Optimizing wheat productivity through integrated management of irrigation, nutrition, and organic amendments.

Enhancing wheat productivity by implementing a comprehensive approach that combines irrigation, nutrition, and organic amendments shows potential for collectively enhancing crop performance. This study examined the individual and combined effects of using irrigation systems (IS), foliar potassium bicarbonate (PBR) application, and compost application methods (CM) on nine traits related to the growth, physiology, and yield of the Giza-171 wheat cultivar. Analysis of variance revealed significant (P ≤ 0.05) main effects of IS, PBR, and CM on wheat growth, physiology, and yield traits over the two growing seasons of the study. Drip irrigation resulted in a 16% increase in plant height, leaf area index, crop growth rate, yield components, and grain yield compared to spray irrigation. Additionally, the application of foliar PBR at a concentration of 0.08 g/L boosted these parameters by up to 22% compared to the control. Furthermore, the application of compost using the role method resulted in enhanced wheat performance compared to the treatment including mix application. Importantly, the combined analysis revealed that the three-way interaction between the three factors had a significant effect (P ≤ 0.05) on all the studied traits, with drip irrigation at 0.08 g PBR rate and role compost application method (referred as Drip_0.08g_Role) resulting in the best performance across all traits, while sprinkle irrigation without PBR and conventional mixed compost method (referred as sprinkle_CK_Mix) produced the poorest results. This highlights the potential to synergistically improve wheat performance through optimized agronomic inputs.

Analysis of pollutant dispersion patterns in rivers under different rainfall based on an integrated water-land model.

In the context of rapid urban expansion, the interaction between humanity and nature has become more prominent. Urban land and rivers often exist as distinct entities with limited material exchange. However, during rainfall, these two systems interconnect, resulting in the transfer of land-derived pollutants into rivers. Such transfer significantly increases river pollutant levels, adversely affecting water quality. Therefore, developing a water quality simulation and prediction model is crucial. This model should effectively illustrate pollutant movement and dispersion during rain events. This study proposes a comprehensive model that merges the Storm Water Management Model (SWMM) with the Environmental Fluid Dynamics Code (EFDC). This integrated model assesses the spread and dispersion of pollutants, including Ammonia Nitrogen (NH3-N), Total Phosphorus (TP), Total Nitrogen (TN), and Chemical Oxygen Demand (COD), within urban water cycles for various rainfall conditions, thus offering critical theoretical support for managing the water environment. The application of this model under different rainfall intensities (light, moderate and heavy) provides vital insights. During light rainfall, the river's natural purification process can sustain surface water quality at Class IV. Moderate rainfall causes accumulation of pollutants, reducing water quality to Class V. Conversely, heavy rainfall rapidly increases pollutant concentrations due to higher inflow, pushing the river to a degraded Class V status, which is beyond its natural purification capacity, necessitating engineering solutions to reattain Class IV quality. Furthermore, pollutant accumulation in downstream river sections is more influenced by flow rate than by rainfall intensity. In summary, the SWMM-EFDC integrated model proves highly effective in predicting river water quality, thereby significantly aiding urban water pollution control.

CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage.

Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury.

Soybean genetic resources contributing to sustainable protein production.

KEY MESSAGE: Genetic resources contributes to the sustainable protein production in soybean. Soybean is an important crop for food, oil, and forage and is the main source of edible vegetable oil and vegetable protein. It plays an important role in maintaining balanced dietary nutrients for human health. The soybean protein content is a quantitative trait mainly controlled by gene additive effects and is usually negatively correlated with agronomic traits such as the oil content and yield. The selection of soybean varieties with high protein content and high yield to secure sustainable protein production is one of the difficulties in soybean breeding. The abundant genetic variation of soybean germplasm resources is the basis for overcoming the obstacles in breeding for soybean varieties with high yield and high protein content. Soybean has been cultivated for more than 5000 years and has spread from China to other parts of the world. The rich genetic resources play an important role in promoting the sustainable production of soybean protein worldwide. In this paper, the origin and spread of soybean and the current status of soybean production are reviewed; the genetic characteristics of soybean protein and the distribution of resources are expounded based on phenotypes; the discovery of soybean seed protein-related genes as well as transcriptomic, metabolomic, and proteomic studies in soybean are elaborated; the creation and utilization of high-protein germplasm resources are introduced; and the prospect of high-protein soybean breeding is described.

