High-frequency rTMS over bilateral primary motor cortex improves freezing of gait and emotion regulation in patients with Parkinson's disease: a randomized controlled trial.

Background: Freezing of gait (FOG) is a common and disabling phenomenon in patients with Parkinson's disease (PD), but effective treatment approach remains inconclusive. Dysfunctional emotional factors play a key role in FOG. Since primary motor cortex (M1) connects with prefrontal areas via the frontal longitudinal system, where are responsible for emotional regulation, we hypothesized M1 may be a potential neuromodulation target for FOG therapy. The purpose of this study is to explore whether high-frequency rTMS over bilateral M1 could relieve FOG and emotional dysregulation in patients with PD. Methods: This study is a single-center, randomized double-blind clinical trial. Forty-eight patients with PD and FOG from the Affiliated Hospital of Xuzhou Medical University were randomly assigned to receive 10 sessions of either active (N = 24) or sham (N = 24) 10 Hz rTMS over the bilateral M1. Patients were evaluated at baseline (T0), after the last session of treatment (T1) and 30 days after the last session (T2). The primary outcomes were Freezing of Gait Questionnaire (FOGQ) scores, with Timed Up and Go Test (TUG) time, Standing-Start 180° Turn (SS-180) time, SS-180 steps, United Parkinson Disease Rating Scales (UPDRS) III, Hamilton Depression scale (HAMD)-24 and Hamilton Anxiety scale (HAMA)-14 as secondary outcomes. Results: Two patients in each group dropped out at T2 and no serious adverse events were reported by any subject. Two-way repeated ANOVAs revealed significant group × time interactions in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14. Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FOGQ, TUG, SS-180 turn time, SS-180 turning steps, UPDRS III, HAMD-24 and HAMA-14 at T1 and T2. No significant improvement was found in the sham group. The Spearman correlation analysis revealed a significantly positive association between the changes in HAMD-24 and HAMA-14 scores and FOGQ scores at T1. Conclusion: High-frequency rTMS over bilateral M1 can improve FOG and reduce depression and anxiety in patients with PD.

Circular RNA PTP4A2 regulates microglial polarization through STAT3 to promote neuroinflammation in ischemic stroke.

OBJECTIVE: Microglial polarization plays a critical role in neuroinflammation and may be a potential therapeutic target for ischemic stroke. This study was to explore the role and underlying molecular mechanism of Circular RNA PTP4A2 (circPTP4A2) in microglial polarization after ischemic stroke. METHODS: C57BL/6J mice underwent transient middle cerebral artery occlusion (tMCAO), while primary mouse microglia and BV2 microglial cells experienced oxygen glucose deprivation/reperfusion (OGD/R) to mimic ischemic conditions. CircPTP4A2 shRNA lentivirus and Colivelin were used to knock down circPTP4A2 and upregulate signal transducer and activator of transcription 3 (STAT3) phosphorylation, respectively. Microglial polarization was assessed using immunofluorescence staining and Western blot. RNA pull-down and RNA binding protein immunoprecipitation (RIP) were applied to detect the binding between circPTP4A2 and STAT3. RESULTS: The levels of circPTP4A2 were significantly increased in plasma and peri-infarct cortex in tMCAO mice. CircPTP4A2 knockdown reduced infarct volume, increased cortical cerebral blood flow (CBF), and attenuated neurological deficits. It also decreased pro-inflammatory factors levels in peri-infarct cortex and plasma, and increased anti-inflammatory factors concentrations 24 h post-stroke. In addition, circPTP4A2 knockdown suppressed M1 microglial polarization and promoted M2 microglial polarization in both tMCAO mice and OGD/R-induced BV2 microglial cells. Moreover, circPTP4A2 knockdown inhibited the phosphorylation of STAT3 induced by oxygen-glucose deprivation. In contrast, increased phosphorylation of STAT3 partly counteracted the effects of circPTP4A2 knockdown. RNA pull-down and RIP assays further certified the binding between circPTP4A2 and STAT3. CONCLUSION: These results revealed regulatory mechanisms of circPTP4A2 that stimulated neuroinflammation by driving STAT3-dependent microglial polarization in ischemic brain injury. CircPTP4A2 knockdown reduced cerebral ischemic injury and promoted microglial M2 polarization, which could be a novel therapeutic target for ischemic stroke.

