WNK kinases sense molecular crowding and rescue cell volume via phase separation.

When challenged by hypertonicity, dehydrated cells must recover their volume to survive. This process requires the phosphorylation-dependent regulation of SLC12 cation chloride transporters by WNK kinases, but how these kinases are activated by cell shrinkage remains unknown. Within seconds of cell exposure to hypertonicity, WNK1 concentrates into membraneless condensates, initiating a phosphorylation-dependent signal that drives net ion influx via the SLC12 cotransporters to restore cell volume. WNK1 condensate formation is driven by its intrinsically disordered C terminus, whose evolutionarily conserved signatures are necessary for efficient phase separation and volume recovery. This disorder-encoded phase behavior occurs within physiological constraints and is activated in vivo by molecular crowding rather than changes in cell size. This allows kinase activity despite an inhibitory ionic milieu and permits cell volume recovery through condensate-mediated signal amplification. Thus, WNK kinases are physiological crowding sensors that phase separate to coordinate a cell volume rescue response.

Loss of mitogen-activated protein kinase phosphate-5 aggravates islet dysfunction in mice with type 1 and type 2 diabetes.

Impaired functionality and loss of islet ß-cells are the primary abnormalities underlying the pathogenesis of both type 1 and 2 diabetes (T1DM and T2DM). However, specific therapeutic and preventive mechanisms underlying these conditions remain unclear. Mitogen-activated protein kinase phosphatase-5 (MKP-5) has been implicated in carcinogenesis, lipid metabolism regulation, and immune cell activation. In a previous study, we demonstrated the involvement of exogenous MKP-5 in the regulation of obesity-induced T2DM. However, the role of endogenous MKP-5 in the T1DM and T2DM processes is unclear. Thus, mice with MKP-5 knockout (KO) were generated and used to establish mouse models of both T1DM and T2DM. Our results showed that MKP-5 KO exacerbated diabetes-related symptoms in mice with both T1DM and T2DM. Given that most phenotypic studies on islet dysfunction have focused on mice with T2DM rather than T1DM, we specifically aimed to investigate the role of endoplasmic reticulum stress (ERS) and autophagy in T2DM KO islets. To accomplish this, we performed RNA sequence analysis to gain comprehensive insight into the molecular mechanisms associated with ERS and autophagy in T2DM KO islets. The results showed that the islets from mice with MKP-5 KO triggered 5' adenosine monophosphate-activated protein kinase (AMPK)-mediated autophagy inhibition and glucose-regulated protein 78 (GRP-78)-dominated ERS. Hence, we concluded that the autophagy impairment, resulting in islet dysfunction in mice with MKP-5 KO, is mediated through GRP-78 involvement. These findings provide valuable insights into the molecular pathogenesis of diabetes and highlight the significant role of MKP-5. Moreover, this knowledge holds promise for novel therapeutic strategies targeting MKP-5 for diabetes management.

A Novel Needle Mouse Model of Vascular Cognitive Impairment and Dementia.

Bilateral common carotid artery (CCA) stenosis (BCAS) is a useful model to mimic vascular cognitive impairment and dementia (VCID). However, current BCAS models have the disadvantages of high cost and incompatibility with magnetic resonance imaging (MRI) scanning because of metal implantation. We have established a new low-cost VCID model that better mimics human VCID and is compatible with live-animal MRI. The right and the left CCAs were temporarily ligated to 32- and 34-gauge needles with three ligations, respectively. After needle removal, CCA blood flow, cerebral blood flow, white matter injury (WMI) and cognitive function were measured. In male mice, needle removal led to ∼49.8% and ∼28.2% blood flow recovery in the right and left CCA, respectively. This model caused persistent and long-term cerebral hypoperfusion in both hemispheres (more severe in the left hemisphere), and WMI and cognitive dysfunction in ∼90% of mice, which is more reliable compared with other models. Importantly, these pathologic changes and cognitive impairments lasted for up to 24 weeks after surgery. The survival rate over 24 weeks was 81.6%. Female mice showed similar cognitive dysfunction, but a higher survival rate (91.6%) and relatively milder white matter injury. A novel, low-cost VCID model compatible with live-animal MRI with long-term outcomes was established.SIGNIFICANCE STATEMENT Bilateral common carotid artery (CCA) stenosis (BCAS) is an animal model mimicking carotid artery stenosis to study vascular cognitive impairment and dementia (VCID). However, current BCAS models have the disadvantages of high cost and incompatibility with magnetic resonance imaging (MRI) scanning due to metal implantation. We established a new asymmetric BCAS model by ligating the CCA to various needle gauges followed by an immediate needle removal. Needle removal led to moderate stenosis in the right CCA and severe stenosis in the left CCA. This needle model replicates the hallmarks of VCID well in ∼90% of mice, which is more reliable compared with other models, has ultra-low cost, and is compatible with MRI scanning in live animals. It will provide a new valuable tool and offer new insights for VCID research.

