The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities.

Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy many mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA-based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.

Construction and validation of somatic mutation-derived long non-coding RNAs signatures of genomic instability to predict prognosis of hepatocellular carcinoma.

BACKGROUND: Long non-coding RNAs (LncRNAs) have been found to be a potential prognostic factor for cancers, including hepatocellular carcinoma (HCC). Some LncRNAs have been confirmed as potential indicators to quantify genomic instability (GI). Nevertheless, GI-LncRNAs remain largely unexplored. This study established a GI-derived LncRNA signature (GILncSig) that can predict the prognosis of HCC patients. AIM: To establish a GILncSig that can predict the prognosis of HCC patients. METHODS: Identification of GI-LncRNAs was conducted by combining LncRNA expression and somatic mutation profiles. The GI-LncRNAs were then analyzed for functional enrichment. The GILncSig was established in the training set by Cox regression analysis, and its predictive ability was verified in the testing set and TCGA set. In addition, we explored the effects of the GILncSig and TP53 on prognosis. RESULTS: A total of 88 GI-LncRNAs were found, and functional enrichment analysis showed that their functions were mainly involved in small molecule metabolism and GI. The GILncSig was constructed by 5 LncRNAs (miR210HG, AC016735.1, AC116351.1, AC010643.1, LUCAT1). In the training set, the prognosis of high-risk patients was significantly worse than that of low-risk patients, and similar results were verified in the testing set and TCGA set. Multivariate Cox regression analysis and stratified analysis confirmed that the GILncSig could be used as an independent prognostic factor. Receiver operating characteristic curve analysis of the GILncSig showed that the area under the curve (0.773) was higher than the two LncRNA signatures published recently. Furthermore, the GILncSig may have a better predictive performance than TP53 mutation status alone. CONCLUSION: We established a GILncSig that can predict the prognosis of HCC patients, which will help to guide prognostic evaluation and treatment decisions.

The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-ß1-induced fibrotic responses in renal fibroblasts and epithelial cells independent of Smad3 phosphorylation. Cellular uptake of Cf48 and its pro-fibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'-untranslated region of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis which operates as an RNA-binding peptide to promote the production of extracellular matrix.

Ill-fitting prosthesis is associated with an increased risk of elevated blood pressures.

OBJECTIVE: Previous studies focused on the benefits of adequate prosthodontic treatment, while few studies have investigated the prosthodontic-related risks to health. As a modifiable oral health indicator, the association of ill-fitting prosthesis (IFP) with hypertension has not been fully explored. METHODS: This cross-sectional study involved 158,659 adults in Beijing (2009-2017) receiving intra-oral examinations and blood pressure measurements. Logistic regression models were applied to assess the association of IFP with the prevalence of hypertension, systolic blood pressure (SBP) ≧ 140 mmHg and diastolic blood pressure (DBP) ≧ 90 mmHg, as well as subgroup analyses by different fixed IFP subgroups (according to involved teeth number) and removable IFP subgroup. We further investigated effect modifications among stratified populations. RESULTS: 158,659 individuals were included for analysis, 346 (26.86%) in IFP group and 27,380 (17.40%) in non-IFP group (p < 0.001) were hypertensive. After adjustment of sex, age, obesity, dyslipidaemia, diabetes, hsCRP, family history of CVD, self-reported smoking, self-reported drinking and WC, ORs of hypertension, SBP ≧ 140 mmHg and DBP ≧ 90 mmHg were 1.330 (95% CI: 1.162-1.522), 1.277 (95% CI: 1.098-1.486) and 1.376 (95% CI: 1.186-1.596), respectively (p < 0.05). Furthermore, after full adjustment, the number of involved teeth showed a significant incremental trend with hypertension risk in the population with and without IFP (p for trend <0.001). The IFP-blood pressure associations were more pronounced in females, 18-60 years, non-obese and diabetic participants. CONCLUSION: As a modifiable oral indicator, IFP was significantly associated with a higher risk of hypertension.

Rapidly enrichment and detection of per-and polyfluoroalkyl substances in foods using a novel bifunctional covalent organic framework.

