Localized uplift, widespread subsidence, and implications for sea level rise in the New York City metropolitan area.

Regional relative sea level rise is exacerbating flooding hazards in the coastal zone. In addition to changes in the ocean, vertical land motion (VLM) is a driver of spatial variation in sea level change that can either diminish or enhance flood risk. Here, we apply state-of-the-art interferometric synthetic aperture radar and global navigation satellite system time series analysis to estimate velocities and corresponding uncertainties at 30-m resolution in the New York City metropolitan area, revealing VLM with unprecedented detail. We find broad subsidence of 1.6 mm/year, consistent with glacial isostatic adjustment to the melting of the former ice sheets, and previously undocumented hot spots of both subsidence and uplift that can be physically explained in some locations. Our results inform ongoing efforts to adapt to sea level rise and reveal points of VLM that motivate both future scientific investigations into surface geology and assessments of engineering projects.

End-binding protein 1 promotes specific motor-cargo association in the cell body prior to axonal delivery of dense core vesicles.

Axonal transport is key to neuronal function. Efficient transport requires specific motor-cargo association in the soma, yet the mechanisms regulating this early step remain poorly understood. We found that EBP-1, the C. elegans ortholog of the canonical-microtubule-end-binding protein EB1, promotes the specific association between kinesin-3/KIF1A/UNC-104 and dense core vesicles (DCVs) prior to their axonal delivery. Using single-neuron, in vivo labeling of endogenous cargo and EBs, we observed reduced axonal abundance and reduced secretion of DCV cargo, but not other KIF1A/UNC-104 cargoes, in ebp-1 mutants. This reduction could be traced back to fewer exit events from the cell body, where EBP-1 colocalized with the DCV sorting machinery at the trans Golgi, suggesting that this is the site of EBP-1 function. EBP-1 calponin homology (CH) domain was required for directing microtubule growth on the Golgi, and mammalian EB1 interacted with KIF1A in an EBH-domain-dependent manner. Loss- and gain-of-function experiments suggest a model in which both kinesin-3 binding and guidance of microtubule growth at the trans Golgi by EBP-1 promote motor-cargo association at sites of DCV biogenesis. In support of this model, tethering either EBP-1 or a kinesin-3/KIF1A/UNC-104-interacting domain from an unrelated protein to the Golgi restored the axonal abundance of DCV proteins in ebp-1 mutants. These results uncover an unexpected role for a microtubule-associated protein and provide insights into how specific kinesin-3 cargo is delivered to the axon.

A well-oxygenated eastern tropical Pacific during the warm Miocene.

The oxygen content of the oceans is susceptible to climate change and has declined in recent decades1, with the largest effect in oxygen-deficient zones (ODZs)2, that is, mid-depth ocean regions with oxygen concentrations <5 µmol kg-1 (ref. 3). Earth-system-model simulations of climate warming predict that ODZs will expand until at least 2100. The response on timescales of hundreds to thousands of years, however, remains uncertain3-5. Here we investigate changes in the response of ocean oxygenation during the warmer-than-present Miocene Climatic Optimum (MCO; 17.0-14.8 million years ago (Ma)). Our planktic foraminifera I/Ca and δ15N data, palaeoceanographic proxies sensitive to ODZ extent and intensity, indicate that dissolved-oxygen concentrations in the eastern tropical Pacific (ETP) exceeded 100 µmol kg-1 during the MCO. Paired Mg/Ca-derived temperature data suggest that an ODZ developed in response to an increased west-to-east temperature gradient and shoaling of the ETP thermocline. Our records align with model simulations of data from recent decades to centuries6,7, suggesting that weaker equatorial Pacific trade winds during warm periods may lead to decreased upwelling in the ETP, causing equatorial productivity and subsurface oxygen demand to be less concentrated in the east. These findings shed light on how warm-climate states such as during the MCO may affect ocean oxygenation. If the MCO is considered as a possible analogue for future warming, our findings seem to support models suggesting that the recent deoxygenation trend and expansion of the ETP ODZ may eventually reverse3,4.

End Binding protein 1 promotes specific motor-cargo association in the cell body prior to axonal delivery of Dense Core Vesicles.

