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Aerodynamic noise resulting from the flow around cylinders is a significant engineering challenge in aviation and wind engineering. The phenomenon of alternating vortex shedding in the flow leads to vibration and noise generation. However, accurately describing both the flow field and the sound field is challenging due to the significant difference in magnitude between them. To tackle this issue, this work introduces the application of the spectral element method (SEM) and flow-acoustic monolithic simulation for solving the two-dimensional compressible Navier–Stokes equations at low Reynolds numbers. This study is to investigate the reduction of flow-induced noise through the implementation of slotting technology on a circular cylinder. This study focuses on examining two different slit width ratios, s/d = 0.15 and 0.25, with a slit angle of attack of 0°. A comparative analysis is conducted between a complete circular cylinder and a slotted circular cylinder. The findings indicate that the slotted cylinder exhibits reduced intensity of vortex shedding and an extended region of downstream vortex generation compared to the complete cylinder. Notably, when s/d = 0.25, the slotted cylinder demonstrates minimal noise generation. Even at s/d = 0.15, a significant reduction in flow-induced noise is observed. These results highlight the potential of utilizing slotting technology on cylinders to effectively mitigate aerodynamic noise. The application of SEM and flow-acoustic monolithic simulation shows their relevance in analyzing and designing noise mitigation techniques in aerodynamics. This work can develop innovative solutions to reduce noise and improve the performance of various applications in aviation and wind engineering.

Abstract Background Multidrug resistance in Enterobacteriaceae including resistance to quinolones is rising worldwide. The development of resistance may lead to the emergence of new transmission mechanisms. In this study, the collection of different E. coli was performed from animals and subjected to subsequent procedures including pulsed-field gel electrophoresis, micro-broth dilution method, polymerase chain reaction. Whole genome sequencing of E. coli C3 was performed to detect the affinity, antimicrobial resistance and major carriers of the isolates. Results A total of 66 E. coli were isolated and their antibiotic resistance genes, frequency of horizontal transfer and genetic environment of E. coli C3 were determined. The results showed there were both different and same types in PFGE typing, indicating clonal transmission of E. coli among different animals. The detection of antimicrobial resistance and major antibiotic resistance genes and the plasmid transfer results showed that strains from different sources had high levels of resistance to commonly used clinical antibiotics and could be spread horizontally. Whole-genome sequencing discovered a novel ICE mobile element. Conclusion In summary, the antimicrobial resistance of E. coli in northeast China is a serious issue and there is a risk of antimicrobial resistance transmission. Meanwhile, a novel ICE mobile element appeared in the process of antimicrobial resistance formation.

BackgroundAggressive pituitary adenoma encircling the internal carotid artery has a poor clinical prognosis because of a high surgical risk and a high recurrence rate. This seriously affects patients’ quality of life and yet there is no effective medical treatment. The European Diagnostic Guidelines have recommended the use of temozolomide (TMZ) for these aggressive pituitary adenomas, but the treatment remission rate has been less than 50%.MethodsIn this study, transcriptome sequencing of pituitary tumour tissues and TMZ-treated pituitary tumour cell lines were employed to explore the significance gene expressions affecting the efficacy of TMZ treatment for pituitary tumours. To clarify the roles of these gene expressions, six adult patients with pituitary adenomas treated in Tiantan Hospital from 2015 to 2020 and a pituitary adenoma cell line (Att20 sensitive to TMZ treatment) were analyzed by mRNA transcriptome sequencing. The differentially expressed genes were assayed by analyzing the sequencing results, and the expression level of these genes was further verified by immunohistochemistry. In addition, Ki67, VEGF, and p53 of the tumour tissues were also verified by immunohistochemistry.ResultsIn tumour tissues, mRNA sequencing showed that PTBP1 and EIF5A were significantly overexpressed in primary pituitary adenomas and SLC27A1 was significantly overexpressed in aggressive pituitary adenomas. Also in the pituitary adenoma cell line (AtT20), SLC27A1 expression levels were suppressed by TMZ treatment. Subsequent immunohistochemistry confirmed the sequencing results.ConclusionHigh expression of SLC27A1 and low expression of EIF5A and PTBP1 may be potential indicators to predict the progression of aggressive pituitary adenomas, and patients with high SLC27A1 subtype may be sensitive to TMZ in clinical treatments.

