The forkhead transcription factor Foxj1 controls vertebrate olfactory cilia biogenesis and sensory neuron differentiation.

In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the differentiation of the OSNs themselves by regulating their cell type-specific gene expression, such as that of olfactory marker protein (omp) involved in odor-evoked signal transduction. In line with this, response to bile acids, odors detected by OMP-positive OSNs, was significantly diminished in foxj1 mutant zebrafish. Taken together, our findings establish how the canonical Foxj1-mediated motile ciliogenic transcriptional program has been repurposed for the biogenesis of immotile olfactory cilia, as well as for the development of the OSNs.

Case Report: Delayed Guillain-Barré syndrome following trauma: A case series and manage considerations.

Aim: To analyze clinical associations between Guillain-Barré syndrome (GBS) and trauma. Material and Methods: We retrospectively reviewed the data of eight patients with post-traumatic GBS between July 2011 and December 2018 at the Second Xiangya Hospital, China, and analyzed the triggers, clinical manifestation, examination results, treatment, prognosis, and potential mechanism related to post-traumatic GBS. Results: The included patients had GBS preceded by no risk factors other than trauma. Their age ranged from 15 to 60 years (the median age was 52 years), and six patients were males. The potential traumatic triggers included spinal surgery (n = 2), high-intensity exercise (n = 2), traumatic brain injury (n = 1), excessive fatigue (n = 1), ischemic stroke (n = 1), and cardiopulmonary resuscitation (n = 1). The major manifestation was symmetrical limb weakness and/or numbness in all patients. The diagnosis of GBS was based on the results of electromyography, albumino-cytological dissociation, or antiganglioside antibody in cerebrospinal fluid, and other diseases were excluded. Immunotherapy improved symptoms, except in one patient who died. Conclusions: Trauma is a probable risk factor for GBS that is very easily overlooked, thereby leading to misdiagnosis in clinical practice. We emphasize a new concept of post-traumatic GBS to promote doctors' awareness when they meet people with weakness and sensory deficits after trauma, which benefit early diagnosis, timely treatment, and reduced mortality rate of GBS.

Effects of butyphthalide on microglia polarization after intracerebral hemorrhage and the underlying mechanisms. / ä¸è‹¯é žå¯¹è„‘å‡ºè¡€åŽå°èƒ¶è´¨ç»†èƒžæžåŒ–çš„å½±å“åŠå ¶æœºåˆ¶.

