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Background: Acupuncture, as an alternative and complementary therapy recommended by the World Health Organization for stroke treatment, holds potential in ameliorating neurofunctional deficits induced by ischemic stroke (IS). Understanding the immediate and long-term effects of acupuncture and their interrelation would contribute to a better comprehension of the mechanisms underlying acupuncture efficacy. Methods: Activation likelihood estimation (ALE) meta-analysis was used to analyze the brain activation patterns reported in 21 relevant functional neuroimaging studies. Among these studies, 12 focused on the immediate brain activation and 9 on the long-term activation. Single dataset analysis were employed to identify both immediate and long-term brain activation of acupuncture treatment in IS patients, while contrast and conjunction analysis were utilized to explore distinctions and connections between the two. Results: According to the ALE analysis, immediately after acupuncture treatment, IS patients exhibited an enhanced cluster centered around the right precuneus (PCUN) and a reduced cluster centered on the left middle frontal gyrus (MFG). After long-term acupuncture treatment, IS patients showed an enhanced cluster in the left PCUN, along with two reduced clusters in the right insula (INS) and hippocampus (HIP), respectively. Additionally, in comparison to long-term acupuncture treatment, the right angular gyrus (ANG) demonstrated higher ALE scores immediately after acupuncture, whereas long-term acupuncture resulted in higher scores in the left superior parietal gyrus (SPG). The intersecting cluster activated by both of them was located in the left cuneus (CUN). Conclusion: The findings provide initial insights into both the immediate and long-term brain activation patterns of acupuncture treatment for IS, as well as the intricate interplay between them. Both immediate and long-term acupuncture treatments showed distinct patterns of brain activation, with the left CUN emerging as a crucial regulatory region in their association. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42023480834.
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Precise measurement of the binding activity changes of therapeutic antibodies is important to determine the potential critical quality attributes (CQAs) in developability assessment at the early stage of antibody development. Here, we report a surface plasmon resonance (SPR)-based relative binding activity method, which incorporates both binding affinity and binding response and allows us to determine relative binding activity of antibodies with high accuracy and precision. We applied the SPR-based relative binding activity method in multiple forced degradation studies of antibody developability assessment. The current developability assessment strategy provided comprehensive, precise characterization of antibody binding activity in the stability studies, enabling us to perform correlation analysis and establish the structure-function relationship between relative binding activity and quality attributes. The impact of a given quality attribute on binding activity could be confidently determined without isolating antibody variants. We identified several potential CQAs, including Asp isomerization, Asn deamidation, and fragmentation. Some potential CQAs affected binding affinity of antibody and resulted in a reduction of binding activity. Certain potential CQAs impaired antibody binding to antigen and led to a loss of binding activity. A few potential CQAs could influence both binding affinity and binding response and cause a substantial decrease in antibody binding activity. Specifically, we identified low abundance Asn33 deamidation in the light chain complementarity-determining region as a potential CQA, in which all the stressed antibody samples showed Asn33 deamidation abundances ranging from 4.2% to 27.5% and a mild binding affinity change from 1.76 nM to 2.16 nM.
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Anticorpos Monoclonais , Ressonância de Plasmônio de Superfície , Ressonância de Plasmônio de Superfície/métodos , Humanos , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Afinidade de Anticorpos , Ligação Proteica , AnimaisRESUMO
Introduction Nodular pulmonary amyloidosis (NPA) is a localized form of AL amyloidosis often found incidentally and typically has an indolent and benign disease course treated with resection or local excision. We present a patient with recurrent localized AL amyloidosis who required further treatment. Case Description A 63-year-old female with MGUS was found to have pulmonary AL amyloid on wedge resection and later had recurrence. The patient did not have signs of a clonal plasma cell proliferation or systemic AL amyloid. She was treated with Daratumumab, Cyclophosphamide, Bortezomib, and Dexamethasone. After initiation of treatment the patient has had significant hematologic and radiographic response. Conclusion The patient had nodular pulmonary amyloidosis recurrence with organ dysfunction without systemic disease. Because the presentation of recurrent pulmonary AL amyloidosis is rare there is no published evidence on treatment. However, the patient has had hematologic and radiographic improvement after initiating treatment with a systemic protocol.
