Herpes simplex viruses (HSVs) rely on capsid-associated tegument complex (CATC) for long-range axonal transport of their genome-containing capsids between sites of infection and neuronal cell bodies. ...Here we report cryo-electron microscopy structures of the HSV-1 capsid with CATC up to 3.5-angstrom resolution and atomic models of multiple conformers of capsid proteins VP5, VP19c, VP23, and VP26 and tegument proteins pUL17, pUL25, and pUL36. Crowning every capsid vertex are five copies of heteropentameric CATC, each containing a pUL17 monomer supporting the coiled-coil helix bundle of a pUL25 dimer and a pUL36 dimer, thus positioning their flexible domains for potential involvement in nuclear capsid egress and axonal capsid transport. Notwithstanding newly discovered fold conservation between triplex proteins and bacteriophage λ protein gpD and the previously recognized bacteriophage HK97 gp5-like fold in VP5, HSV-1 capsid proteins exhibit extraordinary diversity in forms of domain insertion and conformational polymorphism, not only for interactions with tegument proteins but also for encapsulation of large genomes.
Quantum phase transitions (QPTs) are usually associated with many-body systems in the thermodynamic limit when their ground states show abrupt changes at zero temperature with variation of a ...parameter in the Hamiltonian. Recently it has been realized that a QPT can also occur in a system composed of only a two-level atom and a single-mode bosonic field, described by the quantum Rabi model (QRM). Here we report an experimental demonstration of a QPT in the QRM using a
Yb
ion in a Paul trap. We measure the spin-up state population and the average phonon number of the ion as two order parameters and observe clear evidence of the phase transition via adiabatic tuning of the coupling between the ion and its spatial motion. An experimental probe of the phase transition in a fundamental quantum optics model without imposing the thermodynamic limit opens up a window for controlled study of QPTs and quantum critical phenomena.
Using Time History of Events and Macroscale Interactions during Substorms observations from four tail seasons, we study the three‐dimensional structure of the dipolarization front current sheet ...(DFCS), which demarcates the magnetic boundary of a dipolarizing flux bundle (DFB, the strong magnetic field region led by a dipolarization front) in Earth's magnetotail. An equatorial cross section of the DFCS is convex; a meridional cross section is consistent with a dipolarized field line. The equatorial flow pattern in the ambient plasma ahead of the DFCS exhibits diversions of opposite sense on its evening and morning sides. The magnetic field perturbations are consistent with local field‐aligned current generation of region‐2 sense ahead of the front and region‐1 sense at the front. The median thickness of the DFCS increases from 800 to 2000 km with increasing distance from the neutral sheet, indicating bundle compression near the neutral sheet. On a meridional cross section, DFCS's linear current density (1.2–1.8 nA/m) peaks ~±0.55 l from the neutral sheet (where l is the ambient cross‐tail current sheet half‐thickness, l ~1.5 RE in our database). This peak, reminiscent of active‐time cross‐tail current sheet bifurcation noted in past studies, suggests that the intense but thin DFCS (10 to 20 nA/m2) may be produced by redistribution (diversion) of the extended but weaker cross‐tail current (~1 nA/m2). Near the neutral sheet, the average DFCS current over the dipolarization front (DF) thickness is perpendicular to both the magnetic field interior to the DFB and the average field direction over the DF thickness. Away from the neutral sheet, the average current becomes progressively parallel to the internal field and the average field direction. The average current directions are indicative of region‐1‐sense field‐aligned current on the DF. As few as approximately three DFBs can carry sufficient total current that, if redirected into the auroral ionosphere, can account for the substorm current wedge's peak current for a sizable substorm (~1 MA). A collapsing DFB could thus be an elemental substorm current wedge, or “wedgelet,” that can divert a sizable portion of the cross‐tail current into the auroral ionosphere.
