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Aim: To investigate whether interleukin-17A (IL-17A) gets involved in the mechanisms of inflammation-related retinal pigment epithelium (RPE) cells injury and its significance in age-related macular degeneration (AMD)., Mrthods: A sodium iodate (NaIO 3 ) mouse model as well as IL-17A -/- mice were established. The effects of inflammatory cytokines in RPE cells and retinal microglia before and after NaIO 3 modeling in vivo and in vitro , were investigated using immunofluorescence, immunoprotein blotting, and quantitative real-time fluorescence polymerase chain reaction (qRT-PCR), respectively. Interventions using recombinant IL-17A protein (rIL-17A) or IL-17A neutralizing antibody (IL-17A NAb) were used to observe the subsequent differences in fundus, fundus photography and optical coherence tomography (OCT), cell viability, and expression of oxidative stress-related markers before and after modeling, and to screen for key signaling pathways., Results: In the scenario of NaIO 3 stimulation, RPE cells obviously tended to degenerate. Simultaneously proliferation and activation of retinal microglia was confirmed in NaIO 3 -stimulated mice, whereas such effects induced by NaIO 3 were significantly ameliorated with IL-17A NAb intervention or in IL-17A -/- mice. In addition, IL-17A promoted the proliferation and activation of microglia as well as oxidative damage and the secretion of inflammatory cytokines alongside NaIO 3 -induced damage in RPE cells in vivo and ex vivo . Meanwhile, the extracellular signal-regulated kinase (ERK) signaling pathway was shown to be participated in the regulation of NaIO 3 -induced RPE cells injury mediated by IL-17A in vivo and ex vivo , as IL-17A-induced inflammatory cytokines release in the NaIO 3 model was alleviated after blocking the ERK pathway., Conclusion: IL-17A probably promotes the NaIO 3 -induced RPE cells injury through exacerbating inflammation in terms of retinal microglia activation and inflammatory cytokines release via ERK signaling pathway. Inhibition of IL-17A may be a new potential target for dry AMD treatment., Competing Interests: Conflicts of Interest: Zhong HM, None; Shen BQ, None; Chen YH, None; Zhao XH, None; Huang XX, None; Zhou MW, None; Sun XD, None., (International Journal of Ophthalmology Press.)

The shell of Hermetia illucens L. contains considerable amounts of chitin, which has various biological activities. So far, few studies have focused on chitin of Hermetia illucens L. as a source of chitosan and oligosaccharides. There is great potential for utilizing Hermetia illucens L. chitin to produce chitosan films in biomaterials. We studied different extraction conditions for chitin and extracted it from black soldier fly (BSF) (Hermetia illucens L.). Three processing steps were adopted: (1) demineralization, (2) deproteinization, and (3) decolorization. The chemical components (moisture, ash, protein, fat, residual protein, and residual mineral contents) and physicochemical characteristics of the chitin and chitosan extracted under these three conditions were determined. In addition, Fourier transform infrared spectroscopy and X-ray diffraction were used to analyze the extracted chitin and commercial samples, and the results showed that demineralization-deproteinization-decolorization treatments could achieve the highest chitin yield (7.18 ± 0.11 %), chitosan yield (64.22 ± 0.79 %), and the best purity (residual protein 0.56 ± 0.01 % and residual ash 0.58 ± 0.04 %), making it the best treatment method. Using this method, the residues produced from farmed BSF can be recycled and used as a new source of chitin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A 4 4 .6 10 .8 topology hybrid ultramicroporous material (HUM), {[Cu 1.5 F(SiF 6 )(L) 2.5 ]·G} n , (L = 4,4'-bisimidazolylbiphenyl, G = guest molecules), 1, formed by cross-linking interpenetrated 3D four-connected CdSO 4 -type nets with hexafluorosilicate anions is synthesized and evaluated in the context of gas sorption and separation herein. 1 is the first HUM functionalized with two different types of fluorinated sites (SiF 6 2- and F - anions) lining along the pore surface. The optimal pore size (≈5 Å) combining mixed and high-density electronegative fluorinated sites enable 1 to preferentially adsorb C 2 H 2 over CO 2 and C 2 H 4 by hydrogen bonding interactions with a high C 2 H 2 isosteric heat of adsorption (Q st ) of ≈42.3 kJ mol -1 at zero loading. The pronounced discriminatory sorption behaviors lead to excellent separation performance for C 2 H 2 /CO 2 and C 2 H 2 /C 2 H 4 that surpasses many well-known sorbents. Dynamic breakthrough experiments are conducted to confirm the practical separation capability of 1, which reveal an impressive separation factor of 6.1 for equimolar C 2 H 2 /CO 2 mixture. Furthermore, molecular simulation and density functional theory (DFT) calculations validate the strong binding of C 2 H 2 stems from the chelating fix of C 2 H 2 between SiF 6 2- anion and coordinated F - anion., (© 2024 Wiley‐VCH GmbH.)

Stimuli-responsive physisorbents that undergo reversible structural transformations induced by external stimuli (e.g. light, guests, or heat) offer the promise of utility in gas storage and separation. Whereas reports on guest or light-responsive sorbents have increased in recent years, we are unaware of reports on sorbents that exhibit both light and guest-induced structural transformations. Herein, we report that the square lattice, sql, topology coordination network Zn(fba)(bis) ⋅ 2DMF (sql-5,6-Zn-α, 5=trans-4,4'-bis(1-imidazolyl)stilbene=bis, 6=2,2-bis(4-carboxyphenyl)hexafluoropropane=H 2 fba) underwent single-crystal-to-single-crystal transformation (SCSC) upon activation, affording nonporous sql-5,6-Zn-β. Parallel alignment at 3.23 Å of olefinic moieties on adjacent bis ligands in sql-5,6-Zn-α enabled SCSC [2+2] photocycloaddition upon exposure to UV light (365 nm) or sunlight. sql-5,6-Zn-α thereby transformed to mot-5,6-Zn-α, which was subsequently activated to the narrow pore phase mot-5,6-Zn-β. sql-5,6-Zn-β and mot-5,6-Zn-β both exhibited S-shaped adsorption isotherms characteristic of guest-induced structural changes when exposed to CO 2 at 195 K (type-F-IV and type F-I, respectively). Cycling experiments conducted upon sql-5,6-Zn-β reduced particle size after cycle 1 and induced transformation into a rare example of a shape memory coordination network, sql-5,6-Zn-γ. Insight into this smorgasbord of SCSC phase changes was gained from in situ PXRD, single crystal XRD and 1 H NMR spectroscopy experiments., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

On 9 October 2022, the Large High Altitude Air Shower Observatory (LHAASO) reported the observation of the very early TeV afterglow of the brightest-of-all-time gamma-ray burst 221009A, recording the highest photon statistics in the TeV band ever obtained from a gamma-ray burst. We use this unique observation to place stringent constraints on the energy dependence of the speed of light in vacuum, a manifestation of Lorentz invariance violation (LIV) predicted by some quantum gravity (QG) theories. Our results show that the 95% confidence level lower limits on the QG energy scales are E_{QG,1}>10 times the Planck energy E_{Pl} for the linear LIV effect, and E_{QG,2}>6×10^{-8}E_{Pl} for the quadratic LIV effect. Our limits on the quadratic LIV case improve previous best bounds by factors of 5-7.

