ResearchPad - pnas-plus https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Chitin perception in plasmodesmata characterizes submembrane immune-signaling specificity in plants]]> https://www.researchpad.co/article/Ned6a2675-e59e-48b1-9bf2-58914df92500 The plasma membrane (PM) is composed of heterogeneous subdomains, characterized by differences in protein and lipid composition. PM receptors can be dynamically sorted into membrane domains to underpin signaling in response to extracellular stimuli. In plants, the plasmodesmal PM is a discrete microdomain that hosts specific receptors and responses. We exploited the independence of this PM domain to investigate how membrane domains can independently integrate a signal that triggers responses across the cell. Focusing on chitin signaling, we found that responses in the plasmodesmal PM require the LysM receptor kinases LYK4 and LYK5 in addition to LYM2. Chitin induces dynamic changes in the localization, association, or mobility of these receptors, but only LYM2 and LYK4 are detected in the plasmodesmal PM. We further uncovered that chitin-induced production of reactive oxygen species and callose depends on specific signaling events that lead to plasmodesmata closure. Our results demonstrate that distinct membrane domains can integrate a common signal with specific machinery that initiates discrete signaling cascades to produce a localized response.

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<![CDATA[Vip1 is a kinase and pyrophosphatase switch that regulates inositol diphosphate signaling]]> https://www.researchpad.co/article/Nd04d9fc2-a864-4158-9156-bedee43244a3 Inositol diphosphates (PP-IPs), also known as inositol pyrophosphates, are high-energy cellular signaling codes involved in nutrient and regulatory responses. We report that the evolutionarily conserved gene product, Vip1, possesses autonomous kinase and pyrophosphatase domains capable of synthesis and destruction of D-1 PP-IPs. Our studies provide atomic-resolution structures of the PP-IP products and unequivocally define that the Vip1 gene product is a highly selective 1-kinase and 1-pyrophosphatase enzyme whose activities arise through distinct active sites. Kinetic analyses of kinase and pyrophosphatase parameters are consistent with Vip1 evolving to modulate levels of 1-IP7 and 1,5-IP8. Individual perturbations in kinase and pyrophosphatase activities in cells result in differential effects on vacuolar morphology and osmotic responses. Analogous to the dual-functional key energy metabolism regulator, phosphofructokinase 2, Vip1 is a kinase and pyrophosphatase switch whose 1-PP-IP products play an important role in a cellular adaptation.

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<![CDATA[The size of the immune repertoire of bacteria]]> https://www.researchpad.co/article/N0c3b499f-6252-4e1b-a5f5-d83ed90e6dc9

Significance

Some bacteria possess an adaptive immune system that maintains a memory of past viral infections in the CRISPR loci of their genomes. This memory is used to mount targeted responses against later threats but is remarkably shallow: it remembers only a few dozen to a few hundred viruses. We present a statistical theory of CRISPR-based immunity that quantitatively predicts the depth of bacterial immune memory in terms of a tradeoff with fundamental constraints of the cellular biochemical machinery.

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<![CDATA[Cryo-EM analysis of a feline coronavirus spike protein reveals a unique structure and camouflaging glycans]]> https://www.researchpad.co/article/N3a021e5a-1556-476c-8d9e-c18cd3db3026

Significance

We report here a 3.3-Å cryo-EM structure of feline infectious peritonitis virus (FIPV) S protein derived from the serotype I FIPV UU4 strain. The near-atomic EM map enabled ab initio modeling of 27 out of the 33 experimentally verified high-mannose and complex-type N-glycans that mask most of the protein surface. We demonstrated the feasibility to directly visualize the core fucose of a complex-type glycan, which was independently cross-validated by glycopeptide mass spectrometry analyses. There exist 3 N-glycans that wedge between 2 galectin-like domains within the S1 subunit of FIPV-UU4 S protein, resulting in a propeller-like conformation unique to all reported CoV S proteins. The results highlight a structural role of glycosylation in maintaining complex protein structures.