Key Points
The dipolarization front has the shape of a saddleThe dipolarization front current has field‐aligned components in region‐1 senseThe dipolarization front thickness and current density varies with location
Recent observations have suggested that spatially localized flows of high‐temperature, low‐density plasma carrying a dipolarized magnetic field (dipolarizing flux bundles, DFBs) play a key role in ...hot plasma transport toward the inner magnetosphere. What controls plasma heating in DFBs and how do thermodynamic parameters (such as density, temperature, pressure, and specific entropy) and spectral properties of the DFB population depend on ambient plasma sheet properties and geocentric distance R remains unknown. By statistical analysis of 271 DFB events detected by the Time History of Events and Macroscale Interactions during Substorms mission during the 2008–2009 tail seasons, we find that on average, plasma inside DFBs is a factor of 0.6 less dense and a factor of 1.5 to 2 hotter than ambient tail plasma. The radial profiles of average thermodynamic parameters inside and outside DFBs are similar; when fitted by the κ‐function, their energy spectra have similar κ‐exponents, but a factor of 2 larger peak energies inside DFBs. Our analysis suggests that average DFB plasma properties are closely linked to those of the ambient plasma sheet population. Estimations show that on average, adiabatic heating of the ambient plasma in the increased magnetic field is the major factor in DFB plasma heating.
Key Points
Statistical analysis of THEMIS observations
Dependences between plasma parameters inside and outside DFBs
Adiabatic heating is the main mechanism of plasma thermalization in DFBs
Abstract Ketamine exerts fast acting, robust, and lasting antidepressant effects in a sub-anesthetic dose, however, the underlying mechanisms are still not fully elucidated. Recent studies have ...suggested that ketamine's antidepressant effects are probably attributed to the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The present study aimed to observe the effects of AMPA receptor modulators on mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) expression during the procedure of ketamine exerting antidepressant effects. Therefore, we pretreated rats with NBQX, an AMPA receptor antagonist, or CX546, an AMPA receptor agonist, and subsequently observed the immobility time during the forced swimming test (FST) and the hippocampal and prefrontal cortical levels of mTOR and BDNF. The results showed ketamine decreased the immobility time of rats during the FST and increased the hippocampal and prefrontal cortical mTOR and BDNF. NBQX pretreatment significantly increased the immobility time and decreased the levels of mTOR and BDNF when compared with vehicle 1 (DMSO) pretreatment. CX546 pretreatment significantly decreased the immobility time and increased the levels of mTOR and BDNF when compared with vehicle 2 (DMSO + ethanol) pretreatment. Our results suggest ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.
We discuss results of a superposed epoch analysis of dipolarization fronts, rapid (δt < 30 s), high‐amplitude (δBz > 10 nT) increases in the northward magnetic field component, observed during six ...Time History of Events and Macroscale Interactions during Substorms (THEMIS) conjunction events. All six fronts propagated earthward; time delays at multiple probes were used to determine their propagation velocity. We define typical magnetic and electric field and plasma parameter variations during dipolarization front crossings and estimate their characteristic gradient scales. The study reveals (1) a rapid 50% decrease in plasma density and ion pressure, (2) a factor of 2–3 increase in high‐energy (30–200 keV) electron flux and electron temperature, and (3) transient enhancements of ∼5 mV/m in duskward and earthward electric field components. Gradient scales of magnetic field, plasma density, and particle flux were found to be comparable to the ion thermal gyroradius. Current densities associated with the Bz increase are, on average, 20 nA/m2, 5–7 times larger than the current density in the cross‐tail current sheet. Because j · E > 0, the dipolarization fronts are kinetic‐scale dissipative regions with Joule heating rates of 10% of the total bursty bulk flow energy.
Key Points
Superposed epoch analysis of THEMIS dipolarization front events
Common pattern in field and particle variations during front crossings
Particle energization and energetic plasma transport
Since the introduction of Dale’s principle of “one neuron releases one transmitter at all its synapses,” a growing number of exceptions to this principle have been identified. While the concept of ...neurotransmitter co-release by a single neuron is now well accepted, the specific synaptic circuitry and functional advantage of co-neurotransmission remain poorly understood in general. Here we report Ca2+-dependent co-release of a new combination of inhibitory and excitatory neurotransmitters, namely, glycine and glutamate, by the vGluT3-expressing amacrine cell (GAC) in the mouse retina. GACs selectively make glycinergic synapses with uniformity detectors (UDs) and provide a major inhibitory drive that underlies the suppressed-by-contrast trigger feature of UDs. Meanwhile, GACs release glutamate to excite OFF alpha ganglion cells and a few other nonlinear, contrast-sensitive ganglion cells. This coordinated inhibition and excitation of two separate neuronal circuits by a single interneuron suggests a unique advantage in differential detection of visual field uniformity and contrast.
