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1.
Proc Natl Acad Sci U S A ; 121(1): e2313171120, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38147553

RESUMO

Networks allow us to describe a wide range of interaction phenomena that occur in complex systems arising in such diverse fields of knowledge as neuroscience, engineering, ecology, finance, and social sciences. Until very recently, the primary focus of network models and tools has been on describing the pairwise relationships between system entities. However, increasingly more studies indicate that polyadic or higher-order group relationships among multiple network entities may be the key toward better understanding of the intrinsic mechanisms behind the functionality of complex systems. Such group interactions can be, in turn, described in a holistic manner by simplicial complexes of graphs. Inspired by these recently emerging results on the utility of the simplicial geometry of complex networks for contagion propagation and armed with a large-scale synthetic social contact network (also known as a digital twin) of the population in the U.S. state of Virginia, in this paper, we aim to glean insights into the role of higher-order social interactions and the associated varying social group determinants on COVID-19 propagation and mitigation measures.


Assuntos
COVID-19 , Epidemias , Humanos , COVID-19/epidemiologia , Virginia
2.
Am J Pathol ; 193(5): 624-637, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36740185

RESUMO

Advanced-stage prostate tumors metastasize to the bone, often causing death. The protein kinase D (PKD) family has been implicated in prostate cancer development; however, its role in prostate cancer metastasis remains elusive. This study examined the contribution of PKD, particularly PKD2 and PKD3 (PKD2/3), to the metastatic potential of prostate cancer cells and the effect of PKD inhibition on prostate cancer bone metastasis in vivo. Depletion of PKD2/3 by siRNAs or inhibition by the PKD inhibitor CRT0066101 in AR-positive and AR-negative castration-resistant prostate cancer cells potently inhibited colony formation and cell migration. Depletion or inhibition of PKD2/3 significantly blocked tumor cell invasion and suppressed the expression of genes related to bone metastasis in the highly invasive PC3-ML cells. The reduced invasive activity resulting from PKD2/3 depletion was in part mediated by the transcription factor Runx2, as its silencing decreased PKD2/3-mediated metastatic gene expression through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling axis. Furthermore, inhibition of PKD by CRT0066101 potently decreased the frequency of bone micrometastases in a mouse model of bone metastasis based on intracardiac injection of PC3-ML cells. These results indicate that PKD2/3 plays an important role in the bone metastasis of prostate cancer cells, and its inhibition may be beneficial for the treatment of advanced prostate cancer.


Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Humanos , Masculino , Animais , Camundongos , Proteína Quinase C/metabolismo , Proteína Quinase D2 , Sistema de Sinalização das MAP Quinases , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo
3.
Mol Biol Rep ; 51(1): 697, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802698

RESUMO

Natural medicines are a valuable resource for the development of new drugs. However, factors such as low solubility and poor bioavailability of certain constituents have hindered their efficacy and potential as pharmaceuticals. Structural modification of natural products has emerged as an important research area for drug development. Phosphorylation groups, as crucial endogenous active groups, have been extensively utilized for structural modification and development of new drugs based on natural molecules. Incorporating phosphate groups into natural molecules not only enhances their stability, bioavailability, and pharmacological properties, but also improves their biological activity by altering their charge, hydrogen bonding, and spatial structure. This review summarizes the phosphorylation mechanism, modification approaches, and biological activity enhancement of natural medicines. Notably, compounds such as polysaccharides, flavonoids, terpenoids, anthraquinones, and coumarins exhibit increased antioxidation, anticancer, antiviral, immune regulatory, Antiaging, enzyme inhibition, bacteriostasis, liver protection, and lipid-lowering effects following phosphorylation modification.


Assuntos
Produtos Biológicos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Fosforilação , Humanos , Animais , Flavonoides/química , Flavonoides/metabolismo , Flavonoides/farmacologia , Polissacarídeos/química , Polissacarídeos/metabolismo , Antioxidantes/farmacologia , Antioxidantes/química , Antraquinonas/química , Antraquinonas/farmacologia
4.
Neurobiol Dis ; 187: 106305, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37730136