Deletion of Slc9a1 in Cx3cr1+ cells stimulated microglial subcluster CREB1 signaling and microglia-oligodendrocyte crosstalk.

Microglial Na/H exchanger-1 (NHE1) protein, encoded by Slc9a1, plays a role in white matter demyelination of ischemic stroke brains. To explore underlying mechanisms, we conducted single cell RNA-seq transcriptome analysis in conditional Slc9a1 knockout (cKO) and wild-type (WT) mouse white matter tissues at 3 days post-stroke. Compared to WT, Nhe1 cKO brains expanded a microglial subgroup with elevated transcription of white matter myelination genes including Spp1, Lgals3, Gpnmb, and Fabp5. This subgroup also exhibited more acidic pHi and significantly upregulated CREB signaling detected by ingenuity pathway analysis and flow cytometry. Moreover, the Nhe1 cKO white matter tissues showed enrichment of a corresponding oligodendrocyte subgroup, with pro-phagocytosis and lactate shuffling gene expression, where activated CREB signaling is a likely upstream regulator. These findings demonstrate that attenuation of NHE1-mediated H+ extrusion acidifies microglia/macrophage and may underlie the stimulation of CREB1 signaling, giving rise to restorative microglia-oligodendrocyte interactions for remyelination.

Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

Amide proton transfer MRI at 9.4 T for differentiating tissue acidosis in a rodent model of ischemic stroke.

PURPOSE: Differentiating ischemic brain damage is critical for decision making in acute stroke treatment for better outcomes. We examined the sensitivity of amide proton transfer (APT) MRI, a pH-weighted imaging technique, to achieve this differentiation. METHODS: In a rat stroke model, the ischemic core, oligemia, and the infarct-growth region (IGR) were identified by tracking the progression of the lesions. APT MRI signals were measured alongside ADC, T1, and T2 maps to evaluate their sensitivity in distinguishing ischemic tissues. Additionally, stroke under hyperglycemic conditions was studied. RESULTS: The APT signal in the IGR decreased by about 10% shortly after stroke onset, and further decreased to 35% at 5 h, indicating a progression from mild to severe acidosis as the lesion evolved into infarction. Although ADC, T1, and T2 contrasts can only detect significant differences between the IGR and oligemia for a portion of the stroke duration, APT contrast consistently differentiates between them at all time points. However, the contrast to variation ratio at 1 h is only about 20% of the contrast to variation ratio between the core and normal tissues, indicating limited sensitivity. In the ischemic core, the APT signal decreases to about 45% and 33% of normal tissue level at 1 h for the normoglycemic and hyperglycemic groups, respectively, confirming more severe acidosis under hyperglycemia. CONCLUSION: The sensitivity of APT MRI is high in detecting severe acidosis of the ischemic core but is much lower in detecting mild acidosis, which may affect the accuracy of differentiation between the IGR and oligemia.

Dual contrast CEST MRI for pH-weighted imaging in stroke.

