Complete Biosynthetic Pathway of the Phosphonate Phosphonothrixin: Two Distinct Thiamine Diphosphate-Dependent Enzymes Divide the Work to Form a C-C Bond.

Phosphonates often exhibit biological activities by mimicking the phosphates and carboxylates of biological molecules. The phosphonate phosphonothrixin (PTX), produced by the soil-dwelling bacterium Saccharothrix sp. ST-888, exhibits herbicidal activity. In this study, we propose a complete biosynthetic pathway for PTX by reconstituting its biosynthesis in vitro. Our intensive analysis demonstrated that two dehydrogenases together reduce phosphonopyruvate (PnPy) to 2-hydroxy-3-phosphonopropanoic acid (HPPA) to accelerate the thermodynamically unfavorable rearrangement of phosphoenolpyruvate (PEP) to PnPy. The next four enzymes convert HPPA to (3-hydroxy-2-oxopropyl)phosphonic acid (HOPA). In the final stage of PTX biosynthesis, the "split-gene" transketolase homologue, PtxB5/6, catalyzes the transfer of a two-carbon unit attached to the thiamine diphosphate (TPP) cofactor (provided by the acetohydroxyacid synthase homologue, PtxB7) to HOPA to produce PTX. This study reveals a unique C-C bond formation in which two distinct TPP-dependent enzymes, PtxB5/6 and PtxB7, divide the work to transfer an acetyl group, highlighting an unprecedented biosynthetic strategy for natural products.

HMS1 interacts with HMS1I to regulate very-long-chain fatty acid biosynthesis and the humidity-sensitive genic male sterility in rice (Oryza sativa).

Environment-sensitive genic male sterility (EGMS) lines are used widely in two-line hybrid breeding in rice (Oryza sativa). At present, photoperiod-sensitive genic male sterility (PGMS) lines and thermo-sensitive genic male sterility (TGMS) lines are predominantly used in two-line hybrid rice, with humidity-sensitive genic male sterility (HGMS) lines rarely being reported. Here, it is shown that HUMIDITY-SENSITIVE GENIC MALE STERILITY 1 (HMS1), encoding a ß-ketoacyl-CoA synthase, plays key roles in the biosynthesis of very-long-chain fatty acids (VLCFAs) and HGMS in rice. The hms1 mutant displayed decreased seed setting under low humidity, but normal seed setting under high humidity. HMS1 catalyzed the biosynthesis of the C26 and C28 VLCFAs, contributing to the formation of bacula and tryphine in the pollen wall, which protect the pollen from dehydration. Under low-humidity conditions, hms1 pollen showed poor adhesion and reduced germination on the stigmas, which could be rescued by increasing humidity. HMS1-INTERACTING PROTEIN (HMS1I) interacted with HMS1 to coregulate HGMS. Furthermore, both japonica and indica rice varieties with defective HMS1 exhibited HGMS, suggesting that hms1 potentially could be used in hybrid breeding. The results herein reveal the novel mechanism of VLCFA-mediated pollen wall formation, which protects pollen from low-humidity stress in rice, and has a potential use in hybrid crop breeding.

Ipsilateral Ptosis and Contralateral Ataxic Hemiparesis as Initial Symptoms of Combined Tuberothalamic and Paramedian Artery Infarction.

Thalamic infarcts, accounting for approximately 14% of lacunar infarcts, exhibit varied clinical manifestations due to complex anatomy of nuclei and varying blood supply. Pure and combined types of thalamic infarctions have been summarized in some paper, but information of cerebral angiography was not mentioned. Here we report a rare case of combined tuberothalamic and paramedian artery occlusion presenting with ipsilateral ptosis and contralateral ataxic hemiparesis.

Weakness of Eye Closure with Central Facial Paralysis after Unilateral Hemispheric Stroke Predicts a Worse Outcome.

