An Additively Optimal Interpreter for Approximating Kolmogorov Prefix Complexity.

We study practical approximations of Kolmogorov prefix complexity (K) using IMP2, a high-level programming language. Our focus is on investigating the optimality of the interpreter for this language as the reference machine for the Coding Theorem Method (CTM). This method is designed to address applications of algorithmic complexity that differ from the popular traditional lossless compression approach based on the principles of algorithmic probability. The chosen model of computation is proven to be suitable for this task, and a comparison to other models and methods is conducted. Our findings show that CTM approximations using our model do not always correlate with the results from lower-level models of computation. This suggests that some models may require a larger program space to converge to Levin's universal distribution. Furthermore, we compare the CTM with an upper bound on Kolmogorov complexity and find a strong correlation, supporting the CTM's validity as an approximation method with finer-grade resolution of K.

Modes of action of lysophospholipids as endogenous activators of the TRPV4 ion channel.

The Transient Receptor Potential Vanilloid 4 (TRPV4) channel has been shown to function in many physiological and pathophysiological processes. Despite abundant information on its importance in physiology, very few endogenous agonists for this channel have been described, and very few underlying mechanisms for its activation have been clarified. TRPV4 is expressed by several types of cells, such as vascular endothelial, and skin and lung epithelial cells, where it plays pivotal roles in their function. In the present study, we show that TRPV4 is activated by lysophosphatidic acid (LPA) in both endogenous and heterologous expression systems, pinpointing this molecule as one of the few known endogenous agonists for TRPV4. Importantly, LPA is a bioactive glycerophospholipid, relevant in several physiological conditions, including inflammation and vascular function, where TRPV4 has also been found to be essential. Here we also provide mechanistic details of the activation of TRPV4 by LPA and another glycerophospholipid, lysophosphatidylcholine (LPC), and show that LPA directly interacts with both the N- and C-terminal regions of TRPV4 to activate this channel. Moreover, we show that LPC activates TRPV4 by producing an open state with a different single-channel conductance to that observed with LPA. Our data suggest that the activation of TRPV4 can be finely tuned in response to different endogenous lipids, highlighting this phenomenon as a regulator of cell and organismal physiology. KEY POINTS: The Transient Receptor Potential Vaniloid (TRPV) 4 ion channel is a widely distributed protein with important roles in normal and disease physiology for which few endogenous ligands are known. TRPV4 is activated by a bioactive lipid, lysophosphatidic acid (LPA) 18:1, in a dose-dependent manner, in both a primary and a heterologous expression system. Activation of TRPV4 by LPA18:1 requires residues in the N- and C-termini of the ion channel. Single-channel recordings show that TRPV4 is activated with a decreased current amplitude (conductance) in the presence of lysophosphatidylcholine (LPC) 18:1, while LPA18:1 and GSK101 activate the channel with a larger single-channel amplitude. Distinct single-channel amplitudes produced by LPA18:1 and LPC18:1 could differentially modulate the responses of the cells expressing TRPV4 under different physiological conditions.

Clinical Presentation and Outcomes of Kawasaki Disease in Children from Latin America: A Multicenter Observational Study from the REKAMLATINA Network.

OBJECTIVES: To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery aneurysm (CAA). STUDY DESIGN: An observational KD registry-based study was conducted in 64 participating pediatric centers across 19 Latin American countries retrospectively between January 1, 2009, and December 31, 2013, and prospectively from June 1, 2014, to May 31, 2017. Demographic and initial clinical and laboratory data were collected. Logistic regression incorporating clinical factors and maximum coronary artery z-score at initial presentation (between 10 days before and 5 days after intravenous immunoglobulin [IVIG]) was used to develop a prognostic model for CAA during follow-up (>5 days after IVIG). RESULTS: Of 1853 patients with KD, delayed admission (>10 days after fever onset) occurred in 16%, 25% had incomplete KD, and 11% were resistant to IVIG. Among 671 subjects with reported coronary artery z-score during follow-up (median: 79 days; IQR: 36, 186), 21% had CAA, including 4% with giant aneurysms. A simple prognostic model utilizing only a maximum coronary artery z-score ≥2.5 at initial presentation was optimal to predict CAA during follow-up (area under the curve: 0.84; 95% CI: 0.80, 0.88). CONCLUSION: From our Latin American population, coronary artery z-score ≥2.5 at initial presentation was the most important prognostic factor preceding CAA during follow-up. These results highlight the importance of early echocardiography during the initial presentation of KD.