PURPOSE: pH enhanced (pHenh ) CEST imaging combines the pH sensitivity from amide and guanidino signals, but the saturation parameters have not been optimized. We propose pHdual as a variant of pHenh that suppresses background signal variations, while enhancing pH sensitivity and potential for imaging ischemic brain injury of stroke. METHODS: Simulation and in vivo rodent stroke experiments of pHenh MRI were performed with varied RF saturation powers for both amide and guanidino protons to optimize the contrast between lesion/normal tissues, while simultaneously minimizing signal variations across different types of normal tissues. In acute stroke, contrast and volume ratio measured by pHdual imaging were compared with an amide-CEST approach, and perfusion and diffusion MRI. RESULTS: Simulation experiments indicated that amide and guanidino CEST signals exhibit unique sensitivities across different pH ranges, with pHenh producing greater sensitivity over a broader pH regime. The pHenh data of rodent stroke brain demonstrated that the lesion/normal tissue contrast was maximized for an RF saturation power pair of 0.5 µT at 2.0 ppm and 1.0 µT at 3.6 ppm, whereas an optimal contrast-to-variation ratio (CVR) was obtained with a 0.7 µT saturation at 2.0 ppm and 0.8 µT at 3.6 ppm. In acute stroke, CVR optimized pHenh (i.e., pHdual ) achieved a higher sensitivity than the three-point amide-CEST approach, and distinct patterns of lesion tissue compared to diffusion and perfusion MRI. CONCLUSION: pHdual MRI improves the sensitivity of pH-weighted imaging and will be a valuable tool for assessing tissue viability in stroke.

IP3R2 regulates apoptosis by Ca2+ transfer through mitochondria-ER contacts in hypoxic photoreceptor injury.

Mitochondria-associated ER membranes (MAMs) are contact sites that enable bidirectional communication between the ER (endoplasmic reticulum) and mitochondria, including the transfer of Ca2+ signals. MAMs are essential for mitochondrial function and cellular energy metabolism. However, unrestrained Ca2+ transfer to the mitochondria can lead to mitochondria-dependent apoptosis. IP3R2 (Inositol 1,4,5-trisphosphate receptor 2) is an important intracellular Ca2+ channel. This study investigated the contribution of IP3R2-MAMs to hypoxia-induced apoptosis in photoreceptor cells. A photoreceptor hypoxia model was established by subretinal injection of hyaluronic acid (1%) in C57BL/6 mice and 1% O2 treatment in 661W cells. Transmission electron microscopy (TEM), ER-mitochondria colocalization, and the MAM reporter were utilized to evaluate MAM alterations. Cell apoptosis and mitochondrial homeostasis were evaluated using immunofluorescence (IF), flow cytometry, western blotting (WB), and ATP assays. SiRNA transfection was employed to silence IP3R2 in 661W cells. Upon hypoxia induction, MAMs were significantly increased in photoreceptors both in vivo and in vitro. This was accompanied by the activation of mitochondrial apoptosis and disruption of mitochondrial homeostasis. Elevated MAM-enriched IP3R2 protein levels induced by hypoxic injury led to mitochondrial calcium overload and subsequent photoreceptor apoptosis. Notably, IP3R2 knockdown not only improved mitochondrial morphology but also restored mitochondrial function in photoreceptors by limiting MAM formation and thereby attenuating mitochondrial calcium overload under hypoxia. Our results suggest that IP3R2-MAM-mediated mitochondrial calcium overload plays a critical role in mitochondrial dyshomeostasis, ultimately contributing to photoreceptor cell death. Targeting MAM constitutive proteins might provide an option for a therapeutic approach to mitigate photoreceptor death in retinal detachment.

Ophiobolin A derivatives with enhanced activities under tumor-relevant acidic conditions.

Glioblastoma (GBM) is the most common form of malignant primary brain tumor and is one of the most lethal cancers. The difficulty in treating GBM stems from its highly developed mechanisms of drug resistance. Our research team has recently identified the fungal secondary metabolite ophiobolin A (OpA) as an agent with significant activity against drug-resistant GBM cells. However, the OpA's mode of action is likely based on covalent modification of its intracellular target(s) and thus possible off-target reactivity needs to be addressed. This work involves the investigation of an acid-sensitive OpA analogue approach that exploits the elevated acidity of the GBM microenvironment to enhance the selectivity for tumor targeting. This project identified analogues that showed selectivity at killing GBM cells grown in cultures at reduced pH compared to those maintained under normal neutral conditions. These studies are expected to facilitate the development of OpA as an anti-GBM agent by investigating its potential use in an acid-sensitive analogue form with enhanced selectivity for tumor targeting.

Ecotoxicological evaluation and regeneration impairment of planarians by dibutyl phthalate.

