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Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.

In-depth profiling of transmembrane proteins in the brain leads to the identification of GPCR regulators in a disease model., Transmembrane proteins play vital roles in mediating synaptic transmission, plasticity, and homeostasis in the brain. However, these proteins, especially the G protein–coupled receptors (GPCRs), are underrepresented in most large-scale proteomic surveys. Here, we present a new proteomic approach aided by deep learning models for comprehensive profiling of transmembrane protein families in multiple mouse brain regions. Our multiregional proteome profiling highlights the considerable discrepancy between messenger RNA and protein distribution, especially for region-enriched GPCRs, and predicts an endogenous GPCR interaction network in the brain. Furthermore, our new approach reveals the transmembrane proteome remodeling landscape in the brain of a mouse depression model, which led to the identification of two previously unknown GPCR regulators of depressive-like behaviors. Our study provides an enabling technology and rich data resource to expand the understanding of transmembrane proteome organization and dynamics in the brain and accelerate the discovery of potential therapeutic targets for depression treatment.

Gestational diabetes (GDM) is common in pregnancies due to the inflammation and oxidative stress-mediated insulin resistance. In the present study, GDM was induced in the Wistar rats by administering the streptozotocin to elucidate whether the administration of syringin (50 mg/kg/day) during pregnancy could improve maternal glycemia and protect against the complications of GDM. The animals were assessed for their morphological changes in the β-islets of Langerhans and their insulin-producing ability, inflammatory cytokine markers, and the involvement of TLR4/MyD88/NF-κB signaling pathway using RT-PCR. The results demonstrated that the onset of GDM demonstrated pancreatic tissue degeneration in the islets of Langerhans with a significant increase in oxidative stress and reduced antioxidant enzymes. Besides, the mRNA expression levels of TLR4, MyD88, NF-Kβ p65; NLRP3 mRNA were profoundly increased in GDM rats compared to normal pregnant rats. On the other hand, syringin administered GDM rats abrogated the oxidative stress and attenuated the level of the inflammatory cytokines. Intriguingly, the decrease in TLR4 expression and the downstream molecules of MyD88, NF-κB, and NLRP3 were also observed in syringin administered GDM rats that indicate the insulin secretion stimulatory actions of syringin through the suppression of TLR4 signaling. These novel findings of the study provide evidence that syringin could be a probable candidate to be used in the treatment of gestational diabetes in the future.

Inclusion complexes of α,ω-bisimidazolium oligosiloxane (Im-PDMS) and cucurbit[7]uril (CB[7]) in aqueous solution were studied. The binding interactions were monitored by 1H NMR. Their annular aggregate morphologies were confirmed by TEM. The aggregation behavior of free Im-PDMS and Im-PDMS in 10−4 CB[7] were investigated using surface tension measurement.

Summary Data-independent acquisition mass spectrometry (DIA-MS) is a powerful technique that enables relatively deep proteomic profiling with superior quantification reproducibility. DIA data mining predominantly relies on a spectral library of sufficient proteome coverage that, in most cases, is built on data-dependent acquisition-based analysis of the same sample. To expand the proteome coverage for a pre-determined protein family, we report herein on the construction of a hybrid spectral library that supplements a DIA experiment-derived library with a protein family-targeted virtual library predicted by deep learning. Leveraging this DIA hybrid library substantially deepens the coverage of three transmembrane protein families (G protein-coupled receptors, ion channels, and transporters) in mouse brain tissues with increases in protein identification of 37%–87% and peptide identification of 58%–161%. Moreover, of the 412 novel GPCR peptides exclusively identified with the DIA hybrid library strategy, 53.6% were validated as present in mouse brain tissues based on orthogonal experimental measurement., Graphical Abstract, Highlights • A virtual library is built for a selected protein family using deep learning models • The hybrid library strategy vastly deepens the coverage for the targeted protein family • About 53.6% of novel GPCR peptides identified with the DIA hybrid library are validated • Extend the strategy to deep mapping of multiple transmembrane protein families, Analytical Chemistry; Biological Sciences; Classification of Proteins; Proteomics

Summary The axon initial segment (AIS) cytoskeleton undergoes rapid and irreversible disruption prior to cell death after injury, and loss of AIS integrity can produce profound neurological effects on the nervous system. Here we described a previously unrecognized mechanism for ischemia-induced alterations in AIS integrity. We show that in hippocampal CA1 pyramidal neurons Nav1.6 mostly preserves at the AIS after disruption of the cytoskeleton in a mouse model of middle cerebral artery occlusion. Genetic removal of neurofascin-186 leads to rapid disruption of Nav1.6 following injury, indicating that neurofascin is required for Nav1.6 maintenance at the AIS after cytoskeleton collapse. Importantly, calcineurin inhibition with FK506 fully protects AIS integrity and sufficiently prevents impairments of spatial learning and memory from injury. This study provides evidence that calcineurin activation is primarily involved in initiating disassembly of the AIS cytoskeleton and that maintaining AIS integrity is crucial for therapeutic strategies to facilitate recovery from injury., Graphical Abstract, Highlights • Ion channels are mostly retained at the AIS after ischemic injury • Neurofascin is required for clustering ion channels at the AIS after ischemia • Calcineurin inhibition protects AIS structural integrity and function from ischemia • Calcineurin inhibition protects cognitive function against impairment by ischemia, Neuroscience; Molecular Neuroscience; Cellular Neuroscience

