Biological Markers in Lower Jurassic Synrift Lacustrine Black Shales, Hartford Basin, Connecticut, U.S.A.

The East Berlin Formation (Lower Jurassic, Hartford basin, Connecticut, U.S.A.) is distinctive for its six cyclic units of lacustrine black shale and gray mudstone. separated by playa and fluvial redbeds. The black shales arc each about a meter thick and were deposited in subtropical, thermally stratified, oligomictic lakes, the youngest of which (lakes 3 through 6) were large enough to flood most of the basin and attained depths of several tens of meters. The saturate fractions of solvent extracts of organic-rich black shales from each of the six lakes, collected at fresh roadcuts near East Berlin, arc dominated by extended homologous series of n-alkanes, alkylcyclohexanes, and branched chain alkanes. A striking feature of the black shales is the presence of a series of extended tricyclic terpanes from C20 to at least C41. Hopanes arc either not detectable or present only in subordinate quantities relative to the tricyclic terpanes. The samples arc depleted in hopanes in part because of the elevated maturity level (mid to late oil window). Tricyclic terpane concentrations may also have been enhanced by fractionation effects related to oil expulsion out of the black shales. In addition, the original organic matter may have been exceptionally rich in tricyclic terpane precursors, i.e. fossil lipids of prokaryotes present in anoxic, moderately saline, alkaline lakes

Não é bigbang, é o bigboom da live!

Em meio à pandemia de Covid-19 os espaços fí­sicos de circulação dos corpos foram transvertidos em uma maior circulação pelo meio virtual, os corpos antes vistos em materialidade passam para uma imagem que se mostra restrita ao enquadramento da tela. Nesse contexto emergem as mais diversas lives e com elas surge toda uma gama de códigos estabelecidos como normais ao uso dessa plataforma. Tocadas por essas e outras questões, as autoras desse texto desenvolveram a "Performance em Pauta" , uma contra-performance que se mimetiza de live e abre conexões outras de presença, afeto e da própria pesquisa artí­stica de ambas as proponentes. Em duas edições realizadas da ação, a coautoria se torna uma constante: tanto pela atuação do próprio dispositivo digital/rede de internet que dialogam com as performers por meio da oferta de falhas e erros recorrentes e prontamente incorporados ao trabalho, quanto pela coautoria dos espectadores que assistiam ao trabalho e passam a interferir deliberadamente na construção de outras imagens a partir do que recepcionam. Neste artigo analisamos a criação e desenvolvimento deste trabalho no contexto do isolamento social que atravessa nossas pesquisas, da mesma forma que damos atenção às questões que o próprio fazer da "Performance em Pauta" suscita nas pesquisadoras e no público

Organic Geochemistry of a Lower Jurassic Synrift Lacustrine Sequence, Hartford Basin, Connecticut, U.S.A.

Synrift terrestrial strata of the Lower Jurassic East Berlin Formation (Hartford basin, Connecticut, U.S.A.) record cyclical expansion and contraction of major lakes, six of which were deep enough to develop anoxic bottom waters. We have studied one representative lacustrine sequence in detail, sampling a new roadcut near the village of East Berlin. The section examined is 4 m thick, with a gray siltstone at the base, deposited in shallow water, overlain by an organic-rich black shale (deep water), succeeded in turn by another gray siltstone, deposited as the lake waters gradually receded. The upper gray siltstone is chemically distinct from the lower siltstone, as it contains small amounts of corrensite, analcime and gypsum, reflecting the increasing salinity and alkalinity of the contracting lake. The samples in the center of the black shale unit contain laminae of thermally-altered, yellowish orange-fluorescing, mottled telalginite. The fluorescence properties indicate a peak oil generation maturity level, confirmed by a vitrinite reflectance of 1.13% and a Methylphenanthrene Index of 1.08. The other samples have less organic matter, becoming increasingly lean towards the top and bottom of the sequence. Samples in the middle of the black shale unit are distinguished by the presence of an homologous series of tricyclic terpanes extending from C20 to at least C41 , and by the near absence of hopanes and steranes. Moving upsection into the gray siltstone, the samples contain markedly less extractable organic material (EOM) and the concentration of tricyclic terpanes relative to hopanes steadily decreases. In the uppermost sample, hopanes are the predominant terpanes. Moving downsection from the black shale into the lower gray siltstone, EOM and the ratio of tricyclic terpanes also decrease, except in the lowermost samples, which contain terpane distributions like those of the middle part of the black shale. This likely is migrated material, because bitumen fills microfractures and extensive megafractures. The lack of hopanes and steranes in the black shales cannot simply be a maturation effect, as these biomarkers appear in the adjacent beds. Instead, the unusual terpane distributions may indicate a changing depositional environment, documenting the geochemical evolution of the lake. Or, more likely, they may result from fractionation during expulsion of petroleum from these mature source rocks