Commonly utilized as a plasticizer in the food and chemical sectors, Dibutyl phthalate (DBP) poses threats to the environment and human well-being as it seeps or moves into the surroundings. Nevertheless, research on the harmfulness of DBP to aquatic organisms is limited, and its impact on stem cells and tissue regeneration remains unidentified. Planarians, recognized for their robust regenerative capabilities and sensitivity to aquatic pollutants, are emerging animal models in toxicology. This study investigated the comprehensive toxicity effects of environmentally relevant levels of DBP on planarians. It revealed potential toxicity mechanisms through the use of immunofluorescence, chromatin dispersion assay, Western blot, quantitative real-time fluorescence quantitative PCR (qRT-PCR), chromatin behavioral and histological analyses, immunofluorescence, and terminal dUTP nickel-end labeling (TUNEL). Findings illustrated that DBP caused morphological and motor abnormalities, tissue damage, regenerative inhibition, and developmental neurotoxicity. Further research revealed increased apoptosis and suppressed stem cell proliferation and differentiation, disrupting a balance of cell proliferation and death, ultimately leading to morphological defects and functional abnormalities. This was attributed to oxidative stress and DNA damage caused by excessive release of reactive oxygen species (ROS). This exploration furnishes fresh perspectives on evaluating the toxicity peril posed by DBP in aquatic organisms.

TRIM25 inhibition attenuates inflammation, senescence, and oxidative stress in microvascular endothelial cells induced by hyperglycemia.

PURPOSES: This work aimed to assess the possible role of TRIM25 in regulating hyperglycemia-induced inflammation, senescence, and oxidative stress in retinal microvascular endothelial cells, all of which exert critical roles in the pathological process of diabetic retinopathy. METHODS: The effects of TRIM25 were investigated using streptozotocin-induced diabetic mice, human primary retinal microvascular endothelial cells cultured in high glucose, and adenoviruses for TRIM25 knockdown and overexpression. TRIM25 expression was evaluated by western blot and immunofluorescence staining. Inflammatory cytokines were detected by western blot and quantitative real-time PCR. Cellular senescence level was assessed by detecting senescent marker p21 and senescence-associated-ß-galactosidase activity. The oxidative stress state was accessed by detecting reactive oxygen species and mitochondrial superoxide dismutase. RESULTS: TRIM25 expression is elevated in the endothelial cells of the retinal fibrovascular membrane from diabetic patients compared with that of the macular epiretinal membrane from non-diabetic patients. Moreover, we have also observed a significant increase in TRIM25 expression in diabetic mouse retina and retinal microvascular endothelial cells under hyperglycemia. TRIM25 knockdown suppressed hyperglycemia-induced inflammation, senescence, and oxidative stress in human primary retinal microvascular endothelial cells while TRIM25 overexpression further aggregates those injuries. Further investigation revealed that TRIM25 promoted the inflammatory responses mediated by the TNF-α/NF-κB pathway and TRIM25 knockdown improved cellular senescence by increasing SIRT3. However, TRIM25 knockdown alleviated the oxidative stress independent of both SIRT3 and mitochondrial biogenesis. CONCLUSION: Our study proposed TRIM25 as a potential therapeutic target for the protection of microvascular function during the progression of diabetic retinopathy.

Adjusting luminescence properties of ZnAl2O4:Mn2+(Mn4+), Li+ phosphors through cation substitution.

ZnAl2O4 with a typical spinel structure is highly expected to be a novel rare-earth-free ion-activated oxide phosphor with red emission, which holds high actual meaning for advancing phosphor-converted light-emitting diode (pc-LED) lighting. Among the rare-earth-free activators, Mn4+ ions have emerged as one of the most promising activators. Considering the price advantage of MnCO3 generating Mn2+ ions and the charge compensation effect potentially obtaining Mn4+ ions from Mn2+ ions, this research delves into a collection of ZnAl2O4:Mn2+(Mn4+), x Li+ (x = 0%-40%) phosphors with Li+ as co-dopant and MnCO3 as Mn2+ dopant source prepared by a high temperature solid-state reaction method. The lattice structure was investigated using X-ray diffraction (XRD), photoluminescence (PL), and photoluminescence excitation (PLE) spectroscopy. Results suggest a relatively high probability of Li+ ions occupying Zn2+ lattice sites. Furthermore, Li+ ion doping was assuredly found to facilitate the oxidization of Mn2+ to Mn4+, leading to a shift of luminescence peak from 516 to 656 nm. An intriguing phenomenon that the emission color changed with the Li+ doping content was also observed. Meanwhile, the luminescence intensity and quantum yield (QY) at different temperatures, as well as the relevant thermal quenching mechanism, were determined and elucidated detailedly.