Safinamide alleviates hyperalgesia via inhibiting hyperexcitability of DRG neurons in a mouse model of Parkinson's disease.

Pain is a widespread non-motor symptom that presents significant treatment challenges in patients with Parkinson's disease (PD). Safinamide, a new drug recently introduced for PD treatment, has demonstrated analgesic effects on pain in PD patients, though the underlying mechanisms remain unclear. To investigate the analgesic and anti-PD effect of safinamide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was used, and rasagiline as positive control on motor symptoms. Notably, only safinamide alleviated hyperalgesia in MPTP mice. Whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons revealed hyperexcitability in MPTP mice, which safinamide counteracted in a concentration-dependent manner. The voltage clamp further demonstrated that sodium current in DRG neurons of MPTP mice was enhanced and safinamide reduced sodium current density. RT-qPCR identified upregulated Nav1.7 and Nav1.8 transcripts (Scn9a and Scn10a) in DRG neurons of MPTP mice. Our results suggest that safinamide could relieve hyperalgesia by inhibiting DRG neuron hyperexcitability in MPTP mice.

Soil microbial community characteristics and the influencing factors at different elevations on the eastern slope of Helan Mountain, Northwest China.

As an important bridge connecting aboveground communities and belowground biological processes, soil microorganisms play an important role in regulating belowground ecological processes. The altitudinal changes and driving factors of soil microbial community in mountain ecosystem in arid region are still unclear. We measured soil physicochemical properties at seven altitudes in the range of 1300-2800 m in Helan Mountains, and investigated the understory community composition, soil physicochemical properties, and soil microbial community. The driving factor for soil microbial community was explored by variance partitioning analysis and redundancy analysis. The results showed that the total amount of soil microorganisms and bacterial biomass first increased and then decreased with the increases of altitude, fungi, actinomyces, arbuscular mycorrhizal fungi, Gram-positive bacteria, and Gram-negative bacteria groups showed a gradual increase. The variation of fungal-to-bacterial ratio (F/B) along the altitude showed that the cumulative ability of soil bacteria was stronger than that of fungi at low altitudes, while the pattern is opposite at high altitudes. The ratio of Gram-positive bacteria to Gram-negative bacteria (GP/GN) showed an overall decreasing trend with the increases of altitude, indicating that soil bacteria and organic carbon availability changed from "oligotrophic" to "eutrophication" and from "low" to "high" transition as the altitude increased. Vegetation properties, soil physical and chemical properties jointly accounted for 95.7% of the variation in soil microbial community. Soil organic carbon (SOC), soil water content (SWC), and total nitrogen (TN) were significantly correlated with soil microbial community composition. Our results revealed the distribution pattern and driving factors of soil microbial communities at different elevations on the eastern slope of Helan Mountain, which would provide theoretical basis and data support for further understanding the interaction between plant-soil-microorganisms in arid areas.

PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson's disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons.

Pain is a common annoying non-motor symptom in Parkinson's disease (PD) that causes distress to patients. Treatment for PD pain remains a big challenge, as its underlying mechanisms are elusive. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1-R play important roles in regulating a variety of pathophysiological processes. In this study, we investigated whether PACAP/PAC1-R signaling was involved in the mechanisms of PD pain. 6-hydroxydopamine (6-OHDA)-induced PD model was established in rats. Behavioral tests, electrophysiological and Western blotting analysis were conducted 3 weeks later. We found that 6-OHDA rats had significantly lower mechanical paw withdrawal 50% threshold in von Frey filament test and shorter tail flick latency, while mRNA levels of Pacap and Adcyap1r1 (gene encoding PAC1-R) in the spinal dorsal horn were significantly upregulated. Whole-cell recordings from coronal spinal cord slices at L4-L6 revealed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in dorsal horn neurons was significantly increased, which was reversed by application of a PAC1-R antagonist PACAP 6-38 (250 nM). Furthermore, we demonstrated that intrathecal microinjection of PACAP 6-38 (0.125, 0.5, 2 µg) dose-dependently ameliorated the mechanical and thermal hyperalgesia in 6-OHDA rats. Inhibition of PACAP/PAC1-R signaling significantly suppressed the activation of Ca2+/calmodulin-dependent protein kinase II and extracellular signal-regulated kinase (ERK) in spinal dorsal horn of 6-OHDA rats. Microinjection of pAAV-Adcyap1r1 into L4-L6 spinal dorsal horn alleviated hyperalgesia in 6-OHDA rats. Intrathecal microinjection of ERK antagonist PD98059 (10 µg) significantly alleviated hyperalgesia in 6-OHDA rats associated with the inhibition of sEPSCs in dorsal horn neurons. In addition, we found that serum PACAP-38 concentration was significantly increased in PD patients with pain, and positively correlated with numerical rating scale score. In conclusion, activation of PACAP/PAC1-R induces the development of PD pain and targeting PACAP/PAC1-R is an alternative strategy for treating PD pain.