β-arrestins are multifaceted adaptor proteins that regulate various aspects of G protein-coupled receptor (GPCR) signaling. β-arrestins are recruited to agonist-activated and phosphorylated GPCRs at the plasma membrane, thereby preventing G protein coupling, while also targeting GPCRs for internalization via clathrin-coated pits. In addition, β-arrestins can activate various effector molecules to prosecute their role in GPCR signaling; however, the full extent of their interacting partners remains unknown. To discover potentially novel β-arrestin interacting partners, we used APEX-based proximity labeling coupled with affinity purification and quantitative mass spectrometry. We appended APEX in-frame to the C-terminus of β-arrestin1 (βarr1-APEX), which we show does not impact its ability to support agonist-stimulated internalization of GPCRs. By using coimmunoprecipitation, we show that βarr1-APEX interacts with known interacting proteins. Furthermore, following agonist stimulation βarr1-APEX labeled known βarr1-interacting partners as assessed by streptavidin affinity purification and immunoblotting. Aliquots were prepared in a similar manner and analyzed by tandem mass tag labeling and high-content quantitative mass spectrometry. Several proteins were found to be increased in abundance following GPCR stimulation. Biochemical experiments confirmed two novel proteins that interact with β-arrestin1, which we predict are novel ligand-stimulated βarr1 interacting partners. Our study highlights that βarr1-APEX-based proximity labeling represents a valuable approach to identifying novel players involved in GPCR signaling.

Identifying phosphors with good thermal stability and quantum efficiency is a prerequisite to improve the performance of white LED light sources. Here, a combined machine learning and density functional theory method is introduced to identify next generation inorganic phosphors.

While arrestins are mainly associated with GPCR signaling, arrestin-3 can signal independently of receptor interaction. Here the authors present the structure of arrestin-3 bound to inositol hexakisphosphate (IP6) and propose a model for arrestin-3 activation.

Background/Aims: Age-associated and stress-induced involution of the thymus is accompanied by reduced numbers of thymic epithelial cells (TECs) and severe reduction in peripheral T cell repertoire specificities. These events seriously affect immune function, but the mechanisms involved are unclear. Our preliminary findings showed that doxycycline (Dox) could drive the proliferation of a TEC line (MTEC1 cells) partially via the MAPK signaling pathway. Dox can also up-regulate IL-6 and GM-CSF expression via the NF-κB and MAPK/ERK pathways. Herein, we investigate the effects and mechanisms used by Dox that protect against mitomycin C (MMC)-induced MTEC1 cell apoptosis. Methods: MTEC1 cells were treated with Dox, MMC, and Dox plus MMC for different amounts of time. The expression of Trx2, NF-κB, Bcl-2, and Bax proteins were then detected by western blotting. Results: Our findings show that Dox protects MTEC1 cells from MMC-induced apoptosis. Dox up-regulated the expression of Trx2 and promoted NF-κB phosphorylation. Meanwhile, Dox also increased the expression of Bcl-2, partially reduced the expression of Bax, and normalized the ratio of Bcl-2 to Bax. Conclusion: Dox exerts an anti-apoptosis function via the NF-κB-Bcl-2/Bax and Trx2-ASK1/JNK pathways in vitro. Therefore, Dox may represent a drug that could be used to attenuate thymic senescence, rescue thymic function, and promote T cell reconstitution.

