ES2018 adds support for Unicode property escapes of the form p{…} and P{…} to JavaScript regular expressions. This article explains what Unicode property escapes are, how they work, and why they’re useful.

This article highlights what’s happening in the world of JavaScript regular expressions right now. Spoiler: it’s quite a lot — there are more RegExp-related proposals currently advancing through the TC39 standardization process than there have been updates to RegExp in the history of ECMAScript!

Most of them contracted the infection at Koyambedu market

Request for registering retailers, construction professionals as MSMEs to be examined: Gadkari

Now, those registered on Seva Sindhu portal can hire Karnataka STU buses to southern states

Surge in number of returnees without registration

Most of them are from West Bengal

Be wise when it comes to opting for the tax regime from this year

Mammalian Munc18 proteins are essential for membrane fusion and human health. Here, we review the literature describing structural and in vitro data, and identify a possible explanation for the conflicting functional roles that have been reported.

Dr Tim Gregory Works with a Meteorite That's Older Than The Earth  LeftLion

Nanocrystallography has transformed our ability to interrogate the atomic structures of proteins, peptides, organic molecules and materials. By probing atomic level details in ordered sub-10 nm regions of nanocrystals, scanning nanobeam electron diffraction extends the reach of nanocrystallography and in principle obviates the need for diffraction from large portions of one or more crystals. Scanning nanobeam electron diffraction is now applied to determine atomic structures from digitally defined regions of beam-sensitive peptide nanocrystals. Using a direct electron detector, thousands of sparse diffraction patterns over multiple orientations of a given crystal are recorded. Each pattern is assigned to a specific location on a single nanocrystal with axial, lateral and angular coordinates. This approach yields a collection of patterns that represent a tilt series across an angular wedge of reciprocal space: a scanning nanobeam diffraction tomogram. Using this diffraction tomogram, intensities can be digitally extracted from any desired region of a scan in real or diffraction space, exclusive of all other scanned points. Intensities from multiple regions of a crystal or from multiple crystals can be merged to increase data completeness and mitigate missing wedges. It is demonstrated that merged intensities from digitally defined regions of two crystals of a segment from the OsPYL/RCAR5 protein produce fragment-based ab initio solutions that can be refined to atomic resolution, analogous to structures determined by selected-area electron diffraction. In allowing atomic structures to now be determined from digitally outlined regions of a nanocrystal, scanning nanobeam diffraction tomography breaks new ground in nanocrystallography.

The structure of BgaR, a transcriptional regulator of the lactose operon in Clostridium perfringens, has been solved by SAD phasing using a mercury derivative. BgaR is an exquisite sensor of lactose, with a binding affinity in the low-micromolar range. This sensor and regulator has been captured bound to lactose and to lactulose as well as in a nominal apo form, and was compared with AraC, another saccharide-binding transcriptional regulator. It is shown that the saccharides bind in the N-terminal region of a jelly-roll fold, but that part of the saccharide is exposed to bulk solvent. This differs from the classical AraC saccharide-binding site, which is mostly sequestered from the bulk solvent. The structures of BgaR bound to lactose and to lactulose highlight how specific and nonspecific interactions lead to a higher binding affinity of BgaR for lactose compared with lactulose. Moreover, solving multiple structures of BgaR in different space groups, both bound to saccharides and unbound, verified that the dimer interface along a C-terminal helix is similar to the dimer interface observed in AraC.

Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protein quality-control pathway in eukaryotes in which misfolded ER proteins are polyubiquitylated, extracted and ultimately degraded by the proteasome. This process involves ER membrane-embedded ubiquitin E2 and E3 enzymes, as well as a soluble E2 enzyme (Ubc7 in Saccharomyces cerevisiae and UBE2G2 in mammals). E2-binding regions (E2BRs) that recruit these soluble ERAD E2s to the ER have been identified in humans and S. cerevisiae, and structures of E2–E2BR complexes from both species have been determined. In addition to sequence and structural differences between the human and S. cerevisiae E2BRs, the binding of E2BRs also elicits different biochemical outcomes with respect to E2 charging by E1 and E2 discharge. Here, the Schizosaccharomyces pombe E2BR was identified and purified with Ubc7 to resolve a 1.7 Å resolution co-crystal structure of the E2BR in complex with Ubc7. The S. pombe E2BR binds to the back side of the E2 as an α-helix and, while differences exist, it exhibits greater similarity to the human E2BR. Structure-based sequence alignments reveal differences and conserved elements among these species. Structural comparisons and biochemistry reveal that the S. pombe E2BR presents a steric impediment to E1 binding and inhibits E1-mediated charging, respectively.

