Shot-noise-limited photon-counting precoding scheme for MIMO ultraviolet communication in atmospheric turbulence.

Photon counting is a promising solution to detecting low-power optical signals for ultraviolet (UV) communications in the forthcoming sixth-generation (6G) network. Different from the conventional additive white Gaussian noise (AWGN) model, the discrete signal-dependent Poisson shot noise poses challenges to the signal processing of photon-counting systems. In this paper, a joint design of precoder and equalizer is proposed for photon-counting multiple-input multiple-output (PhC-MIMO) UV systems. To circumvent the impasse arising from the signal-dependent shot noise, we propose an alternating optimization algorithm based on the minimum mean squared error (MMSE) criterion. The algorithm decomposes the joint design into convex subproblems solved in an alternating manner, and guarantees at least a stationary point solution. Numerical results corroborate that the proposed system exhibits robustness to turbulence fading and offers high throughput while mitigating the adverse effect of background radiation noise. Specifically, the 32 × 8 system can achieve a bit error rate (BER) of 10-5 at the signal energy of -154.0 dBJ per bit under strong Gamma-Gamma turbulence with the scintillation index (S.I.) of 3.

Kv1.3 Blockade Alleviates White Matter Injury through Reshaping M1/M2 Phenotypes via the NF-κB Signaling Pathway after Intracerebral Hemorrhage.

BACKGROUND: White matter injury (WMI) in basal ganglia usually induces long-term disability post intracerebral hemorrhage (ICH). Kv1.3 is an ion channel expressed in microglia and induces neuroinflammation after ICH. Here, we investigated the functions and roles of Kv1.3 activation-induced inflammatory response in WMI and the Kv1.3 blockade effect on microglia polarization after ICH. METHODS: Mice ICH model was constructed by autologous blood injection. The expression of Kv1.3 was measured using immunoblot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunostaining assays. Then, the effect of administration of 5-(4-Phenoxybutoxy) psoralen (PAP-1), a selectively pharmacological Kv1.3 blocker, was investigated using open field test (OFT) and basso mouse score (BMS). RT-qPCR, immunoblot, and enzyme-linked immunosorbent assay (ELISA) were taken to elucidate the expression of pro-inflammatory or anti-inflammatory factors around hematoma. PAP-1's function in regulating microglia polarization was investigated using immunoblot, RT-qPCR, and immunostaining assays. The downstream PAP-1 signaling pathway was determined by RT-qPCR and immunoblot. RESULTS: Kv1.3 expression was increased in microglia around the hematoma significantly after ICH. PAP-1 markedly improved neurological outcomes and the WMI by reducing pro-inflammatory cytokine accumulation and upregulating anti-inflammatory factors. Mechanistically, PAP-1 reduces NF-κB p65 and p50 activation, thus facilitating microglia polarization into M2-like microglia, which exerts this beneficial effect. CONCLUSIONS: PAP-1 reduced pro-inflammatory cytokines accumulation and increased anti-inflammatory factors by facilitating M2-like microglia polarization via the NF-κB signaling pathway. Thus, the current study shows that the Kv1.3 blockade is capable of ameliorating WMI by facilitating M2-like phenotype microglia polarization after ICH.

Long-Term Mortality Related to Acute Kidney Injury Following Intracerebral Hemorrhage: A 10-Year (2010-2019) Retrospective Study.

OBJECTIVES: Acute kidney injury (AKI) following intracerebral hemorrhage (ICH) is an intractable medical complication and an independent predictor of short-term mortality. However, the correlation between AKI and long-term mortality has not been fully investigated. The aim of the present study was to determine the relationship between AKI following ICH and long-term mortality in a 10-year (2010-2019) retrospective cohort. MATERIALS AND METHODS: A total of 1449 ICH patients were screened and enrolled at the Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University) from January 2010 to December 2016. The endpoint for follow-up was May 31, 2019. The estimated all-cause mortality was determined using Cox proportional hazard regression models. RESULTS: Among 1449 ICH patients, 136 (9.4%) suffered from AKI, and the duration of follow-up was a median of 5.1 years (IQR 3.2-7.2). The results indicated that the risk factors for AKI without preexisting chronic kidney disease (CKD) in the multivariable analysis were age (p = 0.002), nephrotoxic antibiotics (p = 0.000), diabetes mellitus (p = 0.005), sepsis (p = 0.000), antiplatelet therapy (p = 0.002), infratentorial hemorrhage (p = 0.000) and ICH volume (p = 0.003). Age (p = 0.008), ACEIs/ARBs (p = 0.010), nephrotoxic antibiotics (p = 0.014), coronary artery disease (p = 0.009), diabetes mellitus (p = 0.014), hypertension (p = 0.000) and anticoagulant therapy (p = 0.000) were independent predictors of AKI with preexisting CKD. Meanwhile, the data demonstrated that the estimated all-cause mortality was significantly higher in ICH patients with AKI without preexisting CKD (HR 4.208, 95% CI 2.946-6.011; p = 0.000) and in ICH patients with AKI with preexisting CKD (HR 2.470, 95% CI 1.747-3.492; p = 0.000) than in those without AKI. CONCLUSIONS: AKI is a long-term independent predictor of mortality in ICH patients. Thus, renal function needs to be routinely determined in ICH patients during clinical practice.

