Pathogenic PSAT1 Variants and Autosomal Recessive Axonal Charcot-Marie-Tooth Disease With Ichthyosis.

BACKGROUND: Biallelic pathogenic phosphoserine aminotransferase 1 (PSAT1) variants generally cause a severe phenotype predominantly involving the central nervous system. Here, for the first time, we report two patients harboring pathogenic PSAT1 variants only manifested as polyneuropathy and ichthyosis. METHODS: Two patients from unrelated families presenting with polyneuropathy and ichthyosis were enrolled. Whole exome sequencing was performed to identify possible disease-causing variants. Their clinical, electrophysiological, imaging, biochemical, and pathologic changes were in detail assessed and investigated. RESULTS: Homozygous variant c.43G>C and compound heterozygous variants c.112A>C and c.43G>C in PSAT1 were identified in patients 1 and 2, respectively. Nerve conduction studies revealed preserved or mild slowing motor nerve conduction velocities of the median nerves in the two patients, whereas the compound motor action potential in patient 1 was severely decreased. Brain magnetic resonance imaging of the two patients found no abnormalities. Median nerve enlargement was observed on ultrasound in patient 1. Both patients had normal level of serine and glycine in plasma and cerebrospinal fluid. Sural nerve biopsy found severe loss of myelinated fibers. Electron microscopy revealed neurofilament accumulation and mitochondrial aggregation in axons. Both variants in PSAT1 were classified as likely pathogenic or pathogenic variants according to the standard guidelines. CONCLUSIONS: Our study confirms that pathogenic PSAT1 variants can cause a mild phenotype, predominantly as autosomal recessive axonal Charcot-Marie-Tooth disease.

Co-existence and interrelationship between intracranial artery stenosis and extracranial carotid atherosclerosis in an asymptomatic rural population of 13 villages in northern China.

OBJECTIVE: We investigated the characteristics and relationship of co-existing intracranial artery stenosis (ICAS) and extracranial carotid atherosclerosis in an asymptomatic rural population in northern China. METHODS: Asymptomatic residents ≥ 30 years old in 13 villages underwent simultaneous cervical vascular and transcranial Doppler ultrasound. ICAS was defined as ≥ 50% stenosis. Extracranial carotid atherosclerosis severity was classified as increased intimal medial thickness (IMT), plaques, and a plaque with ≥ 50% extracranial artery stenosis (ECAS). Demographic details, medical history, and blood biochemistry results were collected. The relationship between ICAS and extracranial carotid atherosclerosis severity was determined using the chi-square trend test and binary logistic regression analysis. RESULTS: A total of 2598 asymptomatic participants were included; 122 (4.7%) had ICAS, 1071 (41.2%) had extracranial carotid atherosclerosis, and 84 (3.2%) had co-existing extracranial carotid atherosclerosis and ICAS. Those with co-existing ICAS and extracranial carotid atherosclerosis were older (P = 0.006) and had a higher hypertension (HTN) and diabetes mellitus (DM) prevalence (P < 0.001). HTN (95% confidence interval [CI]=1.31-3.55, odds ratio [OR]=2.15) and DM (95% CI=1.17-4.30, OR=2.24) were found to be independent risk factors for asymptomatic ICAS with extracranial carotid atherosclerosis. Among those with ICAS, 38/122 had no extracranial carotid atherosclerosis, 8/122 had increased IMT, 64/122 had a plaque, and 12/122 had ECAS. As extracranial carotid atherosclerosis severity increases, ICAS prevalence increases. CONCLUSION: Co-existing ICAS and extracranial carotid atherosclerosis occurred in 3.2% of asymptomatic populations in rural areas of northern China. As extracranial carotid atherosclerosis severity increased, ICAS prevalence also increased. HTN and DM might be independent indicators of co-existing ICAS and extracranial carotid atherosclerosis.

Three-dimensional ultrasound imaging: An effective method to detect the effect of moderate intensity statin treatment in slowing carotid plaque progression.