OBJECTIVES: Because intracerebral hemorrhage (ICH) has high morbidity, disability and mortality, it is significant to find new and effective treatments for ICH. This study aims to explore the effect of butyphthalide (NBP) on neuroinflammation secondary to ICH and microglia polarization. METHODS: A total of 48 healthy male SD rats were randomly divided into 6 groups: a sham 24 h group, a sham 72 h group, an ICH 24 h group, an ICH 72 h group, an ICH+NBP 24 h group, and an ICH+NBP 72 h group (8 rats per group). After operation, the neurological deficiencies were assessed based on improved Garcia scores and corner test. The expressions of Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), aquaporin-4 (AQP4), zonula occludens-1 (ZO-1), occludin, CD68, CD86, and CD206 were observed by Western blotting. Inflammatory cytokines were detected by ELISA. The immunofluorescence was to detect the polarization of microglia. RESULTS: 1) Compared with the sham groups, the expression of TLR4 (24 h: P<0.05; 72 h: P<0.01), NF-κB (both P<0.01) and Nrf2 (both P<0.01) in the perihematoma of the ICH group was increased, leading to microglia activation (P<0.01). The expressions of IL-6 (24 h: P<0.05; 72 h: P<0.01) and TNF-α (both P<0.01), the pro-inflammatory cytokines were up-regulated, and the expression of anti-inflammatory cytokine IL-4 was down-regulated (both P<0.01). Besides, the expression of AQP4 was enhanced (both P<0.01). The protein level of tightly connected proteins (including ZO-1, occludin) was decreased (all P<0.01). The neurological function of the rats in the ICH group was impaired in the 2 time points (both P<0.01). 2) Compared with the sham group at 24 h and 72 h after the intervention of NBP, the expressions of TLR4 (both P<0.05) and NF-κB (both P<0.01) were significantly declined, and the expression of Nrf2 was further enhanced (both P<0.05) in the perihematoma of the ICH+NBP group. Furthermore, the expression of M1 microglia marker was inhibited (P<0.05), and the polarization of microglia to the M2 phenotype was promoted (P<0.01). 3) In terms of inflammation after ICH, the IL-4 expression in the ICH+NBP group was increased compared with the ICH group (24 h: P<0.05; 72 h: P<0.01); the expression of IL-6 was decreased significantly in the ICH+NBP 72 h group (P<0.01); the level of AQP4 was declined significantly in the ICH+NBP 24 h group (P<0.05), there was a downward trend in the 72-hour intervention group but without significant statistical difference. 4) Compared with the ICH group, the ZO-1 protein levels were increased (24 h: P<0.05; 72 h: P<0.01), and the symptoms of nerve defect were improved eventually (both P<0.05) in the ICH+NBP groups. CONCLUSIONS: After ICH, the TLR4/NF-κB pathway is activated. The M1 microglia is up-regulated along with the release of detrimental cytokines, while the anti-inflammatory cytokines are down-regulated. The expression of AQP4 is increased, the tight junction proteins from the blood-brain barrier (BBB) is damaged, and the neurological function of rats is impaired. On the contrary, NBP may regulate microglia polarization to M2 phenotype and play a role in the neuroprotective effect mediated via inhibiting TLR4/NF-κB and enhancing Nrf2 pathways, which relieves the neuroinflammation, inhibits the expression of AQP4, repairs BBB, and improves neurological functional defects.

Gene Editing of the Catfish Gonadotropin-Releasing Hormone Gene and Hormone Therapy to Control the Reproduction in Channel Catfish, Ictalurus punctatus.

Transcription activator-like effector nuclease (TALEN) plasmids targeting the channel catfish gonadotropin-releasing hormone (cfGnRH) gene were delivered into fertilized eggs with double electroporation to sterilize channel catfish (Ictalurus punctatus). Targeted cfGnRH fish were sequenced and base deletion, substitution, and insertion were detected. The gene mutagenesis was achieved in 52.9% of P1 fish. P1 mutants (individuals with human-induced sequence changes at the cfGnRH locus) had lower spawning rates (20.0−50.0%) when there was no hormone therapy compared to the control pairs (66.7%) as well as having lower average egg hatch rates (2.0% versus 32.3−74.3%) except for one cfGnRH mutated female that had a 66.0% hatch rate. After low fertility was observed in 2016, application of luteinizing hormone-releasing hormone analog (LHRHa) hormone therapy resulted in good spawning and hatch rates for mutants in 2017, which were not significantly different from the controls (p > 0.05). No exogenous DNA fragments were detected in the genome of mutant P1 fish, indicating no integration of the plasmids. No obvious effects on other economically important traits were observed after the knockout of the reproductive gene in the P1 fish. Growth rates, survival, and appearance between mutant and control individuals were not different. While complete knock-out of reproductive output was not achieved, as these were mosaic P1 brood stock, gene editing of channel catfish for the reproductive confinement of gene-engineered, domestic, and invasive fish to prevent gene flow into the natural environment appears promising.

Prediction of Overall Energy Consumption of Data Centers in Different Locations.

The use of big data leads to higher demands for hyperscale data centers (HDCs) in terms of the scale and quantity required for data storage and processing. Before the construction of an HDC, it is necessary to comprehensively analyze the economic budget according to the energy requirements and potential energy cost. We propose a global energy consumption prediction framework based on the power usage effectiveness (PUE) calculation that considers all heat sources and power consumption. The framework integrates physical models and a statistical framework that combines IT equipment energy consumption and data center energy consuming predictions. Furthermore, the framework provides a method to calculate the carbon emissions and electricity cost of the data center. Using hourly meteorological data as climate parameters, combined with a limited range of energy parameters, the annual PUE values of 60 regions were estimated, and a further analysis of the Carbon Usage Effectiveness (CUE) and electricity costs in China was conducted as an example. Based on experimental validation and an evaluation of real-time data, our framework can predict the overall energy consumption of HDCs effectively, filling a gap in HDC research in the Asia-Pacific region and providing a basis for HDC feasibility analysis.