In this Letter we try to search for signals generated by ultraheavy dark matter at the Large High Altitude Air Shower Observatory (LHAASO) data. We look for possible γ rays by dark matter annihilation or decay from 16 dwarf spheroidal galaxies in the field of view of the LHAASO. Dwarf spheroidal galaxies are among the most promising targets for indirect detection of dark matter that have low fluxes of astrophysical γ-ray background while having large amount of dark matter. By analyzing more than 700 days of observational data at LHAASO, no significant dark matter signal from 1 TeV to 1 EeV is detected. Accordingly we derive the most stringent constraints on the ultraheavy dark matter annihilation cross section up to EeV. The constraints on the lifetime of dark matter in decay mode are also derived.

Blood-brain-barrier (BBB) disruption is a pathological hallmark of ischemic stroke, and inflammation occurring at the BBB contributes to the pathogenesis of ischemic brain injury. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, is elevated in patients with acute stroke. The activity of LPS is controlled by acyloxyacyl hydrolase (AOAH), a host enzyme that deacylates LPS to inactivated forms. However, whether AOAH influences the pathogenesis of ischemic stroke remain elusive. We performed in vivo experiments to explore the role and mechanism of AOAH on neutrophil extravasation, BBB disruption, and brain infarction. We found that AOAH was upregulated in neutrophils in peri-infarct areas from mice with transient focal cerebral ischemia. AOAH deficiency increased neutrophil extravasation into the brain parenchyma and proinflammatory cytokine production, broke down the BBB and worsened stroke outcomes in mice. These effects require Toll-like receptor 4 (TLR4) because absence of TLR4 or pharmacologic inhibition of TLR4 signaling prevented the exacerbated inflammation and BBB damage in Aoah -/- mice after ischemic stroke. Importantly, neutrophil depletion or inhibition of neutrophil trafficking by blocking LFA-1 integrin dramatically reduced stroke-induced BBB breakdown in Aoah -/- mice. Furthermore, virus-mediated overexpression of AOAH induced a substantial decrease in neutrophil recruitment that was accompanied by reducing BBB damage and stroke volumes. Our findings show the importance of AOAH in regulating neutrophil-dependent BBB breakdown and cerebral infarction. Consequently, strategies that modulate AOAH may be a new therapeutic approach for treatment of ischemic stroke., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context: Although several epidemiological studies have examined the association between coffee or tea intake and the risk of cognitive disorders, the results to date are inconsistent., Objective: An updated systematic review and dose-response meta-analysis was conducted to confirm the association between coffee, tea, and caffeine consumption and the risk of cognitive disorders., Data Sources: PubMed, Embase, and Web of Science were searched from inception to January 2022 for relevant studies, including dementia, Alzheimer disease (AD), and cognitive impairment or decline., Data Extraction: Two reviewers independently performed data extraction and assessed the study quality., Data Analysis: Restricted cubic splines were used to conduct the dose-response meta-analysis for coffee and tea intake., Results: Twenty-two prospective studies and 11 case-control studies involving 389 505 participants were eligible for this meta-analysis. Coffee and tea consumption was linked to a lower risk of cognitive disorders, with an overall relative risk (RR) of 0.73 (95% CI: 0.60-0.86) and 0.68 (95% CI: 0.56-0.80), respectively. The subgroup analysis revealed that ethnicity, sex, and outcomes had significant effects on this association. Protection was stronger for men than that for women in both coffee and tea consumption. A nonlinear relationship was found between coffee consumption and AD risk, and the strength of protection peaked at approximately 2.5 cups/day (RR: 0.74; 95% CI: 0.59-0.93). A linear relationship was found between tea consumption and cognitive disorders, and the risk decreased by 11% for every 1-cup/day increment., Conclusion: This meta-analysis demonstrated that the consumption of 2.5 cups coffee/day minimizes the risk of AD, and 1 cup/day of tea intake leads to an 11% reduction in cognitive deficits. Effective interventions involving coffee and tea intake might prevent the occurrence of dementia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke., Methods: Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined., Results: We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15., Conclusions: Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke., Competing Interests: Disclosures None.

We present the measurements of all-particle energy spectrum and mean logarithmic mass of cosmic rays in the energy range of 0.3-30 PeV using data collected from LHAASO-KM2A between September 2021 and December 2022, which is based on a nearly composition-independent energy reconstruction method, achieving unprecedented accuracy. Our analysis reveals the position of the knee at 3.67±0.05±0.15  PeV. Below the knee, the spectral index is found to be -2.7413±0.0004±0.0050, while above the knee, it is -3.128±0.005±0.027, with the sharpness of the transition measured with a statistical error of 2%. The mean logarithmic mass of cosmic rays is almost heavier than helium in the whole measured energy range. It decreases from 1.7 at 0.3 PeV to 1.3 at 3 PeV, representing a 24% decline following a power law with an index of -0.1200±0.0003±0.0341. This is equivalent to an increase in abundance of light components. Above the knee, the mean logarithmic mass exhibits a power law trend towards heavier components, which is reversal to the behavior observed in the all-particle energy spectrum. Additionally, the knee position and the change in power-law index are approximately the same. These findings suggest that the knee observed in the all-particle spectrum corresponds to the knee of the light component, rather than the medium-heavy components.