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OBJECTIVE: As the population ages and technology advances, lateral lumbar intervertebral fusion (LLIF) is gaining popularity for the treatment of degenerative lumbar scoliosis (DLS). This study investigated the feasibility, minimally invasive concept, and benefits of LLIF for the treatment of DLS by observing and assessing the clinical efficacy, imaging changes, and complications following the procedure. METHODS: A retrospective analysis was performed for 52 DLS patients (12 men and 40 women, aged 65.84 ± 9.873 years) who underwent LLIF from January 2019 to January 2023. The operation time, blood loss, complications, clinical efficacy indicators (visual analogue scale [VAS], Oswestry disability index [ODI], and 36-Item Short Form Survey), and imaging indicators (coronal position: Cobb angle and center sacral vertical line-C7 plumbline [CSVL-C7PL]; and sagittal position: sagittal vertical axis [SVA], lumbar lordosis [LL], pelvic incidence angle [PI], and thoracic kyphosis angle [TK] were measured). All patients were followed up. The above clinical evaluation indexes and imaging outcomes of patients postoperatively and at last follow-up were compared to their preoperative results. RESULTS: Compared to the preoperative values, the Cobb angle and LL angle were significantly improved after surgery (p < 0.001). Meanwhile, CSVL-C7PL, SVA, and TK did not change much after surgery (p > 0.05) but improved significantly at follow-up (p < 0.001). There was no significant change in PI at either the postoperative or follow-up timepoint. The operation took 283.90 ± 81.62 min and resulted in a total blood loss of 257.27 ± 213.44 mL. No significant complications occurred. Patients were followed up for to 21.7 ± 9.8 months. VAS, ODI, and SF-36 scores improved considerably at postoperative and final follow-up compared to preoperative levels (p < 0.001). After surgery, the Cobb angle and LL angle had improved significantly compared to preoperative values (p < 0.001). CSVL-C7PL, SVA, and TK were stable after surgery (p > 0.05) but considerably improved during follow-up (p < 0.001). PI showed no significant change at either the postoperative or follow-up timepoints. CONCLUSION: Lateral lumbar intervertebral fusion treatment of DLS significantly improved sagittal and coronal balance of the lumbar spine, as well as compensatory thoracic scoliosis, with good clinical and radiological findings. Furthermore, there was less blood, less trauma, and quicker recovery from surgery.
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Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.
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Antivirais , Picornaviridae , Pró-Fármacos , Infecções por Vírus Respiratório Sincicial , Animais , Antivirais/farmacologia , Antivirais/química , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/síntese química , Chlorocebus aethiops , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Humanos , Picornaviridae/efeitos dos fármacos , Relação Estrutura-Atividade , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Descoberta de Drogas , Nucleosídeos/química , Nucleosídeos/farmacologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/virologiaRESUMO
The field of cancer immunotherapy has experienced significant progress, resulting in the emergence of numerous biological drug candidates requiring in vivo efficacy testing and a better understanding of their mechanism of action (MOA). Humanized immune system (HIS) models are valuable tools in this regard. However, there is a lack of systematic guidance on HIS modeling. To address this issue, the present study aimed to establish and optimize a variety of HIS models for immune-oncology (IO) study, including genetically engineered mouse models and HIS models with human immune components reconstituted in severely immunocompromised mice. The efficacy and utility of these models were tested with several marketed or investigational IO drugs according to their MOA, followed by immunophenotypic analysis and efficacy evaluation. The results of the present study demonstrated that the HIS models responded to various IO drugs as expected and that each model had unique niches, utilities and limitations. Researchers should carefully choose the appropriate models based on the MOA and the targeted immune cell populations of the investigational drug. The present study provides valuable methodologies and actionable technical guidance on designing, generating or utilizing appropriate HIS models to address specific questions in translational IO.