Per- and polyfluoroalkyl substances (PFASs) are extensively found in foods, posing potential toxicity to humans. Therefore, rapid analysis and monitoring of PFASs in foods are crucial for public health and also a challenge. To detect trace PFASs in foods, construction of sorbents with multiple interactions could be an effective approach. Herein, a cationic-fluorinated covalent organic framework (CF-COF) was prepared by post-modification and used as a magnetic solid-phase extraction adsorbent for adsorption of PFASs. By combining magnetic solid-phase extraction based on CF-COF with liquid chromatography-tandem mass spectrometry (LC - MS/MS), a novel method was developed for determination of eight long-chain PFASs in foods. Under optimized conditions, the method exhibited low detection limits (0.003-0.019 ng/g) and satisfactory recovery rates (73.5-118%) for PFASs. This study introduces a novel idea for the development of adsorbents targeting PFASs, along with a new analytical method for monitoring of PFASs in foods.

Impact toughness and dynamic constitutive model of geopolymer concrete after water saturation.

The dynamic compression test of geopolymer concrete (GC) before and after water saturation was carried out by the split Hopkinson pressure bar (SHPB). And the effects of water saturation and strain rate on impact toughness of GC were studied. Based on Weibull statistical damage distribution theory, the dynamic constitutive model of GC after water saturation was constructed. The results show that the dynamic peak strain and specific energy absorption of GC have strain rate strengthening effect before or after water saturation. The impact toughness of GC decreases after water saturation. The size distribution of GC fragments has fractal characteristics, and the fractal dimension of GC fragments after water saturation is smaller than that before water saturation. The dynamic constitutive model based on Weibull statistical damage distribution theory can accurately describe the impact mechanical behavior of GC after water saturation, and the model fitting curves are in good agreement with the experimental stress-strain curves.

The effect of part-list cuing on associative recognition.

The modulation of part-list cuing on item memory has been well-documented, whereas its impact on associative memory remains largely unknown. The present study explored the effect of part-list cuing on associative recognition and, more specifically, whether this forgetting effect caused by part-list cuing is more sensitive to recollection or familiarity in recognition memory. Experiments 1a and 1b combined the intact/rearranged/new judgement task of associative recognition with the classical part-list cuing paradigm, and the result showed that part-list cuing impaired the recognition accuracy of "intact" and "rearranged" face-scene pairs. Moreover, the discriminability score of relational recognition and item recognition was significantly decreased in the part-list cuing condition compared to the no-part-list cuing condition. Experiments 2a and 2b further used the Remember/Know/Guess task to explore which recognition processes (recollection vs. familiarity) were sensitive to the presentation of part-list cuing. The results showed that part-list cuing reduced the familiarity of relational recognition and the recollection and familiarity of item recognition. These findings suggest that part-list cuing was harmful to the recognition of relationships (familiarity) and items (recollection and familiarity) in associative memory.

Lactobacillus acidophilus and its metabolite ursodeoxycholic acid ameliorate ulcerative colitis by promoting Treg differentiation and inhibiting M1 macrophage polarization.

Lactobacillus acidophilus (LA) is a common clinical probiotic that improves ulcerative colitis (UC) by restoring intestinal immune balance. However, the interaction of LA with the gut microbiota and its metabolites in the treatment of UC remains unknown. Therefore, this study seeks to elucidate whether the gut microbiota and its metabolites act as pivotal effectors in LA's therapeutic mechanisms and how precisely they modulate intestinal immunity. In this study, we verified that LA can obviously ameliorate the disease severity, and regulate intestinal immune disorders in UC mice. Subsequently, antibiotic (ABX)-mediated depletion of the gut microflora demonstrated that the therapeutic efficiency of LA was closely associated with gut microbiota. In addition, the results of metabolomics revealed that ursodeoxycholic acid (UDCA), a metabolite of intestinal flora, may be a potential effector molecule mediating therapeutic effects of LA. Indeed, we found that UDCA can improve the macro pathological characteristics of UC mice, and through a comprehensive set of in vivo and in vitro experiments, we discovered that UDCA exerts dual effects on immune regulation. Firstly, it promotes the differentiation of Treg cells, resulting in increased secretion of anti-inflammatory cytokines. Secondly, UDCA inhibits the polarization of M1 macrophages, effectively reducing the secretion of pro-inflammatory cytokines. Moreover, we found that UDCA regulation of immune response is directly related to the RapGap/PI3K-AKT/NF-κB signaling pathway. In conclusion, LA and its metabolite, UDCA, may treat UC by activating the RapGap/PI3K-AKT/NF-κB signaling pathway and modulating Treg cells and M1 macrophages. All in all, our findings highlight the potential of microbial metabolites in enhancing probiotic for UC treatment.