Gene therapy has been adapted, from the laboratory to the clinic, to treat retinopathies. In contrast to subretinal route, intravitreal delivery of AAV vectors displays the advantage of bypassing surgical injuries, but the viral particles are more prone to be nullified by the host neutralizing factors. To minimize such suppression of therapeutic effect, especially in terms of AAV2 and its derivatives, we introduced three serine-to-glycine mutations, based on the phosphorylation sites identified by mass spectrum analysis, to the XL32 capsid to generate a novel serotype named AAVYC5. Via intravitreal administration, AAVYC5 was transduced more effectively into multiple retinal layers compared with AAV2 and XL32. AAVYC5 also enabled successful delivery of anti-angiogenic molecules to rescue laser-induced choroidal neovascularization and astrogliosis in mice and non-human primates. Furthermore, we detected fewer neutralizing antibodies and binding IgG in human sera against AAVYC5 than those specific for AAV2 and XL32. Our results thus implicate this capsid-optimized AAVYC5 as a promising vector suitable for a wide population, particularly those with undesirable AAV2 seroreactivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Blood-brain barrier (BBB) breakdown and cerebrovascular dysfunction may contribute to the pathology in white matter lesions and consequent cognitive decline caused by cerebral hypoperfusion. Neddylation is the process of attaching a ubiquitin-like molecule NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8) to specific targets. By modifying protein substrates, neddylation plays critical roles in various important biological processes. However, whether neddylation influences the pathogenesis of hypoperfused brain remains unclear. In the present study, cerebral hypoperfusion-induced white matter lesions were produced by bilateral common carotid artery stenosis in mice. The function of the neddylation pathway, BBB integrity, cerebrovascular dysfunction, myelin density in the corpus callosum and cognitive function were determined. We show that NEDD8 conjugation aberrantly amplified in microvascular endothelium in the corpus callosum following cerebral hypoperfusion. MLN4924, a small-molecule inhibitor of NEDD8-activating enzyme currently in clinical trials, preserved BBB integrity, attenuated glial activation and enhanced oligodendrocyte differentiation, and reduced hypoperfusion-induced white matter lesions in the corpus callosum and thus improved cognitive performance via inactivating cullin-RING E3 ligase (CRL). Administration of MLN4924 caused the accumulation of ERK5 and KLF2. The ERK5 inhibitor BIX 02189, down-regulated MLN4924-induced activation of KLF2 and reversed MLN4924-mediated increase in pericyte coverage and junctional proteins. Furthermore, BIX 02189 blocked MLN4924-afforded protection against BBB disruption and white matter lesions in the corpus callosum. Collectively, our results revealed that neddylation impairs vascular function and thus exacerbated the pathology of hypoperfused brain and that inhibition of neddylation with MLN4924 may offer novel therapeutic opportunities for cerebral hypoperfusion-associated cognitive impairment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Propane (C 3 H 8 ) is a widely used fuel gas. Metal-organic framework (MOF) physisorbents that are C 3 H 8 selective offer the potential to significantly reduce the energy footprint for capturing C 3 H 8 from natural gas, where C 3 H 8 is typically present as a minor component. Here we report the C 3 H 8 recovery performance of a previously unreported lonsdaleite, lon , topology MOF, a chiral metal-organic material, [Ni( S -IEDC)(bipy)(SCN)] n , CMOM-7 . CMOM-7 was prepared from three low-cost precursors: Ni(SCN) 2 , S -indoline-2-carboxylic acid ( S -IDECH), and 4,4'-bipyridine (bipy), and its structure was determined by single crystal X-ray crystallography. Pure gas adsorption isotherms revealed that CMOM-7 exhibited high C 3 H 8 uptake (2.71 mmol g -1 ) at 0.05 bar, an indication of a higher affinity for C 3 H 8 than both C 2 H 6 and CH 4 . Dynamic column breakthrough experiments afforded high purity C 3 H 8 capture from a gas mixture comprising C 3 H 8 /C 2 H 6 /CH 4 (v/v/v = 5/10/85). Despite the dilute C 3 H 8 stream, CMOM-7 registered a high dynamic uptake of C 3 H 8 and a breakthrough time difference between C 3 H 8 and C 2 H 6 of 79.5 min g -1 , superior to those of previous MOF physisorbents studied under the same flow rate. Analysis of crystallographic data and Grand Canonical Monte Carlo simulations provides insight into the two C 3 H 8 binding sites in CMOM-7 , both of which are driven by C-H···π and hydrogen bonding interactions., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Separation of the C 8 aromatic isomers, xylenes (PX, MX, and OX) and ethylbenzene (EB), is important to the petrochemical industry. Whereas physisorptive separation is an energy-efficient alternative to current processes, such as distillation, physisorbents do not generally exhibit strong C 8 selectivity. Herein, we report the mixed-linker square lattice ( sql ) coordination network [Zn 2 (sba) 2 (bis)] n · m DMF ( sql-4,5-Zn , H 2 sba or 4 = 4,4'-sulfonyldibenzoic acid, bis or 5 = trans-4,4'-bis(1-imidazolyl)stilbene) and its C 8 sorption properties. sql-4,5-Zn was found to exhibit high uptake capacity for liquid C 8 aromatics (∼20.2 wt %), and to the best of our knowledge, it is the first sorbent to exhibit selectivity for PX, EB, and MX over OX for binary, ternary, and quaternary mixtures from gas chromatography. Single-crystal structures of narrow-pore, intermediate-pore, and large-pore phases provided insight into the phase transformations, which were enabled by flexibility of the linker ligands and changes in the square grid geometry and interlayer distances. This work adds to the library of two-dimensional coordination networks that exhibit high uptake, thanks to clay-like expansion, and strong selectivity, thanks to shape-selective binding sites, for C 8 isomers., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

We report that linker ligand substitution involving just one atom induces a shape-memory effect in a flexible coordination network. Specifically, whereas SIFSIX-23-Cu, [Cu(SiF 6 )(L) 2 ] n , (L=1,4-bis(1-imidazolyl)benzene, SiF 6 2- =SIFSIX) has been previously reported to exhibit reversible switching between closed and open phases, the activated phase of SIFSIX-23-Cu N , [Cu(SiF 6 )(L N ) 2 ] n (L N =2,5-bis(1-imidazolyl)pyridine), transformed to a kinetically stable porous phase with strong affinity for CO 2 . As-synthesized SIFSIX-23-Cu N , α, transformed to less open, γ, and closed, β, phases during activation. β did not adsorb N 2 (77 K), rather it reverted to α induced by CO 2 at 195, 273 and 298 K. CO 2 desorption resulted in α', a shape-memory phase which subsequently exhibited type-I isotherms for N 2 (77 K) and CO 2 as well as strong performance for separation of CO 2 /N 2 (15/85) at 298 K and 1 bar driven by strong binding (Q st =45-51 kJ/mol) and excellent CO 2 /N 2 selectivity (up to 700). Interestingly, α' reverted to β after re-solvation/desolvation. Molecular simulations and density functional theory (DFT) calculations provide insight into the properties of SIFSIX-23-Cu N ., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The diffuse Galactic γ-ray emission, mainly produced via interactions between cosmic rays and the interstellar medium and/or radiation field, is a very important probe of the distribution, propagation, and interaction of cosmic rays in the Milky Way. In this Letter, we report the measurements of diffuse γ rays from the Galactic plane between 10 TeV and 1 PeV energies, with the square kilometer array of the Large High Altitude Air Shower Observatory (LHAASO). Diffuse emissions from the inner (15°10  TeV). The energy spectrum in the inner Galaxy regions can be described by a power-law function with an index of -2.99±0.04, which is different from the curved spectrum as expected from hadronic interactions between locally measured cosmic rays and the line-of-sight integrated gas content. Furthermore, the measured flux is higher by a factor of ∼3 than the prediction. A similar spectrum with an index of -2.99±0.07 is found in the outer Galaxy region, and the absolute flux for 10≲E≲60  TeV is again higher than the prediction for hadronic cosmic ray interactions. The latitude distributions of the diffuse emission are consistent with the gas distribution, while the longitude distributions show clear deviation from the gas distribution. The LHAASO measurements imply that either additional emission sources exist or cosmic ray intensities have spatial variations.