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Modelos Animais de Doenças , Imunoterapia , Neoplasias , Animais , Humanos , Camundongos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Camundongos TransgênicosRESUMO
BACKGROUND: Electroacupuncture (EA) is considered as an effective treatment for urinary retention (UR). METHODS: Up to April 7, 2023, randomized controlled trials (RCTs) of EA for UR were extensively searched in 8 databases, including Pubmed, Cochrane, Embase, Web of Science, Chinese Biomedical Literature Database, Chinese Journal Full-text Database, Wanfang Data, and VIP Full-text e-Journals Database. The Cochrane Risk of Bias tool and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) were utilized to evaluate the quality of all included RCTs. Meta-analysis was conducted using Stata 15.0 software. RESULTS: A total of 23 trials were included, and the meta-analysis results suggested that compared with the control group, EA can effectively treat various types of UR (risk ratio [RR]â =â 1.22, 95CI%: 1.14, 1.31) and promote bladder function recovery, with a significant reduce in residual urine volume (weighted mean differences [WMD]â =â -49.60, 95CI%: -64.10, -35.11), an increase in maximum bladder capacity (WMDâ =â 47.00, 95CI%: 12.76, 81.24), a shorten in the first urination time (standardized mean difference [SMD]â =â -1.42, 95CI%: -2.08, -0.76), and less adverse reactions (RRâ =â 0.21, 95CI%: 0.07, 0.65). CONCLUSION: EA has significant advantages in treating UR, but the efficacy and safety are still needed to be further verified through large-sample and high-quality RCTs.
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Eletroacupuntura , Retenção Urinária , Retenção Urinária/terapia , Eletroacupuntura/métodos , Eletroacupuntura/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Micção/fisiologiaRESUMO
The purpose of this study was to thoroughly evaluate the clinical features and surgical options for high-grade squamous intraepithelial lesions (HSIL) in postmenopausal women. A total of 308 patients diagnosed with HSIL through colposcopic cervical biopsy and endocervical curettage were included. Their clinical characteristics, surgical treatments, and postoperative pathology were analyzed. Key findings include: 1. Patients with positive preoperative thinprep cytologic test (TCT) results and postoperative pathology indicating HSIL or squamous cell carcinoma (≥HSIL) were significantly more frequent than those with negative preoperative TCT results (Pâ <â .05). 2. Univariate analysis indicated significant impacts of TCT, human papillomavirus (HPV) type, transformation zone (TZ) location, and surgical technique on postoperative pathology (Pâ <â .05). 3. Logistic regression analysis confirmed significant influences of TCT, HPV type, TZ location, and surgical method on postoperative pathology outcomes (Pâ <â .05), showing that each unit increase in TZ raised the probability of ≥HSIL in postoperative pathology by 49.7%. In surgical comparisons, cold knife conization (CKC) and extrafascial hysterectomy resulted in 8.379 and 4.427 times higher probabilities of ≥HSIL in postoperative pathology, respectively, compared to loop electrosurgical excision procedure (LEEP). 4. Surgical methods significantly influenced margin results (Pâ <â .05). After LEEP, 17.5% of cases had positive margins, compared to 9.4% after CKC, and 3.7% after extrafascial hysterectomy, indicating the highest rate of positive surgical margins occurred with LEEP. 1. Combined TCT and HPV screening is crucial for cervical cancer prevention, early detection, and management in postmenopausal women. Women with positive results for both TCT and HPV should undergo colposcopic cervical biopsy and endocervical curettage. 2. For patients with TZ3, CKC is the recommended surgical option. 3. CKC is the preferred treatment for postmenopausal women with HSIL, as it effectively diagnoses and treats the lesion, showing superior outcomes in managing postmenopausal HSIL.
