Ring-like Oligomers of Synaptotagmins and Related C2 Domain Proteins

We recently reported that the C2AB portion of Synaptotagmin 1 (Syt1) could self-assemble into Ca2+-sensitive ring-like oligomers on membranes, which could potentially regulate neurotransmitter release. Here we report that analogous ring-like oligomers assemble from the C2AB domains of other Syt isoforms (Syt2, Syt7, Syt9) as well as related C2 domain containing protein, Doc2B and extended Synaptotagmins (E-Syts). Evidently, circular oligomerization is a general and conserved structural aspect of many C2 domain proteins, including Synaptotagmins. Further, using electron microscopy combined with targeted mutations, we show that under physiologically relevant conditions, both the Syt1 ring assembly and its rapid disruption by Ca2+ involve the well-established functional surfaces on the C2B domain that are important for synaptic transmission. Our data suggests that ring formation may be triggered at an early step in synaptic vesicle docking and positions Syt1 to synchronize neurotransmitter release to Ca2+ influx

Asymmetry to symmetry transition of Fano line-shape: Analytical derivation

An analytical derivation of Fano line-shape asymmetry ratio has been presented here for a general case. It is shown that Fano line-shape becomes less asymmetric as \q is increased and finally becomes completely symmetric in the limiting condition of q equal to infinity. Asymmetry ratios of Fano line-shapes have been calculated and are found to be in good consonance with the reported expressions for asymmetry ratio as a function of Fano parameter. Application of this derivation is also mentioned for explanation of asymmetry to symmetry transition of Fano line-shape in quantum confined silicon nanostructures.Comment: 3 figures, Latex files, Theoretica

Hibernation-like state induced by an opioid peptide protects against experimental stroke

BACKGROUND: Delta opioid peptide [D-ala2,D-leU5]enkephalin (DADLE) induces hibernation in summer ground squirrels, and enhances preservation and survival of isolated or transplanted lungs and hearts. In the present study, we investigated the protective effect of DADLE in the central nervous system. RESULTS: Adult Sprague-Dawley rats were pretreated with DADLE (4 mg/kg every 2 h x 4 injections, i.p.) or saline prior to unilateral occlusion of the middle cerebral artery (MCA). Daily behavioral tests revealed that ischemic animals treated with DADLE did not show any significant behavioral dysfunctions compared with saline-treated ischemic animals. Opioid antagonists only transiently inhibited the protective effect of DADLE, indicating the participation of non-opioid mechanisms in DADLE neuroprotection. Histological examination using triphenyltetrazolium chloride (TTC) revealed that brains from ischemic animals treated with DADLE, either alone or with adjuvant opioid blockers, exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals. CONCLUSION: These results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. The present study demonstrates that delta opioids are crucially involved in stroke, suggesting that the opioid system is important in the study of brain injury and protection

Computational study of reservoir sand production mechanisms

A numerical model is developed to simulate fluid flow conditions around a wellbore and to evaluate mechanisms governing fluid flow, pressure gradients, rock failure and the ensuing sand production. The rock material behaviour matches sandstone described by the Drucker–Prager material failure model. Conditions for erosion are governed through two criteria: a material failure criterion described by the Drucker–Prager model and a sanding criterion expressed by an eroded solid mass generation model. The interplay between controlling operating and reservoir conditions is assessed. In addition, contributions of the following key factors to interstitial fluid velocity, plastic strain, pore pressure variation and sand production are appraised: drawdown, wellbore perforation depth, mud pressure and erosion criteria. Despite a decrease in pore fluid velocity at the vicinity of the wellbore at increasing depth, sand production increases with wellbore/perforation depth. Likewise, at constant drawdown, sand production is aggravated as wellbore/perforation depth increases. The rate of increase in the plastic zone following the onset of sand production is inconstant. Furthermore, mud pressure is demonstrated as an effective tool for attenuating sand production. An understanding of interactions between key parameters governing reservoir responses and the effect on sanding during oil/gas production is imperative if extraction operations are to be optimised.Published onlin