Axonal transport is key to neuronal function. Efficient transport requires specific motor-cargo association in the soma, yet the mechanisms regulating this early step remain poorly understood. We found that EBP-1, the C. elegans ortholog of the canonical microtubule end binding protein EB1, promotes the specific association between kinesin-3/KIF1A/UNC-104 and Dense Core Vesicles (DCVs) prior to their axonal delivery. Using single-neuron, in vivo labelling of endogenous cargo and EBs, we observed reduced axonal abundance and reduced secretion of DCV cargo, but not other KIF1A/UNC-104 cargo, in ebp-1 mutants. This reduction could be traced back to fewer exit events from the cell body, where EBP-1 colocalized with the DCV sorting machinery at the trans Golgi, suggesting that this is the site of EBP-1 function. In addition to its microtubule binding CH domain, mammalian EB1 interacted with mammalian KIF1A in an EBH domain dependent manner, and expression of mammalian EB1 or the EBH domain was sufficient to rescue DCV transport in ebp-1 mutants. Our results suggest a model in which kinesin-3 binding and microtubule binding by EBP-1 cooperate to transiently enrich the motor near sites of DCV biogenesis to promote motor-cargo association. In support of this model, tethering either EBP-1 or a kinesin-3 KIF1A/UNC-104 interacting domain from an unrelated protein to the Golgi restored the axonal abundance of DCV proteins in ebp-1 mutants. These results uncover an unexpected role for a microtubule associated protein and provide insight into how specific kinesin-3 cargo are delivered to the axon.

Total cost of carbon capture and storage implemented at a regional scale: northeastern and midwestern United States.

We model the costs of carbon capture and storage (CCS) in subsurface geological formations for emissions from 138 northeastern and midwestern electricity-generating power plants. The analysis suggests coal-sourced CO2 emissions can be stored in this region at a cost of $52-$60 ton-1, whereas the cost to store emission from natural-gas-fired plants ranges from approximately $80 to $90. Storing emissions offshore increases the lowest total costs of CCS to over $60 per ton of CO2 for coal. Because there apparently is sufficient onshore storage in the northeastern and midwestern United States, offshore storage is not necessary or economical unless there are additional costs or suitability issues associated with the onshore reservoirs. For example, if formation pressures are prohibitive in a large-scale deployment of onshore CCS, or if there is opposition to onshore storage, offshore storage space could probably store emissions at an additional cost of less than $10 ton-1. Finally, it is likely that more than 8 Gt of total CO2 emissions from this region can be stored for less $60 ton-1, slightly more than the $50 ton-1 Section 45Q tax credits incentivizing CCS.

Cenozoic sea-level and cryospheric evolution from deep-sea geochemical and continental margin records.

Using Pacific benthic foraminiferal δ18O and Mg/Ca records, we derive a Cenozoic (66 Ma) global mean sea level (GMSL) estimate that records evolution from an ice-free Early Eocene to Quaternary bipolar ice sheets. These GMSL estimates are statistically similar to "backstripped" estimates from continental margins accounting for compaction, loading, and thermal subsidence. Peak warmth, elevated GMSL, high CO2, and ice-free "Hothouse" conditions (56 to 48 Ma) were followed by "Cool Greenhouse" (48 to 34 Ma) ice sheets (10 to 30 m changes). Continental-scale ice sheets ("Icehouse") began ~34 Ma (>50 m changes), permanent East Antarctic ice sheets at 12.8 Ma, and bipolar glaciation at 2.5 Ma. The largest GMSL fall (27 to 20 ka; ~130 m) was followed by a >40 mm/yr rise (19 to 10 ka), a slowing (10 to 2 ka), and a stillstand until ~1900 CE, when rates began to rise. High long-term CO2 caused warm climates and high sea levels, with sea-level variability dominated by periodic Milankovitch cycles.

De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies.

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.

Sentryn and SAD Kinase Link the Guided Transport and Capture of Dense Core Vesicles in Caenorhabditis elegans.

