Floating debris and organisms can raft to Antarctic coasts from all major Southern Hemisphere landmasses.

Antarctica's unique marine ecosystems are threatened by the arrival of non-native marine species on rafting ocean objects. The harsh environmental conditions in Antarctica prevent the establishment of many such species, but warming around the continent and the opening up of ice-free regions may already be reducing these barriers. Although recent genomic work has revealed that rafts-potentially carrying diverse coastal passengers-reach Antarctica from sub-Antarctic islands, Antarctica's vulnerability to incursions from Southern Hemisphere continents remains unknown. Here we use 0.1° global ocean model simulations to explore whether drift connections exist between more northern, temperate landmasses and the Antarctic coastline. We show that passively floating objects can drift to Antarctica not only from sub-Antarctic islands, but also from continental locations north of the Subtropical Front including Australia, South Africa, South America and Zealandia. We find that the Antarctic Peninsula is the region at highest risk for non-native species introductions arriving by natural oceanic dispersal, highlighting the vulnerability of this region, which is also at risk from introductions via ship traffic and rapid warming. The widespread connections with sub-Antarctic and temperate landmasses, combined with an increasing abundance of marine anthropogenic rafting vectors, poses a growing risk to Antarctic marine ecosystems, especially as environmental conditions around Antarctica are projected to become more suitable for non-native species in the future.

Inhibiting autophagy targets human leukemic stem cells and hypoxic AML blasts by disrupting mitochondrial homeostasis.

Leukemia stem cells (LSCs) and therapy-resistant acute myeloid leukemia (AML) blasts contribute to the reinitiation of leukemia after remission, necessitating therapeutic interventions that target these populations. Autophagy is a prosurvival process that allows for cells to adapt to a variety of stressors. Blocking autophagy pharmacologically by using mechanistically distinct inhibitors induced apoptosis and prevented colony formation in primary human AML cells. The most effective inhibitor, bafilomycin A1 (Baf A1), also prevented the in vivo maintenance of AML LSCs in NSG mice. To understand why Baf A1 exerted the most dramatic effects on LSC survival, we evaluated mitochondrial function. Baf A1 reduced mitochondrial respiration and stabilized PTEN-induced kinase-1 (PINK-1), which initiates autophagy of mitochondria (mitophagy). Interestingly, with the autophagy inhibitor chloroquine, levels of enhanced cell death and reduced mitochondrial respiration phenocopied the effects of Baf A1 only when cultured in hypoxic conditions that mimic the marrow microenvironment (1% O2). This indicates that increased efficacy of autophagy inhibitors in inducing AML cell death can be achieved by concurrently inducing mitochondrial damage and mitophagy (pharmacologically or by hypoxic induction) and blocking mitochondrial degradation. In addition, prolonged exposure of AML cells to hypoxia induced autophagic flux and reduced chemosensitivity to cytarabine (Ara-C), which was reversed by autophagy inhibition. The combination of Ara-C with Baf A1 also decreased tumor burden in vivo. These findings demonstrate that autophagy is critical for mitochondrial homeostasis and survival of AML cells in hypoxia and support the development of autophagy inhibitors as novel therapeutic agents for AML.

Computer managed instruction in a "clinical presentation-based" curriculum.

Many institutions are currently in the process of reorganizing their medical curricula from various traditional forms to a problem-based format. This method of instruction inevitably leads to a shift from traditional lecture and laboratory sessions to a more student oriented, small group session--a self-guided learning approach. This paper discusses the development and use of a system designed to provide the student with the necessary tools to access and control their learning environment.

Low concentrations of hydrogen sulphide alter monoamine levels in the developing rat central nervous system.

