Establishing reaction networks in the 16-electron sulfur reduction reaction.

The sulfur reduction reaction (SRR) plays a central role in high-capacity lithium sulfur (Li-S) batteries. The SRR involves an intricate, 16-electron conversion process featuring multiple lithium polysulfide intermediates and reaction branches1-3. Establishing the complex reaction network is essential for rational tailoring of the SRR for improved Li-S batteries, but represents a daunting challenge4-6. Herein we systematically investigate the electrocatalytic SRR to decipher its network using the nitrogen, sulfur, dual-doped holey graphene framework as a model electrode to understand the role of electrocatalysts in acceleration of conversion kinetics. Combining cyclic voltammetry, in situ Raman spectroscopy and density functional theory calculations, we identify and directly profile the key intermediates (S8, Li2S8, Li2S6, Li2S4 and Li2S) at varying potentials and elucidate their conversion pathways. Li2S4 and Li2S6 were predominantly observed, in which Li2S4 represents the key electrochemical intermediate dictating the overall SRR kinetics. Li2S6, generated (consumed) through a comproportionation (disproportionation) reaction, does not directly participate in electrochemical reactions but significantly contributes to the polysulfide shuttling process. We found that the nitrogen, sulfur dual-doped holey graphene framework catalyst could help accelerate polysulfide conversion kinetics, leading to faster depletion of soluble lithium polysulfides at higher potential and hence mitigating the polysulfide shuttling effect and boosting output potential. These results highlight the electrocatalytic approach as a promising strategy for tackling the fundamental challenges regarding Li-S batteries.

Free-space dissemination of time and frequency with 10-19 instability over 113 km.

Networks of optical clocks find applications in precise navigation1,2, in efforts to redefine the fundamental unit of the 'second'3-6 and in gravitational tests7. As the frequency instability for state-of-the-art optical clocks has reached the 10-19 level8,9, the vision of a global-scale optical network that achieves comparable performances requires the dissemination of time and frequency over a long-distance free-space link with a similar instability of 10-19. However, previous attempts at free-space dissemination of time and frequency at high precision did not extend beyond dozens of kilometres10,11. Here we report time-frequency dissemination with an offset of 6.3 × 10-20 ± 3.4 × 10-19 and an instability of less than 4 × 10-19 at 10,000 s through a free-space link of 113 km. Key technologies essential to this achievement include the deployment of high-power frequency combs, high-stability and high-efficiency optical transceiver systems and efficient linear optical sampling. We observe that the stability we have reached is retained for channel losses up to 89 dB. The technique we report can not only be directly used in ground-based applications, but could also lay the groundwork for future satellite time-frequency dissemination.

FOXM1 transcriptional regulation.

FOXM1 is a key transcriptional regulator involved in various biological processes in mammals, including carbohydrate and lipid metabolism, aging, immune regulation, development, and disease. Early studies have shown that FOXM1 acts as an oncogene by regulating cell proliferation, cell cycle, migration, metastasis, and apoptosis, as well as genes related to diagnosis, treatment, chemotherapy resistance, and prognosis. Researchers are increasingly focusing on FOXM1 functions in tumor microenvironment, epigenetics, and immune infiltration. However, researchers have not comprehensively described FOXM1's involvement in tumor microenvironment shaping, epigenetics, and immune cell infiltration. Here we review the role of FOXM1 in the formation and development of malignant tumors, and we will provide a comprehensive summary of the role of FOXM1 in transcriptional regulation, interacting proteins, tumor microenvironment, epigenetics, and immune infiltration, and suggest areas for further research.

Strong Vertical Piezoelectricity and Broad-pH-Value Photocatalyst in Ferroelastic Y2Se2BrF Monolayer.