Publisher Correction: Stability, affinity, and chromatic variants of the glutamate sensor iGluSnFR.

In the version of this paper originally published, important figure labels in Fig. 3d were not visible. An image layer present in the authors' original figure that included two small dashed outlines and text labels indicating ROI 1 and ROI 2, as well as a scale bar and the name of the cell label, was erroneously altered during image processing. The figure has been corrected in the HTML and PDF versions of the paper.

Author Correction: Stability, affinity, and chromatic variants of the glutamate sensor iGluSnFR.

The version of this paper originally published cited a preprint version of ref. 12 instead of the published version (Proc. Natl. Acad. Sci. USA 115, 5594-5599; 2018), which was available before this Nature Methods paper went to press. The reference information has been updated in the PDF and HTML versions of the article.

The yeast two-component SLN1 branch of the HOG pathway and the scaffolding activity of Pbs2 modulate the response to endoplasmic reticulum stress induced by tunicamycin.

In addition to the UPR pathway, yeast cells require components of the HOG pathway to respond to ER stress. In this work, we found that unphosphorylated Sln1 and Ssk1 are required to mount an appropriate response to Tn. We also found that the MAPKKKs Ssk2 participates in the Tn response, but its osmo-redundant protein Ssk22 does not. We also found that the Pbs2 docking sites for Ssk2 (RDS-I and KD) are partially dispensable when mutated separately; however, the prevention of Ssk2 binding to Pbs2, by the simultaneous mutation of RDS-I and KD, caused strong sensitivity to Tn. In agreement with the lack of Hog1 phosphorylation during Tn treatment, a moderate resistance to Tn is obtained when a Pbs2 version lacking its kinase activity is expressed; however, the presence of mutual Pbs2-Hog1 docking sites is essential for the Tn response. Finally, we detected that Tn induced a transcriptional activation of some components of the SLN1 branch. These results indicate that the Tn response requires a complex formed by the MAPK module and components of the SLN1 branch but not their canonical osmoregulatory activities.

Stability, affinity, and chromatic variants of the glutamate sensor iGluSnFR.

Single-wavelength fluorescent reporters allow visualization of specific neurotransmitters with high spatial and temporal resolution. We report variants of intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) that are functionally brighter; detect submicromolar to millimolar amounts of glutamate; and have blue, cyan, green, or yellow emission profiles. These variants could be imaged in vivo in cases where original iGluSnFR was too dim, resolved glutamate transients in dendritic spines and axonal boutons, and allowed imaging at kilohertz rates.

TRPV4: A Physio and Pathophysiologically Significant Ion Channel.

Transient Receptor Potential (TRP) channels are a family of ion channels whose members are distributed among all kinds of animals, from invertebrates to vertebrates. The importance of these molecules is exemplified by the variety of physiological roles they play. Perhaps, the most extensively studied member of this family is the TRPV1 ion channel; nonetheless, the activity of TRPV4 has been associated to several physio and pathophysiological processes, and its dysfunction can lead to severe consequences. Several lines of evidence derived from animal models and even clinical trials in humans highlight TRPV4 as a therapeutic target and as a protein that will receive even more attention in the near future, as will be reviewed here.

Systematic identification of signal integration by protein kinase A.

Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been well charted, what regulates this conserved regulator remains to be systematically identified to understand how it coordinates biological processes. Using a yeast PKA reporter assay, we identified genes that influence PKA activity by measuring protein-protein interactions between the regulatory and the two catalytic subunits of the PKA complex in 3,726 yeast genetic-deletion backgrounds grown on two carbon sources. Overall, nearly 500 genes were found to be connected directly or indirectly to PKA regulation, including 80 core regulators, denoting a wide diversity of signals regulating PKA, within and beyond the described upstream linear pathways. PKA regulators span multiple processes, including the antagonistic autophagy and methionine biosynthesis pathways. Our results converge toward mechanisms of PKA posttranslational regulation by lysine acetylation, which is conserved between yeast and humans and that, we show, regulates protein complex formation in mammals and carbohydrate storage and aging in yeast. Taken together, these results show that the extent of PKA input matches with its output, because this kinase receives information from upstream and downstream processes, and highlight how biological processes are interconnected and coordinated by PKA.

Ineffective Phosphorylation of Mitogen-Activated Protein Kinase Hog1p in Response to High Osmotic Stress in the Yeast Kluyveromyces lactis.

When treated with a hyperosmotic stimulus, Kluyveromyces lactis cells respond by activating the mitogen-activated protein kinase (MAPK) K. lactis Hog1 (KlHog1) protein via two conserved branches, SLN1 and SHO1. Mutants affected in only one branch can cope with external hyperosmolarity by activating KlHog1p by phosphorylation, except for single ΔKlste11 and ΔKlste50 mutants, which showed high sensitivity to osmotic stress, even though the other branch (SLN1) was intact. Inactivation of both branches by deletion of KlSHO1 and KlSSK2 also produced sensitivity to high salt. Interestingly, we have observed that in ΔKlste11 and ΔKlsho1 ΔKlssk2 mutants, which exhibit sensitivity to hyperosmotic stress, and contrary to what would be expected, KlHog1p becomes phosphorylated. Additionally, in mutants lacking both MAPK kinase kinases (MAPKKKs) present in K. lactis (KlSte11p and KlSsk2p), the hyperosmotic stress induced the phosphorylation and nuclear internalization of KlHog1p, but it failed to induce the transcriptional expression of KlSTL1 and the cell was unable to grow in high-osmolarity medium. KlHog1p phosphorylation via the canonical HOG pathway or in mutants where the SHO1 and SLN1 branches have been inactivated requires not only the presence of KlPbs2p but also its kinase activity. This indicates that when the SHO1 and SLN1 branches are inactivated, high-osmotic-stress conditions activate an independent input that yields active KlPbs2p, which, in turn, renders KlHog1p phosphorylation ineffective. Finally, we found that KlSte11p can alleviate the sensitivity to hyperosmotic stress displayed by a ΔKlsho1 ΔKlssk2 mutant when it is anchored to the plasma membrane by adding the KlSho1p transmembrane segments, indicating that this chimeric protein can substitute for KlSho1p and KlSsk2p.

Pancreas transplant imaging: how I do it.

Pancreas transplantation aims to restore physiologic normoglycemia in diabetic patients with glomerulopathy and avoid or delay the onset of diabetic retinopathy and arteriopathy. Simultaneous pancreas-kidney transplant is the most common approach, using a cadaveric pancreas donation in conjunction with either cadaveric or live donor renal transplant. Alternative techniques include pancreas after kidney transplant, in which the pancreas transplant is performed some years after renal transplant. Pancreas transplant alone is utilized rarely in diabetic patients with compensated renal function. Pancreas grafts have vascular and enteric connections that vary in their anatomic approach, and understanding of this is critical for imaging with ultrasonography, computed tomography, or magnetic resonance imaging. Imaging techniques are directed to display the pancreatic transplant arterial and venous vasculature, parenchyma, and intestinal drainage pathway. Critical vascular information includes venous thrombosis (partial or complete), arterial occlusion, or aneurysm. Parenchymal abnormalities are nonspecific and occur in pancreatitis, graft rejection, and subsequent graft ischemia. Peripancreatic fluid collections include hematoma/seroma, pseudocyst, and abscess. The latter two are related to pancreatitis, duct disruption, or leak from the duodenojejunostomy. An understanding of transplant anatomy and complications will lead to appropriate use of imaging techniques to diagnose or exclude important complications.

Evolutionary Signals in Coronaviral Structural Proteins Suggest Possible Complex Mechanisms of Post-Translational Regulation in SARS-CoV-2 Virus.

