The Reelin Receptors Apoer2 and Vldlr Coordinate the Patterning of Purkinje Cell Topography in the Developing Mouse Cerebellum

The adult cerebellar cortex is comprised of reproducible arrays of transverse zones and parasagittal stripes of Purkinje cells. Adult stripes are created through the perinatal rostrocaudal dispersion of embryonic Purkinje cell clusters, triggered by signaling through the Reelin pathway. Reelin is secreted by neurons in the external granular layer and deep cerebellar nuclei and binds to two high affinity extracellular receptors on Purkinje cells-the Very low density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (Apoer2). In mice null for either Reelin or double null for Vldlr and Apoer2, Purkinje cell clusters fail to disperse. Here we report that animals null for either Vldlr or Apoer2 individually, exhibit specific and parasagittally-restricted Purkinje cell ectopias. For example, in mice lacking Apoer2 function immunostaining reveals ectopic Purkinje cells that are largely restricted to the zebrin II-immunonegative population of the anterior vermis. In contrast, mice null for Vldlr have a much larger population of ectopic Purkinje cells that includes members from both the zebrin II-immunonegative and -immunopositive phenotypes. HSP25 immunoreactivity reveals that in Vldlr null animals a large portion of zebrin II-immunopositive ectopic cells are probably destined to become stripes in the central zone (lobules VI–VII). A small population of ectopic zebrin II-immunonegative Purkinje cells is also observed in animals heterozygous for both receptors (Apoer2+/−: Vldlr+/−), but no ectopia is present in mice heterozygous for either receptor alone. These results indicate that Apoer2 and Vldlr coordinate the dispersal of distinct, but overlapping subsets of Purkinje cells in the developing cerebellum

The Quadruple Squeeze: Defining the safe operating space for freshwater use to achieve a triply green revolution in the Anthropocene

Humanity has entered a new phase of sustainability challenges, the Anthropocene, in which human development has reached a scale where it affects vital planetary processes. Under the pressure from a quadruple squeeze—from population and development pressures, the anthropogenic climate crisis, the anthropogenic ecosystem crisis, and the risk of deleterious tipping points in the Earth system—the degrees of freedom for sustainable human exploitation of planet Earth are severely restrained. It is in this reality that a new green revolution in world food production needs to occur, to attain food security and human development over the coming decades. Global freshwater resources are, and will increasingly be, a fundamental limiting factor in feeding the world. Current water vulnerabilities in the regions in most need of large agricultural productivity improvements are projected to increase under the pressure from global environmental change. The sustainability challenge for world agriculture has to be set within the new global sustainability context. We present new proposed sustainability criteria for world agriculture, where world food production systems are transformed in order to allow humanity to stay within the safe operating space of planetary boundaries. In order to secure global resilience and thereby raise the chances of planet Earth to remain in the current desired state, conducive for human development on the long-term, these planetary boundaries need to be respected. This calls for a triply green revolution, which not only more than doubles food production in many regions of the world, but which also is environmentally sustainable, and invests in the untapped opportunities to use green water in rainfed agriculture as a key source of future productivity enhancement. To achieve such a global transformation of agriculture, there is a need for more innovative options for water interventions at the landscape scale, accounting for both green and blue water, as well as a new focus on cross-scale interactions, feed-backs and risks for unwanted regime shifts in the agro-ecological landscape

Surface-Associated Plasminogen Binding of Cryptococcus neoformans Promotes Extracellular Matrix Invasion