In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals

CACNB4 Overexpression and Dendritic Spine Loss in Schizophrenia

Reduced density of dendritic spines is an intermediate anatomical phenotype for schizophrenia (Sz). This dissertation is a collection of descriptive studies about dendritic spines and the voltage-gated calcium channel protein β4, a study of a Sz-related β4 manipulation, and the impacts of this manipulation on dendritic spine density and morphology. Chapter 2 is a descriptive study of sex differences in dendritic spines in murine sensory cortex over adolescent neurodevelopment. Chapter 3 is an in-depth assessment of the impacts of CACNB4 overexpression (β4OE) on dendritic spines of male and female adult mice. Chapter 4 is a final descriptive study of sex differences in the β4 interactome of adult mice. Sex differences were deliberately assessed at baseline and in the study of the impacts of β4OE on dendritic spines given the importance of sex as a biological factor and known sex differences in the clinical presentation and expression of Sz. In Chapter 2, we identified sex differences in spine density, and in Chapter 3 evidence for volume- as well as sex-specific β4OE-mediated spine loss; small spines were reduced in female β4OE mice only. These findings provide a model for the intermediate phenotype of small spine loss in primary auditory cortex in Sz and support both our group’s previous suggestion to rethink the Feinberg hypothesis, but also the possibility that small mature spines are eliminated excessively in Sz during adolescence, as Feinberg predicted. In Chapter 4 we found that β1b is significantly enriched in the β4 interactome of male mice only, the presence of which may confer protection for males from the effects of β4OE. Moreover, we detail three pathways through which β4OE could reduce small spine density in female mice. These proposed pathways nominate kinases and MAPs in β4-related spine alterations. Overall, the findings described herein underscore the importance of evaluating the biological sex at baseline, over normal neurodevelopment and following a disease-related manipulation, particularly neurodevelopmental disorders, including Sz

A high affinity, partial antagonist effect of 3,4-diaminopyridine mediates action potential broadening and enhancement of transmitter release at NMJs

3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-Approved treatment for neuro muscular weakness caused by Lambert-Eaton myasthenic syn drome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the pre synaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-Target agonist effect on the Cav1 subtype ( L-Type ) of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAPs mecha nism(s) of action, we first used the patch-clamp electrophysi ology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-Affinity (1-10 μM) partial antag onist effect of 3,4-DAP in addition to the well-known low-Af finity (0.1-1 mM) antagonist activity. We also showed that 1.5-μM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5-or 100-μM 3,4-DAP broadened the AP waveform in a dose-dependent manner, in dependent of Cav1 calcium channels. Finally, we demonstrated that 1.5-or 100-μM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv chan nels to mediate AP broadening and enhance transmitter release at the NMJ

Multiple roles of integrin-α3 at the neuromuscular junction

The neuromuscular junction (NMJ) is the synapse between motoneurons and skeletal muscle, and is responsible for eliciting muscle contraction. Neurotransmission at synapses depends on the release of synaptic vesicles at sites called active zones (AZs). Various proteins of the extracellular matrix are crucial for NMJ development; however, little is known about the identity and functions of the receptors that mediate their effects. Using genetically modified mice, we find that integrin-α3 (encoded by Itga3), an adhesion receptor at the presynaptic membrane, is involved in the localisation of AZ components and efficient synaptic vesicle release. Integrin-α3 also regulates integrity of the synapse – mutant NMJs present with progressive structural changes and upregulated autophagy, features commonly observed during ageing and in models of neurodegeneration. Unexpectedly, we find instances of nerve terminal detachment from the muscle fibre; to our knowledge, this is the first report of a receptor that is required for the physical anchorage of pre- and postsynaptic elements at the NMJ. These results demonstrate multiple roles of integrin-α3 at the NMJ, and suggest that alterations in its function could underlie defects that occur in neurodegeneration or ageing