FungiExpresZ: an intuitive package for fungal gene expression data analysis, visualization and discovery.

Bioinformatics analysis and visualization of high-throughput gene expression data require extensive computer programming skills, posing a bottleneck for many wet-lab scientists. In this work, we present an intuitive user-friendly platform for gene expression data analysis and visualization called FungiExpresZ. FungiExpresZ aims to help wet-lab scientists with little to no knowledge of computer programming to become self-reliant in bioinformatics analysis and generating publication-ready figures. The platform contains many commonly used data analysis tools and an extensive collection of pre-processed public ribonucleic acid sequencing (RNA-seq) datasets of many fungal species, including important human, plant and insect pathogens. Users may analyse their data alone or in combination with public RNA-seq data for an integrated analysis. The FungiExpresZ platform helps wet-lab scientists to overcome their limitations in genomics data analysis and can be applied to analyse data of any organism. FungiExpresZ is available as an online web-based tool (https://cparsania.shinyapps.io/FungiExpresZ/) and an offline R-Shiny package (https://github.com/cparsania/FungiExpresZ).

Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson's Disease.

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 µmol/L) and palosetron (10 µmol/L), but not 5-HT3 receptor agonist m-CPBG (30 µmol/L) and SR 57,727 (10 µmol/L), 5-HT1A receptor agonist 8-OH DPAT (10 µmol/L) and eptapirone (10 µmol/L) and 5-HT1A receptor antagonist WAY-100635 (10 µmol/L) and p-MPPI (10 µmol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

Induction of Parkinsonian-Like Changes via Targeted Downregulation of Astrocytic Glutamate Transporter GLT-1 in the Striatum.

BACKGROUND: Previous investigations have suggested that decreased expression of glutamate transporter-1 (GLT-1) is involved in glutamate excitotoxicity and contribute to the development of Parkinson's disease (PD), GLT-1 is decreased in animal models of PD. GLT-1 is mainly expressed in astrocytes, and the striatum is a GLT-1-rich brain area. OBJECTIVE: The aim was to explore the function and mechanism of astrocytic GLT-1 in PD-like changes. METHODS: In the study, PD-like changes and their molecular mechanism in rodents were tested by a behavioral assessment, micro-positron emission tomography/computed tomography (PET/CT), western blotting, immunohistochemical and immunofluorescence staining, and high performance liquid chromatography pre-column derivatization with O-pthaldialdehida after downregulating astrocytic GLT-1 in vivo and in vitro. RESULTS: In vivo, after 6 weeks of brain stereotactic injection of adeno-associated virus into the striatum, rats in the astrocytic GLT-1 knockdown group showed poorer motor performance, abnormal gait, and depression-like feature; but no olfactory disorders. The results of micro-PET/CT and western blotting indicated that the dopaminergic system was impaired in astrocytic GLT-1 knockdown rats. Similarly, tyrosine hydroxylase (TH) positive immune-staining in neurons of astrocytic GLT-1 knockdown rats showed deficit in cell count. In vitro, knockdown of astrocytic GLT-1 via RNA interference led to morphological injury of TH-positive neurons, which may be related to the abnormal calcium signal induced by glutamate accumulation after GLT-1 knockdown. Furthermore, the GLT-1 agonist ceftriaxone showed a protective effect on TH-positive neuron impairment. CONCLUSION: The present findings may shed new light in the future prevention and treatment of PD based on blocking glutamate excitotoxicity.

Functional MRI in Parkinson's disease with freezing of gait: a systematic review of the literature.