Annexin A1 protects against cerebral ischemia-reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated. METHODS: We retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization. RESULTS: The baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2-3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood-brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments. CONCLUSIONS: Ac2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT.

Stochastic modeling reveals kinetic heterogeneity in post-replication DNA methylation.

DNA methylation is a heritable epigenetic modification that plays an essential role in mammalian development. Genomic methylation patterns are dynamically maintained, with DNA methyltransferases mediating inheritance of methyl marks onto nascent DNA over cycles of replication. A recently developed experimental technique employing immunoprecipitation of bromodeoxyuridine labeled nascent DNA followed by bisulfite sequencing (Repli-BS) measures post-replication temporal evolution of cytosine methylation, thus enabling genome-wide monitoring of methylation maintenance. In this work, we combine statistical analysis and stochastic mathematical modeling to analyze Repli-BS data from human embryonic stem cells. We estimate site-specific kinetic rate constants for the restoration of methyl marks on >10 million uniquely mapped cytosines within the CpG (cytosine-phosphate-guanine) dinucleotide context across the genome using Maximum Likelihood Estimation. We find that post-replication remethylation rate constants span approximately two orders of magnitude, with half-lives of per-site recovery of steady-state methylation levels ranging from shorter than ten minutes to five hours and longer. Furthermore, we find that kinetic constants of maintenance methylation are correlated among neighboring CpG sites. Stochastic mathematical modeling provides insight to the biological mechanisms underlying the inference results, suggesting that enzyme processivity and/or collaboration can produce the observed kinetic correlations. Our combined statistical/mathematical modeling approach expands the utility of genomic datasets and disentangles heterogeneity in methylation patterns arising from replication-associated temporal dynamics versus stable cell-to-cell differences.

Genome-wide association study of soybean seed germination under drought stress.

Drought stress, which is increasing with climate change, is a serious threat to agricultural sustainability worldwide. Seed germination is an essential growth phase that ensures the successful establishment and productivity of soybean, which can lose substantial productivity in soils with water deficits. However, only limited genetic information is available about how germinating soybean seeds may exert drought tolerance. In this study, we examined the germinating seed drought-tolerance phenotypes and genotypes of a panel of 259 released Chinese soybean cultivars panel. Based on 4616 Single-Nucleotide Polymorphisms (SNPs), we conducted a mixed-linear model GWAS that identified a total of 15 SNPs associated with at least one drought-tolerance index. Notably, three of these SNPs were commonly associated with two drought-tolerance indices. Two of these SNPs are positioned upstream of genes, and 11 of them are located in or near regions where QTLs have been previously mapped by linkage analysis, five of which are drought-related. The SNPs detected in this study can both drive hypothesis-driven research to deepen our understanding of genetic basis of soybean drought tolerance at the germination stage and provide useful genetic resources that can facilitate the selection of drought stress traits via genomic-assisted selection.

Lycopene alleviates disc degeneration under oxidative stress through the Nrf2 signaling pathway.

Intervertebral disc degeneration (IDD) is a main cause of diseases such as discogenic low back pain, cervical and lumbar disc herniation, degenerative spinal stenosis, and lumbar spondylolisthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important transcription factor, regulates antioxidant genes and induces cellular defense mechanisms against oxidative stress. In this study, the protective effect of plant antioxidant lycopene on nucleus pulposus cells (NPCs) under oxidative stress was investigated. The results indicated that Nrf2 expression decreased in degenerated NPCs. We further found that lycopene was protective in NP tissue under oxidative stress and alleviated oxidative stress-induced apoptosis of degenerative human NPCs via Nrf2. The results also showed that lycopene reduced H2O2-induced decomposition of cartilage extracellular matrix in NPCs. In conclusion, our findings suggested that lycopene may alleviate disc degeneration under oxidative stress through the Nrf2 signaling pathway.