The central nervous system is one of the primary target organs for hydrogen sulphide (H2S) toxicity; however, there are limited data on the neurotoxic effects of low-dose chronic exposure on the developing nervous system. Levels of serotonin and norepinephrine in the developing rat cerebellum and frontal cortex were determined following chronic exposure to 20 and 75 ppm H2S during perinatal development. Both monoamines were altered in rats exposed to 75 ppm H2S compared with controls; serotonin levels were significantly increased at days 14 and 21 postnatal in both brain regions, and norepinephrine levels were significantly increased at days 7, 14, and 21 postnatal in cerebellum and at day 21 in the frontal cortex. Exposure to 20 ppm H2S significantly increased the levels of serotonin in the frontal cortex at day 21, whereas levels of norepinephrine were significantly reduced in the frontal cortex at days 14 and 21, and at day 14 in the cerebellum.

Chronic exposure to low concentrations of hydrogen sulfide produces abnormal growth in developing cerebellar Purkinje cells.

Hydrogen sulfide (H2S) may produce deleterious effects on the developing central nervous system. The dendritic fields of developing cerebellar Purkinje cells were analyzed to determine the effects of chronic exposure to low concentrations of H2S during perinatal development. Treatment with two concentrations (20 and 50 ppm) of H2S produced severe alterations in the architecture and growth characteristics of the Purkinjec cell dendritic fields. The architectural modifications included longer branches, an increase in the vertex path length and variations in the number of branches in particular areas of the dendritic field. The treated cells also exhibited a nonsymmetrical growth pattern at a time when random terminal branching is normally occurring. These findings suggest that developing neurons exposed to low concentrations of H2S are at risk of severe deficits.

Hydrogen sulfide exposure alters the amino acid content in developing rat CNS.

Hydrogen sulfide is a widespread environmental pollutant that may produce severe effects on the developing nervous system. Putative amino acid neurotransmitter levels in the rat cerebrum and cerebellum were determined to evaluate the effects of exposure to hydrogen sulfide during perinatal development. The levels of aspartate, GABA, glutamate, glycine and taurine were quantitated using high-performance liquid chromatography. With the exception of glycine, all of the amino acids examined were affected by the treatment. On day 21 postnatal, which was the last day of the exposure, aspartate, glutamate and GABA in the cerebrum and aspartate and GABA in the cerebellum were significantly depressed. The observed alterations in the amino acid levels during this critical phase of development may have chronically affected the activity of the neurotransmitters, their receptor sensitivity or their individual target areas. The consequence of one or a combination of such alterations may lead to behavioral and structural abnormalities.

The effects of two anticonvulsants on amino acid levels in the developing rat cerebellum.

Two anticonvulsants were administered pre- and postnatally to determine their effects on putative amino acid neurotransmitter levels in the rat cerebellum. The amino acids were quantitated using precolumn fluorescence derivatization and reverse-phase high performance liquid chromatography at various postnatal intervals. Treatment with clonazepam produced an initial depression in levels of most of the amino acids analyised. By three weeks postnatal all the amino acids, with the exception of GABA, had returned to control levels. GABA levels were still depressed five weeks after the cessation of treatment. Phenobarbital treatment produced an initial elevation in the level of GABA. At three weeks postnatal, both GABA and glutamate levels were elevated and remained so at eight weeks postnatal. In conclusion, the data demonstrated that each anticonvulsant produced unique, acute and chronic alterations in the levels of the cerebellar amino acids.

Effect of phenobarbital on Purkinje cell growth patterns in the rat cerebellum.

The effects of low level phenobarbital administration (18 postcoitus to 21 days postnatal) on Purkinje cell growth and remodeling were studied from 3 to 20 weeks postnatal). The Purkinje cell dendritic trees were analyzed both metrically and topologically using the method of vertex analysis. The total segment length, mean terminal path length, and mean vertex path length were reduced in the treated cells. The pattern of segment frequency as related to equivalent orders was abnormal in the treated cells. The Va/Vb vertex ratios and the levels of trichotomy indicated that the treated cells underwent nonrandom remodeling, unlike the control cells which exhibited dichotomous, random terminal branching. These observations confirm that phenobarbital produces distinct long-term morphologic alterations in Purkinje cells.

The effect of chlorpromazine on monoamine levels in the rat cerebellum and hippocampus: a developmental study.