BACKGROUND: Freezing of gait (FOG), a common and disabling symptom of Parkinson's disease (PD), is characterized by an episodic inability to generate effective stepping. Functional MRI (fMRI) has been used to evaluate abnormal brain connectivity patterns at rest and brain activation patterns during specific tasks in patients with PD-FOG. This review has examined the existing functional neuroimaging literature in PD-FOG, including those with treatment. Summarizing these articles provides an opportunity for a better understanding of the underlying pathophysiology in PD-FOG. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a literature review of studies using fMRI to investigate the underlying pathophysiological mechanisms of PD-FOG. RESULTS: We initially identified 201 documents. After excluding the duplicates, reviews, and other irrelevant articles, 39 articles were finally identified, including 18 task-based fMRI studies and 21 resting-state fMRI studies. CONCLUSIONS: Studies using fMRI techniques to evaluate PD-FOG have found dysfunctional connectivity in widespread cortical and subcortical regions. Standardized imaging protocols and detailed subtypes of PD-FOG are furthered required to elucidate current findings.

Carbon Catabolite Repression in Filamentous Fungi Is Regulated by Phosphorylation of the Transcription Factor CreA.

Filamentous fungi of the genus Aspergillus are of particular interest for biotechnological applications due to their natural capacity to secrete carbohydrate-active enzymes (CAZy) that target plant biomass. The presence of easily metabolizable sugars such as glucose, whose concentrations increase during plant biomass hydrolysis, results in the repression of CAZy-encoding genes in a process known as carbon catabolite repression (CCR), which is undesired for the purpose of large-scale enzyme production. To date, the C2H2 transcription factor CreA has been described as the major CC repressor in Aspergillus spp., although little is known about the role of posttranslational modifications in this process. In this work, phosphorylation sites were identified by mass spectrometry on Aspergillus nidulans CreA, and subsequently, the previously identified but uncharacterized site S262, the characterized site S319, and the newly identified sites S268 and T308 were chosen to be mutated to nonphosphorylatable residues before their effect on CCR was investigated. Sites S262, S268, and T308 are important for CreA protein accumulation and cellular localization, DNA binding, and repression of enzyme activities. In agreement with a previous study, site S319 was not important for several here-tested phenotypes but is key for CreA degradation and induction of enzyme activities. All sites were shown to be important for glycogen and trehalose metabolism. This study highlights the importance of CreA phosphorylation sites for the regulation of CCR. These sites are interesting targets for biotechnological strain engineering without the need to delete essential genes, which could result in undesired side effects.IMPORTANCE In filamentous fungi, the transcription factor CreA controls carbohydrate metabolism through the regulation of genes encoding enzymes required for the use of alternative carbon sources. In this work, phosphorylation sites were identified on Aspergillus nidulans CreA, and subsequently, the two newly identified sites S268 and T308, the previously identified but uncharacterized site S262, and the previously characterized site S319 were chosen to be mutated to nonphosphorylatable residues before their effect on CCR was characterized. Sites S262, S268, and T308 are important for CreA protein accumulation and cellular localization, DNA binding, and repression of enzyme activities. In agreement with a previous study, site S319 is not important for several here-tested phenotypes but is key for CreA degradation and induction of enzyme activities. This work characterized novel CreA phosphorylation sites under carbon catabolite-repressing conditions and showed that they are crucial for CreA protein turnover, control of carbohydrate utilization, and biotechnologically relevant enzyme production.

Carbon Catabolite Repression Governs Diverse Physiological Processes and Development in Aspergillus nidulans.