With the development of miniaturized devices, there is an increasing demand for 2D multifunctional materials. Six ferroelastic semiconductors, Y2Se2XX' (X, X' = I, Br, Cl, or F; X ≠ X') monolayers, are theoretically predicted here. Their in-plane anisotropic band structure, elastic and piezoelectric properties can be switched by ferroelastic strain. Moderate energy barriers can prevent the undesired ferroelastic switching that minor interferences produce. These monolayers exhibit high carrier mobilities (up to 104 cm2 V-1 s-1) with strong in-plane anisotropy. Furthermore, their wide bandgaps and high potential differences make them broad-pH-value and high-performance photocatalysts at pH value of 0-14. Strikingly, Y2Se2BrF possesses outstanding d33 (d33 = -405.97 pm/V), greatly outperforming CuInP2S6 by 4.26 times. Overall, the nano Y2Se2BrF is a hopeful candidate for multifunctional devices to generate a direct current and achieve solar-free photocatalysis. This work provides a new paradigm for the design of multifunctional energy materials.

Performance of Metagenomic Next-Generation Sequencing of Cell-Free DNA From Vitreous and Aqueous Humor for Diagnoses of Intraocular Infections.

BACKGROUND: Delayed diagnosis and improper therapy for intraocular infections usually result in poor prognosis. Due to limitations of conventional culture and polymerase chain reaction methods, most causative pathogens cannot be identified from vitreous humor (VH) or aqueous humor (AH) samples with limited volume. METHODS: Patients with suspected intraocular infections were enrolled from January 2019 to August 2021. Metagenomic next-generation sequencing (mNGS) was used to detected causative pathogens. RESULTS: This multicenter prospective study enrolled 488 patients, from whom VH (152) and AH (336) samples were respectively collected and analyzed using mNGS of cell-free DNA (cfDNA). Taking final comprehensive clinical diagnosis as the gold standard, there were 39 patients with indefinite final diagnoses, whereas 288 and 161 patients were diagnosed as definite infectious and noninfectious diseases, respectively. Based on clinical adjudication, the sensitivity (92.2%) and total coincidence rate (81.3%) of mNGS using VH samples were slightly higher than those of mNGS using AH samples (85.4% and 75.4%, respectively). CONCLUSIONS: Using mNGS of cfDNA, an era with clinical experience for more rapid, independent, and impartial diagnosis of bacterial and other intraocular infections can be expected.

Vascularized organoid-on-a-chip: design, imaging, and analysis.

Vascularized organoid-on-a-chip (VOoC) models achieve substance exchange in deep layers of organoids and provide a more physiologically relevant system in vitro. Common designs for VOoC primarily involve two categories: self-assembly of endothelial cells (ECs) to form microvessels and pre-patterned vessel lumens, both of which include the hydrogel region for EC growth and allow for controlled fluid perfusion on the chip. Characterizing the vasculature of VOoC often relies on high-resolution microscopic imaging. However, the high scattering of turbid tissues can limit optical imaging depth. To overcome this limitation, tissue optical clearing (TOC) techniques have emerged, allowing for 3D visualization of VOoC in conjunction with optical imaging techniques. The acquisition of large-scale imaging data, coupled with high-resolution imaging in whole-mount preparations, necessitates the development of highly efficient analysis methods. In this review, we provide an overview of the chip designs and culturing strategies employed for VOoC, as well as the applicable optical imaging and TOC methods. Furthermore, we summarize the vascular analysis techniques employed in VOoC, including deep learning. Finally, we discuss the existing challenges in VOoC and vascular analysis methods and provide an outlook for future development.

Enhancing Point-of-Care Diagnosis of African Swine Fever Virus (ASFV) DNA with the CRISPR-Cas12a-Assisted Triplex Amplified Assay.

Accurate, ultrasensitive, and point-of-care (POC) diagnosis of the African swine fever virus (ASFV) remains imperative to prevent its spread and limit the losses incurred. Herein, we propose a CRISPR-Cas12a-assisted triplex amplified colorimetric assay for ASFV DNA detection with ultrahigh sensitivity and specificity. The specific recognition of recombinase aided amplification (RAA)-amplified ASFV DNA could activate the Cas12a/crRNA/ASFV DNA complex, leading to the digestion of the linker DNA (bio-L1) on magnetic beads (MBs), thereby preventing its binding of gold nanoparticles (AuNPs) network. After magnetic separation, the release of AuNPs network comprising a substantial quantity of AuNPs could lead to a discernible alteration in color and significantly amplify the plasmonic signal, which could be read by spectrophotometers or smartphones. By combining the RAA, CRISPR/Cas12a-assisted cleavage, and AuNPs network-mediated colorimetric amplification together, the assay could detect as low as 0.1 copies/µL ASFV DNA within 1 h. The assay showed an accuracy of 100% for the detection of ASFV DNA in 16 swine tissue fluid samples, demonstrating its potential for on-site diagnosis of ASFV.