PURPOSE: We aimed to evaluate the feasibility of three-dimensional ultrasound imaging (3DUS) in assessing the therapeutic effect of moderate-intensity statin therapy on carotid atherosclerotic plaques. METHODS: Patients with carotid plaques were recruited to the study from January 2016 to September 2018, and were divided into two groups based on whether or not they were taking statins. All participants underwent 3DUS of their carotid plaques at baseline, then 3 months and 2 years after initial examination. The changes of the carotid plaques were compared between the two groups. RESULTS: Were included 97 patients (57 males and 40 females), 65.26 ± 9.53 year-old with 67 into the statin group and 30 in the control group. The baseline levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were lower in the statin group than in the control group (3.79 ± 0.78 mmol/L vs 4.50 ± 1.12 mmol/L; 2.01 ± 0.62 mmol/L vs 2.58 ± 0.91 mmol/L, P < .05). There was no significant difference in the change of total plaque volume (TPV) detected by 3D-US between the statin (median [interquartile range]: 0 [-30-20] mm3 ) and the control group (0 [-22.5-25] mm3 ) at 3 months. Over 2 years, the TPV increased faster in the control group (+70 [25-150] mm3 ), than in the statin group (15 [-57.5-90) mm3 , P < .05). CONCLUSIONS: 3DUS can be an effective tool to observe the development of carotid plaques and the effect of statin treatment.

Pressure-induced phase transitions and structural evolution across the insulator-metal transition in bulk and nanoscale BiFeO3.

The pressure-induced phase-transition sequences and structural evolution across the insulator-metal transition (IMT) in multiferroic BiFeO3 still remain unclear. Here we use a combination of high-pressure XRD, XAFS experiment and first principle calculation to investigate the pressure-derived structural transformations and structure-related properties in bulk and nanoscale BiFeO3 up to 55 GPa. A new Imma structure of BiFeO3 has been discovered in the pressure range of 48-52 GPa, which presents ferromagnetic (FM) metallic properties and therefore plays a key role in the IMT. Local structure study reveals that the Bi3+ cation gradually shifts toward the centrosymmetric position in BiO12 cluster during IMT. Besides, the detailed structural information of post-perovskite Cmcm phase has also been determined and thus the complete phase sequence up to 60 GPa is obtained. Our research provides a structural origin of the IMT and a new way to understand the FM release in BiFeO3 system.

Ultrasonographic detection of chronic type A aortic dissection extending to the right extracranial internal carotid artery: A case report.

We report the case of a patient with chronic type A aortic dissection (AD), who had been admitted, 18 months ago, to another hospital with acute chest-tearing pain accompanied with transient loss of consciousness. His symptoms resolved but he reported after discharge a toothache and fluctuating right mandibular pain. He presented to our outpatient clinic because his facial pain aggravated. Physical examination demonstrated a bruit over the right carotid artery. Transthoracic echocardiography and carotid sonography demonstrated aortic dissection extending into the extracranial right internal carotid artery (ICA), which was tortuous. The patient refused surgery. This case reminds us that AD can involve the extracranial ICA, and that long-term survival is possible with type A acute AD without treatment. Carotid ultrasonography is noninvasive, inexpensive, easily performed, and can lead to the detection of chronic type A AD extending to the extracranial ICA.

The plant-specific transcription factors CBP60g and SARD1 are targeted by a Verticillium secretory protein VdSCP41 to modulate immunity.

The vascular pathogen Verticillium dahliae infects the roots of plants to cause Verticillium wilt. The molecular mechanisms underlying V. dahliae virulence and host resistance remain elusive. Here, we demonstrate that a secretory protein, VdSCP41, functions as an intracellular effector that promotes V. dahliae virulence. The Arabidopsis master immune regulators CBP60g and SARD1 and cotton GhCBP60b are targeted by VdSCP41. VdSCP41 binds the C-terminal portion of CBP60g to inhibit its transcription factor activity. Further analyses reveal a transcription activation domain within CBP60g that is required for VdSCP41 targeting. Mutations in both CBP60g and SARD1 compromise Arabidopsis resistance against V. dahliae and partially impair VdSCP41-mediated virulence. Moreover, virus-induced silencing of GhCBP60b compromises cotton resistance to V. dahliae. This work uncovers a virulence strategy in which the V. dahliae secretory protein VdSCP41 directly targets plant transcription factors to inhibit immunity, and reveals CBP60g, SARD1 and GhCBP60b as crucial components governing V. dahliae resistance.

