Kinematic patterns in performing trunk flexion tasks influenced by various mechanical optimization targets: A simulation study.

BACKGROUND: Low back pain is the most prevalent and disabling condition worldwide, with a high recurrence rate in the general adult population. METHODS: A set of open-sourced trunk musculoskeletal models was used to investigate trunk flexion kinematics under different motor control strategies, including minimizing shearing or compressive loads at the L4/L5 or L5/S1 level. FINDINGS: A control strategy that minimizes the load on the lower lumbar intervertebral disc can result in two kinematic patterns-the "restricted lumbar spine" and the "overflexed lumbar spine"-in performing the trunk flexion task. The "restricted" pattern can reduce the overall load on the lower lumbar levels, whereas the "overflexed" pattern can reduce the shearing force only at the L4/L5 level and increase the compressive and shearing forces at the L5/S1 level and the compressive force at the L4/L5 level. INTERPRETATION: This study investigated the relationships between specific trunk kinematics in patients with low back pain and lumbar intervertebral loading via musculoskeletal modelling and simulation. The results provide insight into individualized treatment for patients with low back pain.

Seasonal microplastic ingestion by carnivorous chaetognaths in Jiaozhou Bay, China: Field evidence revealing microplastic trophic transfer.

Microplastics (MPs) are widely distributed in marine environments and ingested by marine organisms, especially zooplankton. Chaetognaths, typical carnivorous zooplankton, are pivotal in the food chain from secondary producers, such as copepods, to higher trophic level species. However, little is known about their MP ingestion. In this study, based on field observation data, for the first time, we studied seasonal characteristics and risks of MPs ingested by chaetognaths in Jiaozhou Bay and assessed effects of key prey copepods on MP ingestion by chaetognaths. MP/chaetognath values in February, May, August, and November were 0.19, 0.17, 0.15, and 0.39, respectively, showing no significant seasonal variation. Chaetognaths predominantly ingested MPs that were fiberous in shape, 101-400 µm in size and polyester in polymer type, with no significant seasonal variations. The risk of MP load in chaetognaths was low, but there are higher polymeric hazards and potential ecological risks. MP/chaetognath values were positively correlated with the copepod abundance and MP/copepod values. The characteristics of MPs ingested by chaetognaths were also highly similar to those of MPs ingested by copepods. However, the overall risk of biomagnification in the copepod-chaetognath food chain was low. This study provided field evidence for MP transfer in the planktonic food chain.

Association of interleukin-6 with sarcopenia and its components in older adults: a systematic review and meta-analysis of cross-sectional studies.

BACKGROUND: Observational studies have documented increased serum IL-6 levels in elderly individuals afflicted with sarcopenia. Nevertheless, the relationship between serum IL-6 concentrations and sarcopenia prevalence in the aging population is yet to be defined. METHODS: We executed a systematic review and meta-analysis of cross-sectional studies that scrutinized serum IL-6 levels in older adults with and without sarcopenia. Relevant studies were sourced from PubMed, Scopus, Embase, Cochrane Library, and Web of Science from inception until 10 September 2023. The standard mean differences (SMDs) in serum IL-6 levels between studies were synthesized using a random-effects model. To examine the influence of demographic and clinical factors on these outcomes, we performed subgroup analyses and meta-regression, focusing on variables such as sex, age, and body mass index (BMI). We also assessed the relationship between serum IL-6 levels and the defining components of sarcopenia: muscle mass, muscle strength, and physical performance. We used Fisher's Z transformation to standardize the interpretation of effect sizes from these relationships. The transformed values were then converted to summary correlation coefficients (r) for a clear and unified summary of the results. RESULTS: We included twenty-one cross-sectional studies involving 3,902 participants. Meta-analysis revealed significantly elevated serum IL-6 levels in older adults with sarcopenia compared with those without sarcopenia (SMD = 0.31; 95% CI 0.18, 0.44). The difference was highly pronounced in the subgroups of male and those with female percentage below 50% or a mean BMI below 24 kg/m2. Serum IL-6 levels were inversely correlated with muscle mass (summary r = -0.18; 95% CI -0.30, -0.06), but not with handgrip strength (summary r = -0.10; 95%CI: -0.25, 0.05) or gait speed (summary r = -0.09; 95%CI: -0.24, 0.07). CONCLUSIONS: This meta-analysis establishes a link between increased serum IL-6 levels and sarcopenia in the elderly, particularly in relation to decreased muscle mass.

