distribution of eighteen NUP98 segments combined with coarse-grained modeling, we mapped the uncharted biochemical environment inside the nanosized transport channel. We found that ‘good-solvent’ conditions for a polymer dominate the inside of the nanosized NPC, expand the FG-domain in situ and facilitate nuclear transport, in sharp contrast to the collapsed NUP98 FG-chain in aqueous solution. The combination of fluorescence microscopy, high-resolution electron tomography, and molecular simulation opens a window into the so-far unresolved organization of the FG-NUPs at the center of NPC function, allowing us to reconcile scientific models of nuclear transport.
IL11 Stimulates IL33 Expression and Proinflammatory Fibroblast Activation across Tissues

Interleukin 11 (IL11) is upregulated in inflammatory conditions where it is believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 may promote inflammation, via the stroma. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in transient STAT3 phosphorylation and bi-modal ERK activation. RNA sequencing over a time course of IL11 stimulation revealed a robust short-lived transcriptional response, which was enriched for gene set hallmarks of inflammation and characterized by upregulation of SERPINB2, TNFRSF18, IL33, CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, P=9.8×10−5) and IL1RL1, its cognate receptor, was similarly increased (18-fold, P=1.1×10−34). In proteomic studies, IL11 triggered a proinflammatory secretome with notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes and lymphocytes. IL11 induced IL33 expression across fibroblast types and inhibition of STAT3, but not MEK/ERK, prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts.
An RNA binding protein, RNP1A, works with Contractility Kit proteins to facilitate macropinocytosis

Cell shape regulation is important for many biological processes. Some cell shape regulating proteins harbor mechanoresponsive properties that enable them to sense and respond to mechanical cues, allowing for cell adaptation. In Dictyostelium discoideum, mechanoresponsive network proteins include Cortexillin I and IQGAP1, which assemble in the cytoplasm into macromolecular complexes, which we term Contractility Kits. In vivo fluorescence cross-correlation spectroscopy revealed that Cortexillin I also interacts with an RNA-binding protein, RNP1A. The rnp1A knockdown cells have reduced cell growth rate, reduced adhesion, defective cytokinesis, and a gene expression profile that indicates rnp1A knockdown cells shift away from the vegetative growth state. RNP1A binds to transcripts encoding proteins involved in macropinocytosis. One of these, DlpA, facilitates macropinosome maturation, similar to RNP1A. Loss of different CK proteins leads to macropinocytotic defects characterized by reduced macropinocytotic crown size. RNP1A interacts with IQGAP1 in vivo and has cross-talk with IQGAP1 during macropinocytosis. Overall, RNP1A contributes to macropinocytosis, in part through interacting with transcripts encoding macropinocytotic proteins like dlpA, and does so in coordination with the Contractility Kit proteins.
Disentangling Hierarchical and Sequential Computations during Sentence Processing

Sentences in natural language have a hierarchical structure, that can be described in terms of nested trees. To compose sentence meaning, the human brain needs to link successive words into complex syntactic structures. However, such hierarchical-structure processing could co-exist with a simpler, shallower, and perhaps evolutionarily older mechanism for local, word-by-word sequential processing. Indeed, classic work from psycholinguistics suggests the existence of such non-hierarchical processing, which can interfere with hierarchical processing and lead to sentence-processing errors in humans. However, such interference can arise from two, non mutually exclusive, reasons: interference between words in working memory, or interference between local versus long-distance word-prediction signals. Teasing apart these two possibilities is difficult based on behavioral data alone. Here, we conducted a magnetoen-cephalography experiment to study hierarchical vs. sequential computations during sentence processing in the human brain. We studied whether the two processes have distinct neural signatures and whether sequential interference observed behaviorally is due to memory-based interference or to competing word-prediction signals. Our results show (1) a large dominance of hierarchical processing in the human brain compared to sequential processing, and (2) neural evidence for interference between words in memory, but no evidence for competing prediction signals. Our study shows that once words enter the language system, computations are dominated by structure-based processing and largely robust to sequential effects; and that even when behavioral interference occurs, it need not indicate the existence of a shallow, local language prediction system.
The cut site specificity of the influenza A virus endoribonuclease PA-X allows it to discriminate between host and viral mRNAs