Role of Butylphthalide in Immunity and Inflammation: Butylphthalide May Be a Potential Therapy for Anti-Inflammation and Immunoregulation.

Inflammation and immunity play an essential role in disease pathogenesis. 3-N-Butylphthalide (NBP), a group of compounds extracted from seeds of Apium graveolens (Chinese celery), has been demonstrated as an efficient and effective therapy for ischemic stroke. The amount of research on NBP protective effect is increasing at pace, such as microcircular reconstruction, alleviating inflammation, ameliorating brain edema and blood-brain barrier (BBB) damage, mitochondrial function protection, antiplatelet aggregation, antithrombosis, decreasing oxidative damage, and reducing neural cell apoptosis. There has been increasing research emphasizing the association between NBP and immunity and inflammation in the past few years. Hence, it is aimed at reviewing the related literature and summarizing the underlying anti-inflammatory and immunoregulatory function of NBP in various disorders.

Direct and pleiotropic effects of the Masou Salmon Delta-5 Desaturase transgene in F1 channel catfish (Ictalurus punctatus).

Channel catfish (Ictalurus punctatus) is the primary culture species in the US along with its hybrid made with male blue catfish, I. furcatus. In an effort to improve the nutritional value of channel catfish, the masou salmon Δ5-desaturase like gene (D5D) driven by the common carp beta-actin promoter (ßactin) was inserted into channel catfish. The objectives of this study were to determine the effectiveness of ßactin-D5D for improving n-3 fatty acid production in F1 transgenic channel catfish, as well as examine pleiotropic effects on growth, proximate analysis, disease resistance, and other performance traits. Transgenic F1 channel catfish showed a 33% increase in the relative proportion of n-3 fatty acids coupled with a 15% decrease in n-6 fatty acids and a 17% decrease in n-9 fatty acids when compared to non-transgenic full-siblings (P < 0.01, P < 0.01, P < 0.01). However, while the relative proportion of n-3 fatty acids was achieved, the total amount of fatty acids in the transgenic fish decreased resulting in a reduction of all fatty acids. Insertion of the ßactin-D5D transgene into channel catfish also had large effects on the body composition, and growth of channel catfish. Transgenic channel catfish grew faster, were more disease resistant, had higher protein and moisture percentage, but lower fat percentage than full-sib controls. There were sex effects as performance changes were more dramatic and significant in males. The ßactin-D5D transgenic channel catfish were also more uniform in their fatty acid composition, growth and other traits.

Comparative study of AQP4 antibody-related diseases and MOG antibody-related diseases among the population in Hunan, China.

To compare the clinical, imaging, and prognostic characteristics of AQP4 antibody-related diseases and MOG antibody-related diseases. The clinical data of 56 AQP4 antibody-positive patients and 14 MOG antibody-positive patients in the Second Xiangya Hospital of Central South University from June 2016 to June 2019 were collected. 92.9% of the patients with positive AQP4 antibody were females and 64.3% of patients with positive MOG antibody were females (P = 0.004). Patients with positive AQP4 antibody were more likely to have limb movement (P < 0.001) or limb sensory dysfunction (P < 0.001), and were more likely to have limb twitching (P = 0.036). In addition, AQP4 antibody-positive patients were more likely to have positive ANA (P = 0.013) and SSA antibody (P = 0.029), Ro-52 antibody (P = 0.047), immunoglobulin (P = 0.007), thyroid antibody (P = 0.007), abnormal C3 (P = 0.011), abnormal C4 (P = 0.014) than MOG antibody-positive patients. The involvement rate of head in MOG antibody-positive patients was higher than AQP4 antibody-positive patients (P = 0.029). The severity of clinical symptoms in AQP4-positive patients was usually more serious than that in MOG-positive patients (P < 0.001). The residual neurological deficit after treatment in AQP4-positive group was usually more serious than that in MOG-positive group (P < 0.001). AQP4 antibody-positive patients had a higher prevalence in women than MOG antibody-positive patients, and AQP4 antibody-positive patients were more likely to have spinal cord involvement symptoms and connective tissue antibody abnormalities. The EDSS score of them were higher than that of MOG antibody-positive patients after treatment, and the prognosis was worse.