The John Marshall Ju/'hoan Bushman Film and Video Collection, 1950-2000, was among 35 documentary heritage items of exceptional value added to UNESCO’s Memory of the World Register in 2009.

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Based on current hormone analyses, and not having seen a fetus during the ultrasound exams, Zoo researchers have determined that Mei Xiang experienced a pseudopregnancy.

The post National Zoo’s giant panda Mei Xiang is not pregnant appeared first on Smithsonian Insider.

Scientists at the Smithsonian’s National Zoo detected a secondary rise in urinary progesterone levels in the Zoo’s female giant panda Mei Xiang (may-SHONG). This hormone rise indicates that it should be 40 to 50 days before Mei Xiang either gives birth to a cub or comes to the end of a pseudopregnancy, or false pregnancy, which is common in giant pandas.

The post Hormone tests show Mei Xiang, the National Zoo’s female giant panda, may be pregnant appeared first on Smithsonian Insider.

Smithsonian scientists have confirmed that chytridiomycosis, a rapidly spreading amphibian disease, has reached a site near Panama’s Darien region. This was the last area in the entire mountainous neotropics to be free of the disease. This is troubling news for the Panama Amphibian Rescue and Conservation Project, a consortium of nine U.S. and Panamanian institutions that aims to rescue 20 species of frogs in imminent danger of extinction.

The post Deadly amphibian disease detected in the last disease-free region of Central America appeared first on Smithsonian Insider.

A newly described species of toothed whale that lived some 3-4 million years ago during the Pliocene, is causing scientists to reconsider what is known about its living cold-water relatives: narwhals and belugas.

The post New fossil whale species raises mystery regarding why narwhals and belugas live only in cold water appeared first on Smithsonian Insider.

To celebrate its 22nd anniversary in orbit, the Hubble Space Telescope has released a dramatic new image of the star-forming region 30 Doradus, also known […]

The post New image of the star-forming region 30 Doradus, also known as the Tarantula Nebula appeared first on Smithsonian Insider.

Stars form when gravity pulls together material within giant clouds of gas and dust. But gravity isn’t the only force at work. Both turbulence and […]

The post As Stars Form, Magnetic Fields Influence Regions Big and Small appeared first on Smithsonian Insider.

A new study from the Smithsonian Conservation Biology Institute (SCBI) is helping make headway in an area of animal management that has historically proven challenging: […]

The post Early indicator of cheetah pregnancy identified appeared first on Smithsonian Insider.

Scott J. Neal, Qingxiang Zhou, and Francesca Pignoni

The specification of organs, tissues and cell types results from cell fate restrictions enacted by nuclear transcription factors under the control of conserved signaling pathways. The progenitor epithelium of the Drosophila compound eye, the eye imaginal disc, is a premier model for the study of such processes. Early in development, apposing cells of the eye disc are established as either retinal progenitors or support cells of the peripodial epithelium (PE), in a process whose genetic and mechanistic determinants are poorly understood. We have identified Protein Phosphatase 2A (PP2A), and specifically a STRIPAK-PP2A complex that includes the scaffolding and substrate-specificity components Cka, Strip and SLMAP, as a critical player in the retina-PE fate choice. We show that these factors suppress ectopic retina formation in the presumptive PE and do so via the Hippo signaling axis. STRIPAK-PP2A negatively regulates Hpo kinase, and consequently its substrate Wts, to release the transcriptional co-activator Yki into the nucleus. Thus, a modular higher-order PP2A complex refines the activity of this general phosphatase to act in a precise specification of cell fate.

Eric Peterman, Mindaugas Valius, and Rytis Prekeris

During mitotic cell division, the actomyosin cytoskeleton undergoes several dynamic changes that play key roles in progression through mitosis. While the regulators of cytokinetic ring formation and contraction are well-established, proteins that regulate cortical stability during anaphase and telophase have been understudied. Here, we describe a role for CLIC4 in regulating actin and actin-regulators at the cortex and cytokinetic cleavage furrow during cytokinesis. We first describe CLIC4 as a new component of the cytokinetic cleavage furrow that is required for successful completion of mitotic cell division. We also demonstrate that CLIC4 regulates the remodeling of sub-plasma membrane actomyosin network within the furrow by recruiting MST4 kinase and regulating ezrin phosphorylation. This work identifies and characterizes new molecular players involved in regulating cortex stiffness and blebbing during late stages of cytokinetic furrowing.