Chiral metal-organic materials, CMOMs, are of interest as they can offer selective binding sites for chiral guests. Such binding sites can enable CMOMs to serve as chiral crystalline sponges (CCSs) to determine molecular structure and/or purify enantiomers. We recently reported on the chiral recognition properties of a homochiral cationic diamondoid, dia, network {[Ni( S -IDEC)(bipy)(H 2 O)][NO 3 ]} n ( S -IDEC = S -indoline-2-carboxylicate, bipy = 4,4'-bipyridine), CMOM-5[NO 3 ] . The modularity of CMOM-5[NO 3 ] means there are five feasible approaches to fine-tune structures and properties via substitution of one or more of the following components: metal cation (Ni 2+ ); bridging ligand ( S -IDEC); linker (bipy); extra-framework anion (NO 3 - ); and terminal ligand (H 2 O). Herein, we report the effect of anion substitution on the CCS properties of CMOM-5[NO 3 ] by preparing and characterizing {[Ni( S -IDEC)(bipy)(H 2 O)][BF 4 ]} n , CMOM-5[BF 4 ] . The chiral channels in CMOM-5[BF 4 ] enabled it to function as a CCS for determination of the absolute crystal structures of both enantiomers of three chiral compounds: 1-phenyl-1-butanol (1P1B); methyl mandelate (MM); ethyl mandelate (EM). Chiral resolution experiments revealed CMOM-5[BF 4 ] to be highly selective toward the S -isomers of MM and EM with enantiomeric excess, ee, values of 82.6 and 78.4%, respectively. The ee measured for S -EM surpasses the 64.3% exhibited by [DyNaL(H 2 O) 4 ] 6H 2 O and far exceeds that of CMOM-5[NO 3 ] (6.0%). Structural studies of the binding sites in CMOM-5[BF 4 ] provide insight into their high enantioselectivity., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Chloroform is a volatile organic solvent and a contaminant that is slightly soluble in water, making the reversible separation of chloroform from water a critical and challenging task within the chemical and environmental industries. In this study, we present a newly developed coordination framework, [Zn(4-pmntd)(opa)] [4-pmntd, N , N '-bis(4-pyridylmethyl)naphthalene diimide; opa, o -phthalic acid], which demonstrates a high adsorption capacity for chloroform (2.5 mmol/g) and an excellent ability to separate chloroform from water. The effectiveness of chloroform extraction by Zn(4-pmntd)(opa) was confirmed through vapor sorption, grand canonical Monte Carlo simulation, and 1 H nuclear magnetic resonance spectroscopy. The porous framework was also utilized to create a filtration film using natural rubber, which successfully separated chloroform from water with a minimum test concentration of approximately 1 × 10 -6 mol/L and a chloroform purity of 99.2%. [Zn(4-pmntd)(opa)] therefore has significant potential for low-energy separation and recycling of chloroform from water under ambient conditions.

Some gamma-ray bursts (GRBs) have a tera-electron volt (TeV) afterglow, but the early onset of this has not been observed. We report observations with the Large High Altitude Air Shower Observatory (LHAASO) of the bright GRB 221009A, which serendipitously occurred within the instrument's field of view. More than 64,000 photons >0.2 TeV were detected within the first 3000 seconds. The TeV flux began several minutes after the GRB trigger and then rose to a peak ~10 seconds later. This was followed by a decay phase, which became more rapid ~650 seconds after the peak. We interpret the emission using a model of a relativistic jet with half-opening angle of ~0.8°. This is consistent with the core of a structured jet and could explain the high isotropic energy of this GRB.

Ultramicroporous materials can be highly effective at trace gas separations when they offer a high density of selective binding sites. Herein, we report that sql-NbOFFIVE-bpe-Cu , a new variant of a previously reported ultramicroporous square lattice, sql , topology material, sql-SIFSIX-bpe-Zn , can exist in two polymorphs. These polymorphs, sql-NbOFFIVE-bpe-Cu-AA ( AA ) and sql-NbOFFIVE-bpe-Cu-AB ( AB ), exhibit AAAA and ABAB packing of the sql layers, respectively. Whereas NbOFFIVE-bpe-Cu-AA ( AA ) is isostructural with sql-SIFSIX-bpe-Zn , each exhibiting intrinsic 1D channels, sql-NbOFFIVE-bpe-Cu-AB ( AB ) has two types of channels, the intrinsic channels and extrinsic channels between the sql networks. Gas and temperature induced transformations of the two polymorphs of sql-NbOFFIVE-bpe-Cu were investigated by pure gas sorption, single-crystal X-ray diffraction (SCXRD), variable temperature powder X-ray diffraction (VT-PXRD), and synchrotron PXRD. We observed that the extrinsic pore structure of AB resulted in properties with potential for selective C 3 H 4 /C 3 H 6 separation. Subsequent dynamic gas breakthrough measurements revealed exceptional experimental C 3 H 4 /C 3 H 6 selectivity (270) and a new benchmark for productivity (118 mmol g -1 ) of polymer grade C 3 H 6 (purity > 99.99%) from a 1:99 C 3 H 4 /C 3 H 6 mixture. Structural analysis, gas sorption studies, and gas adsorption kinetics enabled us to determine that a binding "sweet spot" for C 3 H 4 in the extrinsic pores is behind the benchmark separation performance. Density-functional theory (DFT) calculations and Canonical Monte Carlo (CMC) simulations provided further insight into the binding sites of C 3 H 4 and C 3 H 6 molecules within these two hybrid ultramicroporous materials, HUMs. These results highlight, to our knowledge for the first time, how pore engineering through the study of packing polymorphism in layered materials can dramatically change the separation performance of a physisorbent.