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Pós-Menopausa , Lesões Intraepiteliais Escamosas Cervicais , Neoplasias do Colo do Útero , Humanos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/diagnóstico , Lesões Intraepiteliais Escamosas Cervicais/cirurgia , Lesões Intraepiteliais Escamosas Cervicais/patologia , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico , Idoso , Conização/métodos , Colposcopia/métodos , Histerectomia/métodos , Infecções por Papillomavirus/cirurgia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/diagnóstico , Colo do Útero/patologia , Colo do Útero/cirurgia , Biópsia/métodos , Displasia do Colo do Útero/cirurgia , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologiaRESUMO
BACKGROUND: Electroacupuncture is often used to treat insomnia. OBJECTIVE: To evaluate the efficacy and safety of electroacupuncture for insomnia. SEARCH STRATEGY: Databases including PubMed, Cochrane Library, Embase, Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang Data and VIP Full-text e-Journals Database were searched up to January 15, 2023. INCLUSION CRITERIA: Randomized clinical trials were included if they compared the clinical efficacy and safety of electroacupuncture with sham acupuncture, no treatment or usual care (UC) and general acupuncture. DATA EXTRACTION AND ANALYSIS: The full texts of the studies were reviewed to remove ineligible literature. The extracted data included authors, publication year, diagnostic criteria, sample size, population characteristics, interventions and outcomes. The above steps were performed independently by two reviewers and the data were cross-checked. Stata15.0 software was used to analyze the extracted outcome data. For continuous data (Pittsburgh Sleep Quality Index [PSQI] score and Insomnia Severity Index score), weighted mean difference (WMD) was calculated and 95% confidence interval (CI) was reported when the same scale was applied. For dichotomous variables (clinical response rate and adverse events), a meta-analysis was performed using risk ratio (RR) as the effect indicator. RESULTS: Thirty-one trials with 2226 subjects were included. The meta-analysis suggested that electroacupuncture was more effective in improving insomnia compared with the control group (sham acupuncture, no treatment, UC and general acupuncture) (RR = 1.21; 95% CI: [1.16, 1.27]), significantly reducing the PSQI score in insomnia patients after treatment and at follow-up (WMD = -3.23; 95% CI: [-4.29, -2.17]; P < 0.001). There was no significant difference in the incidence of adverse events between the EA and control groups (sham acupuncture and no treatment or UC. RR = 1.48; 95% CI: [0.91, 2.40]; P = 0.117). In addition, the regression results revealed that receiving electroacupuncture for seven to nine weeks provided the best efficacy (P < 0.05). CONCLUSION: Electroacupuncture can significantly promote better sleep quality in insomnia patients and is suitable for the treatment of various types of insomnia. However, the articles included were single-center trials with small sample sizes, and some articles were of poor quality. Therefore, further research is still needed to confirm these findings. Please cite this article as: Xu HY, Wu LN, Zhang Y, Ba T, Zhao XF. Efficacy and safety of electroacupuncture for insomnia: A systematic review and meta-analysis. J Integr Med. 2024; 22(4): 460-473.
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Eletroacupuntura , Distúrbios do Início e da Manutenção do Sono , Eletroacupuntura/efeitos adversos , Humanos , Distúrbios do Início e da Manutenção do Sono/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
With the increasing frequency of global heatwaves, the incidence of heatstroke (HS) is significantly rising. The liver plays a crucial role in metabolism and is an organ highly sensitive to temperature. Acute liver injury (ALI) frequently occurs in patients with HS, yet the exact mechanisms driving ALI in HS are still unknown. In this basic study, we investigated the specific molecular mechanisms by which cytosolic phospholipase A2 (cPLA2) mediates ferroptosis, contributing to the development of ALI following HS. We utilized a mouse model of HS and divided the mice into healthy control and HS groups for a series of experiments. Firstly, we assessed oxidative damage markers in tissues and cells, as well as ferroptosis biomarkers. Additionally, we conducted a non-targeted metabolomics analysis to validate the role of key enzymes in metabolism and the ferroptosis pathway. Our results indicated that ferroptosis contributed to the progression of ALI after HS. Administering the ferroptosis inhibitor liproxstatin-1 (10 mg/kg) post-HS onset significantly inhibits HS-induced ALI progression. Mechanistically, heatstroke triggered cPLA2 activation and increased the levels of its metabolic product, arachidonic acid, thereby further promoted the occurrence of ferroptosis. Furthermore, heatstroke mediated cPLA2 activation might involve enhancing transient receptor potential vanilloid subtype 1 (TRPV1) receptor function. Overall, these results highlighted the critical role that cPLA2-mediated ferroptosis plays in the development of ALI following HS, indicating that inhibiting cPLA2 may present a novel therapeutic approach to prevent ALI after HS by limiting liver cell death.