BACKGROUND: Upper facial dysfunction is not generally considered a feature of central facial paralysis after unilateral hemispheric stroke; however, weakness of eye closure (WEC) has been observed in some cases. We aimed to investigate the frequency and characteristics of WEC in unilateral stroke and its association with stroke prognosis. METHODS: Patients with unilateral stroke and central facial paralysis were prospectively recruited within 7 days of onset. Facial paralysis was evaluated via the fourth item in the National Institute of Health Stroke Scale (NIHSS-4) and the Japan Facial Score (JFS) on admission, and at days 7, 14, 21, and 30 after stroke. Eye closure strength was measured daily using an ergometer for 30 days after stroke. Primary outcome was assessed using the modified Rankin Scale (mRS) at 90 and 180 days. Univariate and multivariate analyses were performed to investigate risk factors of WEC. RESULTS: WEC was identified in 16 of 242 patients (6.6%). Baseline characteristics, stroke risk factors, and lesion volume were not significantly different between patients with and patients without WEC. Patients with WEC featured higher NIHSS-4 scores and lower JFS between admission and at 21 days after stroke. Severe central facial paralysis (odds ratio [OR] = 8.1, 95% confidence interval [CI] = 2.3-28.6, P = .001) and right hemispheric stroke (OR = 13.7, 95% CI = 3.7-51.2, P < .001) were potential predictors of WEC. At 180 days after stroke, patients with WEC demonstrated a lower rate of functional independence (mRS = 0-2: 37.5% versus 72.1%, P < .001). CONCLUSIONS: WEC, which predicts a worse functional outcome at 180 days after unilateral stroke, demonstrates an association with severe central facial paralysis and right hemispheric stroke.

Association between angiotensinogen T174M polymorphism and ischemic stroke: A meta-analysis.

BACKGROUND: Numerous studies have evaluated the association between the angiotensinogen (AGT) T174M polymorphism and ischemic stroke(IS) risk. However, the specific association is still controversial. MATERIALS AND METHODS: In order to explore this association more deeply, we performed a meta-analysis. All of the relevant studies were identified from PubMed, Embase, and Chinese National Knowledge Infrastructure database up to October 2014. Statistical analyses were conducted with STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. RESULTS: Six studies with 1290 cases and 1125 controls were included. No significant variation in IS risk was detected in any of the genetic models in the overall (MM vs. TT: OR = 1.64, 95% CI = 0.51-5.28; MT vs. TT: OR = 0.93, 95% CI = 0.66-1.31; dominant model: OR = 1.08, 95% CI = 0.69-1.72; recessive model: OR = 0.61,95% CI = 0.20-1.91). Taking into account the effect of ethnicity, further stratified analyses were performed. The results showed that AGT gene T174M polymorphism might be associated with IS risk in Asians (MM vs. TT: OR = 3.28, 95% CI = 1.79-6.02; recessive model: OR = 0.31, 95% CI = 0.17-0.57). CONCLUSION: In conclusion, the AGT T174M polymorphism may be a susceptible predictor of the risk of IS in Asians. Further, large and well-designed studies are needed to confirm this conclusion.

Substantial decline of organ preservation fluid contamination following adoption of ischemia-free liver transplantation: a post-hoc analysis.

INTRODUCTION: Preservation fluid (PF) contaminations are common in conventional liver transplantation (CLT) and presumably originate from organ or PF exposures to the external environment in a non-strict sterile manner. Such exposures and PF contamination may be avoided in ischaemia-free liver transplantation (IFLT) because of the strict sterile surgical procedures. In this study, the authors evaluated the impact of IFLT on organ PF contamination. METHODS: A post-hoc analysis using data from the first randomized controlled trial of IFLT was performed to compare the incidence, pathogenic spectrum of PF contamination, and incidence of early recipient infection between IFLT and CLT. Multivariable logistic regression was used to explore risk factors for PF contamination. RESULTS: Of the 68 cases recruited in the trial, 64 were included in this post-hoc analysis. The incidence of culture-positive PF was 9.4% (3/32) in the IFLT group versus 78.1% (25/32) in the CLT group ( P <0.001). Three microorganisms were isolated from PF in the IFLT group, while 43 were isolated in the CLT group. The recipient infection rate within postoperative day 14 was 3.1% (1/32) in the IFLT group vs 15.6% (5/32) in the CLT group, although this difference did not reach statistical significance ( P =0.196). Multivariate analysis revealed that adopting IFLT is an independent protective factor for culture-positive PF. CONCLUSION: PF contamination is substantially decreased in IFLT, and IFLT application is an independent protective factor for PF contamination. Using rigorous sterile measures and effective antibiotic therapy during IFLT may decrease PF contamination.