Chiral metal-organic materials (CMOMs), can offer molecular binding sites that mimic the enantioselectivity exhibited by biomolecules and are amenable to systematic fine-tuning of structure and properties. Herein, we report that the reaction of Ni(NO 3 ) 2 , S -indoline-2-carboxylic acid ( S -IDECH), and 4,4'-bipyridine (bipy) afforded a homochiral cationic diamondoid, dia , network, [Ni( S -IDEC)(bipy)(H 2 O)][NO 3 ], CMOM-5 . Composed of rod building blocks (RBBs) cross-linked by bipy linkers, the activated form of CMOM-5 adapted its pore structure to bind four guest molecules, 1-phenyl-1-butanol (1P1B), 4-phenyl-2-butanol (4P2B), 1-(4-methoxyphenyl)ethanol (MPE), and methyl mandelate (MM), making it an example of a chiral crystalline sponge (CCS). Chiral resolution experiments revealed enantiomeric excess, ee , values of 36.2-93.5%. The structural adaptability of CMOM-5 enabled eight enantiomer@ CMOM-5 crystal structures to be determined. The five ordered crystal structures revealed that host-guest hydrogen-bonding interactions are behind the observed enantioselectivity, three of which represent the first crystal structures determined of the ambient liquids R -4P2B, S-4P2B, and R -MPE., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Cerebral small vessel disease (CSVD) is a leading cause of stroke and vascular cognitive impairment and dementia. Studying monogenic CSVD can reveal pathways that are dysregulated in common sporadic forms of the disease and may represent therapeutic targets. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause highly penetrant CSVD as part of a multisystem disorder referred to as Gould syndrome. COL4A1 and COL4A2 form heterotrimers [a1α1α2(IV)] that are fundamental constituents of basement membranes. However, their functions are poorly understood and the mechanism(s) by which COL4A1 and COL4A2 mutations cause CSVD are unknown. We used histological, molecular, genetic, pharmacological, and in vivo imaging approaches to characterize central nervous system (CNS) vascular pathologies in Col4a1 mutant mouse models of monogenic CSVD to provide insight into underlying pathogenic mechanisms. We describe developmental CNS angiogenesis abnormalities characterized by impaired retinal vascular outgrowth and patterning, increased numbers of mural cells with abnormal morphologies, altered contractile protein expression in vascular smooth muscle cells (VSMCs) and age-related loss of arteriolar VSMCs in Col4a1 mutant mice. Importantly, we identified elevated TGFβ signaling as a pathogenic consequence of Col4a1 mutations and show that genetically suppressing TGFβ signaling ameliorated CNS vascular pathologies, including partial rescue of retinal vascular patterning defects, prevention of VSMC loss, and significant reduction of intracerebral hemorrhages in Col4a1 mutant mice aged up to 8 months. This study identifies a novel biological role for collagen α1α1α2(IV) as a regulator of TGFβ signaling and demonstrates that elevated TGFβ signaling contributes to CNS vascular pathologies caused by Col4a1 mutations. Our findings suggest that pharmacologically suppressing TGFβ signaling could reduce the severity of CSVD, and potentially other manifestations associated with Gould syndrome and have important translational implications that could extend to idiopathic forms of CSVD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The kilometer square array (KM2A) of the large high altitude air shower observatory (LHAASO) aims at surveying the northern γ-ray sky at energies above 10 TeV with unprecedented sensitivity. γ-ray observations have long been one of the most powerful tools for dark matter searches, as, e.g., high-energy γ rays could be produced by the decays of heavy dark matter particles. In this Letter, we present the first dark matter analysis with LHAASO-KM2A, using the first 340 days of data from 1/2-KM2A and 230 days of data from 3/4-KM2A. Several regions of interest are used to search for a signal and account for the residual cosmic-ray background after γ/hadron separation. We find no excess of dark matter signals, and thus place some of the strongest γ-ray constraints on the lifetime of heavy dark matter particles with mass between 10^{5} and 10^{9}  GeV. Our results with LHAASO are robust, and have important implications for dark matter interpretations of the diffuse astrophysical high-energy neutrino emission.

Background: Inflammation plays an important role in diabetes mellitus (DM)-related acute ischemic stroke (AIS). The mechanisms of un-resolved inflammation in DM-related AIS are not fully understood. Specialized pro-resolving mediators (SPMs) are key regulators that promote resolution of inflammation. We aimed to examine resolution function in patients with AIS complicated with DM, and explore potential treatment effects of one of the SPMs, resolvin D2 (RvD2) ex vivo and in vivo., Methods: Cultured human macrophages, which were derived from peripheral blood mononuclear cells of AIS and none-AIS patients with or without DM, were stimulated with oxidized-low density lipoprotein (ox-LDL). Levels of SPMs and inflammatory markers were analysed, and RvD2 treatment effects were evaluated in these cells. For experiments in vivo, challenges with high fat diet and low-dose streptozotocin (STZ) were used to induce DM in C57BL/6J mice. AIS model was established by permanent middle cerebral artery occlusion (pMCAO) followed by intra-cerebroventricular injection of RvD2., Results: Compared with macrophages of AIS patients without DM, the ratios of SPMs to leukotriene B4 (LTB 4 ) were decreased in AIS patients with DM, accompanied by reduced expression of SPM synthesis enzyme, 15-lipoxygenase-1. Moreover, the levels of pro-inflammatory pathway markers were increased, and the macrophages were skewed to M1 polarization in AIS patients with DM. In mice, treatment with RvD2 ameliorated pMCAO-induced brain injury, neurological dysfunction, and inflammatory response. Furthermore, RvD2 rescued resolution of inflammation by promoting macrophage/microglia polarization to pro-resolving M2 phenotype ex vivo and in vivo., Conclusions: Our data demonstrate resolution of inflammation is impaired by DM in AIS patients, implicating a novel mechanism of un-resolved inflammation in DM-related AIS. Furthermore, RvD2 promotes inflammation resolution in macrophages/microglia and protects DM-related AIS, and may thus serve as a novel therapeutic target., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Although crystal engineering strategies are generally well explored in the context of multicomponent crystals (cocrystals) formed by neutral coformers (molecular cocrystals), cocrystals comprised of one or more salts (ionic cocrystals, ICCs) are understudied. We herein address the design, preparation, and structural characterization of ICCs formed by phenolic moieties, a common group in natural products and drug molecules. Organic and inorganic bases were reacted with the following phenolic coformers: phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol. Nine ICCs were crystallized, each of them sustained by the phenol-phenolate supramolecular heterosynthon (PhOH···PhO - ). Such ICCs are of potential utility, and there are numerous examples of phenolic compounds that are biologically active, some of which suffer from low aqueous solubility. The propensity to form ICCs sustained by the PhOH···PhO - supramolecular heterosynthon was evaluated through a combination of Cambridge Structural Database (CSD) mining, structural characterization of nine novel ICCs, and calculation of interaction energies. Our analysis of these 9 ICCs and the 41 relevant entries archived in the CSD revealed that phenol groups can reliably form ICCs through charge-assisted PhOH···PhO - interactions. This conclusion is supported by hydrogen-bond strength calculations derived from CrystalExplorer that reveal the PhOH···PhO - interaction to be around 3 times stronger than the phenol-phenol hydrogen bond. The PhOH···PhO - supramolecular heterosynthon could therefore enable crystal engineering studies of a large number of phenolic pharmaceutical and nutraceutical compounds with their conjugate bases., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Blood-brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti-ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Recently, the LHAASO Collaboration published the detection of 12 ultrahigh-energy γ-ray sources above 100 TeV, with the highest energy photon reaching 1.4 PeV. The first detection of PeV γ rays from astrophysical sources may provide a very sensitive probe of the effect of the Lorentz invariance violation (LIV), which results in decay of high-energy γ rays in the superluminal scenario and hence a sharp cutoff of the energy spectrum. Two highest energy sources are studied in this work. No signature of the existence of the LIV is found in their energy spectra, and the lower limits on the LIV energy scale are derived. Our results show that the first-order LIV energy scale should be higher than about 10^{5} times the Planck scale M_{Pl} and that the second-order LIV scale is >10^{-3}M_{Pl}. Both limits improve by at least one order of magnitude the previous results.