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Ácido Araquidônico , Ferroptose , Golpe de Calor , Canais de Cátion TRPV , Animais , Humanos , Masculino , Camundongos , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/metabolismo , Ácido Araquidônico/metabolismo , Modelos Animais de Doenças , Golpe de Calor/metabolismo , Golpe de Calor/patologia , Fígado/patologia , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Fosfolipases A2 Citosólicas/metabolismo , Quinoxalinas , Transdução de Sinais , Compostos de Espiro , Canais de Cátion TRPV/metabolismoRESUMO
Superhydrophobic materials are attractive for industrial development but plagued by poor mechanical stability. Herein, a superdurable full-life superhydrophobic composite block is designed and fabricated by embedding near-zero contractive superhydrophobic silica aerogel into a rigid iron-nickel foam structured similarly to a regular dodecahedron. The synergistic protection afforded by these materials ensures superrobust mechanical stability for the composite block, which features a high compressive strength of up to ≈7.4 MPa, and ultralow Taber abrasion of down to ≈0.567 mm after withstanding 50 000 cycles, and highly efficient water harvesting capability of up to ≈3114.3 mg min-1 cm-2 at a supercooling degree of 40 K. This robust material system provides a novel strategy to design superhydrophobic materials capable of withstanding extreme conditions, including high temperature, humidity, pressure, and abrasion.
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Bipolaris setariae is known to cause brown stripe disease in sugarcane, resulting in significant yield losses. Silicon (Si) has the potential to enhance plant growth and biotic resistance. In this study, the impact of Si on brown stripe disease was investigated across susceptible and resistant sugarcane varieties, utilizing four Si concentrations (0, 15, 30, and 45 g per barrel of Na2SiO3·5H2O). Si significantly reduced the incidence of brown stripe disease (7.41-59.23%) and alleviated damage to sugarcane growth parameters, photosynthetic parameters, and photosynthetic pigments. Submicroscopic observations revealed that Si induced the accumulation of silicified cells in leaves, reduced spore accumulation, decreased stomatal size, and protected organelles from B. setariae damage. In addition, Si increased the activity of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase), reduced reactive oxygen species production (malondialdehyde and hydrogen peroxide) and modulated the expression of genes associated with hormone signalling (PR1, TGA, AOS, AOC, LOX, PYL8, and SnRK2), leading to the accumulation of abscisic acid and jasmonic acid and inhibiting SA synthesis. Si also activated the activity of metabolism-related enzymes (polyphenol oxidase and phenylalanine ammonia lyase) and the gene expression of PAL-dependent genes (PAL, C4H, and 4CL), regulating the accumulation of metabolites, such as chlorogenic acid and lignin. The antifungal test showed that chlorogenic acid (15ug µL-1) had a significant inhibitory effect on the growth of B. setariae. This study is the first to demonstrate the inhibitory effect of Si on B. setariae in sugarcane, highlighting Si as a promising and environmentally friendly strategy for managing brown stripe disease.
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Doenças das Plantas , Reguladores de Crescimento de Plantas , Espécies Reativas de Oxigênio , Saccharum , Silício , Saccharum/efeitos dos fármacos , Saccharum/metabolismo , Saccharum/microbiologia , Saccharum/genética , Saccharum/crescimento & desenvolvimento , Silício/farmacologia , Silício/metabolismo , Doenças das Plantas/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Folhas de Planta/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/microbiologia , Folhas de Planta/genética , Ascomicetos/fisiologia , Ascomicetos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Sequestradores de Radicais Livres/metabolismoRESUMO
Diagnostic features in near-infrared reflectance spectroscopy (NIRS) are the foundation of knowledge-based approach of petroleum hydrocarbon determination. However, a significant challenge arises when analyzing samples with low levels of petroleum hydrocarbon pollution, as they often lack distinctive diagnostic features in their sample NIRS spectra, limiting the effectiveness of this approach. To address this issue, we have developed a technical workflow for diagnostic spectrum construction and parameterization based on spectral subtraction. This method was applied on a set of NIRS spectra from soil samples that were contaminated with petroleum hydrocarbons (ranged between 178 and 1716 mg/kg of total petroleum hydrocarbon). Then two diagnostic features for low-level petroleum hydrocarbon pollution were found: (1) An overall downward concave emerged on diagnostic spectrum within both 2290-2370 nm and 1700-1780 nm for all low pollution levels even below 200 mg/kg; (2) An indicative pattern of asymmetric "W-shaped" double absorption valley occurred for those exceeding 1000 mg/kg, and its valleys located near 2310 nm, 2348 nm or 1727 nm, 1762 nm stably. These two features on diagnostic spectrum could be parameterized to detect, and the detection limit was at least about 10-50 times lower than that based on sample spectrum. These findings update our understanding on the detectability of spectral response from low petroleum hydrocarbon pollution, and widely extend the application of knowledge-based NIRS approach in either field detection or remote sensing identification for environmental management.