Carbon catabolite repression (CCR) is a common phenomenon of microorganisms that enable efficient utilization of carbon nutrients, critical for the fitness of microorganisms in the wild and for pathogenic species to cause infection. In most filamentous fungal species, the conserved transcription factor CreA/Cre1 mediates CCR. Previous studies demonstrated a primary function for CreA/Cre1 in carbon metabolism; however, the phenotype of creA/cre1 mutants indicated broader roles. The global function and regulatory mechanism of this wide-domain transcription factor has remained elusive. Here, we applied two powerful genomics methods (transcriptome sequencing and chromatin immunoprecipitation sequencing) to delineate the direct and indirect roles of Aspergillus nidulans CreA across diverse physiological processes, including secondary metabolism, iron homeostasis, oxidative stress response, development, N-glycan biosynthesis, unfolded protein response, and nutrient and ion transport. The results indicate intricate connections between the regulation of carbon metabolism and diverse cellular functions. Moreover, our work also provides key mechanistic insights into CreA regulation and identifies CreA as a master regulator controlling many transcription factors of different regulatory networks. The discoveries for this highly conserved transcriptional regulator in a model fungus have important implications for CCR in related pathogenic and industrial species. IMPORTANCE The ability to scavenge and use a wide range of nutrients for growth is crucial for microorganisms' survival in the wild. Carbon catabolite repression (CCR) is a transcriptional regulatory phenomenon of both bacteria and fungi to coordinate the expression of genes required for preferential utilization of carbon sources. Since carbon metabolism is essential for growth, CCR is central to the fitness of microorganisms. In filamentous fungi, CCR is mediated by the conserved transcription factor CreA/Cre1, whose function in carbon metabolism has been well established. However, the global roles and regulatory mechanism of CreA/Cre1 are poorly defined. This study uncovers the direct and indirect functions of CreA in the model organism Aspergillus nidulans over diverse physiological processes and development and provides mechanistic insights into how CreA controls different regulatory networks. The work also reveals an interesting functional divergence between filamentous fungal and yeast CreA/Cre1 orthologues.

Requirements for RNA polymerase II preinitiation complex formation in vivo.

Transcription by RNA polymerase II requires assembly of a preinitiation complex (PIC) composed of general transcription factors (GTFs) bound at the promoter. In vitro, some GTFs are essential for transcription, whereas others are not required under certain conditions. PICs are stable in the absence of nucleotide triphosphates, and subsets of GTFs can form partial PICs. By depleting individual GTFs in yeast cells, we show that all GTFs are essential for TBP binding and transcription, suggesting that partial PICs do not exist at appreciable levels in vivo. Depletion of FACT, a histone chaperone that travels with elongating Pol II, strongly reduces PIC formation and transcription. In contrast, TBP-associated factors (TAFs) contribute to transcription of most genes, but TAF-independent transcription occurs at substantial levels, preferentially at promoters containing TATA elements. PICs are absent in cells deprived of uracil, and presumably UTP, suggesting that transcriptionally inactive PICs are removed from promoters in vivo.

The clinical and imaging features of hypertrophic pachymeningitis: a clinical analysis on 22 patients.

OBJECTIVE: To explore the clinical and imaging features of patients with hypertrophic cranial pachymeningitis (HCP). METHODS: A retrospective study was performed on 22 patients with HCP diagnosed at the Affiliated Hospital of Xuzhou Medical University from February 2014 to September 2017. RESULTS: A headache was present as an initial symptom in 18 patients. The headache was associated with the loss of vision (2 cases), facial pain (1 case), and unsteady walking (1 case). Other symptoms included cranial nerve dysfunction (15 cases), cerebellar ataxia (4 cases), and sinus thrombosis (3 cases). In the laboratory tests, 7 patients showed an increased number of white blood cells, higher levels of C-reaction protein (CRP), and erythrocyte sedimentation rate (ESR). An elevated level of immunoglobulin G4 (IgG4) and the presence of the anti-neutrophil cytoplasmic antibody (ANCA) were found in 3 and 2 patients respectively. There were 17 patients who had abnormalities in their cerebrospinal fluid (CSF) on lumbar puncture. On magnetic resonance imaging (MRI), a local or generalized thickening was observed in the cerebral falx, the tentorium of the cerebellum, the fronto-parietal lobe, the occipito-parietal lobe, and the dura of skull base. A dural biopsy obtained in one case showed a variety of inflammatory changes. An immunohistochemical analysis revealed the positivity of CD138, IgG, and IgG4 in some cells. All 22 patients had a good response to corticosteroids. CONCLUSION: HCP mainly leads to a headache and the paralysis of multiple cranial nerves. A biopsy and MRI are often required and serve as the basis for the diagnosis and effective therapy.

The clinical and imaging features of gray matter heterotopia: a clinical analysis on 15 patients.

