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The brains of preterm infants are highly vulnerable to injury caused by hypoxic–ischemic events and inflammation, which can have deleterious consequences both acutely and later in life. In this article, Deng reviews evidence regarding the neurobiology of injury to immature white matter, including the roles of activated microglia and astrogliosis, and discusses potential therapies for this condition. Owing to improved survival rates of premature newborns, the number of very low birth weight infants is rising. Preterm infants display a greater propensity for brain injury caused by hypoxic or ischemic events, infection and/or inflammation that results in prominent white matter injury (WMI) than infants carried to full term. The intrinsic vulnerability of developing oligodendroglia to excitotoxic, oxidative and inflammatory forms of injury is a major factor in the pathogenesis of this condition. Furthermore, activated microglia and astrogliosis are critically involved in triggering WMI. Currently, no specific treatment is available for this kind of injury. Injury to the premature brain can substantially influence brain development and lead to disability. Impairment of the main motor pathways, such as the corticospinal tract, in the perinatal period contributes substantially to clinical outcome. Advanced neuroimaging techniques have led to greater understanding of the nature of both white and gray matter injury in preterm infants. Further research is warranted to examine the translational potential of preclinical therapeutic strategies for controlling such injury and preserving the integrity of motor pathways in preterm infants. Key Points Premature birth remains a substantial economic and public health burden Periventricular leukomalacia is the predominant form of white matter injury (WMI) and the leading cause of cerebral palsy in premature infants Maturation-dependent vulnerability of developing oligodendroglia to excitotoxicity and oxidative and inflammatory forms of injury is an important factor in the pathogenesis of WMI Activated microglia and astrogliosis are critically involved in triggering WMI Impairment of corticospinal tract development and function in the perinatal period contributes extensively to abnormalities of motor system function Advanced neuroimaging techniques have led to greater understanding of the nature of white and gray matter injury in preterm infants

Precise prediction of structural settlement in subway tunnels is crucial for ensuring safety during both construction and operational phases; however, the non-linear characteristics of monitoring data pose a significant challenge to achieving this goal. To address this issue, this study proposes a hybrid predictive model, termed HO-GPR. This model integrates the Hippopotamus Optimization (HO) algorithm—a novel bio-inspired meta-heuristic—with Gaussian Process Regression (GPR), a non-parametric probabilistic machine learning method. Specifically, HO is utilized to globally optimize the hyperparameters of GPR to enhance its adaptability to complex deformation patterns. The model was validated using 52 months of field settlement monitoring data collected from the Urumqi Metro Line 1 tunnel. Through a series of comparative and generalization experiments, the accuracy and adaptability of the model were systematically evaluated. The results demonstrate that the HO-GPR model is superior to five benchmark models—namely Gated Recurrent Unit (GRU), Support Vector Regression (SVR), HO-optimized Back Propagation Neural Network (HO-BP), standard GPR, and ARIMA—in terms of accuracy and stability. It achieved a Coefficient of Determination (R2) of 0.979, while the Root Mean Square Error (RMSE), Mean Absolute Error (MAE), and Mean Absolute Percentage Error (MAPE) were as low as 0.318 mm, 0.240 mm, and 1.83%, respectively, proving its capability for effective prediction with non-linear data. The findings of this research can provide valuable technical support for the structural safety management of subway tunnels.

The invention of iPSC in 2006 has been heralded as a major breakthrough. Wenbin Deng explains the enormous potential of these cells for research into human diseases and development, and discusses the technical and regulatory hurdles to be overcome for their therapeutic use.

Ionospheric delay errors significantly reduce the positioning accuracy of global navigation satellite systems (GNSSs), whereas precise ionospheric modeling can effectively mitigate this issue. The ionosphere exhibits large-scale symmetry, and spherical harmonics (SHs) can effectively describe this property due to their rotational symmetry on the sphere. However, mathematical fitting models such as spherical harmonic functions and polynomial models encounter boundary inaccuracies caused by edge effects. To address this problem, we developed a spherical harmonic–radial basis function (SH-RBF) hybrid method based on the integration of spherical harmonics and radial basis function interpolation techniques. This method leverages the global symmetry of spherical harmonics and utilizes the local adaptability of radial basis functions to correct regional distortions. Validation using European GNSS data during both geomagnetically quiet and active periods, in comparison with the CODE global ionospheric map (GIM), demonstrates that the modeling accuracy of spherical harmonics surpasses that of POLY during geomagnetically quiet periods. Compared to spherical harmonics, SH-RBF improves overall modeling accuracy by 8.87–27.27% and enhances accuracy in edge regions by 34.16–83.91%. During geomagnetically active periods, the SH-RBF method also achieves notable improvements. This study confirms that SH-RBF is a reliable technique for significantly reducing edge effects in regional ionospheric modeling.

Down’s syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo . We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug. Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.

Recent studies demonstrate that astroglial cells can be directly converted into functional neurons or oligodendrocytes. Here, we report that a single transcription factor Sox10 could reprogram astrocytes into oligodendrocyte-like cells, in vivo. For transdifferentiation, Sox10-GFP expressing viral particles were injected into cuprizone-induced demyelinated mice brains after which we assessed for the presence of specific oligodendrocyte lineage cell markers by immunohistofluorescence (IHF). As control, another group of demyelinated mice received GFP expressing viral particles. After 3 weeks, the majority of transduced (GFP+) cells in animals which received control vector were astrocytes, while in animals which received Sox10-GFP vector, the main population of GFP+ cells were positive for oligodendrocyte lineage markers. We also extracted primary astrocytes from mouse pups and purified them. Primary astrocytes were transduced in vitro and then transplanted into demyelinated brains for later fate mapping. After three weeks, in vitro transduced and then transplanted astrocytes showed oligodendrocyte progenitor and mature oligodendrocyte markers. Further confirmation was done by transduction of astrocytes with lentiviral particles that expressed Sox10 and GFP and their culture in the oligodendrocyte progenitor medium. The induced cells expressed oligodendrocyte progenitor cells (iOPCs) markers. Our findings showed the feasibility of reprogramming of astrocytes into oligodendrocyte-like cells in vivo, by using a single transcription factor, Sox10. This finding suggested a master regulatory role for Sox10 which enabled astrocytes to change their fate to OPC-like cells and establish an oligodendroglial phenotype. We hope this approach lead to effective myelin repair in patients suffering from myelination deficit.