Latest updates on the serotonergic system in depression and anxiety.

Psychiatric disorders are among the leading causes of global health burden, with depression and anxiety being the most disabling subtypes. The two common disorders, depression and anxiety, usually coexist and are pathologically polygenic with complicated etiologies. Current drug-based therapies include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and 5-hydroxytryptamine partial agonists. However, these modalities share common limitations, such as slow onset and low efficacy, which is why potential mechanistic insights for new drug targets are needed. In this review, we summarize recent advances in brain localization, pathology, and therapeutic mechanisms of the serotonergic system in depression and anxiety.

Cerebral small vessel disease: Pathological mechanisms and potential therapeutic targets.

Cerebral small vessel disease (CSVD) represents a diverse cluster of cerebrovascular diseases primarily affecting small arteries, capillaries, arterioles and venules. The diagnosis of CSVD relies on the identification of small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, and microbleeds using neuroimaging. CSVD is observed in 25% of strokes worldwide and is the most common pathology of cognitive decline and dementia in the elderly. Still, due to the poor understanding of pathophysiology in CSVD, there is not an effective preventative or therapeutic approach for CSVD. The most widely accepted approach to CSVD treatment is to mitigate vascular risk factors and adopt a healthier lifestyle. Thus, a deeper understanding of pathogenesis may foster more specific therapies. Here, we review the underlying mechanisms of pathological characteristics in CSVD development, with a focus on endothelial dysfunction, blood-brain barrier impairment and white matter change. We also describe inflammation in CSVD, whose role in contributing to CSVD pathology is gaining interest. Finally, we update the current treatments and preventative measures of CSVD, as well as discuss potential targets and novel strategies for CSVD treatment.

A rare case of adult diffuse midline glioma with H3 K27M mutant in the prepontine cistern.

Diffuse midline glioma with the H3.3 histone A (H3F3A) or H3 clustered histone 2/3 (HIST1H3B/C) K27M mutation occurs primarily in children and less frequently in adults involving the midline structures of the central nervous system. This case report describes an adult patient with a diffuse midline glioma H3 K27M mutant in the prepontine cistern, which is an unusual site in clinical practice. The clinical, radiographic and histopathological data from the case are presented. Magnetic resonance imaging showed a progressively enlarged and enhanced nodule in the right prepontine cistern, with diffuse involvement of the meninges and communicating hydrocephalus. Analysis of the cerebrospinal fluid occasionally found suspiciously atypical cells with hyperchromatic nuclei and multiple nucleoli, as well as a severely elevated opening pressure and protein level, slightly elevated white cell count and decreased chloride level. Empirical antituberculosis treatment was administered but eventually proved to be ineffective. The definite diagnosis was made by histopathological analysis of the lesion based on the features of positive H3 K27M mutant protein and diffusely infiltrating growth. A diffuse midline glioma with the H3 K27M mutation may rarely present in an unusual site. A biopsy is recommended at an early stage for suspected cases to facilitate a definite diagnosis.

OsCER1 regulates humidity-sensitive genic male sterility through very-long-chain (VLC) alkane metabolism of tryphine in rice.