OBJECTIVE: To investigate the clinical and imaging features of gray matter heterotopia (GMH) and improve the clinicians' understanding of the disease. METHODS: A retrospective study was performed on 15 patients with GMH diagnosed at The Affiliated Hospital of Xuzhou Medical University from November 2014 to November 2016. Their clinical and imaging features are also summarized. RESULTS: The proportion of male and female patients was 2:1. The age of onset was 2~45 years and the average age was 19.1 years. There were 13 patients with epilepsy who also had cognitive decline (5 cases) and neurological deficit (3 cases). There were 2 patients with headache or dizziness. The imaging findings of GMH are unilateral or multiple spots in the periventricular or subependymal, subcortical, and centrum semiovale and are often accompanied by other cerebral malformations. We found that 10 patients had the subcortical type of GMH and 5 patients had the subependymal type or periventricular nodular heterotopia type. There were 8 cases of ventricular compression, 5 cases of ventriculomegaly, 5 cases of cerebral fissure malformation, 3 cases of pachygyria, 1 case of callosal agenesis, and 1 case of undeveloped septum pellucidum. All the patients were given symptomatic and supportive therapies and 3 patients were treated with antiepileptic drugs. Seizures were, however, poorly controlled. CONCLUSION: GMH should also be suspected in patients with juvenile onset of seizures, cognitive decline, and neurological deficits. Magnetic resonance scans may show lesions in the white matter of the brain with signals similar to the normal gray matter.

Clinical and imaging characteristics of subacute combined degeneration complicated with white matter lesions in the brain: a report of five cases.

PURPOSE: To report five cases of subacute combined degeneration (SCD) with brain involvement and explore its clinical and imaging characteristics. METHODS: A retrospective study was performed on the clinical data and brain MRI of five patients with subacute combined degeneration with brain involvement (out of 107 cases with SCD in total). White matter lesions (WML) assessment was performed qualitatively using Fazekas scale score. RESULTS: The main symptoms in four patients were weakness in both lower extremities and unstable walking (limb weakness in three patients, dizziness in three patients, and blurred vision in one patient). One patient had memory loss and cognitive dysfunction. The MMSE scale indicated mild dementia in one patient. On head MRI (Magnetic Resonance Imaging), multifocal and symmetrical high signals of T2WI and FLAIR were observed in the frontal lobe and periventricular white matter in four patients, while another patient showed preferential atrophy in frontal regions. Fazekas scale scores ranged from 1-6. CONCLUSION: Adult subacute combined degeneration seldom involves the brain. Multifocal and symmetrical high signal white matter lesions can be found on FLAIR and T2WI, as well as frontal atrophy on head MRI.

Arsenic Trioxide Reduces Global Histone H4 Acetylation at Lysine 16 through Direct Binding to Histone Acetyltransferase hMOF in Human Cells.

Histone post-translational modification heritably regulates gene expression involved in most cellular biological processes. Experimental studies suggest that alteration of histone modifications affects gene expression by changing chromatin structure, causing various cellular responses to environmental influences. Arsenic (As), a naturally occurring element and environmental pollutant, is an established human carcinogen. Recently, increasing evidence suggests that As-mediated epigenetic mechanisms may be involved in its toxicity and carcinogenicity, but how this occurs is still unclear. Here we present evidence that suggests As-induced global histone H4K16 acetylation (H4K16ac) partly due to the direct physical interaction between As and histone acetyltransferase (HAT) hMOF (human male absent on first) protein, leading to the loss of hMOF HAT activity. Our data show that decreased global H4K16ac and increased deacetyltransferase HDAC4 expression occurred in arsenic trioxide (As2O3)-exposed HeLa or HEK293T cells. However, depletion of HDAC4 did not affect global H4K16ac, and it could not raise H4K16ac in cells exposed to As2O3, suggesting that HDAC4 might not directly be involved in histone H4K16 de-acetylation. Using As-immobilized agarose, we confirmed that As binds directly to hMOF, and that this interaction was competitively inhibited by free As2O3. Also, the direct interaction of As and C2CH zinc finger peptide was verified by MAIDI-TOF mass and UV absorption. In an in vitro HAT assay, As2O3 directly inhibited hMOF activity. hMOF over-expression not only increased resistance to As and caused less toxicity, but also effectively reversed reduced H4K16ac caused by As exposure. These data suggest a theoretical basis for elucidating the mechanism of As toxicity.

Negative Regulation of p21Waf1/Cip1 by Human INO80 Chromatin Remodeling Complex Is Implicated in Cell Cycle Phase G2/M Arrest and Abnormal Chromosome Stability.