Olivia R. Grafinger, Genya Gorshtein, Tyler Stirling, Megan I. Brasher, and Marc G. Coppolino

Malignant cancer cells can invade extracellular matrix (ECM) through the formation of F-actin-rich subcellular structures termed invadopodia. ECM degradation at invadopodia is mediated by matrix metalloproteinases (MMPs), and recent findings indicate that membrane-anchored membrane type 1-matrix metalloproteinase (MT1-MMP) has a primary role in this process. Maintenance of an invasive phenotype is dependent on internalization of MT1-MMP from the plasma membrane and its recycling to sites of ECM remodeling. Internalization of MT1-MMP is dependent on its phosphorylation, and here we examine the role of β1 integrin-mediated signaling in this process. Activation of β1 integrin using the antibody P4G11 induced phosphorylation and internalization of MT1-MMP and resulted in increased cellular invasiveness and invadopodium formation in vitro. We also observed phosphorylation of Src and epidermal growth factor receptor (EGFR) and an increase in their association in response to β1 integrin activation, and determined that Src and EGFR promote phosphorylation of MT1-MMP on Thr⁵⁶⁷. These results suggest that MT1-MMP phosphorylation is regulated by a β1 integrin-Src-EGFR signaling pathway that promotes recycling of MT1-MMP to sites of invadopodia formation during cancer cell invasion.

Yung-An Huang, Chih-Hsuan Hsu, Ho-Chieh Chiu, Pei-Yu Hsi, Chris T. Ho, Wei-Lun Lo, and Eric Hwang

Microtubule (MT) is the most abundant cytoskeleton in neurons and controls multiple facets of their development. While the MT-organizing center (MTOC) in mitotic cells is typically located at the centrosome, MTOC in neurons switches to non-centrosomal sites. A handful of cellular components have been shown to promote non-centrosomal MT (ncMT) formation in neurons, yet the regulation mechanism remains unknown. Here we demonstrate that the small GTPase Ran is a key regulator of ncMTs in neurons. Using an optogenetic tool that enables light-induced local production of RanGTP, we demonstrate that RanGTP promotes ncMT plus-end growth along the neurite. Additionally, we discovered that actin waves drive the anterograde transport of RanGTP. Pharmacological disruption of actin waves abolishes the enrichment of RanGTP and reduces growing ncMT plus-ends at the neurite tip. These observations identify a novel regulation mechanism of ncMTs and pinpoint an indirect connection between the actin and MT cytoskeletons in neurons.

Osiris Martinez-Guzman, Mathilda M. Willoughby, Arushi Saini, Jonathan V. Dietz, Iryna Bohovych, Amy E. Medlock, Oleh Khalimonchuk, and Amit R. Reddi

Heme is a cofactor and signaling molecule that is essential for much of aerobic life. All heme-dependent processes in eukaryotes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins located throughout the cell. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. Herein, using genetically encoded fluorescent heme sensors, we developed a live cell assay to monitor heme distribution dynamics between the mitochondrial inner-membrane, where heme is synthesized, and the mitochondrial matrix, cytosol, and nucleus. Surprisingly, heme trafficking to the nucleus is ~25% faster than to the cytosol or mitochondrial matrix, which are nearly identical, potentially supporting a role for heme as a mitochondrial-nuclear retrograde signal. Moreover, we discovered that the heme synthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of the mitochondrial dynamics machinery, Mgm1 and Dnm1, and ER contact sites, Gem1, regulate the flow of heme between the mitochondria and nucleus. Overall, our results indicate that there are parallel pathways for the distribution of bioavailable heme.