Evaluating the Cytotoxicity of Ti3C2 MXene to Neural Stem Cells.

MXenes have attracted extensive attention due to their unique physicochemical properties. Especially, the flexibility and good conductivity endow MXenes with a great application prospect in the neural interfaces. However, the cytotoxicity of MXenes to nervous system remains unclear. In this study, we evaluated the cytotoxicity of Ti3C2 (the most studied MXenes) using primary neural stem cells (NSCs) and NSCs-derived differentiated cells in terms of apoptosis, viability, cellular uptake, cell membrane integrity, and global gene expression profiles. We found that 12.5 µg/mL Ti3C2 had no observable adverse effect on NSCs and NSCs-derived differentiated cells. However, 25 µg/mL Ti3C2 induced significant cytotoxicity and were internalized into the NSCs cells with compromised cell membrane. Furthermore, in the NSCs exposure to 25 µg/mL Ti3C2, we identified 198 differently expressed genes (DEGs), which were mainly associated with the extracellular region. Besides, the DEGs were involved in inflammatory, defense, stress, and stimulus response. This work will improve our understanding of biocompatibility of MXenes in the nervous system and promote the biomedical application of MXenes.

MitoQ attenuates brain damage by polarizing microglia towards the M2 phenotype through inhibition of the NLRP3 inflammasome after ICH.

Microglial phenotype plays an important role in secondary injury after intracerebral haemorrhage (ICH), with M1 microglia promoting inflammatory injury and M2 microglia inhibiting neuroinflammation and promoting haematoma absorption. However, there is no effective intervention for regulating the phenotypic transformation of microglia after ICH. This study aimed to elucidate the protective effect of MitoQ, a selective mitochondrial ROS antioxidant, against microglial M1 state polarization and secondary brain injury. The in vivo data showed that MitoQ attenuated neurological deficits and decreased inflammation, oedema and haematoma volume after ICH. In addition, MitoQ decreased the expression of M1 markers and increased the expression of M2 markers both in vivo and in vitro after ICH. Mechanistically, MitoQ blocked overproduction of mitochondrial ROS and activation of the NLRP3 inflammasome in FeCl2-treated microglia. Moreover, NLRP3 siRNA shifted FeCl2-treated microglia from the M1 to the M2 cells, revealing that MitoQ-induce polarization states may be mediated by the mitochondrial ROS/NLRP-3 pathway. In summary, MitoQ alleviates secondary brain injury and accelerates haematoma resolution by shifting microglia towards the M2 phenotype after ICH.

Chondroitin sulfate proteoglycan represses neural stem/progenitor cells migration via PTPσ/α-actinin4 signaling pathway.