We previously identified an ATP-dependent human Ino80 (INO80) chromatin remodeling complex which shares a set of core subunits with yeast Ino80 complex. Although research evidence has suggested that INO80 complex functions in gene transcription and genome stability, the precise mechanism remains unclear. Herein, based on gene expression profiles from the INO80 complex-knockdown in HeLa cells, we first demonstrate that INO80 complex negatively regulates the p21Waf1/Cip1 (p21) expression in a p53-mediated mechanism. In chromatin immunoprecipitation (ChIP) and a sequential ChIP (Re-ChIP) assays, we determined that the INO80 complex and p53 can bind to the same promoter region of p21 gene (-2.2 kb and -1.0 kb upstream of the p21 promoter region), and p53 is required for the recruitment of the INO80 complex to the p21 promoter. RNAi knockdown strategies of INO80 not only led to prolonged progression of cell cycle phase G2/M to G1, but it also resulted in abnormal chromosome stability. Interestingly, high expression of p21 was observed in most morphologically-changed cells, suggesting that negative regulation of p21 by INO80 complex might be implicated in maintaining the cell cycle process and chromosome stability. Together, our findings will provide a theoretical basis to further elucidate the cellular mechanisms of the INO80 complex.

Clinical observation of gastric bypass in treatment of type 2 diabetes.

BACKGROUND: Roux-en-Y gastric bypass (GBP) is the main surgical procedure used in type 2 diabetes. The objective of this study was to evaluate the different types of GBP in treatment of type 2 diabetes. METHODS: Patients with type 2 diabetes were randomly divided into two groups: those who underwent gastrojejunal loop anastomosis bypass and those who underwent gastrojejunal Roux-en-Y bypass. Blood glucose alterations, operation time, and operation complications were observed. RESULTS: Gastrojejunal loop anastomosis bypass and gastrojejunal Roux-en-Y bypass were both effective in the treatment of selected patients with type 2 diabetes. Compared with gastrojejunal Roux-en-Y bypass, gastrojejunal loop anastomosis bypass had the advantages of easier implementation, shorter operation time, and fewer operation complications. CONCLUSIONS: Gastrojejunal loop anastomosis is effective in treatment of type 2 diabetes. It is safe, easy to implement, and worthy of clinical popularization.

[Double-pump implantation chemotherapy for hepatic metastasis from colorectal cancer].

OBJECTIVE: To evaluate the value of infusion chemotherapy by pump implantation via hepatic artery or portal vein or both (double-pump chemotherapy, DPC) for hepatic metastasis from colorectal cancer. METHODS: Thirty patients with hepatic metastasis from colorectal cancer were divided into three groups: 1. Group I-DPC (12 patients). 2. Group II-hepatic artery implantation chemotherapy (10 patients) and 3. Group III-portal vein implantation chemotherapy (8 patients). RESULTS: Response rate was 66.7% in group I, 60% in group II and 37.5% in group III. The 0.5-, 1-, 2-year survival rates were 100.0%, 75.0%, 41.7% in group I, 90.0%, 60.0%, 30.0% in group II and 87.5%, 50.0%, 25.0% in group III. CONCLUSION: Double pump implantation chemotherapy is effective in treating hepatic metastasis from colorectal cancer. It is better than hepatic artery or portal vein pump-implantation chemotherapy alone.

[Super-selective pump-insertion into the target artery and regional intraarterial infusion chemotherapeutant and immunizator in treatment of the latter gastrointestinal cancer].

OBJECTIVE: To evaluate the effect of operative selective pump-insertion into the tumorous target artery, postoperative regional infusion chemotherapeutant and immunizator for treatment the latter gastrointestinal cancer. METHODS: The effect of operative super-selective pump-insertion into the tumorous nutritious artery, postoperative regional infusion chemotherapeutant and immunizator for treatment 88 cases patients suffering from irremovable gastrointestinal cancer was observed. Of them, 45 cases were gastric cancer, 31 cases were rectal cancer, 11cases were colic cancer. RESULTS: Complete response 2 case; Part response 77 cases, 11 cases patients had received secondary resection after intraarterial chemotherapy. Non chang 9 cases; effective rates reach to 89.8%. One, two and three years survival rates were 86.4%, 30.7% and 10.2%. Average survival period were 21.5 mouths. CONCLUSION: Super-selective pump-insertion into the artery and regional intraarterial chemotherapy is an efficient way in treatment of the latter gastrointestinal cancer, which can delay the survival period of patients with tumor, and increase the resectable rate.