Cell survival depends on the balance between protective and apoptotic signals. When the balance of signals tips towards apoptosis, cells undergo programmed cell death. This balance has profound implications in diseases including cancer. Oncogenes and tumor suppressors are mutated to promote cell survival during tumor development, and many chemotherapeutic drugs kill tumor cells by stimulating apoptosis. BAD is a pro-apoptotic member of the Bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to Bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. One of the critical phosphorylation sites is the serine 112 (S112), which can be phosphorylated by several kinases including Pak1.We mapped the Pak phosphorylation sites by making serine to alanine mutations in BAD and testing them as substrates in in vitro kinase assays. We found that the primary phosphorylation site is not S112 but serine 111 (S111), a site that is sometimes found phosphorylated in vivo. In transfection assays of HEK293T cells, we showed that Pak1 required Raf-1 to stimulate phosphorylation on S112. Mutating either S111 or S112 to alanine enhanced binding to Bcl-2, but the double mutant S111/112A bound better to Bcl-2. Moreover, BAD phosphorylation at S111 was observed in several other cell lines, and treating one of them with the Pak1 inhibitor 2,2'-Dihydroxy-1,1'-dinaphthyldisulfide (IPA-3) reduced phosphorylation primarily at S112 and to a smaller extent at S111, while Raf inhibitors only reduced phosphorylation at S112.Together, these findings demonstrate that Pak1 phosphorylates BAD directly at S111, but phosphorylated S112 through Raf-1. These two sites of BAD serve as redundant regulatory sites for Bcl-2 binding.

Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).

Teunia, belonging to the family Cryptococcaceae of the order Tremellales, is a genus of plant-inhabiting fungi distributed across the globe. Its members form associations with different plant parts, including flowers, fruits, leaves, seeds, and twigs. Recent efforts have aimed to explore the diversity of Teunia in China, however, many geographical regions have not yet been explored. In this study, we included results of five Teunia yeast strains that were isolated from plant materials collected in Fujian, Guizhou and Henan provinces, with descriptions, illustrations, and phylogenetic analyses of three new species: T. acericola, T. mussaendrae isolated from leaf surfaces in Fujian, Guizhou and Henan Provinces, and T. qingyuanensis obtained from rotting wood in Fujian Province. [ABSTRACT FROM AUTHOR]

Migraine without aura (MWoA) is a major neurological disorder with unsatisfactory adherence to current medications. Acupuncture has emerged as a promising method for treating MWoA. However, the brain mechanism underlying acupuncture is yet unclear. The present study aimed to examine the effects of acupuncture in regulating brain connectivity of the key regions in pain modulation. In this study, MWoA patients were recruited and randomly assigned to 4 weeks of real or sham acupuncture. Resting-state functional magnetic resonance imaging (fMRI) data were collected before and after the treatment. A modern neuroimaging literature meta-analysis of 515 fMRI studies was conducted to identify pain modulation-related key regions as regions of interest (ROIs). Seed-to-voxel resting state-functional connectivity (rsFC) method and repeated-measures two-way analysis of variance were conducted to determine the interaction effects between the two groups and time (baseline and post-treatment). The changes in rsFC were evaluated between baseline and post-treatment in real and sham acupuncture groups, respectively. Clinical data at baseline and post-treatment were also recorded in order to determine between-group differences in clinical outcomes as well as correlations between rsFC changes and clinical effects. 40 subjects were involved in the final analysis. The current study demonstrated significant improvement in real acupuncture vs sham acupuncture on headache severity (monthly migraine days), headache impact (6-item Headache Impact Test), and health-related quality of life (Migraine-Specific Quality of Life Questionnaire). Five pain modulation-related key regions, including the right amygdala (AMYG), left insula (INS), left medial orbital superior frontal gyrus (PFCventmed), left middle occipital gyrus (MOG), and right middle cingulate cortex (MCC), were selected based on the meta-analysis on brain imaging studies. This study found that 1) after acupuncture treatment, migraine patients of the real acupuncture group showed significantly enhanced connectivity in the right AMYG/MCC-left MTG and the right MCC-right superior temporal gyrus (STG) compared to that of the sham acupuncture group; 2) negative correlations were established between clinical effects and increased rsFC in the right AMYG/MCC-left MTG; 3) baseline right AMYG-left MTG rsFC predicts monthly migraine days reduction after treatment. The current results suggested that acupuncture may concurrently regulate the rsFC of two pain modulation regions in the AMYG and MCC. MTG and STG may be the key nodes linked to multisensory processing of pain modulation in migraine with acupuncture treatment. These findings highlighted the potential of acupuncture for migraine management and the mechanisms underlying the modulation effects.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21–1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15–2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19–1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5–100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention. [ABSTRACT FROM AUTHOR]