Dysregulation of voltage-gated sodium channels (VGSCs) is associated with multiple clinical disorders, including febrile seizures (FS). The contribution of different sodium channel subtypes to environmentally triggered seizures is not well understood. Here we demonstrate that somatic and axonal sodium channels primarily mediated through NaV1.2 and NaV1.6 subtypes, respectively, behave differentially at FT, and might play distinct roles in FS generation. In contrast to sodium channels on the main axonal trunk, somatic ones are more resistant to inactivation and display significantly augmented currents, faster gating rates and kinetics of recovery from inactivation at FT, features that promote neuronal excitabilities. Pharmacological inhibition of NaV1.2 by Phrixotoxin-3 (PTx3) suppressed FT-induced neuronal hyperexcitability in brain slice, while up-regulation of NaV1.2 as in NaV1.6 knockout mice showed an opposite effect. Consistently, NaV1.6 knockout mice were more susceptible to FS, exhibiting much lower temperature threshold and shorter onset latency than wildtype mice. Neuron modeling further suggests that NaV1.2 is the major subtype mediating FT-induced neuronal hyperexcitability, and predicts potential outcomes of alterations in sodium channel subtype composition. Together, these data reveal a role of native NaV1.2 on neuronal excitability at FT and its important contribution to FS pathogenesis.

We report on a low-loss fusion splice between a hollow-core photonic bandgap fiber (NKT's HC-1550-02) and a conventional single mode fiber (Corning's SMF28) using a high V-number intermediate fiber. Compared to the commonly used fiber postprocessing techniques, the intermediate fiber method offers a new adjusting degree of freedom of V-numbers, enabling the reduction of coupling loss to 0.35 dB. Experimentally, a low fusion splice loss of 0.63 dB has been achieved between Nufern's SM1950 (V =2.836) and HC-1550-02 fiber, resulting in an overall insertion loss of 0.73 dB from SMF28 to HC-1550-02 fiber. We believe this is the lowest splice loss value reported for HC-1550-02 fiber using an arc splicer, on the aspect of both using a step-index solid-core fiber (0.63 dB) and a SMF28 fiber (0.73 dB).

Voltage-gated K+ (K-V) channels play critical roles in shaping neuronal signals. K-V channels distributed in the perisomatic regions and thick dendrites of cortical pyramidal neurons have been extensively studied. However, the properties and regulation of K-V channels distributed in the thin axons remain unknown. In this study, by performing somatic and axonal patch-clamp recordings from layer 5 pyramidal neurons of prefrontal cortical slices, we showed that the rapidly inactivating A-currents mediated the transient K+ currents evoked by action potential (AP) waveform command (K-AP) at the soma, whereas the rapidly activating but slowly inactivating K(V)1-mediated D-currents dominated the K-AP at the axon. In addition, activation of D1-like receptors for dopamine decreased the axonal K+ currents, as a result of an increase in the activity of cAMP-PKA pathway. In contrast, activation of D2-like receptors showed an opposite effect on the axonal K+ currents. Further experiments demonstrated that functional D1-like receptors were expressed at the main axon trunk and their activation could broaden the waveforms of axonal APs. Together, these results show that axonal K-V channels were subjected to dopamine modulation, and this modulation could regulate the waveforms of propagating APs at the axon, suggesting an important role of dopaminergic modulation of axonal K-V channels in regulating neuronal signalling.

The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na(+) channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na(+) channel density. We found that low-threshold Na(v)1.6 and high-threshold Na(v)1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na(+) current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Na(v)1.6 promotes action potential initiation, whereas proximal Na(v)1.2 promotes its backpropagation to the soma.

We report on an ultraviolet-enhanced supercontinuum generation in a uniform photonic crystal fiber pumped by a giant-chirped mode-locked Yb-doped fiber laser. We find experimentally that the initial pluses with giant chirp leads more initial energy transferred to the dispersive waves in visible and ultraviolet wavelength. An extremely wide optical spectrum spanning from 370 nm to beyond 2400 nm with a broad 3 dB spectral bandwidth of 367 nm (from 431 nm to 798 nm) is obtained. Over 36% (350 mW) of the total output power locates in the visible and ultraviolet regime between 370 nm and 850 nm with a maximum spectral power density of 1.6 mW/nm at 550 nm. In addition, a blue-enhanced supercontinuum generation pumped by a giant-chirped SESAM mode-locked ytterbium-doped fiber laser is studied. An extremely wide optical spectrum spanning from 380 nm to 2400 nm with total power of 3 W is obtained.

We report on an ultraviolet-enhanced supercontinuum generation in a uniform photonic crystal fiber pumped by a giant-chirped mode-locked Yb-doped fiber laser. We find theoretically and experimentally that the initial pluses with giant chirp leads more initial energy transferred to the dispersive waves in visible and ultraviolet wavelength. An extremely wide optical spectrum spanning from 370 nm to beyond 2400 nm with a broad 3 dB spectral bandwidth of 367 nm (from 431 nm to 798 nm) is obtained. Over 36% (350 mW) of the total output power locates in the visible and ultraviolet regime between 370 nm and 850 nm with a maximum spectral power density of 1.6 mW/nm at 550 nm.

To study the hypoglycemic effect of saponin from Tribulus terrestris L.Alloxan was used to establish the diabetic model in mice. Phenformin Hydrochlride Tables was used as the positive control. The level of glucose, triglyceride, cholesterol and SOD in serum were determined.The level of serum glucose could be significantly reduced by saponin from Tribulus terrestris, which was the rate of 26.25% and 40.67% in normal mice and diabetic mice in respectively. The level of serum triglyceride could be reduced 23.35%. The saporin could also decrease the content of serum cholesterol. Serum SOD activity of the mice was increased by the saponin.Saponin from Tribulue terrestris could significantly reduce the level of serum glucose.