Exploring the impact of high-altitude de-acclimatization on renal function: The roles of oxidative and endoplasmic reticulum stress in rat models.

BACKGROUND: High-altitude de-acclimatization (HADA) significantly impacts physiological functions when individuals acclimatize to high altitudes return to lower altitudes. This study investigates HADA's effects on renal function and structure in rats, focusing on oxidative and endoplasmic reticulum stress as potential mechanisms of renal injury. OBJECTIVE: To elucidate the pathophysiological mechanisms of renal damage in HADA and evaluate the efficacy of antioxidants Vitamin C (Vit C) and tauroursodeoxycholic acid (TUDCA) in mitigating these effects. METHODS: 88 male Sprague-Dawley rats were randomly divided into a control group, a high-altitude (HA) group, a high-altitude de-acclimatization (HADA) group, and a treatment group. The control group was housed in a sea level environment (500 m), while the HA, HADA, and treatment groups were placed in a simulated high-altitude chamber (5000 m) for 90 days. After this period, the HA group completed the modeling phase; the HADA group was further subdivided into four subgroups, each continuing to be housed in a sea level environment for 3, 7, 14, and 30 days, respectively. The treatment group was split into the Vit C group, the TUDCA group, and two placebo groups, receiving medication for 3 consecutive days, once daily upon return to the sea level. The Vit C group received 100 mg/kg Vit C solution via intravenous injection, the TUDCA group received 250 mg/kg TUDCA solution via intraperitoneal injection, and the placebo groups received an equivalent volume of saline similarly. Serum, urine, and kidney tissues were collected immediately after the modeling phase. Renal function and oxidative stress levels were assessed using biochemical and ELISA methods. Renal histopathology was observed with H&E, Masson's trichrome, PAS, and PASM staining. Transmission electron microscopy was used to examine the ultrastructure of glomeruli and filtration barrier. TUNEL staining assessed cortical apoptosis in the kidneys. Metabolomics was employed for differential metabolite screening and pathway enrichment analysis. RESULTS: Compared to the control and HA groups, the HADA 3-day group (HADA-3D) exhibited elevated renal function indicators, significant pathological damage, observable ultrastructural alterations including endoplasmic reticulum expansion and apoptosis. TUNEL-positive cells significantly increased, indicating heightened oxidative stress levels. Various differential metabolites were enriched in pathways related to oxidative and endoplasmic reticulum stress. Early intervention with Vit C and TUDCA markedly alleviated renal injury in HADA rats, significantly reducing the number of apoptotic cells, mitigating endoplasmic reticulum stress, and substantially lowering oxidative stress levels. CONCLUSION: This study elucidates the pivotal roles of oxidative and endoplasmic reticulum stress in the early-stage renal injury in rats undergoing HADA. Early intervention with the Vit C and TUDCA significantly mitigates renal damage caused by HADA. These findings provide insights into the pathophysiological mechanisms of HADA and suggest potential therapeutic strategies for its future management.

Direct angiographic comparison of different velocity-selective saturation, inversion, and DANTE labeling modules on cerebral arteries.

