A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway.

Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1ß⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn's disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn's disease.

The potential role of hydrogen sulfide in cancer cell apoptosis.

For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.

Comparative Study on the Pharmacokinetics of Paeoniflorin, White Peony Root Water Extract, and Taohong Siwu Decoction After Oral Administration in Rats.

BACKGROUND AND OBJECTIVE: Taohong Siwu Decoction (TSD) is a classic traditional Chinese medicine (TCM) compound with pharmacological effects such as vasodilation and hypolipidemia. Paeoniflorin (PF) is one of the active ingredients of TSD. The aim of this study was to evaluate the pharmacokinetics of PF in herbal extracts and their purified forms in rats. METHOD: A sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method for the determination of PF in rat plasma was developed. Rats were divided into three groups, and given PF solution, water extract of white peony root (WPR), or TSD by gavage. At different predetermined timepoints after gavage, blood was collected from the orbital vein. The pharmacokinetic parameters of PF in the plasma of rats in the three groups was determined. RESULTS: The pharmacokinetic studies showed that the time to reach maximum concentration (Tmax) of PF in the purified forms group was relatively high, while the half-lives (T½) of PF in the TSD and WPR groups were longer. Among the three groups, PF in the purified forms group had the maximum area under the concentration-time curve (AUC0-t = 732.997 µg/L·h) and the largest maximum concentration (Cmax = 313.460 µg/L), which showed a significant difference compared with the TSD group (P < 0.05). Compared with the purified group, the clearance (CLz/F = 86.004 L/h/kg) and the apparent volume of distribution (Vz/F = 254.787 L/kg) of PF in the TSD group increased significantly (P < 0.05). CONCLUSIONS: A highly specific, sensitive, and rapid HPLC-MS-MS method was developed and applied for the determination of PF in rat plasma. It was found that TSD and WPR can prolong the action time of paeoniflorin in the body.

[Prevention from PICC-related venous thrombosis in the upper limbs of malignant tumor patients with moxibustion combined with plucking at Jiquan (HT 1): a randomized controlled trial].

OBJECTIVE: To observe the clinical effect of moxibustion combined with plucking technique at Jiquan (HT 1) for preventing peripherally inserted central catheter (PICC)-related venous thrombosis in the upper limbs of malignant tumor patients. METHODS: A total of 80 malignant tumor patients undergoing PICC were randomized into an observation group and a control group, 40 cases in each one. In the control group, the routine care for PICC was exerted. In the observation group, besides the routine care, moxibustion combined with plucking technique at Jiquan (HT 1) was added. Mild moxibustion was exerted along the venous distribution of PICC (avoiding the entry site) for 10 to 15 min, and then, the circling moxibustion was applied to Quchi (LI 11), Xuehai (SP 10) and Tianfu (LU 3), 3 to 5 min at each acupoint. Finally, plucking technique was given at Jiquan (HT 1) for 5 to 10 min. This combined therapy was intervened since the 2nd day of PICC placement, once daily, 5 times a week, for 3 weeks totally. The incidence of the PICC-related venous thrombosis in the upper limbs was compared between the two groups on day 42 of placement. On day 2, 7, 14, 21, 28, 35 and 42 of PICC placement, the peak systolic velocity (PSV) and the end-diastolic velocity (EDV) of the subclavicular vein on the placement side were observed separately in the two groups. RESULTS: The incidence of the PICC-related venous thrombosis in the upper limbs in the observation group was lower than that in the control group (2.5% [1/40] vs 17.5% [7/40], P<0.05). From day 7 to 35 of PICC placement, PSV of the subclavicular vein on the placement side was higher than that on the day 2 of PICC placement in the observation group (P<0.05). On day 28 and 42 of PICC placement, PSV of the subclavicular vein on the placement side was lower than that on the day 2 of PICC placement in the control group (P<0.05). In the observation group, EDV of the subclavicular vein on the placement side was higher than that on the day 2 of PICC placement from day 7 to 28 of PICC placement (P<0.05). In the control group, EDV of the subclavicular vein on the placement side from day 28 to 42 of PICC placement was lower than that on the day 2 of PICC placement (P<0.05). From day 7 to 42 of PICC placement, PSV and EDV of the subclavicular vein on the placement side in the observation group were all higher than those in the control group (P<0.01, P<0.05). CONCLUSION: The combined treatment of moxibustion with plucking technique at Jiquan (HT 1) can effectively prevent PICC-related venous thrombosis in the upper limbs and improve venous blood flow velocity in malignant tumor patients.