Neural stem/progenitor cells (NSPCs) are a promising candidate for the cell-replacement therapy after central nervous system (CNS) injury. However, the short of sufficient NSPCs migration and integration into the lesions is an essential challenge for cell-based therapy after CNS injury due to the disturbance of local environmental homeostasis. Chondroitin sulfate proteoglycan (CSPG) is obviously accumulated at the lesions and destroyed local homeostasis after CNS injury. The previous study has demonstrated that the CSPG is a dominating ingredient inhibiting axonal regrowth of newly born neurons after CNS injury. NSPCs, a strain of special neural subtypes, hold the capacity of leading processes formation to regulate NSPCs migration, which has the same mechanism as axonal regrowth. Hence, it is worth investigating the effect of CSPG on NSPCs migration and its underlying mechanism. Here, different concentration of CSPG was used to evaluate its effect on NSPCs migration. The results showed that the CSPG suppressed NSPCs migration in a dose-dependent manner from 10 to 80 µg/mL with phase-contrast microscopy after 24 hours. Meanwhile, transwell assays were performed to certify the above results. Our data indicated that the 40 µg/mL CSPG obviously suppressed NSPCs migration via decreasing filopodia formation using immunofluorescence staining. Furthermore, data indicated that the 40 µg/mL CSPG upregulated protein tyrosine phosphatase receptor σ (PTPσ) expression and decreased α-actinin4 (ACTN4) expression through immunofluorescence, reverse transcription polymerase chain reaction, and Western blot assays. While the inhibitory effect was attenuated using PTPσ-specific small interfering RNA. In addition, data demonstrated that the 40 µg/mL CSPG facilitated NSPCs differentiation into glial fibrillary acidic protein-positive cells and inhibited NSPCs directing into MAP2- and MBP-positive cells. Collectively, these data demonstrated that the CSPG suppressed NSPCs migration through PTPσ/ACTN4 signaling pathway. Meanwhile, CSPG facilitated NSPCs differentiation into astrocytes and inhibited NSPCs directing into neurons and oligodendrocytes.

Molecular Engineering of an Organic NIR-II Fluorophore with Aggregation-Induced Emission Characteristics for In Vivo Imaging.

Design and synthesis of new fluorophores with emission in the second near-infrared window (NIR-II, 1000-1700 nm) have fueled the advancement of in vivo fluorescence imaging. Organic NIR-II probes particularly attract tremendous attention due to excellent stability and biocompatibility, which facilitate clinical translation. However, reported organic NIR-II fluorescent agents often suffer from low quantum yield and complicated design. In this study, the acceptor unit of a known NIR-I aggregation-induced emission (AIE) luminogen (AIEgen) is molecularly engineered by varying a single atom from sulfur to selenium, leading to redshifted absorption and emission spectra. After formulation of the newly prepared AIEgen, the resultant AIE nanoparticles (referred as L897 NPs) have an emission tail extending to 1200 nm with a high quantum yield of 5.8%. Based on the L897 NPs, noninvasive vessel imaging and lymphatic imaging are achieved with high signal-to-background ratio and deep penetration. Furthermore, the L897 NPs can be used as good contrast agents for tumor imaging and image-guided surgery due to the high tumor/normal tissue ratio, which peaks at 9.0 ± 0.6. This work suggests a simple strategy for designing and manufacturing NIR-II AIEgens and demonstrates the potential of NIR-II AIEgens in vessel, lymphatic, and tumor imaging.

Endogenous hydrogen sulphide attenuates NLRP3 inflammasome-mediated neuroinflammation by suppressing the P2X7 receptor after intracerebral haemorrhage in rats.

BACKGROUND: Emerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H2S) as a gasotransmitter for NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-associated neuroinflammation in the central nervous system. However, the effects of H2S on neuroinflammation after intracerebral haemorrhage (ICH), especially on the NLRP3 inflammasome, remain unknown. METHODS: We employed a Sprague-Dawley rat of collagenase-induced ICH in the present study. The time course of H2S content and the spatial expression of cystathionine-ß-synthase (CBS) after ICH, the effects of endogenous and exogenous H2S after ICH, the effects of endogenous and exogenous H2S on NLRP3 inflammasome activation under P2X7 receptor (P2X7R) overexpression after ICH, and the involvement of the P2X7R in the mechanism by which microglia-derived H2S prevented NLRP3 inflammasome activation were investigated. RESULTS: We found ICH induced significant downregulation of endogenous H2S production in the brain, which may be the result of decreasing in CBS, the predominant cerebral H2S-generating enzyme. Administration of S-adenosyl-L-methionine (SAM), a CBS-specific agonist, or sodium hydrosulfide (NaHS), a classical exogenous H2S donor, not only restored brain and plasma H2S content but also attenuated brain oedema, microglial accumulation and neurological deficits at 1 day post-ICH by inhibiting the P2X7R/NLRP3 inflammasome cascade. Endogenous H2S production, which was derived mainly by microglia and above treatments, was verified by adenovirus-overexpressed P2X7R and in vitro primary microglia studies. CONCLUSIONS: These results indicated endogenous H2S synthesis was impaired after ICH, which plays a pivotal role in the P2X7R/NLRP3 inflammasome-associated neuroinflammatory response in the pathogenesis of secondary brain injury. Maintaining appropriate H2S concentrations in the central nervous system may represent a potential therapeutic strategy for managing post-ICH secondary brain injury and associated neurological deficits.