Several studies have demonstrated elevated serum IL-6 levels in elderly individuals with sarcopenia, while the relationship between serum IL-6 levels and sarcopenia remains unclear.This is a systematic review and meta-analysis of 21 cross-sectional studies for the relationship between serum IL-6 levels and sarcopenia.Elevated serum IL-6 levels appear to be associated with sarcopenia in older adults, especially in relation to reduced muscle mass.

The characteristics of the body mass frequency index in dysmobility syndrome: A pilot study.

BACKGROUND: With the advancement of global aging, there has been an increase in patients with dysmobility syndrome (DS), often accompanied by osteoporosis, sarcopenia, and sarcopenic obesity. The objective of this study was to evaluate the application value of the body mass frequency index (BMFI) in older patients with DS by comprehensively analyzing the differences in BMFI between community-dwelling older subjects using medical and engineering methods. METHODS: A cross-sectional study was conducted to recruit community-dwelling older subjects aged 60-90 years. Various assessments and measurements were performed, including basic information collection, gait analysis, bone mineral density (BMD) and body composition measurement, fall and fracture risk et al. Gait analysis and body mass index (BMI) are in the established model to calculate BMFI. Analysis of BMFI was performed in community-dwelling older subjects, and the specificity and threshold of BMFI in predicting dysmobility syndrome (DS) were further analyzed. RESULTS: Significant differences in BMFI were observed between older adults with DS and those without DS. BMFI in older people was associated with bone quality, fracture risk, body fat percentage, appendicular skeletal muscle mass index (ASMI), grip strength, and speed. The odds ratio (OR) and 95 % confidence interval (CI) for BMFI in the non-DS and DS groups were 0.823 (0.743-0.901), respectively. Receiver operating characteristic (ROC) analysis demonstrated that BMFI had predictive value in distinguishing non-DS from DS (AUC = 0.669) (P < 0.05). The optimal threshold for predicting non-DS and DS was found to be 16.04 (sensitivities = 0.483, specificities = 0.774). CONCLUSION: The measurement of BMFI has demonstrated disparities in musculoskeletal status among older adults with and without DS. Notably, BMFI exhibits a unique predictive capacity for DS among the elderly population.

Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke.

The accumulation of self-renewed polarized microglia in the penumbra is a critical neuroinflammatory process after ischemic stroke, leading to secondary demyelination and neuronal loss. Although known to regulate tumor cell proliferation and neuroinflammation, HDAC3's role in microgliosis and microglial polarization remains unclear. We demonstrated that microglial HDAC3 knockout (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. RNA-seq analysis revealed mitosis as the primary process affected in HDAC3-deficent microglia following stroke. Notably, HDAC3-miKO specifically inhibited proliferation of proinflammatory microglia without affecting anti-inflammatory microglia, preventing microglial transition to a proinflammatory state. Moreover, ATAC-seq showed that HDAC3-miKO induced closing of accessible regions enriched with PU.1 motifs. Overexpressing microglial PU.1 via an AAV approach reversed HDAC3-miKO-induced proliferation inhibition and protective effects on ischemic stroke, indicating PU.1 as a downstream molecule that mediates HDAC3's effects on stroke. These findings uncovered that HDAC3/PU.1 axis, which mediated differential proliferation-related reprogramming in different microglia populations, drove poststroke inflammatory state transition, and contributed to pathophysiology of ischemic stroke.

Rich diversity and active spatial-temporal dynamics of Thalassiosira species revealed by time-series metabarcoding analysis.

Thalassiosira is a species-rich genus in Bacillariophyta that not only contributes positively as primary producer, but also poses negative impacts on ecosystems by causing harmful algal blooms. Although taxonomical studies have identified a large number of Thalassiosira species, however, the composition of Thalassiosira species and their geographical distribution in marine ecosystems were not well understood due primarily to the lack of resolution of morphology-based approaches used previously in ecological expeditions. In this study, we systematically analyzed the composition and spatial-temporal dynamic distributions of Thalassiosira in the model marine ecosystem Jiaozhou Bay by applying metabarcoding analysis. Through analyzing samples collected monthly from 12 sampling sites, 14 Thalassiosira species were identified, including five species that were not previously reported in Jiaozhou Bay, demonstrating the resolution and effectiveness of metabarcoding analysis in ecological research. Many Thalassiosira species showed prominent temporal preferences in Jiaozhou Bay, with some displaying spring-winter preference represented by Thalassiosira tenera, while others displaying summer-autumn preference represented by Thalassiosira lundiana and Thalassiosira minuscula, indicating that the temperature is an important driving factor in the temporal dynamics. The application of metabarcoding analysis, equipped with appropriate molecular markers with high resolution and high specificity and databases of reference molecular marker sequences for potential all Thalassiosira species, will revolutionize ecological research of Thalassiosira species in Jiaozhou Bay and other marine ecosystems.