Structural changes at the active site of an enzyme induced by binding to a substrate molecule can result in enhanced activity in biological systems. Herein, we report that the new hybrid ultramicroporous material sql-SIFSIX-bpe-Zn exhibits an induced fit binding mechanism when exposed to acetylene, C 2 H 2 . The resulting phase change affords exceptionally strong C 2 H 2 binding that in turn enables highly selective C 2 H 2 /C 2 H 4 and C 2 H 2 /CO 2 separation demonstrated by dynamic breakthrough experiments. sql-SIFSIX-bpe-Zn was observed to exhibit at least four phases: as-synthesised (α); activated (β); and C 2 H 2 induced phases (β' and γ). sql-SIFSIX-bpe-Zn-β exhibited strong affinity for C 2 H 2 at ambient conditions as demonstrated by benchmark isosteric heat of adsorption (Q st ) of 67.5 kJ mol -1 validated through in situ pressure gradient differential scanning calorimetry (PG-DSC). Further, in situ characterisation and DFT calculations provide insight into the mechanism of the C 2 H 2 induced fit transformation, binding positions and the nature of host-guest and guest-guest interactions., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar's rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10 -4 to 1.1 peta-electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta-electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron's size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta-electron volt electrons, 2.5 × 10 36 ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta-electron volt protons to the production of the highest-energy gamma rays., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains of tPA-treated mice. Blood-brain barrier (BBB) disruption after ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase I or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase I or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase I-mediated downregulation of the STING pathway and type 1 interferon production and blocked the antihemorrhagic effect of DNase I in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas-/- mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in the ischemic brain and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage., (© 2021 by The American Society of Hematology.)

Objective: Most of the studies on the herb Chuanxiong Rhizoma (CR) have focused on the l -arginine-nitric oxide (NO) pathway, but the nitrate-nitrite-NO (NO 3 - -NO 2 - -NO) pathway was rarely investigated. Therefore, the aim of this study was to evaluate the effects and mechanisms of action of CR in coronary artery disease (CAD)., Methods: The NO 3 - , NO 2 - and NO levels were examined in the NO 3 - -NO 2 - -NO pathway. High-performance ion chromatography was used to quantify NO 3 - and NO 2 - levels. Then, NO was quantified using a multifunctional enzyme marker with a fluorescent probe. The tension of aortic rings was measured using a multi myograph system., Results: High content of NO 3 - and low content of NO 2 - was found in CR, and which could potently convert NO 3 - to NO 2 - in the presence of endogenous reductase enzyme. Incubating human coronary artery endothelial cells (HCAECs) with CR-containing serum showed that CR significantly decreased the NO 3 - content and increased the levels of NO 2 - and NO in the cells under hypoxic conditions. In addition, CR significantly relaxed isolated aortic rings when the l -arginine -NO pathway was blocked. The optimal concentration of CR for relaxation was 200 mg/mL., Conclusion: CR supplements large amounts of NO in cells and vessels to achieve relaxation via the NO 3 - -NO 2 - -NO pathway, thereby making up for the deficiency caused by the lack of NO after the l -arginine-NO pathway is suppressed. This study also supports the potential use of a traditional Chinese herb for future drug development., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)

A series of increasingly large silver nanoclusters with a varied combination of Archimedean and/or Platonic solid arrangements was constructed using a flexible trifurcate TiL 3 (L = Salicylic acid or 5-fluorosalicylic acid) metalloligand: Ag 4 @Ag 4 @Ti 4 ( PTC-85 ), Ag 12 @Ti 4 ( PTC-86 ), Ag 4 @Ag 6 @Ag 12 @Ti 4 ( PTC-87 ), Ag 6 @Ag 24 @Ag 12 @Ti 4 ( PTC-88 ), and Ag 12 @Ag 24 @Ti 4 ( PTC-89 ). The silver nanoclusters are each capped by four TiL 3 moieties, thereby forming {Ti 4 } supertetrahedra with average edge lengths ranging from ∼8.12 Å to ∼17.37 Å. Such {Ti 4 } moieties further induce the tetrahedral geometry of the encapsulated silver nanoclusters. These atomically precise metallic clusters were found to be ultrastable with respect to air for several months, and to water for more than 3 days, due to the stabilizing effects of the TiL 3 metalloligand. Moreover, the obtained clusters exhibit nonlinear optical (NLO) effects in optical limiting tests and also temperature-dependent photoluminescent properties. This work provides an interesting metalloligand method not only to induce the spatial growth of metallic clusters to achieve highly symmetric structures, but also to enhance their stability which is crucial for future application.