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<![CDATA[Early Last Interglacial ocean warming drove substantial ice mass loss from Antarctica]]> https://www.researchpad.co/article/Nea4e9750-1540-4e94-a37a-7d8db7d32938

Significance

Fifty years ago, it was speculated that the marine-based West Antarctic Ice Sheet is vulnerable to warming and may have melted in the past. Testing this hypothesis has proved challenging due to the difficulty of developing in situ records of ice sheet and environmental change spanning warm periods. We present a multiproxy record that implies loss of the West Antarctic Ice Sheet during the Last Interglacial (129,000 to 116,000 y ago), associated with ocean warming and the release of greenhouse gas methane from marine sediments. Our ice sheet modeling predicts that Antarctica may have contributed several meters to global sea level at this time, suggesting that this ice sheet lies close to a “tipping point” under projected warming.

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<![CDATA[TrkB hyperactivity contributes to brain dysconnectivity, epileptogenesis, and anxiety in zebrafish model of Tuberous Sclerosis Complex]]> https://www.researchpad.co/article/N8359e736-5d7c-4f56-bb81-4e670aa4a600

Significance

Tuberous Sclerosis Complex (TSC) is a hereditary disease that presents with early brain malformations, childhood epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Cortical malformations arise in utero and have been linked to childhood epilepsy before. Externally developing zebrafish seem convenient to study elementary neurodevelopment; however, without the in-depth functional analysis, the Tsc2-deficient zebrafish cannot be used for studies of TANDs. Here, we found that Tsc2-deficient zebrafish recapitulated symptoms seen in TSC patients on anatomical and behavioral levels, including aberrant brain morphology, thinning of brain connections, epileptogenesis, and increased anxiety-like behavior, which was rescued by reducing TrkB signaling, revealing a potential drug target. Moreover, we show that commissural thinning cause aberrant regulation of anxiety, providing a link between brain anatomy and emotion.

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<![CDATA[Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1]]> https://www.researchpad.co/article/Na3b7a633-8c3a-4ca4-8202-9f16dcc5fdab

Significance

NEPC is a highly aggressive subtype of prostate cancer that is increasing in incidence, likely due to use of new secondary androgen deprivation therapies. Here, we demonstrate that Trop2 is significantly elevated in CRPC and NEPC and represents a driver of metastatic NEPC. Trop2 overexpression increases tumor growth, drives metastasis and neuroendocrine phenotype, and significantly increases PARP1 levels. Inhibition of PARP1 in Trop2-driven NEPC significantly decreases neuroendocrine features, tumor growth, and metastatic colonization in vivo, suggesting that PARP1 inhibitors may represent a promising therapeutic strategy for metastatic prostate cancer expressing high levels of Trop2.

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<![CDATA[Global trends toward urban street-network sprawl]]> https://www.researchpad.co/article/N0000a0e3-2fb2-4513-b083-9959c0ad0b5b

Significance

The pattern of new urban and residential roads represents an essentially permanent backbone that shapes new urban form and land use in the world’s cities. Thus, today’s choices on the connectivity of streets may restrict future resilience and lock in pathways of energy use and CO2 emissions for a century or more. In contrast to the corrective trend observed in the United States, where streets have become more connected since the late 20th century, we find that most of the world is building ever-more disconnected “street-network sprawl.” A rapid policy response, including regulation and pricing tools, is needed to avoid further costly lock-in during this current, final phase of the urbanization process.

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<![CDATA[Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA]]> https://www.researchpad.co/article/Nbcb4cd25-fd53-4308-87b4-98ad76e3926a

Significance

Parkinson’s disease and its associated dementia can be caused by elevated levels of α-synuclein protein. Despite many efforts, however, targeting α-synuclein at the protein level has been challenging. In this manuscript, we describe the design of a small molecule that selectively targets the messenger RNA that encodes α-synuclein protein and selectively inhibits its translation. Furthermore, the compound is cytoprotective. Collectively, our findings show that difficult-to-target proteins can indeed be regulated by small molecules by binding the encoding mRNA. This strategy is a potentially promising way to slow the progression of Parkinson’s disease and related neurological disorders.