Prevalence and risk factors of intracranial and extracranial artery stenosis in asymptomatic rural residents of 13 villages in China.

BACKGROUND: The present study aimed to investigate the prevalence and risk factors for extracranial carotid artery stenosis (ECAS) and intracranial carotid artery stenosis (ICAS) simultaneously in asymptomatic Chinese pure rural population. METHODS: We analyzed 2589 asymptomatic subjects aged over 30 yr. by ultrasonography and transcranial Doppler simultaneously in 13 isolated villages by door-to-door investigation. Both ECAS and ICAS were defined as more than 50% stenosis. Demographics, medical history documentation, and investigation of biochemical results were performed for each subject. Univariate and multivariate logistic regression analyses were employed to assess the risk factors associated with ECAS and ICAS, respectively. RESULTS: One hundred twenty-two (4.7%) residents with ICAS and 56 (2.2%) with ECAS were found in 2589 subjects. Three factors emerged as independent risk factors for ICAS: age (95% confidence interval [CI] = 1.01-1.04, odds ratio [OR] = 1.07), hypertension (95% CI = 1.98-4.37, OR = 2.94), and diabetes mellitus (95% CI = 1.72-4.38, OR = 2.75). As for ECAS, five factors presented as independent risk factors: age (95% CI = 1.09-1.11, OR = 1.10), male sex (95% CI = 1.01-1.02, OR = 1.01), diabetes mellitus (95% CI = 1.10-2.12, OR = 1.53), systolic blood pressure (95% CI = 1.95-2.88, OR = 2.37), and total cholesterol (95% CI = 1.00-1.13, OR = 1.06). CONCLUSIONS: ICAS and ECAS were relatively common among asymptomatic rural Chinese subjects. Although they shared similar risk factors, differences still existed between them.

An Improved Single-Step Cloning Strategy Simplifies the Agrobacterium tumefaciens-Mediated Transformation (ATMT)-Based Gene-Disruption Method for Verticillium dahliae.

The soilborne fungal pathogen Verticillium dahliae infects a broad range of plant species to cause severe diseases. The availability of Verticillium genome sequences has provided opportunities for large-scale investigations of individual gene function in Verticillium strains using Agrobacterium tumefaciens-mediated transformation (ATMT)-based gene-disruption strategies. Traditional ATMT vectors require multiple cloning steps and elaborate characterization procedures to achieve successful gene replacement; thus, these vectors are not suitable for high-throughput ATMT-based gene deletion. Several advancements have been made that either involve simplification of the steps required for gene-deletion vector construction or increase the efficiency of the technique for rapid recombinant characterization. However, an ATMT binary vector that is both simple and efficient is still lacking. Here, we generated a USER-ATMT dual-selection (DS) binary vector, which combines both the advantages of the USER single-step cloning technique and the efficiency of the herpes simplex virus thymidine kinase negative-selection marker. Highly efficient deletion of three different genes in V. dahliae using the USER-ATMT-DS vector enabled verification that this newly-generated vector not only facilitates the cloning process but also simplifies the subsequent identification of fungal homologous recombinants. The results suggest that the USER-ATMT-DS vector is applicable for efficient gene deletion and suitable for large-scale gene deletion in V. dahliae.

Associations among cerebral microbleeds, cerebral large-artery diseases and endothelial function.