Neovascularization and vascular remodeling are functionally important for brain repair after stroke. We show that neutrophils accumulate in the peri-infarct cortex during all stages of ischemic stroke. Neutrophils producing intravascular and intraparenchymal neutrophil extracellular traps (NETs) peak at 3-5 days. Neutrophil depletion reduces blood-brain barrier (BBB) breakdown and enhances neovascularization at 14 days. Peptidylarginine deiminase 4 (PAD4), an enzyme essential for NET formation, is upregulated in peri-ischemic brains. Overexpression of PAD4 induces an increase in NET formation that is accompanied by reduced neovascularization and increased BBB damage. Disruption of NETs by DNase 1 and inhibition of NET formation by genetic ablation or pharmacologic inhibition of PAD increases neovascularization and vascular repair and improves functional recovery. Furthermore, PAD inhibition reduces stroke-induced STING-mediated production of IFN-β, and STING knockdown and IFN receptor-neutralizing antibody treatment reduces BBB breakdown and increases vascular plasticity. Collectively, our results indicate that NET release impairs vascular remodeling during stroke recovery.

Closed-to-open structural transformations in flexible coordination networks are of potential utility in gas storage and separation. Herein, we report the first example of a flexible SiF 6 2- -pillared square grid material, [Cu(SiF 6 )(L) 2 ] n (L = 1,4-bis(1-imidazolyl)benzene), SIFSIX-23-Cu . SIFSIX-23-Cu exhibits reversible switching between nonporous ( β1 ) and several porous ( α , γ1 , γ2 , and γ3 ) phases triggered by exposure to N 2 , CO 2 , or H 2 O. In addition, heating β1 to 433 K resulted in irreversible transformation to a closed polymorph, β2 . Single-crystal X-ray diffraction studies revealed that the phase transformations are enabled by rotation and geometrical contortion of L. Density functional theory calculations indicated that L exhibits a low barrier to rotation (as low as 8 kJmol -1 ) and a rather flat energy surface. In situ neutron powder diffraction studies provided further insight into these sorbate-induced phase changes. SIFSIX-23-Cu combines stability in water for over a year, high CO 2 uptake (ca. 216 cm 3 /g at 195 K), and good thermal stability.

Background: ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) plays a vital role in preventing microvascular thrombosis and inflammation. Reduced ADAMTS13 levels in plasma have been detected in multiple sclerosis (MS) patients. In the present study, we have determined the role of ADAMTS13 in the disease progression of MS using a mouse model of experimental autoimmune encephalomyelitis (EAE)., Methods: Female C57BL/6 mice were immunized with MOG 35-55 peptide and then treated with ADAMTS13 or vehicle in preventive and therapeutic settings. Mice were analyzed for clinical deficit, white matter demyelination and inflammatory cell infiltration. To explore the underlying mechanism, VWF expression and blood-spinal cord barriers (BSCB) were determined., Results: Plasma ADAMTS13 activity was suppressed in EAE mice. ADAMTS13-treated EAE mice exhibited an ameliorated disease course, reduced demyelination, and decreased T lymphocyte, neutrophil and monocyte infiltration into the spinal cord. Consistently, ADAMTS13 treatment reduced VWF levels and inhibited BSCB breakdown in the spinal cords of EAE mice. However, leukocytes in the blood and spleen of EAE mice remained unaffected by ADAMTS13 administration., Conclusion: Our results demonstrate that ADAMTS13 treatment ameliorates inflammatory responses, demyelination and disease course in EAE mice. Therefore, our study suggests that ADAMTS13 may represent a potential therapeutic strategy for MS patients.

Severe haemorrhagic transformation (HT), a common complication of recombinant tissue plasminogen activator (rtPA) treatment, predicts poor clinical outcomes in acute ischaemic stroke. The search for agents to mitigate this effect includes investigating biomolecules involved in neovascularization. This study examines the role of Cathepsin K (Ctsk) in rtPA-induced HT after focal cerebral ischaemia in mice. After knockout of Ctsk, the gene encoding Ctsk, the outcomes of Ctsk +/+ and Ctsk -/- mice were compared 24 h after rtPA-treated cerebral ischaemia with respect to HT severity, neurological deficits, brain oedema, infarct volume, number of apoptotic neurons and activated microglia/macrophage, blood-brain barrier integrity, vascular endothelial growth factor (VEGF) expression and Akt-mTOR pathway activation. We observed that haemoglobin levels, brain oedema and infarct volume were significantly greater and resulted in more severe neurological deficits in Ctsk -/- than in Ctsk +/+ mice. Consistent with our hypothesis, the number of NeuN-positive neurons was lower and the number of TUNEL-positive apoptotic neurons and activated microglia/macrophage was higher in Ctsk -/- than in Ctsk +/+ mice. Ctsk knockout mice exhibited more severe blood-brain barrier (BBB) disruption, with microvascular endothelial cells exhibiting greater VEGF expression and lower ratios of phospo-Akt/Akt and phospo-mTOR/mTOR than in Ctsk +/+ mice. This study is the first to provide molecular insights into Ctsk-regulated HT after cerebral ischaemia, suggesting that Ctsk deficiency may disrupt the BBB via Akt/mTOR/VEGF signalling, resulting in neurological deficits and neuron apoptosis. Ctsk administration has the potential as a novel modality for improving the safety of rtPA treatment following stroke.

Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-β (Aβ) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and Aβ levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aβ, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral Aβ, reductions in Aβ brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD., Competing Interests: The authorshave declared that no competing interests exist.

Background: Exacerbated blood-brain barrier (BBB) damage is related with tissue plasminogen activator (tPA)-induced brain hemorrhage after stroke. Platelets have long been recognized as the cellular orchestrators of primary haemostasis. Recent studies have demonstrated further that platelets are required for supporting intact mature blood vessels and play a crucial role in maintaining vascular integrity during inflammation. Therefore, we sought to investigate whether platelets could reduce tPA-induced deterioration of cerebrovascular integrity and lead to less hemorrhagic transformation., Methods: Mice were subjected to models of collagenase-induced intracerebral hemorrhage (ICH) and transient middle cerebral artery (MCA) occlusion. After 2 h of MCA occlusion, tPA (10 mg/kg) was administered as an intravenous bolus injection of 1 mg/kg followed by a 9 mg/kg infusion for 30 min. Immediately after tPA treatment, mice were transfused with platelets. Hemorrhagic volume, infarct size, neurological deficit, tight junction and basal membrane damages, endothelial cell apoptosis, and extravascular accumulation of circulating dextran and IgG, and Evans blue were quantified at 24 h., Results: Platelet transfusion resulted in a significant decrease in hematoma volume after ICH. In mice after ischemia, tPA administration increased brain hemorrhage transformation and this was reversed by resting but not activated platelets. Consistent with this, we observed that tPA-induced brain hemorrhage was dramatically exacerbated in thrombocytopenic mice. Transfusion of resting platelets ameliorated tPA-induced loss of cerebrovascular integrity and reduced extravascular accumulation of circulating serum proteins and Evans blue, associated with improved neurological functions after ischemia. No changes were found for infarct volume. Inhibition of platelet receptor glycoprotein VI (GPVI) blunted the ability of platelets to attenuate tPA-induced BBB disruption and hemorrhage after ischemia., Conclusion: Our findings demonstrate the importance of platelets in safeguarding BBB integrity and suggest that transfusion of resting platelets may be useful to improve the safety of tPA thrombolysis in ischemic stroke.