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Integration of extracellular signals by neurons is pivotal for brain development, plasticity, and repair. Axon guidance relies on receptor-ligand interactions crosstalking with extracellular matrix components. Semaphorin-5A (Sema5A) is a bifunctional guidance cue exerting attractive and inhibitory effects on neuronal growth through the interaction with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs), respectively. Sema5A harbors seven thrombospondin type-1 repeats (TSR1-7) important for GAG binding, however the underlying molecular basis and functions in vivo remain enigmatic. Here we dissect the structural basis for Sema5A:GAG specificity and demonstrate the functional significance of this interaction in vivo. Using x-ray crystallography, we reveal a dimeric fold variation for TSR4 that accommodates GAG interactions. TSR4 co-crystal structures identify binding residues validated by site-directed mutagenesis. In vitro and cell-based assays uncover specific GAG epitopes necessary for TSR association. We demonstrate that HS-GAG binding is preferred over CS-GAG and mediates Sema5A oligomerization. In vivo, Sema5A:GAG interactions are necessary for Sema5A function and regulate Plexin-A2 dependent dentate progenitor cell migration. Our study rationalizes Sema5A associated developmental and neurological disorders and provides mechanistic insights into how multifaceted guidance functions of a single transmembrane cue are regulated by proteoglycans.
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Glicosaminoglicanos , Semaforinas , Glicosaminoglicanos/metabolismo , Proteoglicanas/metabolismo , Heparitina Sulfato/metabolismo , Movimento Celular , Semaforinas/genética , Semaforinas/metabolismoRESUMO
Upon peripheral nervous system (PNS) injury, severed axons undergo rapid SARM1-dependent Wallerian degeneration (WD). In mammals, the role of SARM1 in PNS regeneration, however, is unknown. Here we demonstrate that Sarm1 is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site. However, in the distal nerve, Sarm1 is necessary for the timely induction of the Schwann cell (SC) repair response, nerve inflammation, myelin clearance, and regeneration of sensory and motor axons. In Sarm1-/- mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment of Sarm1-/- distal nerve tissue was demonstrated by grafting of Sarm1-/- nerve into WT recipients. SC lineage tracing in injured WT and Sarm1-/- mice revealed morphological differences. In the Sarm1-/- distal nerve, the appearance of p75NTR+, c-Jun+ SCs is significantly delayed. Ex vivo, p75NTR and c-Jun upregulation in Sarm1-/- nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show that Sarm1 is not necessary for the activation of neuron intrinsic growth programs but in the distal nerve is required for the orchestration of cellular programs that underlie rapid axon extension.
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In order to realize the measurement of three-axis acceleration, pressure, and magnetic field, monolithic integrated three-axis acceleration/pressure/magnetic field sensors are proposed in this paper. The proposed sensors were constructed with an acceleration sensor consisting of four L-shaped double beams, two masses, middle double-beams, and twelve piezoresistors, a pressure sensor made of a square silicon membrane, and four piezoresistors, as well as a magnetic field sensor composed of five Hall elements. COMSOL software and TCAD-Atlas software were used to simulate characteristics of integrated sensors, and analyze the working principles of the sensors in measuring acceleration, pressure, and magnetic field. The integrated sensors were fabricated by using micro-electro-mechanical systems (MEMS) technology and packaged by using inner lead bonding technology. When applying a working voltage of 5 V at room temperature, it is possible for the proposed sensors to achieve the acceleration sensitivities of 3.58 mV/g, 2.68 mV/g, and 9.45 mV/g along the x-axis, y-axis, and z-axis (through an amplifying circuit), and the sensitivities towards pressure and magnetic field are 0.28 mV/kPa and 22.44 mV/T, respectively. It is shown that the proposed sensors can measure three-axis acceleration, pressure, and magnetic field.