Objective To evaluate the expression of P62 protein in the characteristic pathological changes of common neurodegenerative diseases and to explore its significance in pathological diagnosis. Methods Eleven cases of neurodegenerative diseases and 3 normal controls which were clinically and pathologically diagnosed from June 1994 to October 2017 were included. The neurodegenerative diseases consisted of 5 cases of Alzheimer's disease (AD) and 2 of which were diagnosed as AD combined with argyrophilic grain disease (AGD), 3 cases of Parkinson's disease (PD), 2 cases of progressive supranuclear palsy (PSP) and 1 case of multiple system atrophy (MSA). Three cases without neurological symptoms, signs and brain pathological changes were used as the normal control. Brain tissues were stained with HE, luxol fast blue (LFB) and Gallyas-Braak silver staining, as well as antibodies to amyloid β-protein (Aβ), AT8, α-synuclein and P62. The staining results were compared under microscope. Results P62 protein was present in the neurofibrillary tangles of AD, in the Lewy body and Lewy neurites of PD, in the tufted astrocyte of PSP, in the argyrophilic grain of AGD and in the glial cytoplasmic inclusion of MSA. The morphological characteristics were consistent with the results of staining with specific antibodies. P62 protein was only expressed in a small amount in the neuritic plaque of AD, and the diffuse plaques were negative. In addition, P62 protein was also deposited in corpora amylacea. No positive pathological structure of P62 immunohistochemical staining was found in normal control brain tissues. Conclusions The P62 protein is expressed in the characteristic pathological changes and corpora amylacea of AD, PD, PSP, MSA and other diseases. Morphological staining results are consistent with histology of various neurodegenerative diseases and corresponding specific protein expression staining results. So the P62 antibody is recommended as the aiding pathological diagnosis of neurodegenerative diseases.

Objective To summarize clinical experience of endoscopic transnasal surgery for treatment of cerebrospinal fluid (CSF) rhinorrhea. Methods From April 2011 to August 2018, 24 cases of CSF rhinorrhea patients were treated by endoscopic transnasal surgery. There were 11 (45.83%) iatrogenic injuries caused by transcranial microsurgical resection of craniopharyngioma (6 cases), endoscopic transnasal surgery for resection of pituitary adenoma (4 cases), or endoscopic transnasal surgery for optic canal decompression (one case). There were also 10 cases (41.67%) of traumatic and 3 cases (12.50%) of spontaneous CSF rhinorrhea. The leaks were located by preoperative CT, MRI, CT cisternography and MR hydrography. Endoscopic transnasal surgery for CSF rhinorrhea repair was performed. Results A total of 27 leaks were found by endoscopy in 24 cases, including 14 iatrogenic, 10 traumatic and 3 spontaneous. They were repaired by materials such as dissociated mucosal flaps, pedicled mucosal flaps, muscle tissue, fat tissue, fascia lata or artificial dura mater via unilateral or bilateral transethmoid, transnaso-sphenoidal or transnasal prelacrimal recess-pterygoid approaches. The success rate of the first operation was 91.67% (22/24), and the success rate of the second operation was 8.33% (2/24), therefore the total success rate was 100%. Two patients (8.33%) suffered from postoperative meningitis, and were cured by intrathecal injection of antibiotics and lumbar cistern drainage. All patients were followed-up for average 20 months, and no one relapsed. Conclusions Endoscopic transnasal approach is an effective technique for treating CSF rhinorrhea. It has the advantages of accurate location, small trauma, less postoperative complications and so on. Lumbar puncture or lumbar cistern drainage helps to improve the effect of surgery. DOI: 10.3969/j.issn.1672-6731.2019.04.007