•vGluT3 amacrine cells co-release glycine and glutamate in a segregated manner•The glycinergic output selectively targets the suppressed-by-contrast circuit•The glutamatergic output targets OFF alpha and other contrast-sensitive circuits•This may provide a strategy for differential detection of uniformity and contrast
Lee et al. show that vGluT3 amacrine cells co-release a new combination of inhibitory-excitatory neurotransmitters and provide segregated glycinergic and glutamatergic drives to two functionally opposite retinal circuits to facilitate differential detection of visual field uniformity and contrast.
α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn ...fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.
Essentials
Perioperative blood loss and inflammatory response can significantly affect recovery after surgery.
We studied the effects of multiple‐dose oral tranexamic acid on blood loss and ...inflammatory response.
A postoperative four‐dose regimen brought about maximum reduction in postoperative blood loss.
A postoperative four‐dose regimen reduced inflammatory response and promoted early rehabilitation.
Summary
Background
Tranexamic acid (TXA) can reduce blood loss and the inflammatory response at multiple doses in total knee arthroplasty patients. However, the optimal regimen has not been determined.
Objectives
To identify the most effective regimen for achieving maximum reductions in blood loss and the inflammatory response.
Patients/Methods
Two hundred and seventy‐five patients were randomized to receive a placebo (group A), a single 2‐g oral dose of TXA 2 h preoperatively followed by 1 g of oral TXA 3 h postoperatively (group B), a single dose followed by 1 g of oral TXA 3 h and 7 h postoperatively (group C), a single dose followed by 1 g of oral TXA 3 h, 7 h and 11 h postoperatively (group D), or a single dose followed by 1 g of oral TXA 3 h, 7 h, 11 h and 15 h postoperatively (group E). The primary outcome was total blood loss on postoperative day (POD) 3. Secondary outcomes included a decrease in the hemoglobin level, coagulation parameters, inflammatory marker levels, and thromboembolic complications.
Results
Groups D and E had significantly lower blood loss and smaller decreases in hemoglobin level than groups A, B, and C, with no significant difference on POD 3 between groups D and E. Significantly enhanced coagulation was identified for the four multiple‐dose regimens; however, all thromboelastographic parameters remained within normal ranges. Group E had the lowest inflammatory marker levels and pain, and the greatest range of motion. No thromboembolic complications were identified.
Conclusion
The four‐dose regimen yielded the maximum reductions in blood loss and inflammatory response, improved analgesia, and promoted early rehabilitation. Further studies are required to ensure that these findings are reproducible.
The putative Plasmodium translocon of exported proteins (PTEX) is essential for transport of malarial effector proteins across a parasite-encasing vacuolar membrane into host erythrocytes, but the ...mechanism of this process remains unknown. Here we show that PTEX is a bona fide translocon by determining structures of the PTEX core complex at near-atomic resolution using cryo-electron microscopy. We isolated the endogenous PTEX core complex containing EXP2, PTEX150 and HSP101 from Plasmodium falciparum in the 'engaged' and 'resetting' states of endogenous cargo translocation using epitope tags inserted using the CRISPR-Cas9 system. In the structures, EXP2 and PTEX150 interdigitate to form a static, funnel-shaped pseudo-seven-fold-symmetric protein-conducting channel spanning the vacuolar membrane. The spiral-shaped AAA+ HSP101 hexamer is tethered above this funnel, and undergoes pronounced compaction that allows three of six tyrosine-bearing pore loops lining the HSP101 channel to dissociate from the cargo, resetting the translocon for the next threading cycle. Our work reveals the mechanism of P. falciparum effector export, and will inform structure-based design of drugs targeting this unique translocon.
PDF