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<![CDATA[Presynaptic MAST kinase controls opposing postsynaptic responses to convey stimulus valence in Caenorhabditis elegans]]> https://www.researchpad.co/article/Nd35a2a3c-19ff-41ab-a125-d71f5ce7fae9

Significance

Animals need to quickly extract the valence information of sensory stimulus and assess whether the stimulus is attractive or aversive. Deciphering the molecular and circuit mechanisms that determine the stimulus valence is fundamental to understand how the nervous system generates the animal behaviors. Here we report that the AFD thermosensory neurons of C. elegans evoke in its postsynaptic AIY interneurons opposing neuronal responses that correlate with the valence of thermal stimuli. The C. elegans homologs of MAST kinase, Stomatin, and Diacylglycerol kinase function in AFD and regulate the opposing AIY responses. Our results further suggest that the alteration between excitatory and inhibitory AIY responses is mediated by controlling the balance of two opposing signals released from the AFD neurons.

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<![CDATA[Biophysical principles of choanoflagellate self-organization]]> https://www.researchpad.co/article/Ne6e23b9f-b81c-411d-b5f7-2f1e4f9b298f

Significance

Comparisons among animals and their closest living relatives, the choanoflagellates, have begun to shed light on the origin of animal multicellularity and development. Here, we complement previous genetic perspectives on this process by focusing on the biophysical principles underlying choanoflagellate colony morphology and morphogenesis. Our study reveals the crucial role of the extracellular matrix in shaping the colonies and leads to a phase diagram that delineates the range of morphologies as a function of the biophysical mechanisms at play.

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<![CDATA[Rotary catalysis of bovine mitochondrial F1-ATPase studied by single-molecule experiments]]> https://www.researchpad.co/article/Nef94e2f5-85a2-4526-bf7f-31ecd5ad0188

Significance

The gold-standard model for structural analysis of F1-ATPase has been bovine mitochondrial F1 (bMF1), but its rotational dynamics remain elusive. This study analyzes rotational characteristics of bMF1. bMF1 showed 3 distinct dwells in rotation, “binding dwell,” “catalytic dwell,” and “short dwell,” in each 120° step of rotation. While the positions of binding and catalytic dwell are similar to those of human mitochondrial F1 (hMF1), bMF1 shows short dwell at a distinctively different position from the corresponding dwell of hMF1, implying variety in the timing of the putative reaction at short dwell, phosphate release or ADP release. Single-molecule manipulation experiments revealed that the affinity change of ATP is a major torque-generating step.

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<![CDATA[Reduction-dependent siderophore assimilation in a model pennate diatom]]> https://www.researchpad.co/article/N35943ba1-f0b4-4022-ae2c-c7ecbca6ead1

Significance

Diatoms can access inorganic iron with remarkable efficiency, but this process is contingent on carbonate ion concentration. As ocean acidification reduces carbonate concentration, inorganic iron uptake may be discouraged in favor of carbonate-independent uptake. We report details of an iron assimilation process that needs no carbonate but requires exogenous compounds produced by cooccurring organisms. We show this process to be critical for diatom growth at high siderophore concentrations, but ineffective at acquiring iron from low-affinity organic chelators or lithogenic particulates. Understanding the caveats associated with iron source preference in diatoms will help predict the impacts of climate change on microbial community structure in high-nitrate low-chlorophyll ecosystems.

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<![CDATA[Evidence for an attentional priority map in inferotemporal cortex]]> https://www.researchpad.co/article/N5f8400e2-13b4-411a-90c8-643a308fc2ca

Significance

A fundamental dogma in the cognitive neurosciences is that attention is controlled by parietal and prefrontal areas. Here, we show that an area in the temporal lobe exhibits the properties of a priority map coding the focus of attention. We show this through whole-brain functional magnetic resonance imaging, electrophysiological single-unit recordings, and causal electrical stimulation. This discovery changes our understanding of the organization of visual pathways and the functions of attention networks.

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<![CDATA[Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina]]> https://www.researchpad.co/article/N1869c613-08c5-47f7-b715-4730e07477bc

Significance

Extracellular tissue debris accumulates with aging and in the most prevalent central-vision-threatening eye disorder, age-related macular degeneration (AMD). In this work, we discovered that lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes, is preferentially expressed in the outermost, neuroepithelial layer of the retina, the retinal pigment epithelium (RPE), and contributes to the prevention of ultrastructural changes in extracellular basolaminar deposits including lipids and apolipoproteins. LAMP2 thus appears to play an important role in RPE biology, and its apparent decrease with aging and in AMD specimens suggests that its deficiency may accelerate the basolaminar deposit formation and RPE dysfunction seen in these conditions.