Post-translational regulation of proteins has emerged as a central topic of research in the field of functional proteomics. Post-translational modifications (PTMs) dynamically control the activities of proteins and are involved in a wide range of biological processes. Crosstalk between different types of PTMs represents a key mechanism of regulation and signaling. Due to the current pandemic of the novel and dangerous SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) virus, here we present an in silico analysis of different types of PTMs in structural proteins of coronaviruses. A dataset of PTM sites was studied at three levels: conservation analysis, mutational analysis and crosstalk analysis. We identified two sets of PTMs which could have important functional roles in the regulation of the structural proteins of coronaviruses. Additionally, we found seven interesting signals of potential crosstalk events. These results reveal a higher level of complexity in the mechanisms of post-translational regulation of coronaviral proteins and provide new insights into the adaptation process of the SARS-CoV-2 virus.

Micro-CT visualization of the CNS: Performance of different contrast-enhancing techniques for documenting the spider brain.

Spider brain and central nervous system (CNS) have remained unexplored, due in part to the difficulty of observing these organs, usually only possible through histological preparations. Recently, internal anatomy studies have been supplemented by the inclusion of X- ray micro-CT. Unmineralized tissue such as the body of invertebrates requires a staining process to enhance tissue X-ray absorption and improve contrast during observation. Many current protocols are based on iodine staining requiring critical point drying (CPD) of the sample for optimal contrast. This process induces shrinking of the soft tissue generating artifacts in the morphology, volume, and even position of internal structures. Phosphotungstic acid (PTA) is an alternative staining agent recently used in marine invertebrate and plant studies. Here, we used several specimens of the common spider Araneus diadematus to visualize the spider brain and compare both contrast-enhancing ethanol-based solutions. We assessed a gradient of staining times, observed and tested the repercussions of CPD, and examined the use of vacuum to accelerate PTA diffusion. We show that PTA provides the best contrast on micro-CT scans in ethanol eliminating the need for CPD, and offering more realistic in situ visualizations of the internal organs. In combination with different scanning settings, PTA allowed observation of internal organs like the CNS, digestive system, muscles, and finer structures like the retina, visual nerves, and optic neuropiles. This fast and less invasive method could facilitate the proper documentation of the internal anatomy in the context of evolutionary, developmental and functional studies.

Broad-Spectrum Antimicrobial ZnMintPc Encapsulated in Magnetic-Nanocomposites with Graphene Oxide/MWCNTs Based on Bimodal Action of Photodynamic and Photothermal Effects.

Microbial diseases have been declared one of the main threats to humanity, which is why, in recent years, great interest has been generated in the development of nanocomposites with antimicrobial capacity. The present work studied two magnetic nanocomposites based on graphene oxide (GO) and multiwall carbon nanotubes (MWCNTs). The synthesis of these magnetic nanocomposites consisted of three phases: first, the synthesis of iron magnetic nanoparticles (MNPs), second, the adsorption of the photosensitizer menthol-Zinc phthalocyanine (ZnMintPc) into MWCNTs and GO, and the third phase, encapsulation in poly (N-vinylcaprolactam-co-poly(ethylene glycol diacrylate)) poly (VCL-co-PEGDA) polymer VCL/PEGDA a biocompatible hydrogel, to obtain the magnetic nanocomposites VCL/PEGDA-MNPs-MWCNTs-ZnMintPc and VCL/PEGDA-MNPs-GO-ZnMintPc. In vitro studies were carried out using Escherichia coli and Staphylococcus aureus bacteria and the Candida albicans yeast based on the Photodynamic/Photothermal (PTT/PDT) effect. This research describes the nanocomposites' optical, morphological, magnetic, and photophysical characteristics and their application as antimicrobial agents. The antimicrobial effect of magnetics nanocomposites was evaluated based on the PDT/PTT effect. For this purpose, doses of 65 mW·cm-2 with 630 nm light were used. The VCL/PEGDA-MNPs-GO-ZnMintPc nanocomposite eliminated E. coli and S. aureus colonies, while the VCL/PEGDA-MNPs-MWCNTs-ZnMintPc nanocomposite was able to kill the three types of microorganisms. Consequently, the latter is considered a broad-spectrum antimicrobial agent in PDT and PTT.