Regulatory T cell expansion promotes white matter repair after stroke.

Recent research highlights the function of regulatory T cells (Tregs) in white matter integrity in CNS diseases. Approaches that expand the number of Tregs have been utilized to improve stroke recovery. However, it remains unclear if Treg augmentation preserves white matter integrity early after stroke or promotes white matter repair. This study evaluates the effect of Treg augmentation on white matter injury and repair after stroke. Adult male C57/BL6 mice randomly received Treg or splenocyte (2 million, iv) transfer 2 h after transient (60 min) middle cerebral artery occlusion (tMCAO). Immunostaining showed improved white matter recovery after tMCAO in Treg-treated mice compared to mice received splenocytes. In another group of mice, IL-2/IL-2 antibody complexes (IL-2/IL-2Ab) or isotype IgG were administered (i.p) for 3 consecutive days starting 6 h after tMCAO, and repeated on day 10, 20 and 30. The IL-2/IL-2Ab treatment boosted the number of Tregs in blood and spleen and increased Treg infiltration into the ischemic brain. Longitudinal in vivo and ex vivo diffusion tensor imaging analysis revealed an increase in fractional anisotropy 28d and 35d, but not 14d, after stroke in IL-2/IL-2Ab-treated mice compared to isotype-treated mice, suggesting a delayed improvement in white matter integrity. IL-2/IL-2Ab also improved sensorimotor functions (rotarod test and adhesive removal test) 35d after stroke. There were correlations between white matter integrity and behavior performance. Immunostaining confirmed the beneficial effects of IL-2/IL-2Ab on white matter structures 35d after tMCAO. IL-2/IL-2Ab treatment starting as late as 5d after stroke still improved white matter integrity 21d after tMCAO, suggesting long-term salutary effects of Tregs on the late-stage tissue repair. We also found that IL-2/IL-2Ab treatment reduced the number of dead/dying OPCs and oligodendrocytes in the brain 3d after tMCAO. To confirm the direct effect of Tregs on remyelination, Tregs were cocultured with lysophosphatidyl choline (LPC)-treated organotypic cerebella. LPC exposure for 17 h induced demyelination in organotypic cultures, followed by gradual spontaneous remyelination upon removal of LPC. Co-culture with Tregs accelerated remyelination in organotypic cultures 7d after LPC. In conclusion, Boosting the number of Tregs protects oligodendrocyte lineage cells early after stroke and promotes long-term white matter repair and functional recovery. IL-2/IL-2Ab represents a feasible approach of Treg expansion for stroke treatment.

BioBulkFoundary: a customized webserver for exploring biosynthetic potentials of bulk chemicals.

SUMMARY: Advances in metabolic engineering have boosted the production of bulk chemicals, resulting in tons of production volumes of some bulk chemicals with very low prices. A decrease in the production cost and overproduction of bulk chemicals makes it necessary and desirable to explore the potential to synthesize higher-value products from them. It is also useful and important for society to explore the use of design methods involving synthetic biology to increase the economic value of these bulk chemicals. Therefore, we developed 'BioBulkFoundary', which provides an elaborate analysis of the biosynthetic potential of bulk chemicals based on the state-of-art exploration of pathways to synthesize value-added chemicals, along with associated comprehensive technology and economic database into a user-friendly framework. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://design.rxnfinder.org/biobulkfoundary/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Universal protocol and standard-spiking strategy for profiling of host cell proteins in therapeutic growth hormone.