Fibroblast growth factor receptor 4 (FGFR4) deficiency improves insulin resistance and glucose metabolism under diet-induced obesity conditions.

The role of fibroblast growth factor receptor 4 (FGFR4) in regulating bile acid synthesis has been well defined; however, its reported role on glucose and energy metabolism remains unresolved. Here, we show that FGFR4 deficiency in mice leads to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat conditions. Mechanism of action studies in FGFR4-deficient mice suggest that the effects are mediated in part by increased plasma levels of adiponectin and the endocrine FGF factors FGF21 and FGF15, the latter of which increase in response to an elevated bile acid pool. Direct actions of increased bile acids on bile acid receptors, and other potential indirect mechanisms, may also contribute to the observed metabolic changes. The results described herein suggest that FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes.

Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study.

BACKGROUND: The objective of the present study was to clarify the relationship between the neuroprotective effects of curcumin and the classical wnt signaling pathway. METHOD: Using Sprague-Dawley rats at a gestational age of 14.5 d, we isolated neural stem cells from the anterior two-thirds of the fetal rat brain. The neural stem cells were passaged three times using the half media replacement method and identified using cellular immunofluorescence. After passaging for three generations, we cultured cells in media without basic fibroblast growth factor and epidermal growth factor. Then we treated cells in five different ways, including a blank control group, a group treated with IWR1 (10 µmol/L), a group treated with curcumin (500 nmol/L), a group treated with IWR1 + curcumin, and a group treated with dimethyl sulfoxide (10 µmol/L). We then measured the protein and RNA expression levels for wnt3a and ß-catenin using Western blotting and Reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Western-blotting: after the third generation of cells had been treated for 72 h, we observed that wnt3a and ß-catenin expression was significantly increased in the group receiving 500 nmol/L curcumin but not in the other groups. Furthermore, cells in the IWR1-treated group showed decreased wnt3a and ß-catenin expression, and wnt3a and ß-catenin was also decreased in the IWR1 + 500 nmol/L curcumin group. No obvious change was observed in the dimethyl sulfoxide group. RT-PCR: RT-PCR showed similar changes to those observed with the Western blotting experiments. CONCLUSIONS: Our study suggests that curcumin can activate the wnt signaling pathway, which provides evidence that curcumin exhibits a neuroprotective effect through the classical wnt signaling pathway.

Dihydroartemisinin exhibits anti-glioma stem cell activity through inhibiting p-AKT and activating caspase-3.

Glioma stem cells (GSCs) have been proven to play key roles in tumorigenesis, metastasis and recurrence. Although dihydroartemisinin (DHA), a derivative of the antimalaria drug artemisinin, has been shown to have anti-cancer activity, it is still unclear whether DHA affects GSCs. This study investigated the effects of DHA on the growth and apoptosis of GSCs, as well as the possible molecular mechanism involved in these processes. GSCs were enriched using a non-adhesive culture system with serum-free neural stem cell medium. Their stemness characteristics were identified by assessment of tumor sphere formation, mRNA expression analysis, and immunofluorescence staining of stem cell markers (CD133, SOX2, and nestin). We found that DHA not only inhibited proliferation, which was determined with the cell counting kit-8 (CCK8) assay, but also induced apoptosis of GSCs, as evaluated with the annexin-V/PI flowcytometric assay. Interestingly, DHA treatment also induced a concentration-dependent cell cycle arrest in the G1 phase according to the cell cycle assay. To reveal the underlying mechanisms, we detected the expression levels of p-Akt and Cleaved Caspase-3. The data showed that Cleaved Caspase-3 increased significantly in a dose-dependent manner (p < 0.05) after the GSCs sphere cells were treated with 20, 40, and 80 µM of DHA for 24 h, which correlated with significantly decreased expression levels of p-Akt (p < 0.05). These data indicate that DHA selectively inhibits proliferation and induces apoptosis of GSCs through the down-regulation of Akt phosphorylation, which is followed by Caspase-3 activation, and these findings offer a new approach for treating gliomas.