The activity of yeast Hog1 MAPK is required during endoplasmic reticulum stress induced by tunicamycin exposure.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the so-called unfolded protein response (UPR), a conserved signaling pathway that drives the transcription of genes such as chaperones and folding enzymes. Nevertheless, the activity of the UPR accounts only for a part of the gene expression program activated upon ER stress. Moreover, the mechanism(s) for how cells adapt and survive to this stress are largely unknown. Here, we show that the yeast high osmolarity glycerol (HOG) pathway plays a role in ER stress resistance. Strains lacking the MAPK Hog1p displayed sensitivity to tunicamycin or beta-mercaptoethanol, whereas hyperactivation of the pathway enhanced their resistance. However, these effects were not due to Hog1p-mediated regulation of the UPR. Northern blot analysis demonstrated that Hog1p controls the tunicamycin-induced transcriptional change of GPD1 and that wild-type cells exposed to the drug accumulated glycerol in a Hog1p-dependent manner. Consistent with this, deletion of genes involved in glycerol synthesis caused increased sensitivity to tunicamycin, whereas overexpression of GPD1 provided higher tolerance to both wild-type and hog1Delta mutant cells. Quite remarkably, these effects were mediated by the basal activity of the MAPK because tunicamycin exposure does not trigger the phosphorylation of Hog1p or its nuclear import. Hence, our results describe new aspects of the yeast response to ER stress and identify additional functions of glycerol and the Hog1p MAPK to provide stress resistance.

First records and three new species of the family Symphytognathidae (Arachnida, Araneae) from Thailand, and the circumscription of the genus Crassignatha Wunderlich, 1995.

The family Symphytognathidae is reported from Thailand for the first time. Three new species: Anapistula choojaiae sp. nov., Crassignatha seeliam sp. nov., and Crassignatha seedam sp. nov. are described and illustrated. Distribution is expanded and additional morphological data are reported for Patu shiluensis Lin & Li, 2009. Specimens were collected in Thailand between July and August 2018. The newly described species were found in the north mountainous region of Chiang Mai, and Patu shiluensis was collected in the coastal region of Phuket. DNA sequences are provided for all the species here studied. The relations of these symphytognathid species were tested using previously published phylogenetic analyses on micro orb-weavers. Also, we used micro CT analysis to build 3D models of the male genitalia and somatic characters of two species of Crassignatha Wunderlich, 1995. The molecular phylogeny and 3D models were used to discuss the taxonomy and circumscription of the currently valid symphytognathid genera, with focus on Crassignatha and Patu Marples, 1951. Based on this, three new combinations are suggested: Crassignatha bicorniventris (Lin & Li, 2009), comb. nov., Crassignatha quadriventris (Lin & Li, 2009), comb. nov., and Crassignatha spinathoraxi (Lin & Li, 2009), comb. nov. A new record of Crassignatha danaugirangensisMiller et al. 2014 is reported from Brunei.

Nanocasting synthesis of BiFeO3 nanoparticles with enhanced visible-light photocatalytic activity.

In this work, monodisperse BiFeO3 nanoparticles with a particle diameter of 5.5 nm were synthesized by a nanocasting technique using mesoporous silica SBA-15 as a hard template and pre-fabricated metal carboxylates as metal precursors. To the best of our knowledge, the synthesized particles are the smallest BiFeO3 particles ever prepared by any method. The samples were characterized by X-ray powder diffraction, transmission electron microscopy and UV-vis diffuse reflectance spectroscopy. The phase purity of the product depends on the type of carboxylic acid used in the synthesis of the metal precursors, the type of solvent in the wet impregnation process, and the calcination procedure. By using tartaric acid in the synthesis of the metal precursors, acidified 2-methoxyethanol in the wet impregnation process and a calcination procedure with intermediate plateaus, monodisperse 5.5 nm BiFeO3 nanoparticles were successfully obtained. Furthermore, the nanoparticles were applied in photodegradation reactions of rhodamine B in aqueous solution under visible-light irradiation. Notably, the cast BiFeO3 nanoparticles demonstrated very high efficiencies and stability under visible-light irradiation, much higher than those of BiFeO3 nanoparticles synthesized by other synthetic methods. The possible mechanism in the photodegradation process has been deeply discussed on the basis of radical trapping experiments.