Circulating Hsa-miR499a-5p as markers in dysmobility syndrome patients: a new index for diagnosing dysmobility syndrome based on osteoporosis and predicting fracture risk.

BACKGROUND: Dysmobility syndrome based on osteoporosis (ODS) is a disease characterized by low bone mass and low muscle mass. Its features are high fracture and high fall risk. Falls and fractures are the most important factors affecting the quality of life and lifespan of ODS. However, there is no serum marker for the evaluation of ODS patients.Our previous studies have shown that the expression of circulating miRNA is stable and is a good marker for disease diagnosis. Therefore, this study aims to explore potential serum markers of ODS. METHODS: A total of 78 subjects were included in this study. The data including appendicular skeletal muscle mass index, bone mineral density, bone metabolism markers, and other relevant information were collected for analysis. Real-time quantitative polymerase chain reaction was used to detect 19 miRNAs associated with muscle mass reduction. The correlation of quantitative data was analyzed by Pearson. The receiver operating characteristic curve was used to evaluate the performance of miRNA as a biomarker. RESULTS: In this study, we found that the muscle mass and strength of patients with ODS are significantly reduced and are negatively correlated with the risk of fracture. The hsa-miR-499a-5p is specifically downregulated in ODS, and is positively correlated with muscle mass and strength, and negatively correlated with the risk of fracture. Compared with muscle mass and strength, hsa-miR-499a-5p has better sensitivity and specificity as a diagnostic marker. CONCLUSION: hsa-miR-499a-5p is a potential serum biomarker for assessing muscle function and predicting fall or fracture risk in the ODS population.

Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury.

The Class-I histone deacetylases (HDACs) mediate microglial inflammation and neurological dysfunction after traumatic brain injury (TBI). However, whether the individual Class-I HDACs play an indispensable role in TBI pathogenesis remains elusive. HDAC2 has been shown to upregulate pro-inflammatory genes in myeloid cells under brain injuries such as intracerebral hemorrhage, thereby worsening outcomes. Thus, we hypothesized that HDAC2 drives microglia toward a pro-inflammatory neurotoxic phenotype in a murine model of controlled cortical impact (CCI). Our results revealed that HDAC2 expression was highly induced in CD16/CD32+ pro-inflammatory microglia 3 and 7d after TBI. Surprisingly, microglia-targeted HDAC2 knockout (HDAC2 miKO) mice failed to demonstrate a beneficial phenotype after CCI/TBI compared to their wild-type (WT) littermates. HDAC2 miKO mice exhibited comparable levels of grey and white matter injury, efferocytosis, and sensorimotor and cognitive deficits after CCI/TBI as WT mice. RNA sequencing of isolated microglia 3d after CCI/TBI indicated the elevation of a panel of pro-inflammatory cytokines/chemokines in HDAC2 miKO mice over WT mice, and flow cytometry showed further elevated brain infiltration of neutrophils and B cells in HDAC2 miKO mice. Together, this study does not support a detrimental role for HDAC2 in microglial responses after TBI and calls for investigation into alternative mechanisms.

Occurrence, characteristics, and factors influencing the atmospheric microplastics around Jiaozhou Bay, the Yellow Sea.

Atmospheric microplastics are attracting increasing attention as an emerging pollutant. However, research on its characteristics and influencing factors is insufficient. This study examines the characteristics and spatiotemporal distribution of atmospheric microplastics around Jiaozhou Bay, the Yellow Sea. The results showed that the dominant shapes of microplastic were fragments (61.9 %) and fibers (25.6 %), and the main types were polyethylene terephthalate (23.8 %), polyethylene (31.6 %) and cellulose (rayon, 34.9 %). The deposition rate of microplastic varied from 8.395 to 80.114 items·m-2·d-1, with a mean of 46.708 ± 21.316 items·m-2·d-1. The deposition rate was higher in the dry season than in the rainy season, indicating the influence of weather condition. The annual mass of atmospheric microplastics entering the bay was estimated to be 7.612 ± 3.474 tons. For the first time, this study reveals that atmospheric microplastics in Jiaozhou Bay change spatiotemporally due to monsoons, which pose a potential threat to marine ecosystems.