Somatostatin Inhibits Cell Migration and Reduces Cell Counts of Human Keratinocytes and Delays Epidermal Wound Healing in an Ex Vivo Wound Model

The peptide hormone somatostatin (SST) and its five G protein-coupled receptors (SSTR1-5) were described to be present in the skin, but their cutaneous function(s) and skin-specific signalling mechanisms are widely unknown. By using receptor specific agonists we show here that the SSTRs expressed in keratinocytes are functionally coupled to the inhibition of adenylate cyclase. In addition, treatment with SSTR4 and SSTR5/1 specific agonists significantly influences the MAP kinase signalling pathway. As epidermal hormone receptors in general are known to regulate re-epithelialization following skin injury, we investigated the effect of SST on cell counts and migration of human keratinocytes. Our results demonstrate a significant inhibition of cell migration and reduction of cell counts by SST. We do not observe an effect on apoptosis and necrosis. Analysis of signalling pathways showed that somatostatin inhibits cell migration independent of its effect on cAMP. Migrating keratinocytes treated with SST show altered cytoskeleton dynamics with delayed lamellipodia formation. Furthermore, the activity of the small GTPase Rac1 is diminished, providing evidence for the control of the actin cytoskeleton by somatostatin receptors in keratinocytes. While activation of all receptors leads to redundant effects on cell migration, only treatment with a SSTR5/1 specific agonist resulted in decreased cell counts. In accordance with reduced cell counts and impaired migration we observe delayed re-epithelialization in an ex vivo wound healing model. Consequently, our experiments suggest SST as a negative regulator of epidermal wound healing

EXPERIMENTAL ANALYSIS OF THE COMPETITION FOR SURVIVAL AMONG DEVELOPING CILIARY GANGLION NEURONS

Naturally occurring neuronal death is a widespread phenomenon in embryogenesis. This normally dramatic reduction in cell number can, to varying degrees, be prevented by excess target tissue, trophic factor, or blockade of the neuromuscular junction. To understand the dependence of developing ciliary ganglion neurons on their targets, it was important to determine the developmental sequence of various characteristics in these tissues.^ The development and pharmacology of neuromuscular and ganglionic transmission is described. Ciliary neurons in the ciliary ganglion innervate the iris and ciliary body muscles of the eye. Synaptic activation of these muscles begins at about St 35 and is mediated via muscarinic ACh receptors on myoepithelial cells. By about St 38, Striated muscle cells develop, and nicotinic ACh receptors predominately mediate iris and ciliary body muscle responses to nerve stimulation.^ The choroid coat of the eye is a smooth muscle sheet which is innervated by the choroid population of the ciliary ganglion. Neuromuscular transmission in the choroid was shown to be possible by about St 35 and is mediated entirely via muscarinic ACh receptors throughout development.^ Experimental manipulations of synaptic activity in the ciliary ganglion system were performed during the normal neuronal death period by administering daily injections of nicotinic or muscarinic ACh receptor blockers to the embryo. In summary, blockade of transmission through the ciliary ganglion increased cell death in both populations of neurons. Neuromuscular blockage at striated muscle synapses delayed neuronal death in the ciliary population, but not in the choroid cell population, where neuromuscular synapses are made with smooth muscle. It is possible that smooth muscle does not respond to synaptic blockade in a manner that supports more neuronal survival.^ Since the effects of ACh receptor blockade on neuronal survival in the ciliary ganglion cannot always be predicted by target muscle activity, the site of action of these effects on neuronal survival was re-evaluated. In general, motoneurons must balance afferent input with target connections during a critical period after both afferent and neuromuscular synapses are made.^ Since opiate peptides have been shown to exist endogenously in preganglionic terminals onto both ciliary and choroid neurons, the opiate agonist morphine was administered daily to the developing chick embryo during the normal neuronal death period. This treatment dramatically increased neuronal survival in both populations of ciliary ganglion neurons, and this effect was completely blocked by naloxone. Morphine appears to regulate neuronal survival via an activity independent mechanism.