Widespread shutoff of host gene expression through RNA degradation is an advantageous way for many viruses to block antiviral responses. However, viruses still need to maintain expression of their own genes and host genes necessary for replication. The influenza A virus host shutoff endoribonuclease PA-X solves this problem by sparing viral mRNAs and some host RNAs. To understand how PA-X distinguishes between RNAs, we characterized PA-X cut sites transcriptome-wide. This analysis shows that PA-Xs from multiple influenza strains cleave RNAs at GCUG tetramers in hairpin loops. Importantly, GCUG tetramers are enriched in the human but not the influenza transcriptome. Moreover, optimal PA-X cut sites inserted in the influenza A virus genome are quickly selected against during viral replication. This finding suggests that PA-X evolved these cleavage characteristics to target host but not viral mRNAs, in a manner reminiscent of cellular self vs. non-self discrimination.
Histogenesis of Conical and Lenticular Papillae in Buffalo Fetus

In literature histomorphological studies on conical and lenticular papillae have reported in mouse no report be traced out in literature on histogenesis of conical and lenticular papillae in buffalo fetus. So the present study was planned. The present study was conducted on tongue of 36 buffalo foeti collected from abattoir and Veterinary Clinics, Ludhiana. Length of the foetii was measured as a curved line along the vertebral column between the most anterior parts of frontal bone to the rump at ischiatic tuberosity and designated as curved crown rump length (CVR length) and the age was estimated as per formula given by Soliman (1975) in buffalo. Depending upon the CVR length the foetii were grouped into Group I (0- up to 20 cm CVRL), group II (From 20 cm up to 40 cm CVRL) and group III (40 cm CVRL onwards). The tissue samples were collected from torus linguae and fixed in neutral buffered formalin and Bouin’s fixatives. The tissues were processed for paraffin blocks preparation by acetone benzene schedule (Luna, 1968) and sections of 5 - 6 ìm were cut with the help of rotary microtome. The sections were stained with hematoxylin and eosin, Masson’s The study was conducted on tongue of 18 buffalo foetii which were divided into three groups after measuring their CVRL viz; Group I-III and their approximate age was calculated. The primitive conical and lenticular papillae were observed in group I at 18.0 cm CVR length on torus linguae. The conical papillae were covered by highly keratinized epithelium. The papillae were better differentiated at 29.0 cm CVRL. In group III at 80.0 cm CVR length, papillae were fully differentiated. Two type of papillae were observed. straight conical and curved conical. The straight conical papillae did not have secondary papillae but the curved one had secondary papillae. In group II at 21.4 cm CVR length, the lenticular papillae were having a broad shape and a connective tissue core The core of the papillae contained mesenchymal cells differentiating into fibroblast, fine collagen fibers and reticular fibers along with large number of blood vessels. The papillae were fully differentiated at 80.0 cm CVR length in group III.
Multinational Firms and Export Dynamics ∗ (Very Preliminary and Incomplete)

This paper provides new evidence on the dynamics of multinational ﬁrms and exporters based on ﬁrm-level panel data for Norway, France, and Germany. First, exit rates for new exporters almost triple the ones for new afﬁliates of multinational ﬁrms, while multinational ﬁrms with previous export experience show the lowest exit rates. Second, new afﬁliates of multinational ﬁrms have ﬂatter sales growth proﬁles than exporters. Finally, ﬁrms that transition from exporting to FDI are larger than continuing multinational ﬁrms. We show that a simple dynamic extension of a model in which ﬁrms choose to serve a foreign market through exports or afﬁliate sales facing a "proximity-concentration tradeoff", as in Helpman, Melitz, and Yeaple (2004), captures these patterns qualitatively. We show that quantitatively the model goes a long way in explaining the dynamic patterns observed in the data.
OP-CBIO200199 3795..3802