Targeted ablation of signal transducer and activator of transduction 1 alleviates inflammation by microglia/macrophages and promotes long-term recovery after ischemic stroke.

BACKGROUND: Brain microglia and macrophages (Mi/MΦ) can shift to a harmful or advantageous phenotype following an ischemic stroke. Identification of key molecules that regulate the transformation of resting Mi/MΦ could aid in the development of innovative therapies for ischemic stroke. The transcription factor signal transducer and activator of transduction 1 (STAT1) has been found to contribute to acute neuronal death (in the first 24 h) following ischemic stroke, but its effects on Mi/MΦ and influence on long-term stroke outcomes have yet to be determined. METHODS: We generated mice with tamoxifen-induced, Mi/MΦ-specific knockout (mKO) of STAT1 driven by Cx3cr1CreER. Expression of STAT1 was examined in the brain by flow cytometry and RNA sequencing after ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). The impact of STAT1 mKO on neuronal cell death, Mi/MΦ phenotype, and brain inflammation profiles were examined 3-5 days after MCAO. Neurological deficits and the integrity of gray and white matter were assessed for 5 weeks after MCAO by various neurobehavioral tests and immunohistochemistry. RESULTS: STAT1 was activated in Mi/MΦ at the subacute stage (3 days) after MCAO. Selective deletion of STAT1 in Mi/MΦ did not alter neuronal cell death or infarct size at 24 h after MCAO, but attenuated Mi/MΦ release of high mobility group box 1 and increased arginase 1-producing Mi/MΦ 3d after MCAO, suggesting boosted inflammation-resolving responses of Mi/MΦ. As a result, STAT1 mKO mice had mitigated brain inflammation at the subacute stage after MCAO and less white matter injury in the long term. Importantly, STAT1 mKO was sufficient to improve functional recovery for at least 5 weeks after MCAO in both male and female mice. CONCLUSIONS: Mi/MΦ-targeted STAT1 KO does not provide immediate neuroprotection but augments inflammation-resolving actions of Mi/MΦ, thereby facilitating long-term functional recovery after stroke. STAT1 is, therefore, a promising therapeutic target to harness beneficial Mi/MΦ responses and improve long-term outcomes after ischemic stroke.

Corrigendum: Loss of hepatic Surf4 depletes lipid droplets in the adrenal cortex but does not impair adrenal hormone production.

[This corrects the article DOI: 10.3389/fcvm.2021.764024.].

Stem cell-derived extracellular vesicles: A novel and potential remedy for primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is an essential cause of young female fertility loss. At present, there are many treatments for primary ovarian insufficiency, but due to the complexity of the pathogenesis of primary ovarian insufficiency, the efficacy still could not be satisfactory. Stem cell transplantation is a feasible intervention protocol for primary ovarian insufficiency. However, its wide application in the clinic is limited by some defects such as tumorigenic and controversial ethical issues. Stem cell-derived extracellular vesicles (EVs) represent an important mode of intercellular communication attracting increasing interest. It is well documented that stem cell-derived extracellular vesicles for primary ovarian insufficiency with exciting therapeutic effects. Studies have found that stem cell-derived extracellular vesicles could improve ovarian reserve, increase the growth of follicles, reduce follicle atresia, and restore hormone levels of FSH and E2. Its mechanisms include inhibiting ovarian granulosa cells (GCs) apoptosis, reactive oxygen species, and inflammatory response and promoting granulosa cells proliferation and angiogenesis. Thus, stem cell-derived extracellular vesicles are a promising and potential method for primary ovarian insufficiency patients. However, stem cell-derived extracellular vesicles are still a long way from clinical translation. This review will provide an overview of the role and the mechanisms of stem cell-derived extracellular vesicles in primary ovarian insufficiency, and further elaborate on the current challenges. It may suggest new directions for future research.

Microplastic load of benthic fauna in Jiaozhou Bay, China.