PURPOSE: This study evaluated the velocity-selective (VS) MRA with different VS labeling modules, including double refocused hyperbolic tangent, eight-segment B1-insensitive rotation, delay alternating with nutation for tailored excitation, Fourier transform-based VS saturation, and Fourier transform-based inversion. METHODS: These five VS labeling modules were evaluated first through Bloch simulations, and then using VSMRA directly on various cerebral arteries of healthy subjects. The relative signal ratios from arterial ROIs and surrounding tissues as well as relative arteria-tissue contrast ratios of different methods were compared. RESULTS: Double refocused hyperbolic tangent and eight-segment B1-insensitive rotation showed very similar labeling effects. Delay alternating with nutation for tailored excitation yielded high arterial signal but with residual tissue signal due to the spatial banding effect. Fourier transform-based VS saturation with half the time of other techniques serves as an efficient nonsubtractive VSMRA method, but the remaining tissue signal still obscured some small distal arteries that were delineated by other subtraction-based VSMRA, allowing more complete cancelation of static tissue. Fourier transform-based inversion produced the highest arterial signal in VSMRA with minimal tissue background. CONCLUSION: This is the first study that angiographically compared five different VS labeling modules. Their labeling characteristics on arteries and tissue and implications for VSMRA and VS arterial spin labeling are discussed.

Evaluating cerebrovascular reactivity measured by velocity selective inversion arterial spin labeling with different post-labeling delays: The effect of fast flow.

PURPOSE: Velocity selective arterial spin labeling (VSASL) quantification assumes that the labeled bolus continuously moves into the imaging voxel during the post-labeling delay (PLD). Faster blood flow could lead to a bolus duration shorter than the applied PLD of VSASL and cause underestimation of cerebral blood flow (CBF). This study aims to evaluate the performance of velocity-selective inversion (VSI) prepared arterial spin labeling (ASL) with different PLDs and pseudo-continuous ASL (PCASL) for quantification of hypercapnia-induced cerebrovascular reactivity (CVR), using phase-contrast (PC) MRI as a global reference. METHODS: We compared CVR obtained by VSI-ASL with PLD of 1520 ms (VSASL-1520), 1000 ms (VSASL-1000), and 500 ms (VSASL-500), PCASL with PLD of 1800 ms (PCASL-1800), and PC MRI on eight healthy volunteers at two sessions. RESULTS: Compared with PC MRI, VSASL-1520 produced significantly lower global CVR values, while PCASL-1800, VSASL-1000, and VSASL-500 yielded more consistent results. The reduced CVR in VSASL-1520 was more pronounced in carotid territories including frontal and temporal lobes than in vertebral territories such as the occipital lobe. This is largely caused by the underestimated perfusion during hypercapnia due to the reduced bolus duration being less than the PLD. CONCLUSION: Although VSASL offers certain advantages over spatially selective ASL due to its reduced susceptibility to delayed ATT, this technique is prone to biases when the ATT is excessively short. Therefore, a short PLD should be employed for reliable perfusion and CVR quantification in populations or conditions with fast flow.

Simultaneous creatine and phosphocreatine mapping of skeletal muscle by CEST MRI at 3T.

PURPOSE: To confirm that CrCEST in muscle exhibits a slow-exchanging process, and to obtain high-resolution amide, creatine (Cr), and phosphocreatine (PCr) maps of skeletal muscle using a POlynomial and Lorentzian Line-shape Fitting (PLOF) CEST at 3T. METHODS: We used dynamic changes in PCr/CrCEST of mouse hindlimb before and after euthanasia to assign the Cr and PCr CEST peaks in the Z-spectrum at 3T and to obtain the optimum saturation parameters. Segmented 3D EPI was employed to obtain multi-slice amide, PCr, and Cr CEST maps of human skeletal muscle. Subsequently, the PCrCEST maps were calibrated using the PCr concentrations determined by 31 P MRS. RESULTS: A comparison of the Z-spectra in mouse hindlimb before and after euthanasia indicated that CrCEST is a slow-exchanging process in muscle (<150.7 s-1 ). This allowed us to simultaneously extract PCr/CrCEST signals at 3T using the PLOF method. We determined optimal B1 values ranging from 0.3 to 0.6 µT for CrCEST in muscle and 0.3-1.2 µT for PCrCEST. For the study on human calf muscle, we determined an optimum saturation time of 2 s for both PCr/CrCEST (B1 = 0.6 µT). The PCr/CrCEST using 3D EPI were found to be comparable to those obtained using turbo spin echo (TSE). (3D EPI/TSE PCr: (2.6 ± 0.3) %/(2.3 ± 0.1) %; Cr: (1.3 ± 0.1) %/(1.4 ± 0.07) %). CONCLUSIONS: Our study showed that in vivo CrCEST is a slow-exchanging process. Hence, amide, Cr, and PCr CEST in the skeletal muscle can be mapped simultaneously at 3T by PLOF CEST.