Acute and chronic alterations of the monoamine levels in the rat cerebellum and hippocampus after late prenatal and early postnatal administration of chlorpromazine, were examined using high performance liquid chromatography with electrochemical detection. During a critical phase of development (one week postnatal), chlorpromazine produced increased levels of both serotonin and dopamine in both brain regions. At 24 weeks postnatal, or 21 weeks after cessation of drug administration, the levels of all 3 monoamines were decreased in the cerebellum and increased in the hippocampus. The early disruption in the normal monoamine levels may be related to abnormal growth patterns observed in previous studies.

Effect of chlorpromazine on Purkinje cell growth patterns.

The phenothiazine, chlorpromazine, when administered perinatally to rats is implicated in the production of both motor and behavioural deficits. In this study the effects of chlorpromazine on dendritic growth of cerebellar Purkinje cells were examined after administering the drug to litters of Long-Evans hooded rats from 18 days postcoitus to 21 days postnatum. Various parameters of Purkinje cell growth were analysed at specific times after treatment utilizing Golgi-prepared specimens. Granule cell density was used as an estimate of parallel fibre numbers. When compared with control Purkinje cells the treated cells at 7 weeks postnatum had established longer segments and increased mean vertex path length. The total number of segments was also increased and the distribution of segments of different orders was abnormal. In addition, the spines on terminal dendritic branches were both longer and of increased density in the chlorpromazine-treated group. These observations confirm that chlorpromazine produces distinct morphological alterations in mature Purkinje cells.

X-ray microscopy using a scanning electron microscope for the purpose of imaging central nervous system structures.

A simple modification of an Hitachi S.450 specimen stage permits point source X-ray microscopy with a scanning electron microscope. Point source X-ray microscopy was applied to nervous tissue to determine the feasibility of utilizing this technique instead of a light microscope mounted camera lucida to produce 2- and 3-dimensional images of whole structures such as neurons. Various target materials, radio-opaque materials and photographic films were examined in this study.

The effects of chlorpromazine and phenobarbital on cerebellar Purkinje cells.

The morphological effects of two chemically different neuroactive drugs (chlorpromazine and phenobarbital) on developing Purkinje cells in the rat cerebellum were examined to determine the presence of cytological alterations. Therapeutic dosages of both drugs were chronically administered to separate groups of maternal rats beginning on day 18 postcoitus. Entire litters were sacrificed on postnatal days 13, 15, 18, and 21. Light microscopic quantitation of Purkinje cells demonstrated a statistically significant reduction in total numbers below control levels at all ages examined for both drugs. Pyknotic Purkinje cells, which appeared more numerous in the drug tested groups, had a paucity of synaptic contacts on both the soma and dendritic branches. Both drugs tested produced similar results within the parameters examined. These alterations have been discussed in relation to possible mechanisms and sites of action.

The effects of chlorpromazine and phenobarbital on vasculogenesis in the cerebellar cortex.

The morphological effects of two chemically different neuroactive drugs (chlorpromazine and phenobarbital) on vasculogenesis in rat cerebellum were examined to determine the presence of vascular alterations. Therapeutic dosages of both drugs were chronically administered to separate groups of maternal rats beginning on days 10, 13, 15, 18, and 21. In chlorpromazine-treated animals the specific length of blood vessels was most severely reduced in the Purkinje cell layer. Animals treated with phenobarbital demonstrated an initial reduction in specific length in the Purkinje cell layer but returned to control values by day 21 postnatal (p.n.). Blood vessels in the molecular and granular layers showed little change. The observed changes have been discussed in relation to possible mechanisms and their relationship to neurogenesis.

Hyperoxia: effects on the vascularization of the developing central nervous system.