Modulation of GPER1 alleviates early brain injury via inhibition of A1 reactive astrocytes activation after intracerebral hemorrhage in mice.

Background: Early brain injury (EBI) caused by inflammatory responses in acute phase of Intracerebral hemorrhage (ICH) plays a vital role in the pathological progression of ICH. Increasing evidences demonstrate A1 reactive astrocytes are associated with the severity of EBI. G-protein coupled estrogen receptor 1 (GPER1) has been proved mediating the neuroprotective effects of estrogen in central nervous system (CNS) disease. However, whether GPER1 plays a protective effect on ICH and A1 reactive astrocytes activation is not well studied. Methods: ICH model was established by infused the autologous whole blood into the right basal ganglia in wild type and GPER1 knockout mice. GPER1 specific agonist G1 and antagonist G15 were administered by intraperitoneal injection at 1 h or 0.5 h after ICH. Neurological function was detected on day 1 and day 3 by open field test and corner turn test following ICH. Besides, A1 reactive astrocytes were determined by immunofluorescence staining after ICH on day 3. To further identify the possible mechanism of GPER1 mediated neuroprotective effect, Western blot assays was performed after ICH on day 3. Results: After ICH, G1 treatment alleviated mice neurobehavior deficits on day 1 and day 3. Meanwhile, G1 treatment also significantly reduced the GFAP positive astrocytes and the C3 positive cells after ICH. Interestingly, G15 reversed the protective effect of G1 on the neurobehavior of ICH mice. Meanwhile, the expression of GFAP+C3+ A1 reactive astrocytes were also reduced by activation of GPER1. Mechanistic studies indicated TLR4 and NF-κB mediated the neuroprotective effect of GPER1. Conclusion: Generally, activation of GPER1 alleviated the EBI through inhibiting A1 reactive astrocytes activation via TLR4/NF-κB pathway after ICH in mice. Additionally, GPER1may be a promising target for ICH treatment.

Targeting Ferroptosis Promotes Functional Recovery by Mitigating White Matter Injury Following Acute Carbon Monoxide Poisoning.

Survivors experiencing acute carbon monoxide poisoning (ACMP) tend to develop white matter injury (WMI). The mechanism of ACMP-induced WMI remains unclear. Considering the role of ferroptosis in initiating oligodendrocyte damage to deteriorate WMI, exploring therapeutic options to attenuate ferroptosis is a feasible approach to alleviating WMI. Our results indicated that ACMP induced accumulation of iron and reactive oxygen species (ROS) eventually leading to WMI and motor impairment after ACMP. Furthermore, ferrostatin-1 reduced iron and ROS deposition to alleviate ferroptosis, thereafter reducing WMI to promote the recovery of motor function. The nuclear factor erythroid-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was found to be involved in alleviating ferroptosis as seen with the administration of ferrostatin-1. The present study rationalizes that targeting ferroptosis to alleviate WMI is a feasible therapeutic strategy for managing ACMP.

Clot removAl with or without decompRessive craniectomy under ICP monitoring for supratentorial IntraCerebral Hemorrhage (CARICH): a randomized controlled trial.

BACKGROUND: Decompressive craniectomy, a surgery to remove part of the skull and open the dura mater, maybe an effective treatment for controlling intracranial hypertension. It remains great interest to elucidate whether decompressive craniectomy is beneficial to intracerebral hemorrhage patients who warrant clot removal to prevent intracranial hypertension. METHODS: The trial was a prospective, pragmatic, controlled trial involving adult patients with intracerebral hemorrhage who were undergoing removal of hematoma. Intracerebral hemorrhage patients were randomly assigned at a 1:1 ratioto undergo clot removal with or without decompressive craniectomy under the monitoring of intracranial pressure. The primary outcome was the proportion of unfavorable functional outcome (modified Rankin Scale 3-6) at 3 months. Secondary outcomes included the mortality at 3 months and the occurrence of re-operation. RESULTS: A total of 102 patients were assigned to the clot removal with decompressive craniectomy group and 102 to the clot removal group. Median hematoma volume was 54.0 mL (range 30-80 mL) and median preoperative Glasgow Coma Scale was 10 (range 5-15). At 3 months, 94 patients (92.2%) in clot removal with decompressive craniectomy group and 83 patients (81.4%) in the clot removal group had unfavorable functional outcome (P=0.023). Fourteen patients (13.7%) in the clot removal with decompressive craniectomy group died versus five patients (4.9%) in the clot removal group (P=0.030). The number of patients with re-operation was similar between the clot removal with decompressive craniectomy group and clot removal group (5.9% vs. 3.9%; P=0.517). Postoperative intracranial pressure values were not significantly different between two groups and the mean values were less than 20 mmHg. CONCLUSIONS: Clot removal without decompressive craniectomy decreased the rate of modified Rankin Scale score of 3-6 and mortality in patients with intracerebral hemorrhage, compared with clot removal with decompressive craniectomy.