Whole-cerebrum guanidino and amide CEST mapping at 3 T by a 3D stack-of-spirals gradient echo acquisition.

PURPOSE: To develop a 3D, high-sensitivity CEST mapping technique based on the 3D stack-of-spirals (SOS) gradient echo readout, the proposed approach was compared with conventional acquisition techniques and evaluated for its efficacy in concurrently mapping of guanidino (Guan) and amide CEST in human brain at 3 T, leveraging the polynomial Lorentzian line-shape fitting (PLOF) method. METHODS: Saturation time and recovery delay were optimized to achieve maximum CEST time efficiency. The 3DSOS method was compared with segmented 3D EPI (3DEPI), turbo spin echo, and gradient- and spin-echo techniques. Image quality, temporal SNR (tSNR), and test-retest reliability were assessed. Maps of Guan and amide CEST derived from 3DSOS were demonstrated on a low-grade glioma patient. RESULTS: The optimized recovery delay/saturation time was determined to be 1.4/2 s for Guan and amide CEST. In addition to nearly doubling the slice number, the gradient echo techniques also outperformed spin echo sequences in tSNR: 3DEPI (193.8 ± 6.6), 3DSOS (173.9 ± 5.6), and GRASE (141.0 ± 2.7). 3DSOS, compared with 3DEPI, demonstrated comparable GuanCEST signal in gray matter (GM) (3DSOS: [2.14%-2.59%] vs. 3DEPI: [2.15%-2.61%]), and white matter (WM) (3DSOS: [1.49%-2.11%] vs. 3DEPI: [1.64%-2.09%]). 3DSOS also achieves significantly higher amideCEST in both GM (3DSOS: [2.29%-3.00%] vs. 3DEPI: [2.06%-2.92%]) and WM (3DSOS: [2.23%-2.66%] vs. 3DEPI: [1.95%-2.57%]). 3DSOS outperforms 3DEPI in terms of scan-rescan reliability (correlation coefficient: 3DSOS: 0.58-0.96 vs. 3DEPI: -0.02 to 0.75) and robustness to motion as well. CONCLUSION: The 3DSOS CEST technique shows promise for whole-cerebrum CEST imaging, offering uniform contrast and robustness against motion artifacts.

The association between the AIP and undiagnosed diabetes in ACS patients with different body mass indexes and LDL-C levels: findings from the CCC-ACS project.

BACKGROUND: The atherogenic index of plasma (AIP) has been demonstrated to be significantly associated with the incidence of prediabetes and diabetes. This study aimed to investigate the association between the AIP and undiagnosed diabetes in acute coronary syndrome (ACS) patients. METHODS: Among 113,650 ACS patients treated with coronary angiography at 240 hospitals in the Improving Care for Cardiovascular Disease in China-ACS Project from 2014 to 2019, 11,221 patients with available clinical and surgical information were included. We analyzed these patients' clinical characteristics after stratification according to AIP tertiles, body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C) levels. RESULTS: The AIP was independently associated with a greater incidence of undiagnosed diabetes. The undiagnosed diabetes was significantly greater in the T3 group than in the T1 group after adjustment for confounders [T3 OR 1.533 (1.199-1.959) p < 0.001]. This relationship was consistent within normal weight patients and patients with an LDL-C level ≥ 1.8 mmol/L. In overweight and obese patients, the AIP was significantly associated with the incidence of undiagnosed diabetes as a continuous variable after adjustment for age, sex, and BMI but not as a categorical variable. The area under the receiver operating characteristic curve (AUC) of the AIP score, triglyceride (TG) concentration, and HDL-C concentration was 0.601 (0.581-0.622; p < 0.001), 0.624 (0.603-0.645; p < 0.001), and 0.493 (0.472-0.514; p = 0.524), respectively. A nonlinear association was found between the AIP and the incidence of undiagnosed diabetes in ACS patients (p for nonlinearity < 0.001), and this trend remained consistent between males and females. The AIP may be a negative biomarker associated with undiagnosed diabetes ranging from 0.176 to 0.738. CONCLUSION: The AIP was significantly associated with the incidence of undiagnosed diabetes in ACS patients, especially in those with normal weight or an LDL-C level ≥ 1.8 mmol/L. A nonlinear relationship was found between the AIP and the incidence of undiagnosed diabetes, and this trend was consistent between male and female patients. The AIP may be a negative biomarker associated with undiagnosed diabetes and ranges from 0.176 to 0.738.

