Methods that directly functionalize pyridines are in high demand due to their presence in pharmaceuticals, agrochemicals, and materials. A reaction that selectively transforms the 4-position C–H ...bonds in pyridines into C–PPh3 + groups that are subsequently converted into heteroaryl ethers is presented. The two step sequence is effective on complex pyridines, pharmaceutical molecules, and other classes of heterocycles. Initial studies show that C–C, C–N, and C–S bond formations are also amenable.
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IJS, KILJ, NUK, PNG, UL, UM
While cilia are recognized as important signaling organelles, the extent of ciliary functions remains unknown because of difficulties in cataloguing proteins from mammalian primary cilia. We present ...a method that readily captures rapid snapshots of the ciliary proteome by selectively biotinylating ciliary proteins using a cilia-targeted proximity labeling enzyme (cilia-APEX). Besides identifying known ciliary proteins, cilia-APEX uncovered several ciliary signaling molecules. The kinases PKA, AMPK, and LKB1 were validated as bona fide ciliary proteins and PKA was found to regulate Hedgehog signaling in primary cilia. Furthermore, proteomics profiling of Ift27/Bbs19 mutant cilia correctly detected BBSome accumulation inside Ift27−/− cilia and revealed that β-arrestin 2 and the viral receptor CAR are candidate cargoes of the BBSome. This work demonstrates that proximity labeling can be applied to proteomics of non-membrane-enclosed organelles and suggests that proteomics profiling of cilia will enable a rapid and powerful characterization of ciliopathies.
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•APEX labeling enables proteomic analyses of a non-membrane-enclosed compartment•Cilia-APEX identifies the kinases PKA, AMPK, and LKB1 in primary cilia•PKA functions inside cilia to phosphorylate GLI3 and regulate Hedgehog signaling•Proteomic profiling of Ift27/Bbs19 cilia detects ciliary accumulation of BBSome
Primary cilia organize cellular signaling events in a specialized microenvironment. Mick et al. apply proximity labeling using cilia-APEX to study the ciliary proteome. They uncover unexpected signaling molecules, including kinases PKA and AMPK, inside cilia and further use a proteomic profiling approach to unravel molecular defects of Ift27/Bbs19 mutant cilia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Democratizing the Supreme Court Doerfler, Ryan D; Moyn, Samuel
California law review,
10/2021, Volume:
109, Issue:
5
Journal Article
Peer reviewed
Progressives are taking Supreme Court reform seriously for the first time in almost a century. Owing to the rise of the political and academic left following the 2008 financial crisis and the hotly ...contested appointments of Justices Neil Gorsuch and Brett Kavanaugh, progressives increasingly view the Supreme Court as posing a serious challenge to the successful implementation of ambitious legislation. Amy Coney Barrett's confirmation to take Justice Ruth Bader Ginsburg's seat after her death in fall 2020 brought these once-marginal concerns to the forefront of American political debate, prompting a promise from now-President Joseph Biden, on the eve of his election, to form a national commission for court reform.
Despite this once-in-a-lifetime energy around the idea of court reform, the popular and academic discussion of how to reform the Supreme Court has been unduly constrained. Even if the commission proves to be a ploy to postpone reform, it is crucial to clarify the debate around possible ends and means of reform, for the debate is unlikely to die out. This is the case with regard to the mechanism and the purpose of reform alike. On the left, historical memory has limited debate almost entirely to "court-packing. "Meanwhile, the center has occupied itself with how to restore the Supreme Court's legitimacy by rescuing the institution from its regrettable slide into partisanship. And now, as the Court appears to moderate itself in an effort to preempt legislative reform of the institution, the concern is that progressives will drop their demands for change, satisfied with a few modest judicial concessions.
This Article aims to keep the discussion of court reform alive for more propitious circumstances and, just as importantly, to significantly expand its bounds. It does so, first, by urging progressives to reject the legitimacy frame of the issue, which treats the problem with the Supreme Court as one of politicization, in favor of an openly progressive frame in which the question is how to enable democracy within our constitutional scheme.
Second, the Article introduces a distinction between two fundamentally different mechanisms of reform. The first type of reform, which we call personnel reforms, includes both aggressive proposals like court-packing and more modest (or politically moderate) reforms such as partisan balance requirements or panel systems. All of these reforms take for granted the tremendous power the Supreme Court wields. What these proposals do is change the partisan or ideological character of the individuals who wield it. The second type of reform, which we call disempowering reforms, includes proposals like jurisdiction stripping and a supermajority requirement for judicial review. These reforms take power away from the Court and redirect it to the political branches instead. As we argue, personnel reforms are mostly addressed to the legitimacy frame that progressives would do well to reject. More still, to the extent such reforms advance progressive ends, they do so only contingently and threaten to do as much harm as good over time. By contrast, disempowering reforms, we argue, advance progressive values systematically. While such reforms would not guarantee advances in social democracy, they would ensure that the battle for such advances takes place in the democratic arena. For progressives, this is where such reforms have to occur now and should occur if they take place anywhere.