Trauma-Related Guillain-Barré Syndrome: Systematic Review of an Emerging Concept.

Guillain-Barré syndrome (GBS) is mainly associated with preceding exposure to an infectious agent, although the precise pathogenic mechanisms and causes remain unknown. Increasing evidence indicates an association between trauma-related factors and GBS. Here, we performed a systematic review, summarized the current scientific literature related to the onset of GBS associated with trauma, and explored the possible pathogenesis. A literature search of various electronic databases was performed up to May 2020 to identify studies reporting diverse trauma-related triggers of GBS. Data were extracted, summarized descriptively, and evaluated with respect to possible mechanisms. In total, 100 publications, including 136 cases and 6 case series involving GBS triggered by injury, surgery, intracranial hemorrhage, and heatstroke, met our eligibility criteria. The median age of the patients was 53 [interquartile range (IQR) 45-63] years, and 72.1% of the patients were male. The median number of days between the trigger to onset of GBS symptoms was 9 (IQR 6.5-13). Overall, 121 patients (89.0%) developed post-injury/surgical GBS, whereas 13 (9.6%) and 2 (1.5%) patients had preexisting spontaneous intracranial hemorrhage and heatstroke, respectively. The main locations of injury or surgeries preceding GBS were the spine and brain. Based on available evidence, we highlight possible mechanisms of GBS induced by these triggers. Moreover, we propose the concept of "trauma-related GBS" as a new research direction, which may help uncover more pathogenic mechanisms than previously considered for typical GBS triggered by infection or vaccination.

Could Sporadic Creutzfeldt-Jakob Disease Be Underdiagnosed in China? Experience From Four Cases.

Background: Creutzfeldt-Jakob Disease (CJD) is a rapidly progressive neurodegenerative disease caused by the misfolded version of the cellular prion protein. Here we report four cases of sporadic CJD (sCJD) and describe the diagnostic methods available in order avoid missed or delayed recognition of CJD in China. Case presentation: We report four patients diagnosed with sCJD between March 2018 and December 2019 at Xiangya Hospital and the Second Xiangya Hospital of Central South University. All patients were admitted to the hospital because of a progressive cognitive decline. Although their routine tests and biochemical indicators in the cerebrospinal fluid (CSF), as well as computed tomography (CT) imaging, did not reveal any apparent abnormalities, the presence of "cortical ribboning" was incidentally found on diffusion-weighted imaging (DWI). The patients were subsequently diagnosed with CJD based on positive testing for 14-3-3 protein in their CSF, and the presence of periodic sharp and slow wave complexes (PSWCs) on their electroencephalograms (EEG). Additionally, two of patients was confirmed pathological examination of cerebral biopsies demonstrating neuronal loss, gliosis, and spongiform changes. Conclusions: CJD is a rare disease and is easily misdiagnosed by clinician in China due to a lack of recognition and awareness of CJD. Based on our experience described in this report, enhanced vigilance for CJD is required for patients with rapidly progressive dementia in China and other developing countries. DWI, EEG and detection of 14-3-3 protein in CSF should be performed in order to achieve a timely diagnosis of CJD.

miR-7-5p Affects Brain Edema After Intracerebral Hemorrhage and Its Possible Mechanism.