Dual actions of fibroblast growth factor 19 on lipid metabolism.

Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fibroblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specificities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.V-Lep(ob)/J leptin-deficient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed significant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising and lipid-lowering actions mediated through different FGF receptors and target tissues, and the results described here provide a potential mechanism that may explain the inconsistency in the reported effects of FGF19 on lipid metabolism.

Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19).

FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Their potent effects on normalizing glucose, lipid, and energy homeostasis in disease models have made them an interesting focus of research for combating the growing epidemics of diabetes and obesity. Despite overlapping functions, FGF19 and FGF21 have many discrete effects, the most important being that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects. Here we identify the structural determinants dictating differential receptor interactions that explain and distinguish these two physiological functions. We also have generated FGF19 variants that have lost the ability to induce hepatocyte proliferation but that still are effective in lowering plasma glucose levels and improving insulin sensitivity in mice. Our results add valuable insight into the structure-function relationship of FGF19/FGF21 and identify the structural basis underpinning the distinct proliferative feature of FGF19 compared with FGF21. In addition, these studies provide a road map for engineering FGF19 as a potential therapeutic candidate for treating diabetes and obesity.

Association between BUN/creatinine ratio and the risk of in-hospital mortality in patients with trauma-related acute respiratory distress syndrome: a single-centre retrospective cohort from the MIMIC database.

OBJECTIVE: Recent studies have shown that blood urea nitrogen to creatinine (BUN/Cr) ratio might be an effective marker for the prognosis of patients with respiratory diseases. Herein, we aimed to assess the association between BUN/Cr ratio and the risk of in-hospital mortality in patients with trauma-related acute respiratory distress syndrome (ARDS). DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: 1034 patients were extracted from the Medical Information Mart for Intensive Care-III (MIMIC-III) database. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome of the study was in-hospital mortality, defined by the vital status at the time of hospital discharge (ie, survivors and non-survivors). RESULTS: Of the total patients, 191 (18.5%) died in hospital. The median follow-up duration was 16.0 (8.3-26.6) days. The results showed that high level of BUN/Cr ratio was significantly associated with an increased risk of in-hospital mortality (15.54-21.43: HR=2.00, 95% CI: (1.18 to 3.38); >21.43: HR=1.76, 95% CI: (1.04 to 2.99)) of patients with trauma-related ARDS. In patients with trauma-related ARDS that aged ≥65 years old, male and female, Onychomycosis Severity Index (OSI)>98, Revised Trauma Score (RTS)>11, Simplified Acute Physiology Score II (SAPS-II)>37 and sequential organ failure assessment (SOFA) scores≤7, BUN/Cr ratio was also related to the increased risk of in-hospital mortality (all p<0.05). The predictive performance of BUN/Cr ratio for in-hospital mortality was superior to BUN or Cr, respectively, with the area under the curve of receiver operator characteristic curve at 0.6, and that association was observed in age, gender, OSI, RTS, SAPS-II and SOFA score subgroups. CONCLUSION: BUN/Cr ratio may be a potential biomarker for the risk of in-hospital mortality of trauma-related ARDS, which may help the clinicians to identify high-risk individuals and to implement clinical interventions.

Targeting ASIC1a Promotes Neural Progenitor Cell Migration and Neurogenesis in Ischemic Stroke.