Litters of experimental and control hamsters were killed on postnatal days 3, 4, 7, 14, 21, and 28 following 7 days of exposure to 85% oxygen at normabaric pressure. Using analysis of variance (ANOVA), light microscopy quantitation of the number of blood vessel profiles per unit area in the region of the frontal cerebral cortex demonstrated that the combined effect of treatment and age on the animals produced a highly statistically significant difference (p less than 0.001) in the numbers of blood vessel profiles. The statistically separated treatment effect was also found to be significant (P less than 0.05). The data are summarized in Table 1. Ultrastructural analysis of animals exposed to oxygen only, i.e., killed without being returned to the normal air environment, demonstrated severe signs of vaso-obliteration. Animals which were returned to a normal atmosphere following 7 days in oxygen showed a progressive decrease in the signs of vaso-obliteration. This present study demonstrated the marked similarity between the effects of hyperoxia on he CNS and on the neuro-retina.

Three-dimensional reconstruction of specialized endoplasmic reticulum in neurons of the rat substantia gelatinosa.

Specializations of the agranular endoplasmic reticulum have been observed in neurons of the rat substantia gelatinosa. Three-dimensional models of immature and mature forms were reconstructed from stereomicrographs obtained with the high voltage electron microscope. The immature specializations consisted of two or more parallel, interconnected agranular cisternae with an electron dense material between adjacent cisternal walls. Mature specializations appeared whorl-like in cross-section. Throughout differentiation and maturity, the specialized agranular cisternae are connected to subsurface cisternae by the granular endoplasmic reticulum. These structures may play a role in chemical storage or synthesis.

Specializations of the ependyma in the third ventricle of the developing hamster.

Ependymal cells in the region of the hypothalamic sulcus, hypothalamus, infundibular recess and supraoptic recess exhibit large apical protrusions between day 12 and day 14 post coitus. The ependyma was examined using light microscopy and transmission and scanning electron microscopy. The protrusions contain ribosomes and cytoplasmic matrix. Occasionally other cytoplasmic organelles were found within the protrusions. The protrusions range in shape from a rounded elevation of the apical surface of the ependymal cell to spherical bodies attached to cell surface by a slender stalk. The unique transitory specialization of the ependyma may represent either a neurosecretory or mechanical folding mechanism.

Three-dimensional development of luminal projections and junctional complexes in the developing central nervous system blood vessels of the rat.

The luminal surface features and junctional complexes from developing blood vessels in the rat central nervous system have been studied by high-voltage electron microscopy and scanning electron microscopy. Developing blood vessels exhibit three types of luminal projections; marginal folds or ridges at junctional complexes, ridges not at junctional complexes and microvilli. Both types of ridges are associated with troughs or depressions in the luminal surface of the endothelial cell. Those ridges not associated with junctional complexes take part inthe production of enclosed tunnels in the endothelial cell cytoplasm. Fusion of the external leaflets of junctional complexes between adjacent endothelial cells occurred, initially, near the luminal surface of the blood vemina secondarily. Further fusion activity to produce the zonula occludens type junction appeared to spread outwards from the smaller fusion sites.

Ultrastructural studies on postnatal differentiation of neurons in the substantia gelatinosa of rat cervical spinal cord.

Neuroblasts of the substantia gelatinosa at birth were small with large oval nuclei and scanty cytoplasm. The cytoplasm possessed ribosomes and mitochondria. Granular endoplasmic reticulum and Golgi complexes were generally absent or rudimentary. Electron dense bodies were seldom observed. By the end of the first week, the nuclei of several cells demonstrated early nuclear invaginations; cytoplasm exhibited growth cones, a well developed granular endoplasmic reticulum and Golgi complexes. At several points the channels of endoplasmic reticulum became continuous with the perinuclear space. By the end of the second week, differentiation of the neuroblasts was more advanced. More nuclei showed invagination of their contour. The cytoplasm revealed well dev-loped granular endoplasmic reticulum and multiple Golgi complexes. Numerous vesicles and dense bodies were found adjacent to the Golgi complexes. Arrays of agranular endoplasmic reticulum also appeared late in the second week. By the third week, features of neuronal differentiation, such as nuclear invagination, granular endoplasmic reticulum agranular membrane configurations, multiple Golgi complexes and dense bodies in the cytoplasm became well established.