Humidity-sensitive genic male sterility (HGMS) is a novel type of environment-sensitive male sterility (EGMS) which plants are male sterile at low humidity and male fertile at high humidity. Previous studies have revealed that OsCER1 contributes to very-long-chain (VLC) alkanes biosynthesis in rice (Oryza sativa L.). Here, applying the CRISPR/Cas9 technique, we obtained two independent OsCER1 knockout lines (OsCER1Cas). Both OsCER1Cas lines exhibited HGMS. Mutant pollen showed defects in adhesion and germination on stigmas at low humidity, whereas high humidity enhanced the pollen germination rate. Transmission electron microscopy (TEM) observations of mutant pollen revealed abnormal tryphine structure, potentially representing the basis of HGMS. Furthermore, co-pollination with mixed OsCER1Cas mutant and maize (Zea mays L.) pollen could rescue the fertility of the mutant, thereby establishing the key role of tryphine in germination on stigmas. OsCER1 knockout might affect VLC alkane metabolism and therefore alter the lipid composition of tryphine. It could lead to the defects in pollen grain adhesion, hydration and germination, resulting in HGMS. This work identified the mechanism of HGMS induced by VLC alkanes in rice and the generality of tryphine in different species of Gramineae.

Pure Thalamic Infarct: 8-Year Follow-Up Study in a Hospital in China.

Pure thalamic infarct is a rare lacunar stroke type, with little known about long-term outcomes. This 8-year, single-center, retrospective study evaluated the clinical background, etiology, Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, and 8-year follow-up results in 27 patients with pure thalamic infarcts identified by MR diffusion-weighted imaging in Dalian, China. All patients presented chief complaints of limb weakness or sensory disturbances. Hypertension (24/27, 88.9%), diabetes (12/27, 44.4%), atrial fibrillation (1/27, 3.7%), hyperlipidemia (10/27, 37%), hyperhomocysteinemia (6/27, 22.2%), smoking history (10/27, 37%; 9/15, 60% for men; 1/12, 8.3% for women), and excessive alcohol consumption history (7/27, 25.9%; 7/15, 46.7% for men; 0 for women) were observed in our patient population. Based on TOAST classification, 1 patient had large artery atherosclerosis (7.14%), 23 had small vessel occlusion (SVO; 85.2%), and 3 patients were unidentified due to lack of cerebral angiography. The thalamic blood supply classification were as follows: 23 (85.2%), inferolateral territory; 1 (3.7%), tuberothalamic territory; 2 (7.4%), combination of tuberothalamic and paramedian arteries; 1 (3.7%), combination of inferolateral and paramedian arteries; 0, posterior choroidal arteries. During the 8-year follow-up, 3 patients died of colon cancer, multi-organ failure, and kidney failure, respectively; 7 presented with a recurrent stroke; while 10 recovered well with their risk factors under control. In conclusion, our cohort of pure thalamic infarcts were mainly due to SVO (TOAST), with hypertension as the main risk factor, and the inferolateral artery as the most implicated arterial territory. Less severe outcome or stroke recurrence are identified in long-term follow-up of pure thalamic infarcts. Other comorbidities would be cause of death in aged patients.

Stem-Cell Therapy as a Potential Strategy for Radiation-Induced Brain Injury.

Radiation therapy is a standard and effective non-surgical treatment for primary brain tumors and metastases. However, this strategy inevitably results in damage of normal brain tissue, causing severe complications, especially the late-delayed cognitive impairment. Due to the multifactorial and complex pathological effects of radiation, there is a lack of effective preventative and restorative treatments for the irradiated brain. Stem-cell therapy has held considerable promise for decades in the treatment of central nervous system (CNS) disorders because of its unique capacity for tissue repair and functional integrity. Currently, there is growing interest in using stem cells as a novel option to attenuate the adverse effects of irradiation. In the present review, we discuss recent studies evaluating stem-cell therapies for the irradiated brain and their therapeutic effects on ameliorating radiation-related brain injury as well as their potential challenges in clinical applications. We discuss these works in context of the pathogenesis of radiation-induced injury to CNS tissue in an attempt to elucidate the potential mechanisms of engrafted stem cells to reverse radiation-induced degenerative processes.