Motivation: Improved DNA technology has made it practical to estimate single-nucleotide polymorphism (SNP)-heritability among distantly related individuals with unknown relationships. For growthand development-related traits, it is meaningful to base SNP-heritability estimation on longitudinal data due to the time-dependency of the process. However, only few statistical methods have been developed so far for estimating dynamic SNP-heritability and quantifying its full uncertainty. Results: We introduce a completely tuning-free Bayesian Gaussian process (GP)-based approach for estimating dynamic variance components and heritability as their function. For parameter estimation, we use a modern Markov Chain Monte Carlo method which allows full uncertainty quantification. Several datasets are analysed and our results clearly illustrate that the 95% credible intervals of the proposed joint estimation method (which ‘borrows strength’ from adjacent time points) are significantly narrower than of a two-stage baseline method that first estimates the variance components at each time point independently and then performs smoothing. We compare the method with a random regression model using MTG2 and BLUPF90 software and quantitative measures indicate superior performance of our method. Results are presented for simulated and real data with up to 1000 time points. Finally, we demonstrate scalability of the proposed method for simulated data with tens of thousands of individuals. Availability and implementation: The Cþþ implementation dynBGP and simulated data are available in GitHub: https://github.com/aarjas/dynBGP. The programmes can be run in R. Real datasets are available in QTL archive: https://phenome.jax. org/centers/QTLA. Contact: mikko.sillanpaa@oulu.fi Supplementary information: Supplementary data are available at Bioinformatics online.
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Vivo Regulation During Negative Selection In Characterization of Transcriptional

Negative selection is the process whereby immature thymocytes expressing TCRs with high afﬁnity for self-peptide:MHC complexes are induced to undergo apoptosis. The transcriptional events that occur as a result of TCR signaling during negative selection are not well-characterized. Using oligonucleotide arrays, we have identiﬁed 33 genes that exhibit changes in RNA levels in CD4 (cid:1) CD8 (cid:1) thymocytes during negative selection in vivo. Of 18 genes that have been further characterized, 13 are regulated in response to stimulation with Ag or anti-CD3 and anti-CD28 Abs ex vivo, indicating that these genes are regulated independently of activation of the peripheral immune system. These data also support the idea that anti-CD3/CD28-mediated thymocyte apoptosis is a valid model for negative selection in vivo. A detailed examination of the regulation of many of the identiﬁed genes in response to treatment with dexamethasone or gamma-radiation or in response to anti-CD3/anti-CD28 stimulation in the presence of pharmacological inhibitors of mitogen-activated protein kinase kinase kinase 1, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase, calcineurin, and cyclin-dependent kinase 2 has facilitated the elucidation of a map of the transcriptional events that occur downstream of the TCR. These studies support a model whereby similar signal transduction pathways are activated by stimuli that induce positive and negative selection and are consistent with the idea that the balance between opposing proapoptotic and antiapoptotic pathways determines cell fate. The data presented in this study also suggest that calcineurin functions to amplify TCR signals by promoting sustained increases in the levels of speciﬁc transcripts. The Journal of Immunology, 2003, 171: 802–811.
Antibacterial and Antioxidant Studies of Green Synthesized Silver Nanoparticles using Azadirachta indica (Neem) Leaf Extract

Silver nanoparticles (AgNPs) have been synthesized by green synthesis using Azadirachta indica leaf extract as both reducing and stabilizing agent. Synthesis of colloidal AgNPs was monitored by UV- visible spectroscopy. The UV- visible spectrum showed a peak at 455 nm corresponding to the plasmon absorbance of the silver nanoparticles. Crystallite structure of silver nanoparticles was studied using X-ray diffraction (XRD) analysis which revealed the face-centered cubic structure (FCC) with average particle size of 8.9 nm, calculated using Debye-Scherrer’s equation. Transmission electron microscopy (TEM) image revealed the agglomeration of small grain with particle size ranging from 2 to 14 nm. FCC crystalline nature was also evident from selected area electron diffraction (SAED) analysis. High purity of as-synthesized AgNPs was analyzed using energy dispersive X-ray (EDX) spectroscopy. Band gap energy was calculated to be 2.7 eV from UV- Visible spectra. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was stabilized by AgNPs which reveals its antioxidant efficacy. Well diffusion method showed 7 mm to 12 mm zone of inhibition (ZOI) against Gram-positive and Gram-negative bacteria, respectively confirming the antibacterial potential of AgNPs. Int. J. Appl. Sci. Biotechnol. Vol 9(3): 220-226.
TRANSAPICAL AND TRANSFEMORAL AORTIC VALVE IMPLANTATION: OPERATIVE OUTCOME IN 180 CONSECUTIVE PATIENTS