A population-based study of race-specific risk for placental abruption

<p>Abstract</p> <p>Background</p> <p>Efforts to elucidate risk factors for placental abruption are imperative due to the severity of complications it produces for both mother and fetus, and its contribution to preterm birth. Ethnicity-based differences in risk of placental abruption and preterm birth have been reported. We tested the hypotheses that race, after adjusting for other factors, is associated with the risk of placental abruption at specific gestational ages, and that there is a greater contribution of placental abruption to the increased risk of preterm birth in Black mothers, compared to White mothers.</p> <p>Methods</p> <p>We conducted a population-based cohort study using the Missouri Department of Health's maternally-linked database of all births in Missouri (1989–1997) to assess racial effects on placental abruption and the contribution of placental abruption to preterm birth, at different gestational age categories (n = 664,303).</p> <p>Results</p> <p>Among 108,806 births to Black mothers and 555,497 births to White mothers, 1.02% (95% CI 0.96–1.08) of Black births were complicated by placental abruption, compared to 0.71% (95% CI 0.69–0.73) of White births (aOR 1.32, 95% CI 1.22–1.43). The magnitude of risk of placental abruption for Black mothers, compared to White mothers, increased with younger gestational age categories. The risk of placental abruption resulting in term and extreme preterm births (< 28 weeks) was higher for Black mothers (aOR 1.15, 95% CI 1.02–1.29 and aOR 1.98, 95% CI 1.58–2.48, respectively). Compared to White women delivering in the same gestational age category, there were a significantly higher proportion of placental abruption in Black mothers who delivered at term, and a significantly lower proportion of placental abruption in Black mothers who delivered in all preterm categories (p < 0.05).</p> <p>Conclusion</p> <p>Black women have an increased risk of placental abruption compared to White women, even when controlling for known coexisting risk factors. This risk increase is greatest at the earliest preterm gestational ages when outcomes are the poorest. The relative contribution of placental abruption to term births was greater in Black women, whereas the relative contribution of placental abruption to preterm birth was greater in White women.</p

Structural basis for the clamping and Ca²⁺ activation of SNARE-mediated fusion by synaptotagmin

Synapotagmin-1 (Syt1) interacts with both SNARE proteins and lipid membranes to synchronize neurotransmitter release to calcium (Ca2+) influx. Here we report the cryo-electron microscopy structure of the Syt1–SNARE complex on anionic-lipid containing membranes. Under resting conditions, the Syt1 C2 domains bind the membrane with a magnesium (Mg2+)-mediated partial insertion of the aliphatic loops, alongside weak interactions with the anionic lipid headgroups. The C2B domain concurrently interacts the SNARE bundle via the ‘primary’ interface and is positioned between the SNAREpins and the membrane. In this configuration, Syt1 is projected to sterically delay the complete assembly of the associated SNAREpins and thus, contribute to clamping fusion. This Syt1–SNARE organization is disrupted upon Ca2+-influx as Syt1 reorients into the membrane, likely displacing the attached SNAREpins and reversing the fusion clamp. We thus conclude that the cation (Mg2+/Ca2+) dependent membrane interaction is a key determinant of the dual clamp/activator function of Synaptotagmin-1

CARDIAN: a novel computational approach for real-time end-diastolic frame detection in intravascular ultrasound using bidirectional attention networks

INTRODUCTION: Changes in coronary artery luminal dimensions during the cardiac cycle can impact the accurate quantification of volumetric analyses in intravascular ultrasound (IVUS) image studies. Accurate ED-frame detection is pivotal for guiding interventional decisions, optimizing therapeutic interventions, and ensuring standardized volumetric analysis in research studies. Images acquired at different phases of the cardiac cycle may also lead to inaccurate quantification of atheroma volume due to the longitudinal motion of the catheter in relation to the vessel. As IVUS images are acquired throughout the cardiac cycle, end-diastolic frames are typically identified retrospectively by human analysts to minimize motion artefacts and enable more accurate and reproducible volumetric analysis. METHODS: In this paper, a novel neural network-based approach for accurate end-diastolic frame detection in IVUS sequences is proposed, trained using electrocardiogram (ECG) signals acquired synchronously during IVUS acquisition. The framework integrates dedicated motion encoders and a bidirectional attention recurrent network (BARNet) with a temporal difference encoder to extract frame-by-frame motion features corresponding to the phases of the cardiac cycle. In addition, a spatiotemporal rotation encoder is included to capture the IVUS catheter's rotational movement with respect to the coronary artery. RESULTS: With a prediction tolerance range of 66.7 ms, the proposed approach was able to find 71.9%, 67.8%, and 69.9% of end-diastolic frames in the left anterior descending, left circumflex and right coronary arteries, respectively, when tested against ECG estimations. When the result was compared with two expert analysts’ estimation, the approach achieved a superior performance. DISCUSSION: These findings indicate that the developed methodology is accurate and fully reproducible and therefore it should be preferred over experts for end-diastolic frame detection in IVUS sequences