BACKGROUND:The fungal pathogen Cryptococcus neoformans is a leading cause of illness and death in persons with predisposing factors, including: malignancies, solid organ transplants, and corticosteroid use. C. neoformans is ubiquitous in the environment and enters into the lungs via inhalation, where it can disseminate through the bloodstream and penetrate the central nervous system (CNS), resulting in a difficult to treat and often-fatal infection of the brain, called meningoencephalitis. Plasminogen is a highly abundant protein found in the plasma component of blood and is necessary for the degradation of fibrin, collagen, and other structural components of tissues. This fibrinolytic system is utilized by cancer cells during metastasis and several pathogenic species of bacteria have been found to manipulate the host plasminogen system to facilitate invasion of tissues during infection by modifying the activation of this process through the binding of plasminogen at their surface. METHODOLOGY:The invasion of the brain and the central nervous system by penetration of the protective blood-brain barrier is a prerequisite to the establishment of meningoencephalitis by the opportunistic fungal pathogen C. neoformans. In this study, we examined the ability of C. neoformans to subvert the host plasminogen system to facilitate tissue barrier invasion. Through a combination of biochemical, cell biology, and proteomic approaches, we have shown that C. neoformans utilizes the host plasminogen system to cross tissue barriers, providing support for the hypothesis that plasminogen-binding may contribute to the invasion of the blood-brain barrier by penetration of the brain endothelial cells and underlying matrix. In addition, we have identified the cell wall-associated proteins that serve as plasminogen receptors and characterized both the plasminogen-binding and plasmin-activation potential for this significant human pathogen. CONCLUSIONS:The results of this study provide evidence for the cooperative role of multiple virulence determinants in C. neoformans pathogenesis and suggest new avenues for the development of anti-infective agents in the prevention of fungal tissue invasion

A Noncoding Point Mutation of Zeb1 Causes Multiple Developmental Malformations and Obesity in Twirler Mice

Heterozygous Twirler (Tw) mice develop obesity and circling behavior associated with malformations of the inner ear, whereas homozygous Tw mice have cleft palate and die shortly after birth. Zeb1 is a zinc finger protein that contributes to mesenchymal cell fate by repression of genes whose expression defines epithelial cell identity. This developmental pathway is disrupted in inner ears of Tw/Tw mice. The purpose of our study was to comprehensively characterize the Twirler phenotype and to identify the causative mutation. The Tw/+ inner ear phenotype includes irregularities of the semicircular canals, abnormal utricular otoconia, a shortened cochlear duct, and hearing loss, whereas Tw/Tw ears are severely malformed with barely recognizable anatomy. Tw/+ mice have obesity associated with insulin-resistance and have lymphoid organ hypoplasia. We identified a noncoding nucleotide substitution, c.58+181G>A, in the first intron of the Tw allele of Zeb1 (Zeb1Tw). A knockin mouse model of c.58+181G>A recapitulated the Tw phenotype, whereas a wild-type knockin control did not, confirming the mutation as pathogenic. c.58+181G>A does not affect splicing but disrupts a predicted site for Myb protein binding, which we confirmed in vitro. In comparison, homozygosity for a targeted deletion of exon 1 of mouse Zeb1, Zeb1ΔEx1, is associated with a subtle abnormality of the lateral semicircular canal that is different than those in Tw mice. Expression analyses of E13.5 Twirler and Zeb1ΔEx1 ears confirm that Zeb1ΔEx1 is a null allele, whereas Zeb1Tw RNA is expressed at increased levels in comparison to wild-type Zeb1. We conclude that a noncoding point mutation of Zeb1 acts via a gain-of-function to disrupt regulation of Zeb1Tw expression, epithelial-mesenchymal cell fate or interactions, and structural development of the inner ear in Twirler mice. This is a novel mechanism underlying disorders of hearing or balance

Assessing recent trends in high-latitude Southern Hemisphere surface climate

Understanding the causes of recent climatic trends and variability in the high-latitude Southern Hemisphere is hampered by a short instrumental record. Here, we analyse recent atmosphere, surface ocean and sea-ice observations in this region and assess their trends in the context of palaeoclimate records and climate model simulations. Over the 36-year satellite era, significant linear trends in annual mean sea-ice extent, surface temperature and sea-level pressure are superimposed on large interannual to decadal variability. However, most observed trends are not unusual when compared with Antarctic paleoclimate records of the past two centuries. With the exception of the positive trend in the Southern Annular Mode, climate model simulations that include anthropogenic forcing are not compatible with the observed trends. This suggests that natural variability likely overwhelms the forced response in the observations, but the models may not fully represent this natural variability or may overestimate the magnitude of the forced response