Almost fifty years ago, America's industrial cities-Detroit, Philadelphia, Cleveland, Baltimore, and others-began shedding people and jobs. Today they are littered with tens of thousands of abandoned ...houses, shuttered factories, and vacant lots. With population and housing losses continuing in the wake of the 2007 financial crisis, the future of neighborhoods in these places is precarious. How we will rebuild shrinking cities and what urban design vision will guide their future remain contentious and unknown.
InDesign After Decline, Brent D. Ryan reveals the fraught and intermittently successful efforts of architects, planners, and city officials to rebuild shrinking cities following mid-century urban renewal. With modern architecture in disrepute, federal funds scarce, and architects and planners disengaged, politicians and developers were left to pick up the pieces. In twin narratives, Ryan describes how America's two largest shrinking cities, Detroit and Philadelphia, faced the challenge of design after decline in dramatically different ways. While Detroit allowed developers to carve up the cityscape into suburban enclaves, Philadelphia brought back 1960s-style land condemnation for benevolent social purposes. Both Detroit and Philadelphia "succeeded" in rebuilding but at the cost of innovative urban design and planning.
Ryan proposes that the unprecedented crisis facing these cities today requires a revival of the visionary thinking found in the best modernist urban design, tempered with the lessons gained from post-1960s community planning. Depicting the ideal shrinking city as a shifting patchwork of open and settled areas, Ryan concludes that accepting the inevitable decline and abandonment of some neighborhoods, while rebuilding others as new neighborhoods with innovative design and planning, can reignite modernism's spirit of optimism and shape a brighter future for shrinking cities and their residents.
Characterizing changes in precipitation patterns over time is critical for hydrologically dependent fields like water resource management and agriculture. Here, we explore observed trends in ...interannual precipitation variability using a suite of metrics that describe changes in precipitation over time. We analyze daily in situ Global Historical Climatology Network precipitation data from 1970 to present over 17 internally consistent sub‐national United States domains using a regional Mann‐Kendall trend test. We find robustly increasing trends in annual mean precipitation and wet day frequency for most of the central and eastern U.S., but decreasing trends in the western U.S. Importantly, we identify widespread significant trends in interannual precipitation variability, with increasing variability in the southeast, decreasing variability in the far west, and mixed signals in the Rocky Mountains and north‐central U.S. Our results provide important context for water resource managers and a new observational standard for climate model performance assessments.
Plain Language Summary
While many studies have examined how annual precipitation totals and precipitation frequency have changed, few examine the variability, or consistency, of year‐over‐year precipitation. We test for these trends in daily observations across 17 regions within the United States. We find changes in yearly precipitation variability for most regions, though results in the central U.S. are mixed. We also identify rising average annual precipitation and precipitation frequency for the central and eastern U.S. and falling average annual precipitation and frequency for the western U.S. Our results are important for agriculture and water resource management and can be compared against historical climate model simulations to determine how well they reproduce observations.
Key Points
We find widespread robust changes in two measures of interannual precipitation variability across the United States
We detect increases (decreases) in annual mean precipitation and wet day frequency across the eastern (western) United States
We explore the interaction of changes in precipitation frequency and wet day precipitation intensity on interannual variability
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Tropical cyclone (TC) intensity forecasts are impacted by errors in atmosphere and ocean initial conditions and the model formulation, which motivates using an ensemble approach. This study evaluates ...the impact of uncertainty in atmospheric and oceanic initial conditions, as well as stochastic representations of the drag C
d
and enthalphy C
k
exchange coefficients on ensemble Advanced Hurricane WRF (AHW) TC intensity forecasts of multiple Atlantic TCs from 2008 to 2011. Each ensemble experiment is characterized by different combinations of either deterministic or ensemble atmospheric and/or oceanic initial conditions, as well as fixed or stochastic representations of C
d
or C
k
. Among those experiments with a single uncertainty source, atmospheric uncertainty produces the largest standard deviation in TC intensity. While ocean uncertainty leads to continuous growth in ensemble standard deviation, the ensemble standard deviation in the experiments with C
d
and C
k
uncertainty levels off by 48 h. Combining atmospheric and oceanic uncertainty leads to larger intensity standard deviation than atmosphere or ocean uncertainty alone and preferentially adds variability outside of the TC core. By contrast, combining C
d
or C
k
uncertainty with any other source leads to negligible increases in standard deviation, which is mainly due to the lack of spatial correlation in the exchange coefficient perturbations. All of the ensemble experiments are deficient in ensemble standard deviation; however, the experiments with combinations of uncertainty sources generally have an ensemble standard deviation closer to the ensemble-mean errors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Global environmental drivers of influenza Deyle, Ethan R.; Maher, M. Cyrus; Hernandez, Ryan D. ...