Sustainable inflammatory activation following spinal cord injury is driven by thrombin-mediated dynamic expression of astrocytic chemokines.

Acute spinal cord injury (SCI) always results in sustainable recruitment of inflammatory cells driven by sequentially generated chemokines, thereby eliciting excessive neuroinflammation. However, the underlying mechanism of temporally produced chemokines remains elusive. Reactive astrocytes are known to be the main sources of chemokines at the lesion site, which can be immediately activated by thrombin following SCI. In the present study, SCI was shown to induce a sequential production of chemokines CCL2 and CCL5 from astrocytes, which were associated with a persistent infiltration of macrophages/microglia. The rapidly induced CCL2 and later induced CCL5 from astrocytes were regulated by thrombin at the damaged tissues. Investigation of the regulatory mechanism revealed that thrombin facilitated astrocytic CCL2 production through activation of ERK/JNK/NFκB pathway, whereas promoted CCL5 production through PLCß3/NFκB and ERK/JNK/NFκB signal pathway. Inhibition of thrombin activity significantly decreased production of astrocytic CCL2 and CCL5, and reduced the accumulation of macrophages/microglia at the lesion site. Accordingly, the locomotor function of rats was remarkably improved. The present study has provided a new regulatory mechanism on thrombin-mediated sequential production of astrocytic chemokines, which might be beneficial for clinical therapy of CNS neuroinflammation.

All-in-one strategy to construct bifunctional covalent triazine-based frameworks for simultaneous extraction of per- and polyfluoroalkyl substances and polychlorinated naphthalenes in foods.

Per- and polyfluoroalkyl substances (PFASs) and polychlorinated naphthalenes (PCNs) are of growing concern due to their toxic effects on the environment and human health. There is an urgent need for strategies to monitor and analyze the coexistence of PFASs and PCNs, especially in food samples at trace levels, to ensure food safety. Herein, a novel ß-cyclodextrin (ß-CD) derived fluoro-functionalized covalent triazine-based frameworks named CD-F-CTF was firstly synthesized. This innovative framework effectively combines the porous nature of the covalent organic framework and the host-guest recognition property of ß-CD enabling the simultaneous extraction of PFASs and PCNs. Under the optimal conditions, a simple and rapid method was developed to analyze PFASs and PCNs by solid-phase extraction (SPE) based simultaneous extraction and stepwise elution (SESE) strategy for the first time. When coupled with liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS), this method achieved impressive detection limits for PFASs (0.020 -0.023 ng/g) and PCNs (0.016 -0.075 ng/g). Furthermore, the excellent performance was validated in food samples with recoveries of 76.7-107 % (for PFASs) and 78.0-108 % (for PCNs). This work not only provides a simple and rapid technique for simultaneous monitoring of PFASs and PCNs in food and environmental samples, but also introduces a new idea for the designing novel adsorbents with multiple recognition sites.

Non­functional paraganglioma: A case report.

Paraganglioma (PGL) usually presents as the elevation of blood pressure and metabolic changes in patients, and its common symptoms are persistent or paroxysmal hypertension. However, some patients have no typical clinical symptoms, such as patients with non-functional PGL. Therefore, the present study reviewed the literature and summarized the present rare case to provide more accurate and in-depth help for clinical diagnosis and comprehensive treatment. The case was a 64-year-old female with epigastrium malaise for 1 year and aggravation for 7 days. Contrast-enhanced CT revealed that the soft tissue of the irregular mass was in the front of the kidney on the right abdomen with a clear boundary and the size was ~6.5x5.4x6.6 cm. Large vessels were observed in the interior and edge of the lesion. The present study prepared for retroperitoneal tumour resection according to the diagnosis of PGL. After the operation, the patient recovered smoothly and was discharged from the hospital. As of March 2023, the general condition of the patient is good.