Connecting the Dots Between Hypercholesterolemia and Alzheimer's Disease: A Potential Mechanism Based on 27-Hydroxycholesterol.

Alzheimer's disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects ß-amyloid (Aß) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.

Application of Metabolomics to the Discovery of Biomarkers for Ischemic Stroke in the Murine Model: a Comparison with the Clinical Results.

Ischemic stroke (IS) is a major cause of mortality and disability worldwide. However, the pathogenesis of IS remains unknown, and methods for early prediction and diagnosis of IS are lacking. Metabolomics can be applied to biomarker discovery and mechanism exploration of IS by exploring metabolic alterations. In this review, 62 IS metabolomics studies in the murine model published from January 2006 to December 2020 in the PubMed and Web of Science databases were systematically reviewed. Twenty metabolites (e.g., lysine, phenylalanine, methionine, tryptophan, leucine, lactate, serine, N-acetyl-aspartic acid, and glutathione) were reported consistently in more than two-third murine studies. The disturbance of metabolic pathways, such as arginine biosynthesis; alanine, aspartate and glutamate metabolism; aminoacyl-tRNA biosynthesis; and citrate cycle, may be implicated in the development of IS by influencing the biological processes such as energy failure, oxidative stress, apoptosis, and glutamate toxicity. The transient middle cerebral artery occlusion model and permanent middle cerebral artery occlusion model exhibit both common and distinct metabolic patterns. Furthermore, five metabolites (proline, serine, LysoPC (16:0), uric acid, glutamate) in the blood sample and 7 metabolic pathways (e.g., alanine, aspartate, and glutamate metabolism) are shared in animal and clinical studies. The potential biomarkers and related pathways of IS in the murine model may facilitate the biomarker discovery for early diagnosis of IS and the development of novel therapeutic targets.

Cortical Neural Stem Cell Lineage Progression Is Regulated by Extrinsic Signaling Molecule Sonic Hedgehog.

Neural stem cells (NSCs) in the prenatal neocortex progressively generate different subtypes of glutamatergic projection neurons. Following that, NSCs have a major switch in their progenitor properties and produce γ-aminobutyric acid (GABAergic) interneurons for the olfactory bulb (OB), cortical oligodendrocytes, and astrocytes. Herein, we provide evidence for the molecular mechanism that underlies this switch in the state of neocortical NSCs. We show that, at around E16.5, mouse neocortical NSCs start to generate GSX2-expressing (GSX2+) intermediate progenitor cells (IPCs). In vivo lineage-tracing study revealed that GSX2+ IPC population gives rise not only to OB interneurons but also to cortical oligodendrocytes and astrocytes, suggesting that they are a tri-potential population. We demonstrated that Sonic hedgehog signaling is both necessary and sufficient for the generation of GSX2+ IPCs by reducing GLI3R protein levels. Using single-cell RNA sequencing, we identify the transcriptional profile of GSX2+ IPCs and the process of the lineage switch of cortical NSCs.

Constructing the Microbial Association Network from Large-Scale Time Series Data Using Granger Causality.