Processes driving sea ice variability in the Bering Sea in an eddying ocean/sea ice model: anomalies from the mean seasonal cycle

A fine-resolution (1/10°) ocean/sea ice model configured in the Community Earth System Model framework is compared with observations and studied to determine the basin-scale and local balances controlling the variability of sea ice anomalies from the mean seasonal cycle in the Bering Sea for the time period 1980–1989. The model produces variations in total Bering Sea ice area anomalies that are highly correlated with observations. Surface air temperature, which is specified from reanalysis atmospheric forcing, strongly controls the ice volume variability in this simulation. The thermodynamic ice volume change is dominated by surface energy flux via atmosphere-ice sensible heat flux, except near the southern ice edge where it is largely controlled by ocean-ice heat flux. While thermodynamic processes dominate the variations in ice volume in the Bering Sea on the large scale, dynamic processes are important on the local scale near ice margins (both oceanic and land), where dynamic and thermodynamic ice volume changes have opposite signs and nearly cancel each other. Ice motion is generally consistent with winds driving the flow, except near certain straits in the north where ice motion largely follows ocean currents. Two key climate events, strong ice growth with cold air temperature and northerly wind anomalies in February 1984 and weak ice growth with warm air temperature and southerly wind anomalies in February 1989, are studied here in detail. While the processes controlling the ice changes are generally similar to those in other years, these large events help reveal the characteristic spatial patterns of ice growth/melt and transport anomalies

Processes driving sea ice variability in the Bering Sea in an eddying ocean/sea ice model: anomalies from the mean seasonal cycle

A fine-resolution (1/10°) ocean/sea ice model configured in the Community Earth System Model framework is compared with observations and studied to determine the basin-scale and local balances controlling the variability of sea ice anomalies from the mean seasonal cycle in the Bering Sea for the time period 1980–1989. The model produces variations in total Bering Sea ice area anomalies that are highly correlated with observations. Surface air temperature, which is specified from reanalysis atmospheric forcing, strongly controls the ice volume variability in this simulation. The thermodynamic ice volume change is dominated by surface energy flux via atmosphere-ice sensible heat flux, except near the southern ice edge where it is largely controlled by ocean-ice heat flux. While thermodynamic processes dominate the variations in ice volume in the Bering Sea on the large scale, dynamic processes are important on the local scale near ice margins (both oceanic and land), where dynamic and thermodynamic ice volume changes have opposite signs and nearly cancel each other. Ice motion is generally consistent with winds driving the flow, except near certain straits in the north where ice motion largely follows ocean currents. Two key climate events, strong ice growth with cold air temperature and northerly wind anomalies in February 1984 and weak ice growth with warm air temperature and southerly wind anomalies in February 1989, are studied here in detail. While the processes controlling the ice changes are generally similar to those in other years, these large events help reveal the characteristic spatial patterns of ice growth/melt and transport anomalies

Processes driving sea ice variability in the Bering Sea in an eddying ocean/sea ice model: Mean seasonal cycle

The seasonal cycle of sea ice variability in the Bering Sea, together with the thermodynamic and dynamic processes that control it, are examined in a fine resolution (1/10°) global coupled ocean/sea-ice model configured in the Community Earth System Model (CESM) framework. The ocean/sea-ice model consists of the Los Alamos National Laboratory Parallel Ocean Program (POP) and the Los Alamos Sea Ice Model (CICE). The model was forced with time-varying reanalysis atmospheric forcing for the time period 1970-1989. This study focuses on the time period 1980-1989. The simulated seasonal-mean fields of sea ice concentration strongly resemble satellite-derived observations, as quantified by root-mean-square errors and pattern correlation coefficients. The sea ice energy budget reveals that the seasonal thermodynamic ice volume changes are dominated by the surface energy flux between the atmosphere and the ice in the northern region and by heat flux from the ocean to the ice along the southern ice edge, especially on the western side. The sea ice force balance analysis shows that sea ice motion is largely associated with wind stress. The force due to divergence of the internal ice stress tensor is large near the land boundaries in the north, and it is small in the central and southern ice-covered region. During winter, which dominates the annual mean, it is found that the simulated sea ice was mainly formed in the northern Bering Sea, with the maximum ice growth rate occurring along the coast due to cold air from northerly winds and ice motion away from the coast. South of St Lawrence Island, winds drive the model sea ice southwestward from the north to the southwestern part of the ice-covered region. Along the ice edge in the western Bering Sea, model sea ice is melted by warm ocean water, which is carried by the simulated Bering Slope Current flowing to the northwest, resulting in the S-shaped asymmetric ice edge. In spring and fall, similar thermodynamic and dynamic patterns occur in the model, but with typically smaller magnitudes and with season-specific geographical and directional differences