Temperature dependence of spring carbon uptake in northern high latitudes during the past four decades.

In the northern high latitudes, warmer spring temperatures generally lead to earlier leaf onsets, higher vegetation production, and enhanced spring carbon uptake. Yet, whether this positive linkage has diminished under climate change remains debated. Here, we used atmospheric CO2 measurements at Barrow (Alaska) during 1979-2020 to investigate the strength of temperature dependence of spring carbon uptake reflected by two indicators, spring zero-crossing date (SZC) and CO2 drawdown (SCC). We found a fall and rise in the interannual correlation of temperature with SZC and SCC (RSZC-T and RSCC-T ), showing a recent reversal of the previously reported weakening trend of RSZC-T and RSCC-T . We used a terrestrial biosphere model coupled with an atmospheric transport model to reproduce this fall and rise phenomenon and conducted factorial simulations to explore its potential causes. We found that a strong-weak-strong spatial synchrony of spring temperature anomalies per se has contributed to the fall and rise trend in RSZC-T and RSCC-T , despite an overall unbroken temperature control on net ecosystem CO2 fluxes at local scale. Our results provide an alternative explanation for the apparent drop of RSZC-T and RSCC-T during the late 1990s and 2000s, and suggest a continued positive linkage between spring carbon uptake and temperature during the past four decades. We thus caution the interpretation of apparent climate sensitivities of carbon cycle retrieved from spatially aggregated signals.

The SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle insulin resistance in old male rat offspring.

Maternal hypoxia is strongly linked to insulin resistance (IR) in adult offspring, and altered insulin signaling for muscle glucose uptake is thought to play a central role. However, whether the SIRT3/GSK-3ß/GLUT4 axis is involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring has not been investigated. Maternal hypoxia was established from Days 5 to 21 of pregnancy by continuous infusion of nitrogen and air. The biochemical parameters and levels of key insulin signaling molecules of old male rat offspring were determined through a series of experiments. Compared to the control (Ctrl) old male rat offspring group, the hypoxic (HY) group exhibited elevated fasting blood glucose (FBG) (∼30%), fasting blood insulin (FBI) (∼35%), total triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), as well as results showing impairment in the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) revealed impaired cellular structures and mitochondria in the longitudinal sections of skeletal muscle from HY group mice, which might be associated with decreased SIRT3 expression. Furthermore, the expression of insulin signaling molecules, such as GSK-3ß and GLUT4, was also altered. In conclusion, the present results indicate that the SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring.

Mechanisms and clinical landscape of N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers.

Epigenetics encompasses reversible and heritable chemical modifications of non-nuclear DNA sequences, including DNA and RNA methylation, histone modifications, non-coding RNA modifications, and chromatin rearrangements. In addition to well-studied DNA and histone methylation, RNA methylation has emerged as a hot topic in biological sciences over the past decade. N6-methyladenosine (m6A) is the most common and abundant modification in eukaryotic mRNA, affecting all RNA stages, including transcription, translation, and degradation. Advances in high-throughput sequencing technologies made it feasible to identify the chemical basis and biological functions of m6A RNA. Dysregulation of m6A levels and associated modifying proteins can both inhibit and promote cancer, highlighting the importance of the tumor microenvironment in diverse biological processes. Gastrointestinal tract cancers, including gastric, colorectal, and pancreatic cancers, are among the most common and deadly malignancies in humans. Growing evidence suggests a close association between m6A levels and the progression of gastrointestinal tumors. Global m6A modification levels are substantially modified in gastrointestinal tumor tissues and cell lines compared to healthy tissues and cells, possibly influencing various biological behaviors such as tumor cell proliferation, invasion, metastasis, and drug resistance. Exploring the diagnostic and therapeutic potential of m6A-related proteins is critical from a clinical standpoint. Developing more specific and effective m6A modulators offers new options for treating these tumors and deeper insights into gastrointestinal tract cancers.