Imperfect and askew: A review of asymmetric genitalia in araneomorph spiders (Araneae: Araneomorphae).

Bilateral asymmetry in the genitalia is a rare but widely dispersed phenomenon in the animal tree of life. In arthropods, occurrences vary greatly from one group to another and there seems to be no common explanation for all the independent origins. In spiders, genital asymmetry appears to be especially rare. Most known species show almost perfectly symmetrical genitals with the right and left sides being mirror images of each other. However, some examples of asymmetric genitalia have been studied and many other reports are scattered in the taxonomic literature. Based on a broad literature survey, we found several species in thirteen families with evidence of genital asymmetry, mostly expressed only in females. Our review suggests that spider genital asymmetries, although rare, are more common than previously thought and taxonomic descriptions and illustrations are a useful but not entirely reliable tool for studying them. Here we also report on directional asymmetry in the liocranid spider Teutamus politus, the first known case of morphologically asymmetric male genitals in Entelegynae spiders. Generalities, evolution and categorization of asymmetry in spiders are further discussed.

Use of Adjunctive Therapy in Acute Kawasaki Disease in Latin America.

Objective: To characterize the use of adjunctive therapy in Kawasaki disease (KD) in Latin America. Methods: The study included 1,418 patients from the Latin American KD Network (REKAMLATINA) treated for KD between January 1, 2009, and May 31, 2017. Results: Of these patients, 1,152 received only a single dose of IVIG, and 266 received additional treatment. Age at onset was similar in both groups (median 2 vs. 2.2 years, respectively). The majority of patients were male (58 vs. 63.9%) and were hospitalized with the first 10 days of fever (85.1 vs. 84.2%). The most common adjunctive therapy administered was steroids for IVIG-resistance, followed by additional doses of IVIG. The use of biologics such as infliximab was limited. KD patients who received adjunctive therapy were more likely to have a lower platelet count and albumin level as well as a higher Z score of the coronary arteries. Conclusion: This is the first report of adjunctive therapies for KD across Latin America. IVIG continues to be the initial and resistance treatment, however, steroids are also used and to a lesser extent, biological therapy such as infliximab. Future studies should address the barriers to therapy in children with acute KD throughout Latin America.

Presentation and Outcomes of Kawasaki Disease in Latin American Infants Younger Than 6 Months of Age: A Multinational Multicenter Study of the REKAMLATINA Network.

Objective: To characterize the clinical presentation and outcomes of Kawasaki disease (KD) in infants <6 months of age as compared to those ≥6 months in Latin America. Methods: We evaluated 36 infants <6 months old and 940 infants ≥6 months old diagnosed with KD in Latin America. We compared differences in laboratory data, clinical presentation, treatment response, and coronary artery outcomes between the two cohorts. Results: The majority (78.1%) of infants and children ≥6 months of age were initially diagnosed with KD, as compared to only 38.2% of infants <6 months. Clinical features of KD were more commonly observed in the older cohort: oral changes (92 vs. 75%, P = 0.0023), extremity changes (74.6 vs. 57.1%, P = 0.029), and cervical lymphadenopathy (67.6 vs. 37.1%, P = 0.0004). Whether treated in the first 10 days of illness or after the 10th day, infants <6 months were at greater risk of developing a coronary artery aneurysm compared to KD patients ≥6 months treated at the same point in the course of illness [ ≤ 10 days (53.8 vs. 9.4%, P = 0.00012); >10 days (50 vs. 7.4%, P = 0.043)]. Conclusion: Our data show that despite treatment in the first 10 days of illness, infants <6 months of age in Latin America have a higher risk of developing a coronary artery aneurysm. Delay in the diagnosis leads to larger coronary artery aneurysms disproportionately in these infants. Thus, suspicion for KD should be high in this vulnerable population.