The prevalence of microplastic pollution in the ocean has caused widespread concern. Many studies have focused on the occurrence of microplastics in the marine environment and organisms, but the fate of microplastics in the ocean is still unclear, and the factors affecting the distribution of microplastics have not yet been consistently concluded. The aims of this study were to estimate the load of microplastics in benthic organisms as a temporary storage and to analyze the factors affecting microplastic ingestion by benthic organisms. For the purpose of this study, the benthic organisms in Jiaozhou Bay, China, were collected quarterly and were divided into the following six groups: polychaetes, mollusks, crustaceans, echinoderms, fish, and others. We concluded that the microplastic abundance in the benthos in Jiaozhou Bay was 1.00 ± 0.11 items/ind. (15.5 ± 3.5 items/g). The total load of microplastics in the benthic fauna in the bay with an area of 374 km2 was estimated to be 36.4 kg. On an individual basis, the fish contained significantly more microplastics than the other taxa. Furthermore, the characteristics of the microplastics in the benthic organisms were mainly fibrous, black, polyethylene, and <500 µm in size. In addition, the microplastic ingestion by benthic organisms was regulated by multiple factors, including biological characteristics and the environment. The masses of the organisms, the ambient seawater and sediment, and the spatial variations all influenced the microplastic ingestion by the organisms. The results of this study demonstrate that benthic organisms are an important storage for microplastics as they transferred through the ocean, and they provide an unbiased comparison of microplastic pollution among multiple organisms and the relevant pollution factors.

Quality of life in postmenopausal women with osteoporosis: a systematic review and meta-analysis.

PURPOSE: Postmenopausal osteoporosis has become a global trend, which seriously affects women's quality of life. However, the differences remain unclear in health-related quality of life (HRQoL) among postmenopausal women with normal bone mineral density, osteoporosis, and osteoporotic fractures. The aim of this study was to assess health-related quality of life in women with three different bone states. METHODS: Databases of PubMed, Embase, Cochrane, and Web of Science were based on the search terms, and the search time was set from the inception of each database to January 2022. A study was included if the researchers used a validated quality of life questionnaire to investigate the quality of life of postmenopausal women with osteoporosis or osteoporotic fractures. The random-effect model was used for meta-analysis, and the mean difference with a 95% confidence interval (95%CI) was calculated. RESULTS: Thirteen studies that met the inclusion criteria were systematically reviewed, involving 2897 postmenopausal women, and 12 of them were included in the meta-analysis. Postmenopausal women with osteoporosis had worse overall HRQoL and different HRQoL dimensions compared with postmenopausal women with normal bone density. Compared with postmenopausal women with osteoporosis, postmenopausal women with osteoporotic fractures had worse overall HRQoL and individual dimensions of HRQoL, especially physical component summary (SMD = - 0.61, 95% CI, - 0.98 to - 0.24). Bone mineral density was positively associated with HRQoL, while fragility fracture severity was negatively associated with HRQoL. CONCLUSIONS: Postmenopausal osteoporosis and fragility fractures reduce HRQoL to varying degrees in women. More research should be done to reduce the incidence of the disease.

The effects of ß-carotene on osteoporosis: a systematic review and meta-analysis of observational studies.

PURPOSE: The aim is to evaluate the effect of ß-carotene for osteoporosis and provide quantitative evidence. METHOD: PubMed, Embase, Web of Science, and Cochrane Library were searched for eligible studies. Fifteen studies were included. Random-effect model was applied to pool the odds ratio (OR). The risk of osteoporosis and fracture were compared between low ß-carotene intake group and high ß-carotene intake group. RESULT: The intake of ß-carotene was unassociated with the overall risk of osteoporosis [OR = 0.733, 95% Cl (0.528, 1.018), p = 0.064]. Subgroup analysis showed that the intake of ß-carotene was negatively associated with the risk of osteoporosis in both male subgroup [OR = 0.7, 95% Cl (0.549, 0.893), I2 = 40.40%, p = 0.004] and female subgroup [OR = 0.684, 95% Cl (0.487, 0.960), I2 = 86.40%, p = 0.028]. There was also a negative association between ß-carotene intake and osteoporosis in Asia subgroup [OR = 0.512, 95% Cl (0.403, 0.650), I2 = 0.00%, p = 0], whereas no association was observed in Western subgroup [OR = 1.107, 95% Cl (0.908, 1.350), I2 = 2.30%, p = 0.314]. In addition, random-effect model was adopted to pool the standard mean difference (SMD), and the results showed that ß-carotene intake was positively associated with overall bone mineral density (BMD) [SMD = - 0.213, 95% Cl (- 0.391, - 0.034), I2 = 87.30%, p = 0.019]. Subgroup analysis showed that ß-carotene intake was positively associated with BMD in Asian participants [SMD = - 0.394, 95% Cl (- 0.461, - 0.328), I2 = 0, p = 0], while unassociated in Western participants [SMD = - 0.047, 95% Cl (- 0.314, 0.219), I2 = 78.9%, p = 0.727]. CONCLUSION: ß-carotene may improve BMD and reduce the risk of osteoporosis and fracture. However, these effects could vary by gender and race and need to be further validated by longitudinal studies.