First Report of Didymella americana causing corn stalk rot in China.

Corn (Zea mays L.) is an important food crop and feedstuff worldwide. However, Corn stalk rot, caused by multiple pathogens, is globally an economic soil-borne disease worldwide. In September 2019, a survey was carried out to characterize pathogenic fungi in corn stalks in Nehe city (48.48°N 124.88°E), Heilongjiang Province, China. Stalk rot incidence was approximately 5% in three of the fields sampled (5 ha/per field). Symptoms included wilting of whole plants, drooping ears or rapid death of the upper leaves or whole plant from blister stage to physiological maturity (growth stages R2- R6) stage with drooping ears or rapid death of the upper leaves or whole plant. A brown to black dry rot or necrosis was observed throughout the central pith and internal tissues of the stalk and crown were observed, which resulted in hollow and soft stalks. Fifteen tissue samples (0.25 cm2) from 15 individual diseased plants were surface disinfested with 75% ethanol for 2 s, followed by 0.5% NaOCl for 5 min, rinsed three times in sterile distilled water and cultured on potato dextrose agar (PDA) with 50 µg/mL streptomycin at 26°C in darkness. After 3 days, a total of eight fungal isolates with consistent characteristics were obtained from three sampling points and subcultured by transferring hyphal tips onto a new PDA plate. Single-conidium isolates were generated with methods reported previously (Leslie and Summerell 2006). Cultures on PDA were honey to olivaceous buff in the center with dense aerial mycelia and wide buff colored margins. The dimensions of conidia from 30-day-old PDA cultures were 4.5 to 15.3 µm × 1.5 to 4.3 µm (n = 50). Often, one to two oil bodies were present within the conidia. Based on these morphological features, the isolates were identified as Didymella americana (Aveskamp et al. 2010; Gorny et al. 2016). Genomic DNA was extracted from a representative isolate YJDA8 and the internal transcribed spacer regions (ITS) and translation elongation factor 1-alpha gene (TEF-1ɑ) were amplified and sequenced using the primers ITS1/ITS4 (Yin et al. 2012) and EF1-728F/EF1-986R (Carbone and Kohn 1999), respectively. The sequences of YJDA8 (accession nos. MT995077 for ITS and MW003707 for TEF-1a ) showed 99.6% (529/531 bp) and 97.6% (283/290 bp), identity to the sequences of D. americana isolate YSGYE6 (accession no. MK945663.1) and isolate K_INSO2_6_10 (MN554764.1) respectively. Pathogenicity tests were conducted by root injection of corn plants at the blister stage in the field. Conidia were obtained from 30-day-old PDA cultures grown at 20°C with a 12 h photoperiod. A conidial suspension (1.5 ml of 1×105 conidia/mL) was injected into the base of the maize stems using a 5 ml syringe. For each treatment, 5 plants were inoculated. Plants injected with 1.5 ml distilled sterile water served as the control. After inoculation, the plants were managed using conventional methods. All inoculated plants showed symptoms 25 days after inoculation that were similar to those observed in the field, while no symptoms were observed on the control plants. The fungus was re-isolated and confirmed to be D. americana. D. americana has previously been reported on corn roots and soybean pods in the USA (Aveskamp et al. 2009 as Peyronellaea americana), on lima bean in Delaware and Maryland (Everts et al. 2020). To our knowledge, this is the first report of D. americana causing stalk rot on corn in China. Therefore, its distribution needs to be investigated, monitored and managed with effective disease management strategies to protect corn.

Depletion of microglia augments the dopaminergic neurotoxicity of MPTP.