Dense core vesicles (DCVs) can transmit signals by releasing neuropeptides from specialized synaptic regions called active zones. DCVs reach the active zone by motorized transport through a long axon. A reverse motor frequently interrupts progress by taking DCVs in the opposite direction. "Guided transport" refers to the mechanism by which outward movements ultimately dominate to bring DCVs to the synaptic region. After guided transport, DCVs alter their interactions with motors and enter a "captured" state. The mechanisms of guided transport and capture of DCVs are unknown. Here, we discovered two proteins that contribute to both processes in Caenorhabditis elegans SAD kinase and a novel conserved protein we named Sentryn are the first proteins found to promote DCV capture. By imaging DCVs moving in various regions of single identified neurons in living animals, we found that DCV guided transport and capture are linked through SAD kinase, Sentryn, and Liprin-α. These proteins act together to regulate DCV motorized transport in a region-specific manner. Between the cell body and the synaptic region, they promote forward transport. In the synaptic region, where all three proteins are highly enriched at active zones, they promote DCV pausing by inhibiting transport in both directions. These three proteins appear to be part of a special subset of active zone-enriched proteins because other active zone proteins do not share their unique functions.

Sentryn Acts with a Subset of Active Zone Proteins To Optimize the Localization of Synaptic Vesicles in Caenorhabditis elegans.

Synaptic vesicles (SVs) transmit signals by releasing neurotransmitters from specialized synaptic regions of neurons. In the synaptic region, SVs are tightly clustered around small structures called active zones. The motor KIF1A transports SVs outward through axons until they are captured in the synaptic region. This transport must be guided in the forward direction because it is opposed by the dynein motor, which causes SVs to reverse direction multiple times en route. The core synapse stability (CSS) system contributes to both guided transport and capture of SVs. We identified Sentryn as a CSS protein that contributes to the synaptic localization of SVs in Caenorhabditis elegans Like the CSS proteins SAD Kinase and SYD-2 (Liprin-α), Sentryn also prevents dynein-dependent accumulation of lysosomes in dendrites in strains lacking JIP3. Genetic analysis showed that Sentryn and SAD Kinase each have at least one nonoverlapping function for the stable accumulation of SVs at synapses that, when combined with their shared functions, enables most of the functions of SYD-2 (Liprin-α) for capturing SVs. Also like other CSS proteins, Sentryn appears enriched at active zones and contributes to active zone structure, suggesting that it is a novel, conserved active zone protein. Sentryn is recruited to active zones by a process dependent on the active zone-enriched CSS protein SYD-2 (Liprin-α). Our results define a specialized group of active zone enriched proteins that can affect motorized transport throughout the neuron and that have roles in both guided transport and capture of SVs.

Local microtubule organization promotes cargo transport in C. elegans dendrites.

The specific organization of the neuronal microtubule cytoskeleton in axons and dendrites is an evolutionarily conserved determinant of neuronal polarity that allows for selective cargo sorting. However, how dendritic microtubules are organized and whether local differences influence cargo transport remains largely unknown. Here, we use live-cell imaging to systematically probe the microtubule organization in Caenorhabditiselegans neurons, and demonstrate the contribution of distinct mechanisms in the organization of dendritic microtubules. We found that most non-ciliated neurons depend on unc-116 (kinesin-1), unc-33 (CRMP) and unc-44 (ankyrin) for correct microtubule organization and polarized cargo transport, as previously reported. Ciliated neurons and the URX neuron, however, use an additional pathway to nucleate microtubules at the tip of the dendrite, from the base of the cilium in ciliated neurons. Since inhibition of distal microtubule nucleation affects distal dendritic transport, we propose a model in which the presence of a microtubule-organizing center at the dendrite tip ensures correct dendritic cargo transport.

Keeping Neuronal Cargoes on the Right Track: New Insights into Regulators of Axonal Transport.

In neurons, a single motor (dynein) transports large organelles as well as synaptic and dense core vesicles toward microtubule minus ends; however, it is unclear why dynein appears more active on organelles, which are generally excluded from mature axons, than on synaptic and dense core vesicles, which are maintained at high levels. Recent studies in Zebrafish and Caenorhabditis elegans have shown that JIP3 promotes dynein-mediated retrograde transport to clear some organelles (lysosomes, early endosomes, and Golgi) from axons and prevent their potentially harmful accumulation in presynaptic regions. A JIP3 mutant suppressor screen in C. elegans revealed that JIP3 promotes the clearance of organelles from axons by blocking the action of the CSS system (Cdk5, SAD Kinase, SYD-2/Liprin). A synthesis of results in vertebrates with the new findings suggests that JIP3 blocks the CSS system from disrupting the connection between dynein and organelles. Most components of the CSS system are enriched at presynaptic active zones where they normally contribute to maintaining optimal levels of captured synaptic and dense core vesicles, in part by inhibiting dynein transport. The JIP3-CSS system model explains how neurons selectively regulate a single minus-end motor to exclude specific classes of organelles from axons, while at the same time ensuring optimal levels of synaptic and dense core vesicles.