Universality of pseudogap and emergent order in lightly doped Mott insulators

It is widely believed that high-temperature superconductivity in the cuprates emerges from doped Mott insulators. The physics of the parent state seems deceivingly simple: The hopping of the electrons from site to site is prohibited because their on-site Coulomb repulsion U is larger than the kinetic energy gain t. When doping these materials by inserting a small percentage of extra carriers, the electrons become mobile but the strong correlations from the Mott state are thought to survive; inhomogeneous electronic order, a mysterious pseudogap and, eventually, superconductivity appear. How the insertion of dopant atoms drives this evolution is not known, nor whether these phenomena are mere distractions specific to hole-doped cuprates or represent the genuine physics of doped Mott insulators. Here, we visualize the evolution of the electronic states of (Sr1-xLax)2IrO4, which is an effective spin-1/2 Mott insulator like the cuprates, but is chemically radically different. Using spectroscopic-imaging STM, we find that for doping concentration of x=5%, an inhomogeneous, phase separated state emerges, with the nucleation of pseudogap puddles around clusters of dopant atoms. Within these puddles, we observe the same glassy electronic order that is so iconic for the underdoped cuprates. Further, we illuminate the genesis of this state using the unique possibility to localize dopant atoms on topographs in these samples. At low doping, we find evidence for much deeper trapping of carriers compared to the cuprates. This leads to fully gapped spectra with the chemical potential at mid-gap, which abruptly collapse at a threshold of around 4%. Our results clarify the melting of the Mott state, and establish phase separation and electronic order as generic features of doped Mott insulators.Comment: This version contains the supplementary information and small updates on figures and tex

Observation of Bose-Einstein Condensation in a Strong Synthetic Magnetic Field

Extensions of Berry's phase and the quantum Hall effect have led to the discovery of new states of matter with topological properties. Traditionally, this has been achieved using gauge fields created by magnetic fields or spin orbit interactions which couple only to charged particles. For neutral ultracold atoms, synthetic magnetic fields have been created which are strong enough to realize the Harper-Hofstadter model. Despite many proposals and major experimental efforts, so far it has not been possible to prepare the ground state of this system. Here we report the observation of Bose-Einstein condensation for the Harper-Hofstadter Hamiltonian with one-half flux quantum per lattice unit cell. The diffraction pattern of the superfluid state directly shows the momentum distribution on the wavefuction, which is gauge-dependent. It reveals both the reduced symmetry of the vector potential and the twofold degeneracy of the ground state. We explore an adiabatic many-body state preparation protocol via the Mott insulating phase and observe the superfluid ground state in a three-dimensional lattice with strong interactions.Comment: 6 pages, 5 figures. Supplement: 6 pages, 4 figure

The intestinal expulsion of the roundworm Ascaris suum is associated with eosinophils, intra-epithelial T cells and decreased intestinal transit time

Ascaris lumbricoides remains the most common endoparasite in humans, yet there is still very little information available about the immunological principles of protection, especially those directed against larval stages. Due to the natural host-parasite relationship, pigs infected with A. suum make an excellent model to study the mechanisms of protection against this nematode. In pigs, a self-cure reaction eliminates most larvae from the small intestine between 14 and 21 days post infection. In this study, we investigated the mucosal immune response leading to the expulsion of A. suum and the contribution of the hepato-tracheal migration. Self-cure was independent of previous passage through the liver or lungs, as infection with lung stage larvae did not impair self-cure. When animals were infected with 14-day-old intestinal larvae, the larvae were being driven distally in the small intestine around 7 days post infection but by 18 days post infection they re-inhabited the proximal part of the small intestine, indicating that more developed larvae can counter the expulsion mechanism. Self-cure was consistently associated with eosinophilia and intra-epithelial T cells in the jejunum. Furthermore, we identified increased gut movement as a possible mechanism of self-cure as the small intestinal transit time was markedly decreased at the time of expulsion of the worms. Taken together, these results shed new light on the mechanisms of self-cure that occur during A. suum infections