The activation of microglia and the various substances they produce have been linked to the pathologic development of Parkinson's disease (PD), but the precise role of microglia in PD remains to be defined. The survival of microglia depends on colony-stimulating factor 1 receptor (CSF1R) signaling, and CSF1R inhibition results in rapid elimination of microglia in the central nervous system. Using a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment, we showed that the depletion of microglia via the CSF1R inhibitor PLX3397 exacerbated the impairment of locomotor activities and the loss of dopaminergic neurons. Further, depletion of microglia augmented the production of inflammatory mediators and infiltration of leukocytes in the brain after MPTP exposure. Microglia depletion-induced aggravation of MPTP neurotoxicity was also seen in lymphocyte-deficient mice. In addition, the depletion of microglia did not affect the production of brain-derived neurotrophic factor, but it dramatically augmented the production of inflammatory mediators by astrocytes after MPTP treatment. Our findings suggest microglia play a protective role against MPTP-induced neuroinflammation and dopaminergic neurotoxicity.-Yang, X., Ren, H., Wood, K., Li, M., Qiu, S., Shi, F.-D., Ma, C., Liu, Q. Depletion of microglia augments the dopaminergic neurotoxicity of MPTP.

Selective NLRP3 (Pyrin Domain-Containing Protein 3) Inflammasome Inhibitor Reduces Brain Injury After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. As a key component of the innate immune system, the NOD-like receptor (NLR) family, NLRP3 (pyrin domain-containing protein 3) inflammasome, when activated after ICH, promotes neuroinflammation and brain edema. MCC950 is a potent, selective, small-molecule NLRP3 inhibitor that blocks NLRP3 activation at nanomolar concentrations. Here, we examined the effect of MCC950 on brain injury and inflammation in 2 models of ICH in mice. METHODS: In mice with ICH induced by injection of autologous blood or bacterial collagenase, we determined the therapeutic potential of MCC950 and its mechanisms of neuroprotection. RESULTS: MCC950 reduced IL-1ß (interleukin-1ß) production and attenuated neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In mice with autologous blood-induced ICH, the protection of MCC950 was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6. MCC950 improved blood-brain barrier integrity and diminished cell death. Notably, the protective effect of MCC950 was abolished in mice depleted of either microglia or Gr-1+ myeloid cells. CONCLUSIONS: These results indicate that the NLRP3 inflammasome inhibitor, MCC950, attenuates brain injury and inflammation after ICH. Hence, NLRP3 inflammasome inhibition is a potential therapy for ICH that warrants further investigation.

Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury.

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow cytometry, and immunofluorescence assays were utilized to analyze post-traumatic NLRP3 inflammasome expression and determine its cellular source. We found that NLRP3 inflammasome expression was significantly increased in the peri-contusional cortex and that microglia were the primary source of this expression. The effects of MCC950 on mice with TBI were then determined using post-assessments including analyses of neurological deficits, brain water content, traumatic lesion volume, neuroinflammation, blood-brain barrier (BBB) integrity, and cell death. MCC950 treatment resulted in a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions. The therapeutic window for MCC950 against TBI was as long as 6 h. Furthermore, the neuroprotective effect of MCC950 was associated with reduced microglial activation, leukocyte recruitment, and pro-inflammatory cytokine production. In addition, MCC950 preserved BBB integrity, alleviated TBI-induced loss of tight junction proteins, and attenuated cell death. Notably, the efficacy of MCC950 was abolished in microglia-depleted mice. These results indicate that microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to TBI, and specific NLRP3 inflammasome inhibition using MCC950 may be a promising therapeutic approach for patients with TBI.

A TSPO ligand attenuates brain injury after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. After ICH, the immediate infiltration of leukocytes and activation of microglia are accompanied by a rapid up-regulation of the 18-kDa translocator protein (TSPO). TSPO ligands have shown anti-inflammatory and neuroprotective properties in models of CNS injury. In this study, we determined the impact of a TSPO ligand, etifoxine, on brain injury and inflammation in 2 mouse models of ICH. TSPO was up-regulated in Iba1+ cells from brains of patients with ICH and in CD11b+CD45int cells from mice subjected to collagenase-induced ICH. Etifoxine significantly reduced neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In collagenase-induced ICH mice, the protection of etifoxine was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6 and TNF-α. Etifoxine improved blood-brain barrier integrity and diminished cell death. Notably, the protective effect of etifoxine was abolished in mice depleted of microglia by using a colony-stimulating factor 1 receptor inhibitor. These results indicate that the TSPO ligand etifoxine attenuates brain injury and inflammation after ICH. TSPO may be a viable therapeutic target that requires further investigations in ICH.-Li, M., Ren, H., Sheth, K. N., Shi, F.-D., Liu, Q. A TSPO ligand attenuates brain injury after intracerebral hemorrhage.