Proceedings of the National Academy of Sciences - PNAS,
11/2016, Volume:
113, Issue:
46
Journal Article
Peer reviewed
Open access
In temperate countries, influenza outbreaks are well correlated to seasonal changes in temperature and absolute humidity. However, tropical countries have much weaker annual climate cycles, and ...outbreaks show less seasonality and are more difficult to explain with environmental correlations. Here, we use convergent cross mapping, a robust test for causality that does not require correlation, to test alternative hypotheses about the global environmental drivers of influenza outbreaks from country-level epidemic time series. By moving beyond correlation, we show that despite the apparent differences in outbreak patterns between temperate and tropical countries, absolute humidity and, to a lesser extent, temperature drive influenza outbreaks globally. We also find a hypothesized U-shaped relationship between absolute humidity and influenza that is predicted by theory and experiment, but hitherto has not been documented at the population level. The balance between positive and negative effects of absolute humidity appears to be mediated by temperature, and the analysis reveals a key threshold around 75 °F. The results indicate a unified explanation for environmental drivers of influenza that applies globally.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Age is a major risk factor for severe coronavirus disease-2019 (COVID-19). Here, we interrogate the transcriptional features and cellular landscape of the aging human lung. By intersecting these ...age-associated changes with experimental data on SARS-CoV-2, we identify several factors that may contribute to the heightened severity of COVID-19 in older populations. The aging lung is transcriptionally characterized by increased cell adhesion and stress responses, with reduced mitochondria and cellular replication. Deconvolution analysis reveals that the proportions of alveolar type 2 cells, proliferating basal cells, goblet cells, and proliferating natural killer/T cells decrease with age, whereas alveolar fibroblasts, pericytes, airway smooth muscle cells, endothelial cells and IGSF21
dendritic cells increase with age. Several age-associated genes directly interact with the SARS-CoV-2 proteome. Age-associated genes are also dysregulated by SARS-CoV-2 infection in vitro and in patients with severe COVID-19. These analyses illuminate avenues for further studies on the relationship between age and COVID-19.
The vast majority of fast inhibitory transmission in the brain is mediated by GABA acting on GABA
receptors (GABA
Rs), which provides inhibitory balance to excitatory drive and controls neuronal ...output. GABA
Rs are also effectively targeted by clinically important drugs for treatment in a number of neurological disorders. It has long been hypothesized that function and pharmacology of GABA
Rs are determined by the channel pore-forming subunits. However, recent studies have provided new dimensions in studying GABA
Rs due to several transmembrane proteins that interact with GABA
Rs and modulate their trafficking and function. In this review, we summarize recent findings on these novel GABA
R transmembrane regulators and highlight a potential avenue to develop new GABA
R psychopharmacology by targeting these receptor-associated membrane proteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cognitive deficits are central to schizophrenia, but the underlying mechanisms still remain unclear. Imaging studies performed in patients point to decreased activity in the mediodorsal thalamus (MD) ...and reduced functional connectivity between the MD and prefrontal cortex (PFC) as candidate mechanisms. However, a causal link is still missing. We used a pharmacogenetic approach in mice to diminish MD neuron activity and examined the behavioral and physiological consequences. We found that a subtle decrease in MD activity is sufficient to trigger selective impairments in prefrontal-dependent cognitive tasks. In vivo recordings in behaving animals revealed that MD-PFC beta-range synchrony is enhanced during acquisition and performance of a working memory task. Decreasing MD activity interfered with this task-dependent modulation of MD-PFC synchrony, which correlated with impaired working memory. These findings suggest that altered MD activity is sufficient to disrupt prefrontal-dependent cognitive behaviors and could contribute to the cognitive symptoms observed in schizophrenia.
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► A mild decrease in MD activity triggers impairments in PFC-dependent cognitive tasks ► MD-PFC beta synchrony is selectively modulated during a spatial working memory task ► Decreasing MD activity disrupts MD-PFC synchrony during high working memory demand ► Decreasing MD activity delays task acquisition and correlated increases in synchrony
Brain imaging studies associate decreased activity of the mediodorsal thalamus with cognitive deficits in schizophrenia. Parnaudeau et al. show that a primary decrease in mouse mediodorsal activity is sufficient to cause cognitive deficits and to alter functional thalamofrontal connectivity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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