Liquid chromatography coupled to mass spectrometry (LC-MS) is widely used for host cell proteins (HCP) identification in antibody drug development because of its sensitivity, selectivity, and adaptability. However, LC-MS based identification of HCP in biotherapeutics produced from the prokaryotic Escherichia coli-derived growth hormone (GH) has rarely been reported. Herein, we developed a universal and powerful workflow by combining optimized sample preparation with one-dimension ultra-high performance LC-MS based shotgun proteomics to support HCP profiling in GH samples from downstream pools and the final product, which would be beneficial to direct the purification process development and compare the difference of impurity of different products for guiding the development of the biosimilar. A standard-spiking strategy was also developed to increase the depth of HCP identification. Spiking with standards enables additional identification of HCP species, which is promising for trace-level HCP analysis. Our universal and standard-spiking protocols would open an avenue for profiling HCP in biotherapeutics derived from prokaryotic host cells.

Applying dimensional psychopathology: transdiagnostic prediction of executive cognition using brain connectivity and inflammatory biomarkers.

BACKGROUND: The association between executive dysfunction, brain dysconnectivity, and inflammation is a prominent feature across major psychiatric disorders (MPDs), schizophrenia, bipolar disorder, and major depressive disorder. A dimensional approach is warranted to delineate their mechanistic interplay across MPDs. METHODS: This single site study included a total of 1543 participants (1058 patients and 485 controls). In total, 1169 participants underwent diffusion tensor and resting-state functional magnetic resonance imaging (745 patients and 379 controls completed the Wisconsin Card Sorting Test). Fractional anisotropy (FA) and regional homogeneity (ReHo) assessed structural and functional connectivity, respectively. Pro-inflammatory cytokine levels [interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α] were obtained in 325 participants using blood samples collected with 24 h of scanning. Group differences were determined for main measures, and correlation and mediation analyses and machine learning prediction modeling were performed. RESULTS: Executive deficits were associated with decreased FA, increased ReHo, and elevated IL-1ß and IL-6 levels across MPDs, compared to controls. FA and ReHo alterations in fronto-limbic-striatal regions contributed to executive deficits. IL-1ß mediated the association between FA and cognition, and IL-6 mediated the relationship between ReHo and cognition. Executive cognition was better predicted by both brain connectivity and cytokine measures than either one alone for FA-IL-1ß and ReHo-IL-6. CONCLUSIONS: Transdiagnostic associations among brain connectivity, inflammation, and executive cognition exist across MPDs, implicating common neurobiological substrates and mechanisms for executive deficits in MPDs. Further, inflammation-related brain dysconnectivity within fronto-limbic-striatal regions may represent a transdiagnostic dimension underlying executive dysfunction that could be leveraged to advance treatment.

Tumour-pleura relationship on CT is a risk factor for occult lymph node metastasis in peripheral clinical stage IA solid adenocarcinoma.

OBJECTIVES: To investigate whether the tumour-pleura relationship on computed tomography (CT) is a risk factor for occult lymph node metastasis (OLNM) in peripheral clinical stage IA solid adenocarcinoma. METHODS: A total of 232 patients were included in the study. The tumour-pleura relationship was divided into four types: type 1, the tumour was unrelated to the pleura; type 2, the tumour was not in contact with the pleura, and one or more linear or striated pleural tags were visible; type 3, the tumour was not in contact with the pleura, and one or more linear or striated pleural tags with soft tissue component at the pleural end were visible; and type 4, the tumour was in contact with the pleura. Univariate and multivariate logistic regression analyses were used to identify the predictive factors, including the tumour-pleura relationship, clinical factors, conventional CT findings, and pathology-reported visceral pleural invasion, for OLNM. RESULTS: Type 3 and 4 tumour-pleura relationships were more likely to have visceral pleural invasion than type 1 and 2 tumour-pleura relationships (p < 0.001). Univariate and multivariate logistic regression analyses revealed that the type 3 or 4 tumour-pleura relationship (OR: 3.261, p = 0.026), carcinoembryonic antigen level (OR: 3.361, p = 0.006), cytokeratin 19 fragments level (OR: 2.539, p = 0.025), and mediastinal window tumour size (OR: 1.078, p = 0.020) were predictive factors for OLNM. CONCLUSIONS: The type 3 or 4 tumour-pleura relationship is correlated with a greater risk of OLNM in peripheral clinical stage IA solid adenocarcinoma. KEY POINTS: • The tumour-pleura relationship on CT is a risk factor for occult lymph node metastasis in peripheral clinical stage IA solid adenocarcinoma. • Other risk factors for OLNM include CEA level, CYFRA level, and mediastinal window tumour size. • Pathology-reported visceral pleural invasion is not a risk factor for OLNM.

miR-186-5p targets TGFßR2 to inhibit RAW264.7 cell migration and proliferation during mouse skin wound healing.