Prediction of osteoporosis and osteopenia by routine computed tomography of the lumbar spine in different regions of interest.

BACKGROUND: We aimed to investigate the utility of Hounsfield units (HU) obtained from different regions of interest in opportunistic lumbar computed tomography (CT) to predict osteoporosis coupling with data of dual-energy X-ray absorptiometry (DXA). METHODS: A total of 100 patients who attended a university hospital in Shanghai, China, and had undergone CT and DXA tests of the lumbar spine within 3 months were included in this retrospective review. Images were reviewed on axial sections, and regions of interest (ROI) markers were placed on the round, oval, anterior, left, and right of the L1-L4 vertebra to measure the HU. The mean values of CT HU were then compared to the bone mineral density (BMD) measured by DXA. Receiver operator characteristic curves were generated to determine the threshold for diagnosis and its sensitivity and specificity values. RESULTS: The differences in CT HU of different ROI based on DXA definitions of osteoporosis, osteopenia, and normal individuals were statistically significant (p < 0.01). The HU values of the different ROI correlated well with the BMD values (Spearman coefficient all > 0.75, p < 0.01). The threshold for diagnosing osteoporosis varies from 87 to 111 HU in different ROIs, and the threshold for excluding osteoporosis or osteopenia is 99-125 HU. CONCLUSION: This is the first study on osteoporosis diagnosis of different ROI with routine CT lumbar scans. There is a strong correlation between CT HU of different ROI in the lumbar spine and BMD, and HU measurements can be used to predict osteoporosis.

Microglia-specific deletion of histone deacetylase 3 promotes inflammation resolution, white matter integrity, and functional recovery in a mouse model of traumatic brain injury.

BACKGROUND: Histone deacetylases (HDACs) are believed to exacerbate traumatic brain injury (TBI) based on studies using pan-HDAC inhibitors. However, the HDAC isoform responsible for the detrimental effects and the cell types involved remain unknown, which may hinder the development of specific targeting strategies that boost therapeutic efficacy while minimizing side effects. Microglia are important mediators of post-TBI neuroinflammation and critically impact TBI outcome. HDAC3 was reported to be essential to the inflammatory program of in vitro cultured macrophages, but its role in microglia and in the post-TBI brain has not been investigated in vivo. METHODS: We generated HDAC3LoxP mice and crossed them with CX3CR1CreER mice, enabling in vivo conditional deletion of HDAC3. Microglia-specific HDAC3 knockout (HDAC3 miKO) was induced in CX3CR1CreER:HDAC3LoxP mice with 5 days of tamoxifen treatment followed by a 30-day development interval. The effects of HDAC3 miKO on microglial phenotype and neuroinflammation were examined 3-5 days after TBI induced by controlled cortical impact. Neurological deficits and the integrity of white matter were assessed for 6 weeks after TBI by neurobehavioral tests, immunohistochemistry, electron microscopy, and electrophysiology. RESULTS: HDAC3 miKO mice harbored specific deletion of HDAC3 in microglia but not in peripheral monocytes. HDAC3 miKO reduced the number of microglia by 26%, but did not alter the inflammation level in the homeostatic brain. After TBI, proinflammatory microglial responses and brain inflammation were markedly alleviated by HDAC3 miKO, whereas the infiltration of blood immune cells was unchanged, suggesting a primary effect of HDAC3 miKO on modulating microglial phenotype. Importantly, HDAC3 miKO was sufficient to facilitate functional recovery for 6 weeks after TBI. TBI-induced injury to axons and myelin was ameliorated, and signal conduction by white matter fiber tracts was significantly enhanced in HDAC3 miKO mice. CONCLUSION: Using a novel microglia-specific conditional knockout mouse model, we delineated for the first time the role of microglial HDAC3 after TBI in vivo. HDAC3 miKO not only reduced proinflammatory microglial responses, but also elicited long-lasting improvement of white matter integrity and functional recovery after TBI. Microglial HDAC3 is therefore a promising therapeutic target to improve long-term outcomes after TBI.