Objectives The new Transcatheter Aortic Valve Replacement (TAVR) represents a valid alternative to the standard surgical approach for the treatement of aortic stenosis in patients with prohibitive surgical risk, and at the moment, the two main access routes employed are transapical and transfemoral TAVR. Aim of the study is to compare the outcome of 180 consecutive patients who underwent transapical and transfemoral aortic valve procedures. From 2008 to 2014, 180 consecutive patients underwent transapical (90 patients) or transfemoral (90 patients) TAVR procedures at our institute. Preoperative, intraoperative and postoperative variables were retrospectively collected and analysed to identify risk factors for mortality, vascular and neurological complications. Surgical outcomes were compared. Hospital mortality was similar (TA: 9%, TF: 10%, p=0.799) and early extubation seems to be a protective factor against hospital mortality (p=0.001). Access related vascular complications occurred more often in TF (TA: 3%, TF: 11%, p=0.081) whereas major or life threatening bleeding (TA: 3%, TF: 4%, p=1) and major stroke (TA: 2%, TF: 3%, p=1) were equally distributed. Postoperative acute renal failure and the need for a postoperative dialysis was associated with impaired neurological outcome (respectively p=0.035 and p=0.020). Paravalvular leaks (degree 2-4) were more prevalent in TF patients (TA: 6%, TF: 26%, p<0.001). include different risk profiles (the TA being at higher risk) and a The transfemoral approach carries a higher risk of vascular complications and paravalulvar leaks (degree 2 or greater).
Cloud of Assets and Threats: A Playful Method to Raise Awareness for Cloud Security in Industry

Cloud computing has become a convenient technology widely used in industry, providing profit and flexibility to companies. Many enterprises embrace cloud service by migrating their products and solutions from on-premise to cloud environments. Cloud assets and applications are vulnerable to security challenges if not adequately protected. Regulations, standards and guidelines aim to enforce cloud security controls in the industry and practitioners need training to raise awareness of cloud security issues and learn about the defense mechanisms and controls. We propose a serious game Cloud of Assets and Threats (CAT) for enhancing cloud security awareness of industrial practitioners. This study extends first results of applying such a serious game in industry [25] and refines its design in two iterations. In the first design iteration, we implemented a digital game platform with six attack scenarios and developed a new player versus environment gaming mode. In the second design iteration, we adjusted the attack scenarios and introduced different difficulty levels for the scenarios. We present, analyse, and discuss the game events. We conclude that CAT is a promising method to raise awareness for cloud security in the industry
On the Range Avoidance Problem for Circuits

We consider the range avoidance problem (called Avoid): given the description of a circuit with more output gates than input gates, find a string that is not in the range of the circuit. This problem is complete for the class APEPP that corresponds to explicit constructions of objects whose existence follows from the probabilistic method (Korten, FOCS 2021). Motivated by applications in explicit constructions and complexity theory, we initiate the study of the range avoidance problem for weak circuit classes, and obtain the following results: 1)Generalising Williams’s connections between circuitanalysis algorithms and circuit lower bounds (J. ACM 2014), we present a framework for solving $\mathscr{C}$-Avoid in FPNP using circuit-analysis data structures for $\mathscr{C}$, for “typical” multi-output circuit classes $\mathscr{C}$. As an application, we present a non-trivial FPNP range avoidance algorithm for De Morgan formulas. /inlp>An important technical ingredient is a construction of rectangular PCPs of proximity, building on the rectangular PCPs by Bhangale, Harsha, Paradise, and Tal (FOCS 2020). 2)Using the above framework, we show that circuit lower bounds for ENP are equivalent to circuit-analysis algorithms with ENP preprocessing. This is the first equivalence result regarding circuit lower bounds for ENP. Our equivalences have the additional advantages that they work in both infinitely-often and almost-everywhere settings, and that they also hold for larger (e.g., subexponential) size bounds.3)Complementing the above results, we show that in some settings, solving $\mathscr{C}$-Avoid would imply breakthrough lower bounds, even for very weak circuit classes $\mathscr{C}$. In particular, an algorithm for AC0-Avoid with polynomial stretch implies lower bounds against NC1, and an algorithm for $NC_{4}^{0}$-Avoid with very small stretch implies lower bounds against NC1 and branching programs.4)We show that Avoid is in FNP if and only if there is a propositional proof system that breaks every non-uniform proof complexity generator. This result connects the study of range avoidance with fundamental questions in proof complexity.