The selective separation of ethanol/acetonitrile by porous materials has rarely been observed owing to their similar physicochemical properties. In this work, we report a new coordination network, [Cu 2 (4-pmntd) 2 (opd) 2 ](4-pmntd = N , N '-bis(4-pyridymethy)naphthalene diimide, opd = disodium 1,2-benzenedicarboxylate), which exhibits selective separation of ethanol over acetonitrile. The weak coordination bonds formed by unsaturated Cu 2+ sites and hydroxyl groups are the key to such performance., Competing Interests: The authors declare no competing financial interest.

Background: Growth differentiation factor 11 (GDF11), a member of transforming growth factor-β (TGF-β) superfamily, was shown to rejuvenate cardiac and skeletal muscle function and to improve cerebral vasculature and neurogenesis in old mice. However, recent experimental data reported that raising GDF11 levels inhibited skeletal muscle regeneration and had no effect on cardiac hypertrophy. Our aim was to investigate the effects of GDF11 on brain repair during the recovery phase after stroke. Methods: Mice were subjected to distal middle cerebral artery occlusion, and recombinant GDF11 (rGDF11) was injected intraperitoneally once a day during days 7-13 after stroke. Neuronal precursor cells (NPCs) proliferation and angiogenesis were assayed at 14 days. Neuronal regeneration was assayed at 42 days. The beam-walking test and CatWalk were used to evaluate behavioral functions. Downstream pathways of GDF11 were also investigated. Results: GDF11 was upregulated in the ipsilateral peri-infarct cortex and subventricular zone (SVZ) at 14 days after stroke. Treatment with rGDF11 enhanced the number of newborn NPCs and endothelial cells, microvascular length and area, and brain capillary perfusion. Western blots showed that rGDF11 upregulated brain-derived neurotrophic factor (BDNF) and increased the levels of proangiogenic factor angiopoietin-2 (Ang-2) and phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2). We also found that rGDF11 upregulated the transcription factors Smad2 and Smad3 phosphorylation, but these activations were blocked by a TGF-β receptor inhibitor SB431542. Moreover, rGDF11-induced angiogenic remodeling and NPCs proliferation were reversed by injection of SB431542, suggesting that GDF11 may exert its effect via the TGF-β/Smad2/3 signaling pathway. Finally, treating mice with rGDF11 resulted in a significant increase in neuronal regeneration and functional recovery. Conclusion: GDF11 promoted neurogenesis and angiogenesis and contributed to functional recovery after stroke in mice.

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.

Immune challenge in early life has been observed to influence the long-term reproductive dysfunction. On PNDs 3 and 5, female offsprings were administered with LPS (50μg/kg, i.p.) or saline. Vaginal opening was recorded, and oestrous cyclicity was monitored immediately post puberty and again at 56-70 days. At 10 weeks of age, the ovaries were removed for immunostaining and RNA analysis. Neonatal exposure to LPS resulted in a significant delay puberty onset as well as destroyed expression of ovulation related genes. At PND 42 and 70, a significant increase in Kiss1 mRNA and Kisspeptin expression was detected at proestrus and oestrus in neo-LPS treated rats compared with the counterparts. Therefore, neonatal LPS exposure had a long-term effect on reproductive function and the up-regulated expression of ovarian Kiss1 and kisspeptin during the ovulatory transition stage may contribute to ovulatory dysfunction induced by peripheral LPS administration in early life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13 -/- mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13 -/- mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13 -/- mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery., (© 2017 by The American Society of Hematology.)

Continuous fixed bed reactors filled by three kinds of packing which were glass bead, glass spring and Dixon rings were investigated. The effect of temperature, pressure, the molar ratio of methanol to oil, flow rate, the size and shape of the packing were researched. The highest yield 90.84% of FAME was obtained by filling Dixon rings as packing with the condition of the temperature was 350°C, the pressure was 22MPa, the molar ratio of methanol to oil was 42:1. In addition, the reusability of Dixon rings was perfect. Numerical simulation was researched to provide theoretical basis for experimental results, besides the kinetics and thermodynamics behavior were investigated to explore the reaction mechanism., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB 1 ) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB 1 antagonist rimonabant that once was marketed for the treatment of obesity, suggesting a new chemical entity for the discovery of antiobesity drugs. To increase structural diversity of this class of CB 1 ligands, we designed and synthesized two classes of novel analogues, in which the pyridine ring of 2 was replaced by a pyrimidine ring. These positively modulate the binding of the CB 1 orthosteric agonist CP55,940 while exhibiting an antagonism of G-protein coupling activity. Interestingly, compounds 7d and 8d demonstrated ERK1/2 phosphorylation mediated via β-arrestin unlike the orthosteric CP55,940 that does so in a G protein-dependent manner. These can serve as new lead compounds for the future development of CB 1 allosteric modulators that show biased agonism and potentially antiobesity behavior via a new mechanism.

We have demonstrated for the first time that isostructural homochiral metal-organic frameworks (MOFs) can be synthesized directly from chiral ligands and indirectly from achiral ligands via spontaneous resolution combined with cooperative chirality induction, respectively. Moreover, the usage of different ligands leads to distinct proton conduction behaviors.

To analyze the tradeoff relationship between twigs and leaves, the traits of Pinus hwang-shanensis including leaf area, leaf number, twig length and twig diameter were investigated in Wuyi Mountains along an altitudinal gradient. The results indicated that leaf number, twig length, twig diameter, leafing intensity and twig stem cross-sectional area of P. hwangshanensis increased gra-dually with the increasing altitude, while individual leaf area decreased gradually. Leafing intensity of P. hwangshanensis at different altitudes had significant negative relationships with leaf area. The cross-sectional area of P. hwangshanensis had significant positive relationship with total leaf area. Twig length and twig diameter of P. hwangshanensis correlated negatively with leafing intensity, but positively with leaf area, leaf number and total leaf area. To enhance the competitiveness and resource utilization efficiency, P. hwangshanensis at low altitude tended to have relatively few large leaves on short twigs, and those at high altitude tended to have a large number of small leaves on long twigs. Such tradeoff between twigs and leaves reflected the strategy of resource utilization and the balance of biomass allocation mechanism of P. hwangshanensis responding to the altitudinal change.