Cell replacement therapy using neural progenitor cells (NPCs) has been shown to be an effective treatment for ischemic stroke. However, the therapeutic effect is unsatisfactory due to the imbalanced homeostasis of the local microenvironment after ischemia. Microenvironmental acidosis is a common imbalanced homeostasis in the penumbra and could activate acid-sensing ion channels 1a (ASIC1a), a subunit of proton-gated cation channels following ischemic stroke. However, the role of ASIC1a in NPCs post-ischemia remains elusive. Here, our results indicated that ASIC1a was expressed in NPCs with channel functionality, which could be activated by extracellular acidification. Further evidence revealed that ASIC1a activation inhibited NPC migration and neurogenesis through RhoA signaling-mediated reorganization of filopodia formation, which could be primarily reversed by pharmacological or genetic disruption of ASIC1a. In vivo data showed that the knockout of the ASIC1a gene facilitated NPC migration and neurogenesis in the penumbra to improve behavioral recovery after stroke. Subsequently, ASIC1a gain of function partially abrogated this effect. Moreover, the administration of ASIC1a antagonists (amiloride or Psalmotoxin 1) promoted functional recovery by enhancing NPC migration and neurogenesis. Together, these results demonstrate targeting ASIC1a is a novel strategy potentiating NPC migration toward penumbra to repair lesions following ischemic stroke and even for other neurological diseases with the presence of niche acidosis.

A redox-reactive delivery system via neural stem cell nanoencapsulation enhances white matter regeneration in intracerebral hemorrhage mice.

Intracerebral hemorrhage (ICH) poses a great threat to human health because of its high mortality and morbidity. Neural stem cell (NSC) transplantation is promising for treating white matter injury following ICH to promote functional recovery. However, reactive oxygen species (ROS)-induced NSC apoptosis and uncontrolled differentiation hindered the effectiveness of the therapy. Herein, we developed a single-cell nanogel system by layer-by-layer (LbL) hydrogen bonding of gelatin and tannic acid (TA), which was modified with a boronic ester-based compound linking triiodothyronine (T3). In vitro, NSCs in nanogel were protected from ROS-induced apoptosis, with apoptotic signaling pathways downregulated. This process of ROS elimination by material shell synergistically triggered T3 release to induce NSC differentiation into oligodendrocytes. Furthermore, in animal studies, ICH mice receiving nanogels performed better in behavioral evaluation, neurological scaling, and open field tests. These animals exhibited enhanced differentiation of NSCs into oligodendrocytes and promoted white matter tract regeneration on Day 21 through activation of the αvß3/PI3K/THRA pathway. Consequently, transplantation of LbL(T3) nanogels largely resolved two obstacles in NSC therapy synergistically: low survival and uncontrolled differentiation, enhancing white matter regeneration and behavioral performance of ICH mice. As expected, nanoencapsulation with synergistic effects would efficiently provide hosts with various biological benefits and minimize the difficulty in material fabrication, inspiring next-generation material design for tackling complicated pathological conditions.

Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice.

FGF19 is a hormone that regulates bile acid and glucose homeostasis. Progress has been made in identifying cofactors for receptor activation. However, several functions of FGF19 have not yet been fully defined, including the actions of FGF19 on target tissues, its FGF receptor specificity, and the contributions of other cofactors, such as heparin. Here, we explore the requirements for FGF19-FGFR/co-receptor interactions and signaling in detail. We show that betaKlotho was essential for FGF19 interaction with FGFRs 1c, 2c, and 3c, but FGF19 was able to interact directly with FGFR4 in the absence of betaKlotho in a heparin-dependent manner. Further, FGF19 activated FGFR4 signaling in the presence or absence of betaKlotho, but activation of FGFRs 1c, 2c, or 3c was completely betaKlotho dependent. We then generated an FGF19 molecule, FGF19dCTD, which has a deletion of the C-terminal region responsible for betaKlotho interaction. We determined that betaKlotho-dependent FGFR1c, 2c, and 3c interactions and activation were abolished, and betaKlotho-independent FGFR4 activation was preserved; therefore, FGF19dCTD is an FGFR4-specific activator. This unique FGF19 molecule specifically activated FGFR4-dependent signaling in liver and suppressed CYP7A1 expression in vivo, but was unable to activate signaling in adipose where FGFR4 expression is very low. Interestingly, unlike FGF19, treatment of ob/ob mice with FGF19dCTD failed to improve glucose levels and insulin sensitivity. These results suggest that FGF19-regulated liver bile acid metabolism could be independent of its glucose-lowering effect, and direct FGFR activation in adipose tissue may play an important role in the regulation of glucose homeostasis.