BACKGROUND: Active peptides play a vital role in the development of new drugs and the identification and discovery of drug targets. As the first reported native peptide homodimer with pro-regenerative potency, OA-GP11d could potentially be used as a novel molecular probe to help elucidate the molecular mechanism of skin wound repair and provide new drug targets. METHODS: Bioinformatics analysis and luciferase assay were adopted to determine microRNAs (miRNAs) and its target. The prohealing potency of the miRNA was determined by MTS and a Transwell experiment against mouse macrophages. Enzyme-linked immunosorbent assay, realtime polymerase chain reaction, and western blotting were performed to explore the molecular mechanisms. RESULTS: In this study, OA-GP11d was shown to induce Mus musculus microRNA-186-5p (mmu-miR-186-5p) down-regulation. Results showed that miR-186-5p had a negative effect on macrophage migration and proliferation as well as a targeted and negative effect on TGF-ß type II receptor (TGFßR2) expression and an inhibitory effect on activation of the downstream SMAD family member 2 (Smad2) and protein-p38 kinase signaling pathways. Importantly, delivery of a miR-186-5p mimic delayed skin wound healing in mice. CONCLUSION: miR-186-5p regulated macrophage migration and proliferation to delay wound healing through the TGFßR2/Smad2/p38 molecular axes, thus providing a promising new pro-repair drug target.

A Sensitivity-Optimized Flexible Capacitive Pressure Sensor with Cylindrical Ladder Microstructural Dielectric Layers.

Flexible capacitive pressure sensors have attracted extensive attention due to their dynamic response and good sensing capability for static and small pressures. Using microstructural dielectric layers is an effective method for improving performance. However, the current state of microstructure design is primarily focused on basic shapes and is largely limited by simulation results; there is still a great deal of potential for further innovation and improvement. This paper innovatively proposes to increase the ladder structure based on the basic microstructures, for example, the long micro-ridge ladder, the cuboid ladder, and cylindrical ladder microstructures. By comparing 9 kinds of microstructures including ladder structure through finite element simulation, it is found that the sensor with a cylindrical ladder microstructure dielectric layer has the highest sensitivity. The dielectric layers with various microstructures are obtained by 3D printed molds, and the sensor with cylindrical ladder microstructure dielectric layer has the sensitivity of 0.12 kPa-1, which is about 3.9 times higher than that without microstructure. The flexible pressure sensor developed by us boasts sensitivity-optimized and operational stability, making it an ideal solution for monitoring rainfall frequency in real time.

Pharmacological Inhibition of NHE1 Protein Increases White Matter Resilience and Neurofunctional Recovery after Ischemic Stroke.

To date, recanalization interventions are the only available treatments for ischemic stroke patients; however, there are no effective therapies for reducing stroke-induced neuroinflammation. We recently reported that H+ extrusion protein Na+/H+ exchanger-1 (NHE1) plays an important role in stroke-induced inflammation and white matter injury. In this study, we tested the efficacy of two potent NHE1 inhibitors, HOE642 and Rimeporide, with a delayed administration regimen starting at 24 h post-stroke in adult C57BL/6J mice. Post-stroke HOE642 and Rimeporide treatments accelerated motor and cognitive function recovery without affecting the initial ischemic infarct, neuronal damage, or reactive astrogliosis. However, the delayed administration of NHE1 blockers after ischemic stroke significantly reduced microglial inflammatory activation while enhanced oligodendrogenesis and white matter myelination, with an increased proliferation and decreased apoptosis of the oligodendrocytes. Our findings suggest that NHE1 protein plays an important role in microglia-mediated inflammation and white matter damage. The pharmacological blockade of NHE1 protein activity reduced microglia inflammatory responses and enhanced oligodendrogenesis and white matter repair, leading to motor and cognitive function recovery after stroke. Our study reveals the potential of targeting NHE1 protein as a therapeutic strategy for ischemic stroke therapy.