The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities.

Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA- based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.

Extralobar pulmonary sequestration: A case report and literature review.

Pulmonary sequestration is a congenital malformation of lung development in which part of the lung tissue is separated from the normal lung during the embryonic phase and develops separately and receives blood supply from an aberrant systemic artery forming a nonrespiratory mass. In brief, early in embryonic development, certain tissues that should have atrophied and been gradually absorbed are left behind due to impairment of the atrophy process and form anomalous branches of the aorta, which pull parts of the lung tissue, isolating them from normal lung tissue and bronchi, and thus forming separate lung tissue. According to the relationship of the mass to the pleural covering, pulmonary sequestration can be divided into two types, intralobar pulmonary sequestration (ILS) and extralobar pulmonary sequestration (ELS), of which approximately 75% of cases are ILS, but ELS is less common. Symptoms are not obvious in either type, making diagnosis and differential diagnosis more difficult. Here we report a 33-year-old patient with only insignificant abdominal distension who was eventually diagnosed with retroperitoneal ELS.

Structural Analysis and Antioxidant and Immunoregulatory Activities of an Exopolysaccharide Isolated from Bifidobacterium longum subsp. longum XZ01.

Bifidobacterium longum subsp. longum XZ01 (BLSL1) is a new strain (isolated from the intestines of healthy people and deposited with the preservation number GDMCC 61618). An exopolysaccharide, S-EPS-1, was successfully isolated from the strain and then systematically investigated for the first time. Some structural features of S-EPS-1 were analyzed by chemical component, HPLC, ultraviolet, infrared, and nuclear magnetic resonance spectrum analyses. These analyses revealed that S-EPS-1 is a neutral heteropolysaccharide with an α-configuration. It contains mainly mannose and glucose, as well as small amounts of rhamnose and galactose. The molecular weight of S-EPS-1 was calculated to be 638 kDa. Several immunoregulatory activity assays indicated that S-EPS-1 could increase proliferation, phagocytosis, and NO production in vitro. In addition, S-EPS-1 could upregulate the expression of cytokines at the mRNA level through TLR4-mediated activation of the NF-κB signaling pathway in RAW 264.7 cells. Finally, S-EPS-1 was demonstrated to exhibit antioxidant activity by ABTS+• scavenging, DPPH• scavenging, and ferric-ion reducing power assays. Furthermore, S-EPS-1 can protect cells from oxidative stress and shows no cytotoxicity. These beneficial effects can be partly attributed to its antioxidant ability. Thus, the antioxidant S-EPS-1 may be applied as a functional food in the future.

Association between questionnaire-based and accelerometer-based physical activity and the incidence of chronic kidney disease using data from UK Biobank: a prospective cohort study.

Background: Prior studies on the relationship between chronic kidney disease (CKD) and physical activity (PA) mainly relied on subjective PA data and rarely considered the genetic risk. This study aims to thoroughly investigate this relationship by utilizing both accelerometer-measured and questionnaire-measured PA data. Methods: This prospective cohort study encompasses two cohorts from the UK Biobank. The questionnaire-based cohort involves 448,444 CKD-free participants who completed an International Physical Activity Questionnaire between 2006 and 2010 and had genetic data. PA was categorized into distinct activities: leisure, housework, job-related, and transportation. The accelerometer-based cohort involves 89,296 CKD-free participants who provided a full week of accelerometer-based physical activity data between 2013 and 2015 and had genetic data. PA was classified as light-intensity, moderate-intensity, vigorous-intensity, moderate to vigorous-intensity PA (LPA, MPA, VPA, MVPA), and total PA. Incident CKD was ascertained from linked hospital inpatient and death records. Genetic risk was assessed using polygenic risk scores. Cox proportional hazard models with restricted cubic splines were used for the analysis. Findings: In the questionnaire-based cohort, 18,184 (4.05%) participants developed CKD during 13.6 years of follow-up. Engaging in strenuous sports, other exercises, walking for pleasure, stair climbing, and heavy DIY were associated with a reduced risk of CKD. In the accelerometer-based cohort, 2297 (2.57%) participants developed CKD during 7.9 years of follow-up. Higher levels [highest quartile vs lowest quartile] of MPA (HR 0.639, 95% CI 0.554-0.737), VPA (HR 0.639, 95% CI 0.549-0.745), MVPA (HR 0.630, 95% CI 0.545-0.729), and total PA (HR 0.649, 95% CI 0.563-0.750) were associated with a lower CKD risk. There were significant interactions between MPA and genetic risk on the risk of CKD incidence (P for interaction = 0.025). A linear dose-response relationship was observed between MPA, total PA, and the risk of CKD incidence with no minimal or maximal threshold. These associations are robust in different subgroups and a series of sensitivity analyses. Interpretation: Engaging in multiple types of PA and higher levels of total PA, MPA, VPA, and MVPA may be associated with a lower risk of developing CKD, regardless of genetic risk. This finding holds substantial implications for clinical approaches to CKD prevention and provides evidence to inform future PA guideline development. Funding: Medical Science Advancement Program of Wuhan University, and the National Science Foundation of China.