Bidirectional degeneration in the visual pathway in neuromyelitis optica spectrum disorder (NMOSD).

OBJECTIVE: This study aims to investigate whether bidirectional degeneration occurs within the visual pathway and, if so, the extent of such changes in neuromyelitis optica spectrum disorder (NMOSD). METHODS: In total, 36 NMOSD and 24 healthy controls (HCs) were enrolled. Three-dimensional T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging were used to analyze damage to the posterior visual pathway. Damage to the anterior visual pathway was measured by optical coherence tomography. RESULTS: In total, 24 NMOSD with prior optic neuritis (NMOON) patients showed significant reduction of peripapillary retinal nerve fiber layer, inner and outer retinal thickness, lateral geniculate nucleus volume, primary visual cortex volume, and decreased integrity of optic radiations, compared with 12 NMOSD without prior optic neuritis (NMONON) patients and 24 HCs. In NMONON, only the inner retinal thickness and the integrity of optic radiations were significantly reduced in comparison with HCs. Moreover, patients with optic neuritis showed severe bidirectional degeneration, the loss of the RNFL was greater than the atrophy of V1. CONCLUSION: Our study indicated the presence of trans-synaptic degeneration in NMOSD. Damage to the inner retina and optic radiations can be observed even in NMONON. After an episode of optic neuritis, the anterior visual pathway damage is greater than the posterior visual pathway damage.

DRα1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury.

Traumatic brain injury (TBI) results in severe neurological impairments without effective treatments. Inflammation appears to be an important contributor to key pathogenic events such as secondary brain injury following TBI and therefore serves as a promising target for novel therapies. We have recently demonstrated the ability of a molecular construct comprised of the human leukocyte antigen (HLA)-DRα1 domain linked covalently to mouse (m)MOG-35-55 peptide (DRα1-MOG-35-55 construct) to reduce CNS inflammation and tissue injury in animal models of multiple sclerosis and ischemic stroke. The aim of the current study was to determine if DRα1-MOG-35-55 treatment of a fluid percussion injury (FPI) mouse model of TBI could reduce the lesion size and improve disease outcome measures. Neurodeficits, lesion size, and immune responses were determined to evaluate the therapeutic potential and mechanisms of neuroprotection induced by DRα1-MOG-35-55 treatment. The results demonstrated that daily injections of DRα1-MOG-35-55 given after FPI significantly reduced numbers of infiltrating CD74+ and CD86+ macrophages and increased numbers of CD206+ microglia in the brain concomitant with smaller lesion sizes and improvement in neurodeficits. Conversely, DRα1-MOG-35-55 treatment of TBI increased numbers of circulating CD11b+ monocytes and their expression of CD74 but had no detectable effect on cell numbers or marker expression in the spleen. These results demonstrate that DRα1-MOG-35-55 therapy can reduce CNS inflammation and significantly improve histological and clinical outcomes after TBI. Future studies will further examine the potential of DRα1-MOG-35-55 for treatment of TBI.

Semantic clustering and sleep in patients with amnestic mild cognitive impairment or with vascular cognitive impairment-no dementia.