RESUMO

Ischemic stroke, constituting 80-90% of all strokes, is a leading cause of death and long-term disability in adults. There is an urgent need to discover new targets and therapies for this devastating condition. Protein kinase D (PKD), as a key target of diacylglycerol involved in ischemic responses, has not been well studied in ischemic stroke, particularly PKD2. In this study, we found that PKD2 expression and activity were significantly upregulated in the ipsilateral side of the brain after transient focal cerebral ischemia, which coincides with the upregulation of PKD2 in primary neurons in response to in vitro ischemia, implying a potential role of PKD2 in neuronal survival in ischemic stroke. Using kinase-dead PKD2 knock-in (PKD2-KI) mice, we examined whether loss of PKD2 activity affected stroke outcomes in mice subjected to 1 h of transient middle cerebral artery occlusion (tMCAO) and 24 h of reperfusion. Our data demonstrated that PKD2-KI mice exhibited larger infarction volumes and worsened neurological scores, indicative of increased brain injury, as compared to the wild-type (WT) mice, confirming a neuroprotective role of PKD2 in ischemia/reperfusion (I/R) injury. Mouse primary neurons obtained from PKD2-KI mice also exhibited increased cell death as compared to the WT neurons when subjected to in vitro ischemia. We have further identified AKT and CREB as two main signaling nodes through which PKD2 regulates neuronal survival during I/R injury. In summary, PKD2 confers neuroprotection in ischemic stroke by promoting AKT and CREB activation and targeted activation of PKD2 may benefit neuronal survival in ischemic stroke.


Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , AVC Isquêmico , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Camundongos , Animais , Neuroproteção , Proteínas Proto-Oncogênicas c-akt/metabolismo , Isquemia Encefálica/metabolismo , Proteína Quinase D2 , Transdução de Sinais , Fármacos Neuroprotetores/farmacologia , Infarto da Artéria Cerebral Média
5.
Opt Lett ; 48(17): 4508-4511, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37656540

RESUMO

This Letter reports a new optical fiber gas sensor for measuring breath acetone. The sensor is based on photonic bandgap (PBG) mode laser emission sensing technology using liquid crystal (LC), which is combined with silica fiber and chiral nematic liquid crystal (CNLC), thus providing an ultra-compact, fast-response and simple-to-produce sensing system with a fast response that can accurately and quantitatively determine the concentration of respiratory acetone within the normal oral temperature range (35-38°C). Since LCs are affected by temperature, we propose a method that eliminates the influence of the temperature to solve the problem of the temperature influence when measuring gas. The detection of acetone leads to splitting of the dual laser peaks, with a linear correlation of 0.99. The sensor has a limit of detection of 65 ppm for acetone vapor and thus is suitable for breath acetone detection in diabetic patients.

6.
Opt Lett ; 48(14): 3773-3776, 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37450747

RESUMO

This Letter introduces a novel laser emission probe for liquid-crystal microspheres based on a tapered fiber. A cholesteric liquid crystal (CLC) is injected into a hollow glass microsphere (HGM) attached at the front end of a tapered fiber in order to produce laser. Tapered fibers are preferable to rectangular fibers for liquid-crystal microsphere laser emission. The whispering gallery mode (WGM) laser is significantly suppressed by the tapered fiber-based liquid-crystal microsphere, which also displays an apparent single-mode photonic bandgap (PBG) laser peak. The stimulation response of tapered fiber-based liquid-crystal microspheres to organic vapors causes a modification of the laser peak wavelength with increasing gas concentration. In addition, laser emission generated by tapered fiber-based liquid-crystal microspheres is expected to be used in fields such as microenvironmental biosensing.


Assuntos
Cristais Líquidos , Microesferas , Cristais Líquidos/química , Lasers , Óptica e Fotônica , Vidro
7.
Appl Opt ; 62(13): 3387-3397, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37132839

RESUMO

The extraction of the center of a laser stripe is a key step in line-structure measurement, where noise interference and changes in the surface color of an object are the main factors affecting extraction accuracy. To obtain sub-pixel level center coordinates under such non-ideal conditions, we propose LaserNet, a novel deep learning-based algorithm, to the best of our knowledge, which consists of a laser region detection sub-network and a laser position optimization sub-network. The laser region detection sub-network is used to determine potential stripe regions, and the laser position optimization sub-network uses the local image of these regions to obtain the accurate center position of the laser stripe. The experimental results show that LaserNet can eliminate noise interference, handle color changes, and give accurate results under non-ideal conditions. The three-dimensional reconstruction experiments further demonstrate the effectiveness of the proposed method.

8.
BMC Surg ; 23(1): 192, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37407952

RESUMO

BACKGROUND: Considering the high reoperation rate in degenerative lumbar spondylolisthesis (DLS) patients undergoing lumbar surgeries and controversial results on the risk factors for the reoperation, we performed a systematic review and meta-analysis to explore the reoperation rate and risk factors for the reoperation in DLS patients undergoing lumbar surgeries. METHODS: Literature search was conducted from inception to October 28, 2022 in Pubmed, Embase, Cochrane Library, and Web of Science. Odds ratio (OR) was used as the effect index for the categorical data, and effect size was expressed as 95% confidence interval (CI). Heterogeneity test was performed for each outcome effect size, and subgroup analysis was performed based on study design, patients, surgery types, follow-up time, and quality of studies to explore the source of heterogeneity. Results of all outcomes were examined by sensitivity analysis. Publication bias was assessed using Begg test, and adjusted using trim-and-fill analysis. RESULTS: A total of 39 cohort studies (27 retrospective cohort studies and 12 prospective cohort studies) were finally included in this systematic review and meta-analysis. The overall results showed a 10% (95%CI: 8%-12%) of reoperation rate in DLS patients undergoing lumbar surgeries. In surgery types subgroup, the reoperation rate was 11% (95%CI: 9%-13%) for decompression, 10% (95%CI: 7%-12%) for fusion, and 9% (95%CI: 5%-13%) for decompression and fusion. An increased risk of reoperation was found in patients with obesity (OR = 1.91, 95%CI: 1.04-3.51), diabetes (OR = 2.01, 95%CI: 1.43-2.82), and smoking (OR = 1.51, 95%CI: 1.23-1.84). CONCLUSIONS: We found a 10% of reoperation rate in DLS patients after lumbar surgeries. Obesity, diabetes, and smoking were risk factors for the reoperation.