Advanced porous organic materials for sample preparation in pharmaceutical analysis.

The development of novel sample preparation media plays a crucial role in pharmaceutical analysis. To facilitate the extraction and enrichment of pharmaceutical molecules in complex samples, various functionalized materials have been developed and prepared as adsorbents. Recently, some functionalized porous organic materials have become adsorbents for pharmaceutical analysis due to their unique properties of adsorption and recognition. These advanced porous organic materials, combined with consequent analytical techniques, have been successfully used for pharmaceutical analysis in complex samples such as environmental and biological samples. This review encapsulates the progress of advanced porous materials for pharmaceutical analysis including pesticides, antibiotics, chiral drugs, and other compounds in the past decade. In addition, we also address the limitations and future trends of these porous organic materials in pharmaceutical analysis.

Omega-3 Polyunsaturated Fatty Acids Alleviate Intestinal Barrier Dysfunction in Obstructive Jaundice Rats.

Obstructive jaundice (OJ) can cause multiple pathophysiological consequences including intestinal barrier dysfunction. Omega-3 has been indicated to have a promising therapeutic effect on OJ. This study aimed to further investigate the functions of omega-3 on OJ-induced intestinal injury. A rat OJ model was established by bile duct ligation with or without omega-3 administration. ELISA was utilized for measuring serum levels of inflammatory cytokines. Hematoxylin-eosin staining and TUNEL staining were employed for detecting the morphological changes and cell apoptosis in rat intestine. Western blotting was utilized for evaluating expression of tight junction proteins in the intestinal tissues. Omgea-3 offset the reduction in body weight of OJ rats. Omega-3 alleviated inflammatory response, pathological damages and cell apoptosis in the intestine of OJ rats. Additionally, omega-3 enhanced levels of tight junction proteins in the intestinal tissues of OJ rats. Omega-3 ameliorates OJ-triggered impairment of intestinal barrier function in rats.

Gcc1 homologs regulate growth, oxidative stress, conidiation and appressorium formation in Colletotrichum siamense and Colletotrichum graminicola.

The Zn2Cys6 transcription factor is a fungal-specific zinc finger protein, which plays an important role in regulating growth, development and pathogenicity of pathogenic fungi. In this study, we characterized two Zn2Cys6 transcription factors, CsGcc1 and CgrGcc1 in Colletotrichum siamense and C. graminicola, respectively, which are homologous to Gcc1 in Magnaporthe oryzae. Both CsGcc1 and CgrGcc1 contain a typical GAL4 DNA-binding domain. Deletion of CsGCC1 or CgrGCC1 decreased the growth rate and lowered the tolerance to H2O2. In addition, disrupting CsGCC1 reduced conidial yield and lowered the germination rate and appressorium formation rate of C. siamense. Cellophane assays showed that deletion of CsGCC1 also weakened the penetration ability of appressoria. In C. graminicola, CgrGcc1 did not affect the production and germination of oval conidia, but its deletion significantly decreased the yield of the falcate conidium, and led to abnormal appressorium formation. In terms of pathogenicity, CsGcc1 slightly reduced the virulence of C. siamense, while deleting CgrGcc1 did not affect virulence of C. graminicola. In conclusion, the Zn2Cys6 transcription factors CsGcc1 and CgrGcc1 are involved in the regulation of vegetative growth, oxidative stress, conidial/falcate conidial production and appressorium formation in C. siamense and C. graminicola.