Cognitive Decline in Chronic Migraine with Nonsteroid Anti-inflammation Drug Overuse: A Cross-Sectional Study.

Background: Chronic migraine with medication overuse headache (CM-MOH) is the most common type of chronic migraine, and it increases risk of stroke and white matter lesions. These pathologic changes could induce cognitive decline. However, the alteration of cognitive function in CM-MOH patients is not established. Therefore, we took this study to reveal the cognitive performances in CM-MOH. Methods: This cross-sectional study was conducted between December 2015 and January 2017. Patients were divided into CM-MOH, CMwoMOH (chronic migraine without medication overuse), and MO (migraine without aura) groups. Cognitive function was assessed in all cases during interictal periods using Addenbrooke's Cognitive Examination Test (ACE-R), Trail Making Test A/B (TMT A/B), and Digit Symbol Test (DST). Detailed headache characteristics and evaluation of anxiety, depression, and living and sleep quality were collected. Results: 116 patients were included in this study. There were 21 CM-MOHs, 20 CMwoMOHs, 35 MOs, and 40 controls. Age and education were the independent risk factors of cognitive decline (P < 0.05). After adjusting, the risk of cognitive decline was higher in CM compared with control in ACE-R score and language fluency (P < 0.05). In addition, CM-MOH sufferers were in higher risk of memory and executive dysfunction (P < 0.05). The cognitive function had no difference between CM-MOH and CMwoMOH (P > 0.05). Meanwhile, CM-MOH got significantly higher scores than MO in anxiety and depression, with poorer performances in sleep and life quality (P < 0.05). Conclusion: The risk of cognitive decline increased in chronic migraine patients. Nonsteroid anti-inflammatory drugs overuse had no influence on cognitive performances among chronic migraine sufferers.

Effects of the transcription factor Olig1 on the differentiation and remyelination of oligodendrocyte precursor cells after focal cerebral ischemia in rats.

The differentiation and maturation of oligodendrocyte precursor cells (OPCs) is important for remyelination in the central nervous system. Nevertheless, this process is often limited and incomplete in ischemic injury. Oligodendrocyte transcription factor 1 (Olig1) is important for the maturation of OPCs and the repair of demyelinated lesions. However, how Olig1 modulates the development of OPCs or the remyelination associated with ischemic injury remains unclear. The present study aimed to examine alterations in OPCs, and the expression of myelin and Olig1, at different time-points after focal cerebral ischemia using immunohistochemistry and western blot techniques to elucidate the role of Olig1 in the maturation of OPCs and remyelination. The present results showed that the expression of Olig1 significantly decreased at 1 day after middle cerebral artery occlusion (MCAO) and returned to normal levels from day 3 to 28. Additionally, Olig1 was found to translocate into the nucleus following ischemia in the brain. The number of OPCs in the ischemic striatum significantly declined at days 1 and 3 following MCAO, and increased at days 7, 14 and 28 compared with the control. The expression of myelin basic protein, a marker of mature oligodendrocytes and myelin, gradually decreased from day 1 to 7 after ischemia and recovered at day 14 and 28; however, the levels were lower than those in the control group. The present results indicated that the restored normal level of Olig1 following ischemia may play an important role in the maturation of OPCs through its translocation into the nucleus, where it may promote the growth and development of myelin under pathological conditions. However, this endogenous recovery mechanism fails to fully repair the demyelinated lesion. The data of the present study may help clinicians understand the expression pattern of Olig1 and its potential role in endogenous remyelination after ischemia, which may have implications for the treatment of diseases that lead to demyelination.

[Influence of different drying temperatures for solid substrate after fermentation on conidia characteristics of the entomopathogenic fungus Beauveria bassiana].