Comparative Analysis of Bacillariophyceae Chloroplast Genomes Uncovers Extensive Genome Rearrangements Associated with Speciation.

The Bacillariophyceae is a species-rich, ecologically significant class of Bacillariophyta. Despite their critical importance in marine ecosystems as primary producers and in the development of harmful algal blooms (HABs), taxonomic research on Bacillariophyceae species has been hindered because of their limited morphological features, plasticity of morphologies, and the low resolution of common molecular markers. Hence molecular markers with improved resolution are urgently needed. Organelle genomes, which can be constructed efficiently with the recent development of high throughput DNA sequencing technologies and the advancement of bioinformatics tools, have been proposed as super barcodes for their higher resolution for distinguishing different species and intra-species genomic variations. In this study, we tested the value of full-length chloroplast genomes (cpDNAs) as super barcodes for distinguishing diatom species, by constructing cpDNAs of 11 strains of the class Bacillariophyceae, including Nitzschia ovalis, Nitzschia traheaformis, Cylindrotheca spp., Psammodictyon constrictum, Bacillaria paxillifer, two strains of Haslea tsukamotoi, Haslea avium, Navicula arenaria, and Pleurosigma sp. Comparative analysis of cpDNAs revealed that cpDNAs were not only adequate for resolving different species, but also for enabling recognition of high levels of genome rearrangements between cpDNAs of different species, especially for species of the genera Nitzschia, Cylindrotheca, Navicula and Haslea. Additionally, comparative analysis suggested that the positioning of species in the genus Haslea should be transferred to the genus Navicula. Chloroplast genome-based evolutionary analysis suggested that the Bacillariophyceae species first appeared during the Cretaceous period and the diversity of species rose after the mass extinction about 65 Mya. This study highlighted the value of cpDNAs in research on the biodiversity and evolution of Bacillariophyceae species, and, with the construction of more cpDNAs representing additional genera, deeper insight into the biodiversity and evolutionary relationships of Bacillariophyceae species will be gained.

STAT1 contributes to microglial/macrophage inflammation and neurological dysfunction in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) triggers a plethora of inflammatory events in the brain that aggravate secondary injury and impede tissue repair. Resident microglia (Mi) and blood-borne infiltrating macrophages (MΦ) are major players of inflammatory responses in the post-TBI brain and possess high functional heterogeneity. However, the plasticity of these cells has yet to be exploited to develop therapies that can mitigate brain inflammation and improve the outcome after TBI. This study investigated the transcription factor STAT1 as a key determinant of proinflammatory Mi/MΦ responses and aimed to develop STAT1 as a novel therapeutic target for TBI using a controlled cortical impact model of TBI on adult male mice. TBI induced robust upregulation of STAT1 in the brain at the subacute injury stage, which occurred primarily in Mi/MΦ. Intraperitoneal administration of fludarabine, a selective STAT1 inhibitor, markedly alleviated proinflammatory Mi/MΦ responses and brain inflammation burden after TBI. Such phenotype-modulating effects of fludarabine on post-TBI Mi/MΦ were reproduced by tamoxifen-induced, selective knockout of STAT1 in Mi/MΦ (STAT1 mKO). By propelling Mi/MΦ away from a detrimental proinflammatory phenotype, STAT1 mKO was sufficient to reduce long-term neurological deficits and brain lesion size after TBI. Importantly, short-term fludarabine treatment after TBI elicited long-lasting improvement of TBI outcomes, but this effect was lost on STAT1 mKO mice. Together, our study provided the first line of evidence that STAT1 causatively determines the proinflammatory phenotype of brain Mi/MΦ after TBI. We also showed promising preclinical data supporting the use of fludarabine as a novel immunomodulating therapy to TBI.SIGNIFICANCE STATEMENTThe functional phenotype of microglia and macrophages (Mi/MΦ) critically influences brain inflammation and the outcome after traumatic brain injury (TBI); however, no therapies have been developed to modulate Mi/MΦ functions to treat TBI. Here we report for the first time that the transcription factor STAT1 is a key mediator of proinflammatory Mi/MΦ responses in the post-TBI brain, the specific deletion of which ameliorates neuroinflammation and improves long-term functional recovery after TBI. We also show excellent efficacy of a selective STAT1 inhibitor fludarabine against TBI-induced functional deficits and brain injury using a mouse model, presenting STAT1 as a promising therapeutic target for TBI.