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<![CDATA[RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization]]> https://www.researchpad.co/article/N9183d878-a555-4917-929f-911afcdf5b58

Significance

Pathological angiogenesis has been implicated in diverse pathologies. Infiltrating macrophages, especially those activated to M2-like phenotype, are critically important for angiogenesis. Although the role of RIP1 kinase in the regulation of apoptosis, necroptosis, and inflammation has been well-established, its role in angiogenesis remains elusive, despite being abundantly expressed in angiogenesis-related infiltrating macrophages. This study demonstrates that RIP1 kinase inhibition attenuates angiogenesis in multiple mouse models of pathological angiogenesis in vivo and suggests a therapeutic role of RIP1 kinase inhibition in pathological angiogenesis. Mechanistically, the inhibitory effect on angiogenesis depends on RIP kinase inhibition-mediated caspase activation in infiltrating macrophages through suppression of M2-like polarization, and subsequent attenuation of pathological angiogenesis.

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<![CDATA[Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells]]> https://www.researchpad.co/article/N0cc1a82d-57aa-4bcb-889b-eef438f4e7a9

Significance

While there is a clear understanding of how invariant NKT (iNKT) cells are activated in foreign infection, it remains unclear how they are activated during sterile inflammation, including cancer, where they have a well-defined role in tumor immunosurveillance. Here we elucidate a mechanism by which iNKT cells are activated through 1) the presentation of self-lipid antigens by endoplasmic reticulum-stressed antigen-presenting cells and 2) enhanced functional avidity driven by actin cytoskeletal remodeling. We further provide evidence that this mechanism of activation is at play in tumor settings. Here we describe a physiological context, relevant to human health and disease, that drives the presentation of immunogenic self-lipids to activate iNKT cells during sterile inflammation.

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<![CDATA[Mercury source changes and food web shifts alter contamination signatures of predatory fish from Lake Michigan]]> https://www.researchpad.co/article/N36efadf2-489f-4b7d-b66b-a0373ba0df5e

Significance

Elevated mercury in fish poses risks to fish-consuming wildlife and humans. Tracing sources of mercury by analyzing stable isotope ratios leads to improved source-receptor understanding and natural resource management. This work utilizes fish and sediment archives to trace the response to recent domestic mercury mitigation actions. Fish and sediments rapidly responded to a source perturbation contemporaneous with the reduction of mercury in the late 1980s. Subsequently, energetic pathways were altered due to dreissenid invasions, which dampened the expected decrease in fish mercury concentration. These findings reveal the importance of domestic mercury sources relative to global mercury to the Great Lakes. Results also show methylmercury concentrations in fish are sensitive to changes in trophic structure and diet driven by invasive species.

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<![CDATA[Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration]]> https://www.researchpad.co/article/Ne916d5ab-3c6c-4be3-a078-f49cd7224b9c

Significance

Exercise is a powerful antiaging intervention that protects against cardiovascular disease, dementia, diabetes, sarcopenia, and cancer. How exercise promotes health benefits to multiple tissues in the body, however, remains poorly understood. We establish a young adult swim exercise regimen for the short-lived nematode Caenorhabditis elegans that induces health benefits at the neuromuscular, intestinal, and cognitive levels and protects against neurodegeneration in models of tauopathy, Alzheimer’s disease, and Huntington’s disease. Importantly, we found that swim exercise performed exclusively in early adulthood promotes long-lasting systemic benefits that are still detectable in midlife. The advantages of C. elegans as a short-lived genetic model will allow for dissection of the molecular circuitry involved in system-wide exercise benefits.

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<![CDATA[Overexpression of zmm28 increases maize grain yield in the field]]> https://www.researchpad.co/article/N0da4ca32-4363-44a8-8562-5d6f47039fea

Significance

In the approaching decades, food security will likely be more of an issue as there will be an increased demand for grain which will need to be met in an environmentally sustainable manner. To date, commercial transgenic maize has primarily targeted resistance to insects and herbicides. Here we describe a transgenic approach to improve the yield and yield stability of maize. We have demonstrated that increasing and extending the expression of a maize gene, zmm28, alters vegetative and reproductive growth parameters and significantly enhances yield in large-scale field trials conducted over multiple years. We conclude that alteration in expression of a native maize gene in maize can create a substantially positive change in a complex trait like grain yield.

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