OBJECTIVE: This study was to evaluate the effect of drying temperature for solid substrate after fermentation on conidia characteristics of entomopathogenic fungus Beauveria bassiana. METHODS: Seven constant or varied temperatures between 28 degrees C and 35 degrees C were designed for drying the solid substrate and the quality of harvested conidia was analyzed. RESULTS: The results showed that the drying treatments at varied temperatures significantly decreased bacterial contamination in the harvested conidia powder. The conidia viability and germination speed were varied with different drying treatments. After drying at 35 degrees C for 5 h, there was no significant difference in viability between the dried and fresh conidia, while the median germination time (9.6 h) of the dried conidia was shortened by 9.3%. The tolerance of conidia to heat and UV radiation was increased by drying treatment. Compared to the drying treatment at a constant temperature at 28 degrees C or 35 degrees C, some varied temperature treatments were in favor of enhancing the stress tolerance of conidia. Drying treatments influenced accumulation of trehalose in harvested conidia, while neither heat resistance nor UV tolerance of conidia was obvious correlation with trehalose level. Optimizing drying temperature could increase the virulence of B. bassiana. After drying at 28 degrees C for 24 h and then 35 degrees C for 2 h or at 35 degrees C for 5 h, the LT(50S) to Myzus persicae at the dose of 370-450 conidia /mm2 were shortened by 10.6 h and 7.5 h, respectively. CONCLUSION: The results suggested that the drying temperature for post-fermentation solid substrate has an important influence on bacterial contamination in the harvested conidia powder, spore viability, stress tolerance and virulence in B. bassiana.

dl-3n-butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP.

The purpose of the study is to establish a model of cold-induced stroke in hypertensive rats, and to study the preventive effect of dl-3n-butylphthalide ( NBP ) on stroke. Stroke-prone renovascular hypertension(RHRSP) was created in Sprague-Dawley rats. The animals were assigned randomly to NBP, aspirin treated and vehicle control group, with administration of the medications for 7 days, and then subjected to cold treatment in an environmentally controlled chamber for 3 days to induce the occurrence of stroke. The incidence of stroke, the volume of the brain lesion, patency of the microvessels by FITC-dextran perfusion and the number of microvessels by immunohisochemical detection of vwF were investigated. Cold induced different types of stroke in RHRSP. The incidence of ischemic stroke and the volume of the infarct were decreased, and the perfused microvessels were increased with NBP pretreatment. Our data suggest that NBP prevents cold-induced ischemic stroke via improvement of cerebral microvessels.

Telomerase: a target for therapeutic effects of curcumin and a curcumin derivative in Aß1-42 insult in vitro.

This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimer's disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aß1-42 (10 µg/ml) to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aß1-42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aß1-42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1.

Clinical and molecular research of neuroacanthocytosis.

Neuroacanthocytosis is an autosomal recessive or dominant inherited disease characterized by widespread, non-specific nervous system symptoms, or spiculated "acanthocytic" red blood cells. The clinical manifestations typically involve chorea and dystonia, or a range of other movement disorders. Psychiatric and cognitive symptoms may also be present. The two core neuroacanthocytosis syndromes, in which acanthocytosis is atypical, are autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. Acanthocytes are found in a smaller proportion of patients with Huntington's disease-like 2 and pantothenate kinase-associated neurodegeneration. Because the clinical manifestations are diverse and complicated, in this review we present features of inheritance, age of onset, neuroimaging and laboratory findings, as well as the spectrum of central and peripheral neurological abnormalities and extraneuronal involvement to help distinguish the four specific syndromes.

Trigeminal nerve and facial nerve palsy after combined spinal-epidural anesthesia for cesarean section.

A case of emergency cesarean section due to a prolonged second stage of labor in a 29 year-old woman is presented. She had trigeminal nerve and facial nerve palsy after combined spinal-epidural anesthesia for cesarean section.