Synapse-Assembly Proteins Maintain Synaptic Vesicle Cluster Stability and Regulate Synaptic Vesicle Transport in Caenorhabditis elegans.

The functional integrity of neurons requires the bidirectional active transport of synaptic vesicles (SVs) in axons. The kinesin motor KIF1A transports SVs from somas to stable SV clusters at synapses, while dynein moves them in the opposite direction. However, it is unclear how SV transport is regulated and how SVs at clusters interact with motor proteins. We addressed these questions by isolating a rare temperature-sensitive allele of Caenorhabditis elegans unc-104 (KIF1A) that allowed us to manipulate SV levels in axons and dendrites. Growth at 20° and 14° resulted in locomotion rates that were ∼3 and 50% of wild type, respectively, with similar effects on axonal SV levels. Corresponding with the loss of SVs from axons, mutants grown at 14° and 20° showed a 10- and 24-fold dynein-dependent accumulation of SVs in their dendrites. Mutants grown at 14° and switched to 25° showed an abrupt irreversible 50% decrease in locomotion and a 50% loss of SVs from the synaptic region 12-hr post-shift, with no further decreases at later time points, suggesting that the remaining clustered SVs are stable and resistant to retrograde removal by dynein. The data further showed that the synapse-assembly proteins SYD-1, SYD-2, and SAD-1 protected SV clusters from degradation by motor proteins. In syd-1, syd-2, and sad-1 mutants, SVs accumulate in an UNC-104-dependent manner in the distal axon region that normally lacks SVs. In addition to their roles in SV cluster stability, all three proteins also regulate SV transport.

UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons.

The conserved protein UNC-16 (JIP3) inhibits the active transport of some cell soma organelles, such as lysosomes, early endosomes, and Golgi, to the synaptic region of axons. However, little is known about UNC-16's organelle transport regulatory function, which is distinct from its Kinesin-1 adaptor function. We used an unc-16 suppressor screen in Caenorhabditis elegans to discover that UNC-16 acts through CDK-5 (Cdk5) and two conserved synapse assembly proteins: SAD-1 (SAD-A Kinase), and SYD-2 (Liprin-α). Genetic analysis of all combinations of double and triple mutants in unc-16(+) and unc-16(-) backgrounds showed that the three proteins (CDK-5, SAD-1, and SYD-2) are all part of the same organelle transport regulatory system, which we named the CSS system based on its founder proteins. Further genetic analysis revealed roles for SYD-1 (another synapse assembly protein) and STRADα (a SAD-1-interacting protein) in the CSS system. In an unc-16(-) background, loss of the CSS system improved the sluggish locomotion of unc-16 mutants, inhibited axonal lysosome accumulation, and led to the dynein-dependent accumulation of lysosomes in dendrites. Time-lapse imaging of lysosomes in CSS system mutants in unc-16(+) and unc-16(-) backgrounds revealed active transport defects consistent with the steady-state distributions of lysosomes. UNC-16 also uses the CSS system to regulate the distribution of early endosomes in neurons and, to a lesser extent, Golgi. The data reveal a new and unprecedented role for synapse assembly proteins, acting as part of the newly defined CSS system, in mediating UNC-16's organelle transport regulatory function.

Paleoceanography. Antarctic role in Northern Hemisphere glaciation.

Earth's climate underwent a major transition from the warmth of the late Pliocene, when global surface temperatures were ~2° to 3°C higher than today, to extensive Northern Hemisphere glaciation (NHG) ~2.73 million years ago (Ma). We show that North Pacific deep waters were substantially colder (4°C) and probably fresher than the North Atlantic Deep Water before the intensification of NHG. At ~2.73 Ma, the Atlantic-Pacific temperature gradient was reduced to <1°C, suggesting the initiation of stronger heat transfer from the North Atlantic to the deep Pacific. We posit that increased glaciation of Antarctica, deduced from the 21 ± 10-meter sea-level fall from 3.15 to 2.75 Ma, and the development of a strong polar halocline fundamentally altered deep ocean circulation, which enhanced interhemispheric heat and salt transport, thereby contributing to NHG.