Processes driving sea ice variability in the Bering Sea in an eddying ocean/sea ice model: Mean seasonal cycle

The seasonal cycle of sea ice variability in the Bering Sea, together with the thermodynamic and dynamic processes that control it, are examined in a fine resolution (1/10°) global coupled ocean/sea-ice model configured in the Community Earth System Model (CESM) framework. The ocean/sea-ice model consists of the Los Alamos National Laboratory Parallel Ocean Program (POP) and the Los Alamos Sea Ice Model (CICE). The model was forced with time-varying reanalysis atmospheric forcing for the time period 1970-1989. This study focuses on the time period 1980-1989. The simulated seasonal-mean fields of sea ice concentration strongly resemble satellite-derived observations, as quantified by root-mean-square errors and pattern correlation coefficients. The sea ice energy budget reveals that the seasonal thermodynamic ice volume changes are dominated by the surface energy flux between the atmosphere and the ice in the northern region and by heat flux from the ocean to the ice along the southern ice edge, especially on the western side. The sea ice force balance analysis shows that sea ice motion is largely associated with wind stress. The force due to divergence of the internal ice stress tensor is large near the land boundaries in the north, and it is small in the central and southern ice-covered region. During winter, which dominates the annual mean, it is found that the simulated sea ice was mainly formed in the northern Bering Sea, with the maximum ice growth rate occurring along the coast due to cold air from northerly winds and ice motion away from the coast. South of St Lawrence Island, winds drive the model sea ice southwestward from the north to the southwestern part of the ice-covered region. Along the ice edge in the western Bering Sea, model sea ice is melted by warm ocean water, which is carried by the simulated Bering Slope Current flowing to the northwest, resulting in the S-shaped asymmetric ice edge. In spring and fall, similar thermodynamic and dynamic patterns occur in the model, but with typically smaller magnitudes and with season-specific geographical and directional differences

Multiple sea-ice states and abrupt MOC transitions in a general circulation ocean model

Sea ice has been suggested, based on simple models, to play an important role in past glacial–interglacial oscillations via the so-called “sea-ice switch” mechanism. An important requirement for this mechanism is that multiple sea-ice extents exist under the same land ice configuration. This hypothesis of multiple sea-ice extents is tested with a state-of-the-art ocean general circulation model coupled to an atmospheric energy–moisture-balance model. The model includes a dynamic-thermodynamic sea-ice module, has a realistic ocean configuration and bathymetry, and is forced by annual mean forcing. Several runs with two different land ice distributions represent present-day and cold-climate conditions. In each case the ocean model is initiated with both ice-free and fully ice-covered states. We find that the present-day runs converge approximately to the same sea-ice state for the northern hemisphere while for the southern hemisphere a difference in sea-ice extent of about three degrees in latitude between the different runs is observed. The cold climate runs lead to meridional sea-ice extents that are different by up to four degrees in latitude in both hemispheres. While approaching the final states, the model exhibits abrupt transitions from extended sea-ice states and weak meridional overturning circulation, to less extended sea ice and stronger meridional overturning circulation, and vice versa. These transitions are linked to temperature changes in the North Atlantic high-latitude deep water. Such abrupt changes may be associated with Dansgaard–Oeschger events, as proposed by previous studies. Although multiple sea ice states have been observed, the difference between these states is not large enough to provide a strong support for the sea-ice-switch mechanism