Benjamin Ziman, Peter Karabinis, Paul Barghouth, and Nestor J. Oviedo

Nutrient availability upon feeding leads to an increase in body size in the planarian Schmidtea mediterranea. However, it remains unclear how food consumption integrates with cell division at the organismal level. Here we show that Sirtuins is evolutionarily conserved in planarians and specifically demonstrate that Sirtuin-1 (Smed-Sirt-1) regulates organismal growth by impairing both feeding behavior and intestinal morphology. Disruption of Smed-Sirt-1 with either RNAi or pharmacological treatment leads to reduced animal growth. Conversely, enhancement of Smed-Sirt-1 with resveratrol accelerates growth. Differences in growth rates were associated with changes in the amount of time to locate food and overall consumption. Furthermore, Smed-Sirt-1(RNAi) animals displayed reduced cell death and increased stem cell proliferation accompanied by impaired expression of intestinal lineage progenitors and reduced branching of the gut. Altogether, our findings indicate Sirtuin-1 is a crucial metabolic hub capable of controlling animal behavior, tissue renewal and morphogenesis of the adult intestine.

Bipasha Dey and Richa Rikhy

Cell shape morphogenesis from spherical to polygonal occurs in epithelial cell formation in metazoan embryogenesis. In syncytial Drosophila embryos, the plasma membrane incompletely surrounds each nucleus and is organized as a polygonal epithelial-like array. Each cortical syncytial division cycle shows circular to polygonal plasma membrane transition along with furrow extension between adjacent nuclei from interphase to metaphase. In this study, we assess the relative contribution of DE-cadherin and Myosin II at the furrow for polygonal shape transition. We show that polygonality initiates during each cortical syncytial division cycle when the furrow extends from 4.75 to 5.75 µm. Polygon plasma membrane organization correlates with increased junctional tension, increased DE-cadherin and decreased Myosin II mobility. DE-cadherin regulates furrow length and polygonality. Decreased Myosin II activity allows for polygonality to occur at a lower length than controls. Increased Myosin II activity leads to loss of lateral furrow formation and complete disruption of polygonal shape transition. Our studies show that DE-cadherin-Myosin II balance regulates an optimal lateral membrane length during each syncytial cycle for polygonal shape transition.

Kristina Drizyte-Miller, Jing Chen, Hong Cao, Micah B. Schott, and Mark A. McNiven

Epithelial cells such as liver-resident hepatocytes rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rabs can manifest in metabolic diseases or cancer. Rab32 is expressed in many secretory epithelial cells but its role in cellular metabolism is virtually unknown. In this study, we find that Rab32 associates with lysosomes and regulates proliferation and cell size of Hep3B hepatoma and HeLa cells. Specifically, we identify that Rab32 supports mTORC1 signaling under basal and amino acid stimulated conditions. Consistent with inhibited mTORC1, an increase in nuclear TFEB localization and lysosome biogenesis is also observed in Rab32-depleted cells. Finally, we find that Rab32 interacts with mTOR kinase and that loss of Rab32 reduces the association of mTOR and mTORC1 pathway proteins with lysosomes, suggesting that Rab32 regulates lysosomal mTOR trafficking. In summary, these findings suggest that Rab32 functions as a novel regulator of cellular metabolism through supporting mTORC1 signaling.

Tara L. Mastro, Vishnu P. Tripathi, and Susan L. Forsburg

Translesion synthesis polymerases (TLSPs) are non-essential error-prone enzymes that ensure cell survival by facilitating DNA replication in the presence of DNA damage. In addition to their role in bypassing lesions, TLSPs have been implicated in meiotic double strand break repair in several systems. Here we examine the joint contribution of four TLS polymerases to meiotic progression in the fission yeast S. pombe. We observed the dramatic loss of spore viability in fission yeast lacking all four TLSPs which is accompanied by disruptions in chromosome segregation during meiosis I and II. Rec8 cohesin dynamics are altered in the absence of the TLSPs. These data suggest that the TLSPs contribute to multiple aspects of meiotic chromosome dynamics.

Aparna Sherlekar, Gayatri Mundhe, Prachi Richa, Bipasha Dey, Swati Sharma, and Richa Rikhy

Branched actin networks driven by Arp2/3 collaborate with actomyosin filaments in processes such as cell migration. The syncytial Drosophila blastoderm embryo also shows expansion of apical caps by Arp2/3 driven actin polymerization in interphase and buckling at contact edges by MyosinII to form furrows in metaphase. Here we study the role of Syndapin (Synd), an F-BAR domain containing protein in apical cap remodelling prior to furrow extension. synd depletion showed larger apical caps. STED super-resolution and TIRF microscopy showed long apical actin protrusions in caps in interphase and short protrusions in metaphase in control embryos. synd depletion led to sustained long protrusions even in metaphase. Loss of Arp2/3 function in synd mutants partly reverted defects in apical cap expansion and protrusion remodelling. MyosinII levels were decreased in synd mutants and MyosinII mutant embryos have been previously reported to have expanded caps. We propose that Syndapin function limits branching activity during cap expansion and affects MyosinII distribution in order to shift actin remodeling from apical cap expansion to favor lateral furrow extension.