Kallistatin leads to cognition impairment via downregulating glutamine synthetase.

In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin.

Electrochemical Benzylic C(sp3)-H Imidation Enabled by Benzoic Acid Derived Radicals.

We developed an electrochemical approach for benzylic C(sp3)-H imidation by virtue of the in situ generated oxygen-centered radicals (OCRs). The electrochemical imidation provides a complementary approach to giving distinct imide products compared with previous acyloxylation products. This protocol exhibits good site selectivity and broad substrate generality. Moreover, the utility of the OCR-mediated protocol was extended to the electrochemical oxidation of silane, and its robustness was also highlighted by the imidation of complex substrates, which would otherwise be inaccessible for previous approaches. A plausible reaction mechanism was proposed to rationalize the experimental observations.

Widespread seasonal compensation effects of spring warming on northern plant productivity.

Climate change is shifting the phenological cycles of plants1, thereby altering the functioning of ecosystems, which in turn induces feedbacks to the climate system2. In northern (north of 30° N) ecosystems, warmer springs lead generally to an earlier onset of the growing season3,4 and increased ecosystem productivity early in the season5. In situ6 and regional7-9 studies also provide evidence for lagged effects of spring warmth on plant productivity during the subsequent summer and autumn. However, our current understanding of these lagged effects, including their direction (beneficial or adverse) and geographic distribution, is still very limited. Here we analyse satellite, field-based and modelled data for the period 1982-2011 and show that there are widespread and contrasting lagged productivity responses to spring warmth across northern ecosystems. On the basis of the observational data, we find that roughly 15 per cent of the total study area of about 41 million square kilometres exhibits adverse lagged effects and that roughly 5 per cent of the total study area exhibits beneficial lagged effects. By contrast, current-generation terrestrial carbon-cycle models predict much lower areal fractions of adverse lagged effects (ranging from 1 to 14 per cent) and much higher areal fractions of beneficial lagged effects (ranging from 9 to 54 per cent). We find that elevation and seasonal precipitation patterns largely dictate the geographic pattern and direction of the lagged effects. Inadequate consideration in current models of the effects of the seasonal build-up of water stress on seasonal vegetation growth may therefore be able to explain the differences that we found between our observation-constrained estimates and the model-constrained estimates of lagged effects associated with spring warming. Overall, our results suggest that for many northern ecosystems the benefits of warmer springs on growing-season ecosystem productivity are effectively compensated for by the accumulation of seasonal water deficits, despite the fact that northern ecosystems are thought to be largely temperature- and radiation-limited10.

Aurantio-obtusin Alleviates Dry Eye Disease by Targeting NF-κB/NLRP3 Signaling in Rodent Models.

Dry eye disease (DED) is a common inflammatory ocular surface disorder, seriously affecting the quality of life of patients. Aurantio-obtusin (AO) is a bioactive anthraquinone compound isolated from Semen Cassiae which has multiple pharmacological activities. Nonetheless, the specific function of AO in DED is unclarified. In this study, a rodent DED model was established by benzalkonium chloride (BAC) induction, followed by topical administration of AO. The results showed that topical application of AO increased tear production, mitigated ocular surface disruption and maintained the number of goblet cells in BAC-induced DED rats (p˂0.05). ELISA revealed that AO treatment significantly (p˂0.001) reduced the production of proinflammatory cytokines and chemokines in the conjunctiva and cornea of BAC-induced DED rats. Immunohistochemical staining and western blotting showed that AO treatment suppressed the expression levels of NLR family pyrin domain containing 3 (NLRP3) inflammasome-related proteins, and inhibited activation of nuclear factor kappa B (NF-κB) signaling pathway in rat conjunctiva and cornea (p˂0.001). In conclusion, AO treatment alleviates BAC-induced DED in rats by inhibiting NF-κB/NLRP3 inflammasome signaling pathway.