Case report: High-frequency repetitive transcranial magnetic stimulation for treatment of hereditary spastic paraplegia type 11.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders that currently have no cure. HSP type 11 (SPG11-HSP) is a complex form carrying mutations in the SPG11 gene. Neuropathological studies demonstrate that motor deficits in these patients are mainly attributed to axonal degeneration of the corticospinal tract (CST). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that can induce central nervous system plasticity and promote neurological recovery by modulating the excitability of cortical neuronal cells. Although rTMS is expected to be a therapeutic tool for neurodegenerative diseases, no previous studies have applied rTMS to treat motor symptoms in SPG11-HSP. Here, we report a case of SPG11-HSP with lower extremity spasticity and gait instability, which were improved by applying high-frequency rTMS (HF-rTMS) at the primary motor cortex (M1). Clinical and physiological features were measured throughout the treatment, including the Modified Ashworth Scale (MAS), Berg Balance Scale (BBS), the timed up and go (TUG) test and the 10-meter walk test time (10 MWT). The structure and excitability of the CST were assessed by diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS), respectively. After treatment, the patient gained 17 points of BBS, along with a gradual decrease in MAS scores of the bilateral lower extremity. In addition, the TUG test and 10 MWT improved to varying degrees. TMS assessment showed increased motor evoked potential (MEP) amplitude, decreased resting motor threshold (RMT), decreased central motor conduction time (CMCT), and decreased difference in the cortical silent period (CSP) between bilateral hemispheres. Using the DTI technique, we observed increased fractional anisotropy (FA) values and decreased mean diffusivity (MD) and radial diffusivity (RD) values in the CST. It suggests that applying HF-rTMS over the bilateral leg area of M1 (M1-LEG) is beneficial for SPG11-HSP. In this study, we demonstrate the potential of rTMS to promote neurological recovery from both functional and structural perspectives. It may provide a clinical rationale for using rTMS in the rehabilitation of HSP patients.

HIF-1α promotes astrocytic production of macrophage migration inhibitory factor following spinal cord injury.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is an important mediator of neuropathology in various central nervous system (CNS) diseases. However, little is known about its inducers for production from the nerve cells, as well as the underlying regulatory mechanism. Injury-induced HIF-1α has been shown to exacerbate neuroinflammation by activating multiple downstream target molecules. It is postulated that HIF-1α is involved in the regulation of MIF following spinal cord injury (SCI). METHODS: SCI model of Sprague-Dawley rats was established by cord contusion at T8-T10. The dynamic changes of HIF-1α and MIF protein levels at lesion site of rat spinal cord were determined by Western blot. The specific cell types of HIF-1α and MIF expression were examined by immunostaining. Primary astrocytes were isolated from the spinal cord, cultured and stimulated with various agonist or inhibitor of HIF-1α for analysis of HIF-1α-mediated expression of MIF. Luciferase report assay was used to determine the relationship between HIF-1α and MIF. The Basso, Beattie, and Bresnahan (BBB) locomotor scale was used to assess the locomotor function following SCI. RESULTS: The protein levels of HIF-1α and MIF at lesion site were significantly elevated by SCI. Immunofluorescence demonstrated that both HIF-1α and MIF were abundantly expressed in the astrocytes of the spinal cord. By using various agonists or inhibitors of HIF-1α, it was shown that HIF-1α sufficiently induced astrocytic production of MIF. Mechanistically, HIF-1α promoted MIF expression through interaction with MIF promoter. Inhibition of HIF-1α activity using specific inhibitor markedly reduced the protein levels of MIF at lesion site following SCI, which in turn favored for the functional recovery. CONCLUSION: SCI-induced activation of HIF-1α is able to promote MIF production from astrocytes. Our results have provided new clues for SCI-induced production of DAMPs, which may be helpful for clinical treatment of neuroinflammation.