A novel CaM kinase II pathway controls the location of neuropeptide release from Caenorhabditis elegans motor neurons.

Neurons release neuropeptides via the regulated exocytosis of dense core vesicles (DCVs) to evoke or modulate behaviors. We found that Caenorhabditis elegans motor neurons send most of their DCVs to axons, leaving very few in the cell somas. How neurons maintain this skewed distribution and the extent to which it can be altered to control DCV numbers in axons or to drive release from somas for different behavioral impacts is unknown. Using a forward genetic screen, we identified loss-of-function mutations in UNC-43 (CaM kinase II) that reduce axonal DCV levels by ∼90% and cell soma/dendrite DCV levels by ∼80%, leaving small synaptic vesicles largely unaffected. Blocking regulated secretion in unc-43 mutants restored near wild-type axonal levels of DCVs. Time-lapse video microscopy showed no role for CaM kinase II in the transport of DCVs from cell somas to axons. In vivo secretion assays revealed that much of the missing neuropeptide in unc-43 mutants is secreted via a regulated secretory pathway requiring UNC-31 (CAPS) and UNC-18 (nSec1). DCV cargo levels in unc-43 mutants are similarly low in cell somas and the axon initial segment, indicating that the secretion occurs prior to axonal transport. Genetic pathway analysis suggests that abnormal neuropeptide function contributes to the sluggish basal locomotion rate of unc-43 mutants. These results reveal a novel pathway controlling the location of DCV exocytosis and describe a major new function for CaM kinase II.

An organelle gatekeeper function for Caenorhabditis elegans UNC-16 (JIP3) at the axon initial segment.

Neurons must cope with extreme membrane trafficking demands to produce axons with organelle compositions that differ dramatically from those of the cell soma and dendrites; however, the mechanism by which they accomplish this is not understood. Here we use electron microscopy and quantitative imaging of tagged organelles to show that Caenorhabditis elegans axons lacking UNC-16 (JIP3/Sunday Driver) accumulate Golgi, endosomes, and lysosomes at levels up to 10-fold higher than wild type, while ER membranes are largely unaffected. Time lapse microscopy of tagged lysosomes in living animals and an analysis of lysosome distributions in various regions of unc-16 mutant axons revealed that UNC-16 inhibits organelles from escaping the axon initial segment (AIS) and moving to the distal synaptic part of the axon. Immunostaining of native UNC-16 in C. elegans neurons revealed a localized concentration of UNC-16 at the initial segment, although UNC-16 is also sparsely distributed in distal regions of axons, including the synaptic region. Organelles that escape the AIS in unc-16 mutants show bidirectional active transport within the axon commissure that occasionally deposits them in the synaptic region, where their mobility decreases and they accumulate. These results argue against the long-standing, untested hypothesis that JIP3/Sunday Driver promotes anterograde organelle transport in axons and instead suggest an organelle gatekeeper model in which UNC-16 (JIP3/Sunday Driver) selectively inhibits the escape of Golgi and endosomal organelles from the AIS. This is the first evidence for an organelle gatekeeper function at the AIS, which could provide a regulatory node for controlling axon organelle composition.

Impact of Antarctic Circumpolar Current development on late Paleogene ocean structure.

Global cooling and the development of continental-scale Antarctic glaciation occurred in the late middle Eocene to early Oligocene (~38 to 28 million years ago), accompanied by deep-ocean reorganization attributed to gradual Antarctic Circumpolar Current (ACC) development. Our benthic foraminiferal stable isotope comparisons show that a large δ(13)C offset developed between mid-depth (~600 meters) and deep (>1000 meters) western North Atlantic waters in the early Oligocene, indicating the development of intermediate-depth δ(13)C and O(2) minima closely linked in the modern ocean to northward incursion of Antarctic Intermediate Water. At the same time, the ocean's coldest waters became restricted to south of the ACC, probably forming a bottom-ocean layer, as in the modern ocean. We show that the modern four-layer ocean structure (surface, intermediate, deep, and bottom waters) developed during the early Oligocene as a consequence of the ACC.