BACKGROUND: Cognition and sleep deficits occur in amnestic mild cognitive impairment (aMCI) and vascular cognitive impairment-no dementia (VCIND). However, how memory and sleep deficits differ between aMCI and VCIND remains unclear. METHODS: Fifty aMCI and 50 VCIND patients and 38 sex- and age-matched healthy controls (HCs) were administered the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test-A/B (TMT-A/B), Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Benton Judgment of Line Orientation (JLO) test, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Insomnia Severity Index (ISI) to quantify cognitive deficits and subjective sleep disturbance. RESULTS: Compared with VCIND patients, aMCI patients had lower HVLT-R scores for total recall (p < 0.001), delayed recall (p < 0.001) and recognition (p = 0.001), and for total-recall (p = 0.002) and delayed-recall (p < 0.001) semantic clustering ratios (SCRs). However, VCIND patients exhibited more obvious executive dysfunction (TMT-A, p < 0.001; TMT-B, p < 0.001; WCST, p < 0.001), lower information processing speed (PASAT, p = 0.003; SDMT, p < 0.001), and more severe sleep disturbance (PSQI, p < 0.001; ESS, p < 0.001; ISI, p < 0.001). Additionally, sleep quality and efficiency were related to total and delayed recall (all r values from -0.31 to -0.60, p < 0.05) in aMCI and VCIND. CONCLUSIONS: aMCI and VCIND differ in cognitive function, memory strategy and sleep impairment; these characteristics are helpful to identify and distinguish patients with very early cognitive impairment. Our results also suggest that memory deficits are associated with sleep disturbance in aMCI and VCIND.

Skull and vertebral bone marrow in central nervous system inflammation.

Emerging evidence has highlighted the capacity of hematogenous cells in skull and vertebral bone marrow to enter the meningeal borders via ossified vascular channels and maintain immune homeostasis in the central nervous system (CNS). CNS-adjacent skull and vertebral bone marrow comprises hematopoietic niches that can sense CNS injury and supply specialized immune cells to fine-tune inflammatory responses. Here, we review recent advances in our understanding of skull and vertebral bone marrow-derived immune cells in homeostasis and inflammatory CNS diseases. Further, we discuss the implications for future development of therapies to mitigate CNS inflammation and its detrimental sequelae in neurological disorders.

A noval noninvasive targeted therapy for osteosarcoma: the combination of LIFU and ultrasound-magnetic-mediated SPIO/TP53/PLGA nanobubble.

Purpose: Osteosarcoma (OS) is the most common type of primary malignant bone tumor. Transducing a functional TP53 gene can effectively inhibit OS cell activity. Poly lactic acid-glycolic acid (PLGA) nanobubbles (NBs) mediated by focused ultrasound (US) can introduce exogenous genes into target cells in animal models, but this technique relies on the passive free diffusion of agents across the body. The inclusion of superparamagnetic iron oxide (SPIO) in microbubbles allows for magnetic-based tissue localization. A low-intensity-focused ultrasound (LIFU) instrument was developed at our institute, and different intensities of LIFU can either disrupt the NBs (RLI-LIFU) or exert cytocidal effects on the target tissues (RHI-LIFU). Based on these data, we performed US-magnetic-mediated TP53-NB destruction and investigated its ability to inhibit OS growth when combined with LIFU both in vitro and in vivo. Methods: Several SPIO/TP53/PLGA (STP) NB variants were prepared and characterized. For the in vitro experiments, HOS and MG63 cells were randomly assigned into five treatment groups. Cell proliferation and the expression of TP53 were detected by CCK8, qRT-PCR and Western blotting, respectively. In vivo, tumor-bearing nude mice were randomly assigned into seven treatment groups. The iron distribution of Perls' Prussian blue-stained tissue sections was determined by optical microscopy. TUNEL-DAPI was performed to examine apoptosis. TP53 expression was detected by qRT-PCR and immunohistochemistry. Results: SPIO/TP53/PLGA NBs with a particle size of approximately 200 nm were prepared successfully. For in vitro experiments, ultrasound-targeted transfection of TP53 overexpression in OS cells and efficient inhibition of OS proliferation have been demonstrated. Furthermore, in a tumor-bearing nude mouse model, RLI-LIFU-magnetic-mediated SPIO/TP53/PLGA NBs increased the transfection efficiency of the TP53 plasmid, resulting in apoptosis. Adding RHI-LIFU to the treatment regimen significantly increased the apoptosis of OS cells in vivo. Conclusion: Combining LIFU and US-magnetic-mediated SPIO/TP53/PLGA NB destruction is potentially a novel noninvasive and targeted therapy for OS.

Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution.

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood-brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood-brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.