Objective: To explore the relationship between miR-7-5p and brain edema after intracerebral hemorrhage and the role of butylphthalide (NBP) in brain edema after intracerebral hemorrhage. Method: Routine blood testing, C-reactive protein results, and computed tomography data were collected 1, 7, and 14 days after intracerebral hemorrhage in six patients. Levels of MMP-9, ZO-1, occludin, IL-6, TNF-α, and miR-7-5p were detected in each patient's serum. Sixty male Sprague-Dawley rats were randomly divided into sham operation, intracerebral hemorrhage, and NBP treatment groups. Dry-wet weight was used to assess brain edema, and Evans blue staining was used to assess the permeability of the blood-brain barrier. Expression levels of IL-6, TNF-α, ZO-1 and occludin, PI3K, AKT, p-AKT, AQP4, and miR-7-5p were analyzed in the rat brains. Result: The blood neutrophil-lymphocyte ratio (NLR) on day 1 was associated with the area of brain edema on day 7. The expression of miR-7-5p decreased after intracerebral hemorrhage, and as a result, the inhibition of the PI3K/AKT pathway was weakened. The decreased inhibition of the PI3K/AKT pathway resulted in an increase in AQP4 expression, which further aggravated brain edema. NBP can upregulate the expression of miR-7-5p, affecting these pathways to reduce brain edema. Conclusion: After intracerebral hemorrhage, miR-7-5p expression in brain tissue is reduced, which may increase the expression of AQP4 by activating the PI3K/AKT pathway. NBP can inhibit this process and reduce brain edema.

Mcidas mutant mice reveal a two-step process for the specification and differentiation of multiciliated cells in mammals.

Motile cilia on multiciliated cells (MCCs) function in fluid clearance over epithelia. Studies with Xenopus embryos and individuals with the congenital respiratory disorder reduced generation of multiple motile cilia (RGMC), have implicated the nuclear protein MCIDAS (MCI), in the transcriptional regulation of MCC specification and differentiation. Recently, a paralogous protein, geminin coiled-coil domain containing (GMNC), was also shown to be required for MCC formation. Surprisingly, in contrast to the presently held view, we find that Mci mutant mice can specify MCC precursors. However, these precursors cannot produce multiple basal bodies, and mature into single ciliated cells. We identify an essential role for MCI in inducing deuterosome pathway components for the production of multiple basal bodies. Moreover, GMNC and MCI associate differentially with the cell-cycle regulators E2F4 and E2F5, which enables them to activate distinct sets of target genes (ciliary transcription factor genes versus basal body amplification genes). Our data establish a previously unrecognized two-step model for MCC development: GMNC functions in the initial step for MCC precursor specification. GMNC induces Mci expression that drives the second step of basal body production for multiciliation.

Distinct requirements of E2f4 versus E2f5 activity for multiciliated cell development in the zebrafish embryo.

Multiciliated cells (MCCs) differentiate arrays of motile cilia that beat to drive fluid flow over epithelia. Recent studies have established two Geminin family coiled-coil containing nuclear regulatory proteins, Gmnc and Multicilin (Mci), in the specification and differentiation of the MCCs. Both Gmnc and Mci are devoid of a DNA binding domain: they regulate transcription by associating with E2f family transcription factors, notably E2f4 and E2f5. Here, we have studied the relative contribution of these two E2f factors in MCC development using the zebrafish embryo, which differentiates MCCs within kidney tubules and the nose. We found that while E2f4 is fully dispensable, E2f5 is essential for MCCs to form in the kidney tubules. Moreover, using a variety of double mutant combinations we show that E2f5 has a more prominent role in MCC development in the zebrafish than E2f4. This contrasts with current evidence from the mouse, where E2f4 seems to be more important. Thus, distinct combinatorial activities of the E2f4 and E2f5 proteins regulate the specification and differentiation of MCCs in zebrafish and mice.

The unusual flagellar-targeting mechanism and functions of the trypanosome ortholog of the ciliary GTPase Arl13b.

The small GTPase Arl13b is one of the most conserved and ancient ciliary proteins. In human and animals, Arl13b is primarily associated with the ciliary membrane, where it acts as a guanine-nucleotide-exchange factor (GEF) for Arl3 and is implicated in a variety of ciliary and cellular functions. We have identified and characterized Trypanosoma brucei (Tb)Arl13, the sole Arl13b homolog in this evolutionarily divergent, protozoan parasite. TbArl13 has conserved flagellar functions and exhibits catalytic activity towards two different TbArl3 homologs. However, TbArl13 is distinctly associated with the axoneme through a dimerization/docking (D/D) domain. Replacing the D/D domain with a sequence encoding a flagellar membrane protein created a viable alternative to the wild-type TbArl13 in our RNA interference (RNAi)-based rescue assay. Therefore, flagellar enrichment is crucial for TbArl13, but mechanisms to achieve this could be flexible. Our findings thus extend the understanding of the roles of Arl13b and Arl13b-Arl3 pathway in a divergent flagellate of medical importance.This article has an associated First Person interview with the first author of the paper.