Background Alzheimer’s disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. Main content Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron–glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. Conclusion Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.

Messenger RNA (mRNA)-based therapeutics hold great potential for effectively treating various diseases. However, the targeting of mRNA delivered by systemically administered lipid nanoparticles (LNP) is currently limited to the liver. Safe and efficient systemic delivery of mRNA to specific organs and cells remains a major challenge, and it is still unclear whether the positional isomerism of individual compounds within LNP affects their activity. Here, we synthesize a library of meta/ortho/para-ionizable lipidoids and prepare three-component lipid nanoparticles (tLNP) without PEG-lipids. Our findings show that tLNP containing meta-ionizable lipidoids (meta-tLNP) exhibits higher mRNA delivery efficiency than those containing ortho-/para-ionizable lipidoids (ortho-/para-tLNP). Additionally, we report a strategy termed Sequential Selective Organ-to-Cell Targeting (SSOCT), which enables the systemic administration of meta/ortho/para-tLNP to first achieve selective mRNA expression in the spleen, followed by targeted mRNA expression in dendritic cells within the spleen. Notably, we demonstrate that delivering the mRNA vaccine (mXO10 tLNP@mIDH1) using meta-tLNP effectively treats glioma in mice, particularly when combined with Anti-PD-1 therapy. This combination further enhances therapeutic efficacy, even completely eradicating glioma, reducing hepatotoxicity, and minimizing PEG-lipid-induced allergic reactions. This study establishes that mRNA therapy, developed by selectively targeting splenic dendritic cells via SSOCT, represents a promising therapeutic intervention for glioma. Targeted delivery of mRNA with lipid nanoparticles has potential in cancer therapy. Here this group reports a sequential selective organ-to-cell targeting strategy which enables selective mRNA expression in dendritic cells within the spleen.

Increased dietary salt intake is a well-established risk factor for hypertension and related cardiovascular diseases, involving complex vascular remodeling processes. However, the specific role of hypoxia-inducible factor-1α (HIF-1α) in vascular pathophysiology under high-salt conditions remains poorly understood. This study investigates the role of HIF-1α in high-salt-induced vascular remodeling using human aortic vascular smooth muscle cells (HA-VSMCs) cultured in vitro. HA-VSMCs were divided into three groups: high-salt with HIF-1α knockdown (shHIF-1α + HS), negative control (shcontrol), and high-salt (HS). Cell viability, migration, gene expression, and protein levels were evaluated. High-salt conditions significantly increased mRNA expression of α-smooth muscle actin (α-SMA), smooth muscle protein 22 (SM22), angiotensin II type 1 receptor (AT1R), collagen I, and collagen III (p < 0.0001). HIF-1α knockdown partially attenuated these increases, particularly for α-SMA, SM22, and AT1R (p < 0.01). At the protein level, high-salt exposure markedly elevated expression of collagen III, HIF-1α, osteopontin (OPN), and angiotensin II (Ang II) (p < 0.0001). HIF-1α knockdown significantly reduced the high-salt-induced increases in collagen III and HIF-1α protein levels (p < 0.001) but had a limited effect on OPN and Ang II upregulation. Interestingly, SM22 protein expression was significantly decreased under high-salt conditions (p < 0.0001), an effect partially reversed by HIF-1α knockdown (p < 0.0001). These findings demonstrate that high-salt conditions induce complex changes in gene and protein expression in HA-VSMCs, with HIF-1α playing a crucial role in mediating many of these alterations. The study highlights the differential effects of HIF-1α on various markers of vascular remodeling and suggests that HIF-1α may be a potential therapeutic target for mitigating salt-induced vascular pathology. Further research is warranted to elucidate the mechanisms underlying the HIF-1α-dependent and -independent effects observed in this study.

Advanced gastric cancer (GCa) remains highly lethal due to the lack of effective therapies. Identifying promising therapeutic targets and developing effective treatment against GCa are urgently needed. Through mRNA and protein analysis of GCa clinical tumor samples, we found that autophagy-related gene 4B (ATG4B) was overexpressed in GCa tumors and that its high expression was associated with patients’ poor prognosis. Knockdown of ATG4B significantly inhibited GCa cell survival and tumor growth. To further probe the role of ATG4B in GCa by pharmacological means, we screened an in-house marine natural compound library against ATG4B and identified Azalomycin F4a (Am-F4a) as a novel and potent ATG4B inhibitor. Am-F4a directly bound to ATG4B with high affinity and effectively suppressed GCa cell autophagy via inhibition of ATG4B both in vitro and in vivo. Moreover, Am-F4a or ATG4B knockdown significantly suppressed tumor growth as well as GCa cell migration and invasion. Am-F4a effectively blocked the metastatic progression of primary GCa and sensitized tumors to chemotherapy. Taken together, our findings indicate that ATG4B is a potential therapeutic target against GCa and the natural product Am-F4a is a novel ATG4B inhibitor that can be further developed for the treatment of GCa.