The increasing availability of large-scale time series data allows the inference of microbial community dynamics by association network analysis. However, correlation-based association network analyses are noninformative of causal, mediating and time-dependent relationships between microbial community functional factors. To address this insufficiency, we introduced the Granger causality model to the analysis of a recent marine microbial time series dataset. We systematically constructed a directed acyclic network, representing both internal and external causal relationships among the microbial and environmental factors. We further optimized the network by removing false causal associations using the conditional Granger causality. The final network was visualized as a Granger graph, which was analyzed to identify causal relationships driven by key functional operators in the environment, such as Gammaproteobacteria, which was Granger caused by total organic nitrogen and primary production (p < 0.05 and Q < 0.05).

Statistical significance approximation in local trend analysis of high-throughput time-series data using the theory of Markov chains.

BACKGROUND: Local trend (i.e. shape) analysis of time series data reveals co-changing patterns in dynamics of biological systems. However, slow permutation procedures to evaluate the statistical significance of local trend scores have limited its applications to high-throughput time series data analysis, e.g., data from the next generation sequencing technology based studies. RESULTS: By extending the theories for the tail probability of the range of sum of Markovian random variables, we propose formulae for approximating the statistical significance of local trend scores. Using simulations and real data, we show that the approximate p-value is close to that obtained using a large number of permutations (starting at time points >20 with no delay and >30 with delay of at most three time steps) in that the non-zero decimals of the p-values obtained by the approximation and the permutations are mostly the same when the approximate p-value is less than 0.05. In addition, the approximate p-value is slightly larger than that based on permutations making hypothesis testing based on the approximate p-value conservative. The approximation enables efficient calculation of p-values for pairwise local trend analysis, making large scale all-versus-all comparisons possible. We also propose a hybrid approach by integrating the approximation and permutations to obtain accurate p-values for significantly associated pairs. We further demonstrate its use with the analysis of the Polymouth Marine Laboratory (PML) microbial community time series from high-throughput sequencing data and found interesting organism co-occurrence dynamic patterns. AVAILABILITY: The software tool is integrated into the eLSA software package that now provides accelerated local trend and similarity analysis pipelines for time series data. The package is freely available from the eLSA website: http://bitbucket.org/charade/elsa.

Three-dimensional mesoporous carbon aerogels: ideal catalyst supports for enhanced H(2)S oxidation.

Impregnated mesoporous carbon aerogels serve as novel catalysts for the first time with respect to low-temperature oxidation of H(2)S to elemental sulfur, and exhibit particularly high activity (up to 3 g sulfur per gram of catalyst) and high selectivity.

Biomolecular adsorption behavior on spherical carbon aerogels with various mesopore sizes.

Spherical carbon aerogels (SCAs) with controlled particle size and mesopore size were synthesized by an emulsified sol-gel polymerization of phenol, melamine and formaldehyde. The adsorption rate and capacity of biomolecules with different molecular dimensions, including L-phenylalanine (Phe), vitamin B(12) (VB), alpha-chymotrypsin (Chy) and bovine serum albumin (BSA) onto SCAs were investigated. The mesopore size can be easily tuned in the range from 5 to 10 nm by simply adjusting catalyst concentration in the initial solution and the spherical particle size can be controlled in 50-500 microm by changing stirring speed. The as-prepared SCAs have high specific surface area (>600 m(2)/g) and large pore volume (>1 cm(3)/g). The hardness of SCAs is ca. 10 times as large as that of commercial spherical activated carbon particles. The adsorption rate of VB is strongly depended on the mesopore size and particle size, and show an increasing tread with the increase of mesopore size and the decrease of particle size. For small molecule Phe, the specific surface area is key factor to determine the adsorption capacity, but the adsorption capacity of large molecules (VB, Chy and BSA) is dependent on the pore size of SCAs, which should be suitably larger than the molecule size of biomolecules.

Suspension assisted synthesis of triblock copolymer-templated ordered mesoporous carbon spheres with controlled particle size.

A general strategy in terms of large-scale and shape-controlled synthesis was used to design highly ordered mesoporous carbon spheres with controlled size from 50 to 500 microm by an evaporation induced organic-organic self-assembly inside ethanol-in-oil emulsions.