Transcriptional responses in the hepatopancreas of Eriocheir sinensis exposed to deltamethrin.

Deltamethrin is an important pesticide widely used against ectoparasites. Deltamethrin contamination has resulted in a threat to the healthy breeding of the Chinese mitten crab, Eriocheir sinensis. In this study, we investigated transcriptional responses in the hepatopancreas of E. sinensis exposed to deltamethrin. We obtained 99,087,448, 89,086,478, and 100,117,958 raw sequence reads from control 1, control 2, and control 3 groups, and 92,094,972, 92,883,894, and 92,500,828 raw sequence reads from test 1, test 2, and test 3 groups, respectively. After filtering and quality checking of the raw sequence reads, our analysis yielded 79,228,354, 72,336,470, 81,859,826, 77,649,400, 77,194,276, and 75,697,016 clean reads with a mean length of 150 bp from the control and test groups. After deltamethrin treatment, a total of 160 and 167 genes were significantly upregulated and downregulated, respectively. Gene ontology terms "biological process," "cellular component," and "molecular function" were enriched with respect to cell killing, cellular process, other organism part, cell part, binding, and catalytic. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes showed that the metabolic pathways were significantly enriched. We found that the CYP450 enzyme system, carboxylesterase, glutathione-S-transferase, and material (including carbohydrate, lipid, protein, and other substances) metabolism played important roles in the metabolism of deltamethrin in the hepatopancreas of E. sinensis. This study revealed differentially expressed genes related to insecticide metabolism and detoxification in E. sinensis for the first time and will help in understanding the toxicity and molecular metabolic mechanisms of deltamethrin in E. sinensis.

Transcriptome differences between enrofloxacin-resistant and enrofloxacin-susceptible strains of Aeromonas hydrophila.

Enrofloxacin is the most commonly used antibiotic to control diseases in aquatic animals caused by A. hydrophila. This study conducted de novo transcriptome sequencing and compared the global transcriptomes of enrofloxacin-resistant and enrofloxacin-susceptible strains. We got a total of 4,714 unigenes were assembled. Of these, 4,122 were annotated. A total of 3,280 unigenes were assigned to GO, 3,388 unigenes were classified into Cluster of Orthologous Groups of proteins (COG) using BLAST and BLAST2GO software, and 2,568 were mapped onto pathways using the Kyoto Encyclopedia of Gene and Genomes Pathway database. Furthermore, 218 unigenes were deemed to be DEGs. After enrofloxacin treatment, 135 genes were upregulated and 83 genes were downregulated. The GO terms biological process (126 genes) and metabolic process (136 genes) were the most enriched, and the terms for protein folding, response to stress, and SOS response were also significantly enriched. This study identified enrofloxacin treatment affects multiple biological functions of A. hydrophila. Enrofloxacin resistance in A. hydrophila is closely related to the reduction of intracellular drug accumulation caused by ABC transporters and increased expression of topoisomerase IV.

Recent patents on oligonucleotide synthesis and gene synthesis.

Gene synthesis is an emerging field which has widespread implications in synthetic biology and molecular biology. The field is constantly evolving which has led to key advances in oligonucleotide synthesis and gene synthesis technologies, with simplicity, cost effectiveness and high throughput. The miniaturization, multiplexing, microfluidic processing and the integrated microchip engineering will drive down cost and increase productivity without compromising DNA synthesis fidelity, whereas the gigantic amount of genome information provides infinite source of DNA elements and genes as raw material for synthetic biology. This article describes some of the recent patents on oligonucleotide synthesis and gene synthesis.