Kelly L. Dunlevy, Valentina Medvedeva, Jade E. Wilson, Mohammed Hoque, Trinity Pellegrin, Adam Maynard, Madison M. Kremp, Jason S. Wasserman, Andrey Poleshko, and Richard A. Katz

A large fraction of epigenetically silent heterochromatin is anchored to the nuclear periphery via "tethering proteins" that function to bridge heterochromatin and the nuclear membrane or nuclear lamina. We identified previously a human tethering protein, PRR14, that binds heterochromatin through an N-terminal domain, but the mechanism and regulation of nuclear lamina association remained to be investigated. Here we identify an evolutionarily conserved PRR14 nuclear lamina binding domain (LBD) that is both necessary and sufficient for positioning of PRR14 at the nuclear lamina. We also show that PRR14 associates dynamically with the nuclear lamina, and provide evidence that such dynamics are regulated through phosphorylation-dephosphorylation of the LBD. Furthermore, we identified a PP2A phosphatase recognition motif within the evolutionarily conserved PRR14 C-terminal Tantalus domain. Disruption of this motif affected PRR14 localization to the nuclear lamina. The overall findings demonstrate a heterochromatin anchoring mechanism whereby the PRR14 tether simultaneously binds heterochromatin and the nuclear lamina through two separable, modular domains. The findings also describe an optimal PRR14 LBD fragment that could be used for efficient targeting of fusion proteins to the nuclear lamina.

Sanjeev Chavan Nayak and Vegesna Radha

C3G (RapGEF1) plays a role in cell differentiation and is essential for early embryonic development in mice. In this study, we identify C3G as a centrosomal protein colocalizing with cenexin at the mother centriole in interphase cells. C3G interacts through its catalytic domain with cenexin, and they show interdependence for localization to the centrosome. C3G depletion caused a decrease in cellular cenexin levels. Centrosomal localization is lost as myocytes differentiate to form myotubes. Stable clone of cells depleted of C3G by CRISPR/Cas9 showed the presence of supernumerary centrioles. Overexpression of C3G, or a catalytically active deletion construct inhibited centrosome duplication. Cilia length is longer in C3G knockout cells, and the phenotype could be reverted upon reintroduction of C3G or its catalytic domain. Association of C3G with the basal body is dynamic, decreasing upon serum starvation, and increasing upon reentry into the cell cycle. C3G inhibits cilia formation and length dependent on its catalytic activity. We conclude that C3G inhibits centrosome duplication and maintains ciliary homeostasis, properties that may be important for its role in embryonic development.

Thomas O'Loughlin, Antonina J. Kruppa, Andre L. R. Ribeiro, James R. Edgar, Abdulaziz Ghannam, Andrew M. Smith, and Folma Buss

Optineurin (OPTN) is a multifunctional protein involved in autophagy, secretion as well as NF-B and IRF3 signalling and OPTN mutations are associated with several human diseases. Here we show that, in response to viral RNA, OPTN translocates to foci in the perinuclear region, where it negatively regulates NF-B and IRF3 signalling pathways and downstream pro-inflammatory cytokine secretion. These OPTN foci consist of a tight cluster of small membrane vesicles, which are positive for ATG9A. Disease mutations linked to POAG cause aberrant foci formation in the absence of stimuli, which correlates with the ability of OPTN to inhibit signalling. Using proximity labelling proteomics, we identify the LUBAC complex, CYLD and TBK1 as part of the OPTN interactome and show that these proteins are recruited to this OPTN-positive perinuclear compartment. Our work uncovers a crucial role for OPTN in dampening NF-B and IRF3 signalling through the sequestration of LUBAC and other positive regulators in this viral RNA-induced compartment leading to altered pro-inflammatory cytokine secretion.

Maintaining natural movement of animals that live in the tropical rainforest canopy in South America is important for the health of the ecosystem. As development […]

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The history of African American music in the United States is the history of music in the United States. From Prince’s iconic musical blends to […]

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From lunch counters to bus boycotts, the African American fight for integration and equality touched every aspect of life. What you may not be familiar […]

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