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In adult mammals, injured retinal ganglion cells (RGCs) fail to spontaneously regrow severed axons, resulting in permanent visual deficits. Robust axon growth, however, is observed after intra-ocular injection of particulate ß-glucan isolated from yeast. Blood-borne myeloid cells rapidly respond to ß-glucan, releasing numerous pro-regenerative factors. Unfortunately, the pro-regenerative effects are undermined by retinal damage inflicted by an overactive immune system. Here, we demonstrate that protection of the inflamed vasculature promotes immune-mediated RGC regeneration. In the absence of microglia, leakiness of the blood-retina barrier increases, pro-inflammatory neutrophils are elevated, and RGC regeneration is reduced. Functional ablation of the complement receptor 3 (CD11b/integrin-αM), but not the complement components C1q-/- or C3-/-, reduces ocular inflammation, protects the blood-retina barrier, and enhances RGC regeneration. Selective targeting of neutrophils with anti-Ly6G does not increase axogenic neutrophils but protects the blood-retina barrier and enhances RGC regeneration. Together, these findings reveal that protection of the inflamed vasculature promotes neuronal regeneration.
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Traumatismos do Nervo Óptico , beta-Glucanas , Animais , Neutrófilos , Regeneração Nervosa/fisiologia , Células Ganglionares da Retina/fisiologia , Axônios/fisiologia , MamíferosRESUMO
In nonclinical toxicology studies, lab animals are fasted typically overnight, to reduce variability in some clinical pathology parameters. However, fasting adds undue stress, and this is particularly concerning in rodents given their fast metabolic rates. Furthermore, as rodents are nocturnal animals, an overnight fasting may cause a protracted negative metabolic state even when the fasting has technically ended, given their minimal activity and food consumption during the day. Therefore, to evaluate the impacts of different fasting durations (±DietGel supplementation) on rats' welfare, we assessed the traditional and ancillary clinical pathology parameters in Sprague-Dawley rats, along with body weight, organ weight, and histopathology. Although most endpoints were comparable between the different fasting durations (±DietGel supplementation), the long fasting times (≥8 hr) without DietGel supplementation caused significant decreases in body weight, liver weight, liver glycogen content, serum glucose, triglyceride, and creatinine concentrations-all findings suggestive of a negative energy balance that could impact animal welfare and consequently, data quality; while the short fasting time (4 hr) and DietGel supplementation were associated with higher triglycerides variability. Hence, we propose that short fasting time should be adequate for most toxicology studies in rats, and long fasting times should only be accommodated with scientific justification.
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Bem-Estar do Animal , Peso Corporal , Jejum , Ratos Sprague-Dawley , Animais , Jejum/fisiologia , Masculino , Ratos , Tamanho do Órgão , Fígado/metabolismo , Feminino , Suplementos Nutricionais , GlicemiaRESUMO
Solid materials with ultra-low thermal conductivity (κ) are of great interest in thermoelectrics for energy conversion or as thermal barrier coatings for thermal insulation. Many low-κ materials exhibit unique properties, such as weak or even insignificant dependence on temperature (T) for κ, i.e., an anomalous glass-like behavior. However, a comprehensive theoretical model elucidating the microscopic phonon mechanism responsible for the glass-like κ-T relationship is still absent. Herein, we take rare-earth tantalates (RE3TaO7) as examples to reexamine phonon thermal transport in defective crystals. By combining experimental studies and atomistic simulations up to 1800 K, we revealed that diffusion-like phonons related to inhomogeneous interatomic bonding contribute more than 70% to the total κ, overturning the conventional understanding that low-frequency phonons dominate heat transport. Furthermore, due to the bridging effects of interatomic bonding, the κ of high-entropy tantalates is not necessarily lower than that of medium-entropy materials, suggesting that attempts to reduce κ through high-entropy engineering are limited, at least in defective fluorite tantalates. The new physical mechanism of multimodal phonon thermal transport in defective structures demonstrated in this work provides a reference for the analysis of phonon transport and offers a new strategy to develop and design low-κ materials by regulating the inhomogeneity of interatomic bonding.