BACKGROUND: Endothelial dysfunction is not only an early stage of atherosclerosis, but also involved in the pathogenesis of cerebral small-vessel diseases. Patients with cerebral microbleeds (CMBs) may have arteriolosclerosis as well as systemic atherosclerosis. However, little is known about the associations among CMBs, atherosclerosis of cerebral large arteries, and endothelial function. Our study aimed to investigate the relationships among them. METHODS: This was a cross-sectional study. Ninety patients hospitalized in Peking University First Hospital with acute ischemic stroke were enrolled consecutively between November 1, 2007 and January 31, 2008. All subjects underwent transcranial Doppler and carotid color duplex ultrasonography to record the intima-media thickness (IMT) of common carotid artery, carotid plaque, and cerebral artery stenosis. Brain magnetic resonance imaging (MRI) routine sequences and gradient recall-echo T2(*)-weighted imaging were performed to count CMBs with clinical data blindness. Endothelial function was evaluated using flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of the brachial artery. FMD and NMD were examined by an experienced vascular sonographer using a high-resolution ultrasound. RESULTS: Thirty cases (33.3%) had CMBs with counts ranging from 1 to 30. Both FMD ((9.9 ± 4.8)% vs. (15. 2 ± 7.4)%, P = 0.001) and NMD ((13.7 ± 6.1)% vs. (19.0 ± 7.4)%, P = 0.001) were significantly decreased in CMB-positive patients than in CMB-negative patients. No significant relationships were demonstrated between CMBs and intracranial and/or extracranial artery stenosis. The frequencies of CMBs in patients with IMT≥1.0 mm, carotid plaque, and extracranial artery stenosis were 37.5%, 39.4%, and 47.6% respectively, with no significant difference, but much higher than in patients with IMT <1.0 mm (5%, P < 0.05). In Logistic regression analysis, impaired FMD (OR = 5.783, 95% CI 1.652-6.718, P = 0.007) and high pulse pressure (OR = 6.228, 95% CI 1.594-3.891, P = 0.009) were independently associated with the presence of CMBs, as well as previous ischemic stroke. In contrast, NMD was not correlated with CMBs. CONCLUSIONS: CMBs may coexist with cerebral atherosclerosis in ischemic stroke. Endothelial dysfunction may play a role in the pathogenesis of CMBs, but may not simply reflect functional alterations of large arteries.

Ultrasound-triggered thrombolysis using urokinase-loaded nanogels.

To find a way to modulate the effect of thrombolytic proteins by increasing their specificity, minimizing their adverse effect as well as lengthening their circulation time for the treatment of ischemic vascular disease holds great promise. In this work, urokinase-type plasminogen activator (uPA) was encapsulated into hollow nanogels which are generated by the reaction of glycol chitosan and aldehyde capped poly(ethylene glycol) (OHC-PEG-CHO) through a one-step approach of ultrasonic spray. The uPA-loaded nanogels, with size of 200-300 nm, have longer circulation time than that of the nude urokinase in vivo, besides the protein can be triggered to release in faster rate under diagnostic ultrasonic condition of 2 MHz, which significantly enhanced the thrombolysis of clots. The results are promising for increasing the specificity and positive effects of thrombolytic agents like recombinant tissue plasminogen activator (rt-PA) for the current treatment of ischemic vascular disease.

[Incidence and prognosis of intra-and extracranial large-artery stenosis in the rural community of Beijing].

OBJECTIVE: To assess the prevalence rates of intra- and extracranial large-artery stenosis in the rural community population and its related risk to the development of stroke. METHODS: The study subjects included 1337 residents in the rural community of Beijing. Transcranial Doppler was carried our to examine the relation between intra- and extracranial large-artery stenosis and subsequent cerebrovascular events, with a mean follow-up period of 16.7 months. RESULTS: The incidence densities of cerebral infarction and cerebral hemorrhage in persons without cerebral large-artery stenosis were 410.6 and 351.9/100-thousand person-years, respectively. In the group with large-artery stenosis, the incidence density of cerebral infarction was 3303.7/100-thousand person-years. Data from The Fisher's Exact test showed a significant difference in the two groups (P = 0.004). Cerebral large-artery stenosis (OR = 6.593, 95%CI: 1.712 - 25.390) and smoking (OR = 8.437, 95%CI: 2.327 - 30.598) appeared to be independent risk factors to cerebral infarction. CONCLUSION: Cerebral large-artery stenosis and smoking were independent risk factors to cerebral infarction.