Assuntos
Diabetes Mellitus , Fusão Vertebral , Estenose Espinal , Espondilolistese , Humanos , Reoperação/métodos , Espondilolistese/cirurgia , Estudos Retrospectivos , Estudos Prospectivos , Resultado do Tratamento , Estenose Espinal/cirurgia , Descompressão Cirúrgica/métodos , Fusão Vertebral/métodos , Fatores de Risco , Vértebras Lombares/cirurgia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/cirurgia , Obesidade/cirurgia
9.
Arthroscopy ; 38(11): 2972-2983.e3, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35817378

RESUMO

PURPOSE: To investigate the effects of the number and location of anchors for remplissage on postoperative glenohumeral biomechanics. METHODS: A biomechanical study was conducted involving finite element model constructed based on data from the intact glenohumeral joint. Seven models were established, including a normal model, a model of Bankart lesion combined with "off-track" Hill-Sachs lesion, a model of Bankart repair alone, and 4 models of Bankart repair with remplissage based on different remplissage anchor numbers and locations. The effects of the number and location of the remplissage anchors on glenohumeral stability were studied through calculation and comparison of (1) the stress and its distribution on the joint capsule, cartilage, labrum and anchors as well as (2) the displacement of the humeral head. RESULTS: Finite element analysis demonstrated that contact stress on the glenohumeral cartilage decreased when medial or 2 anchors were used and was minimized in the combined repair model with 2 medial anchors. The stress on remplissage anchors was greater when the anchors were placed medially. The humeral head displacement was maximized in the combined lesion model. The combined repair models with 2 medially placed anchors showed the largest slope on the force-displacement curve, indicating the largest strain on the humeral head. CONCLUSIONS: Based on a finite element analysis, Bankart repair with remplissage restored better shoulder stability compared with Bankart repair alone in the treatment of anterior shoulder instability involving Bankart lesion combined with "off-track" Hill-Sachs lesion. When the anchor for remplissage was medially placed or 2 anchors were used, the stability of the glenohumeral joint increased but with a loss of range of motion. CLINICAL RELEVANCE: The results of this study will assist in choosing the number and location of anchors for remplissage during shoulder stabilization surgery although with some limitations.


Assuntos
Lesões de Bankart , Instabilidade Articular , Luxação do Ombro , Articulação do Ombro , Humanos , Lesões de Bankart/cirurgia , Luxação do Ombro/cirurgia , Articulação do Ombro/cirurgia , Instabilidade Articular/cirurgia , Ombro , Análise de Elementos Finitos , Artroscopia/métodos , Amplitude de Movimento Articular
10.
Opt Lett ; 46(14): 3324-3327, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34264204

RESUMO

External temperature variations inevitably affect the accuracy of a liquid crystal sensor. Therefore, we propose a novel temperature-compensated fiber volatile organic compound (VOC, using acetone as a model compound) gas sensor. The proposed sensor consists of a short segment of hollow-core fiber (HCF), which is spliced on a multimode fiber. Cholesteric liquid crystal (CLC) is sealed into HCF to sense the temperature, and another type of CLC is coated on the end face of HCF for VOC gas detection. The VOC gas concentration and ambient temperature can be simultaneously measured by monitoring the wavelength shifts of two Bragg reflection peaks caused by two types of CLCs. The effects of the CLC thickness on the sensitivities of temperature and acetone concentration are investigated, and optimal parameters are chosen. An optimal sensor can reach a temperature sensitivity of 2.53 nm/°C and acetone concentration sensitivity of 48.46 nm·L/mmol at 8-44°C. In addition, temperature compensation capability, repeatability, response time, and stability are also researched. The experimental results prove this sensor has great application potential in high-precision real-time VOC gas monitoring and detection.

11.
Chemistry ; 27(3): 1057-1065, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051913

RESUMO

For plasmonic copper-deficient Cu2-x S nanoparticles (NPs), accurate control of the crystal phase and morphology is highly desirable as both of which are known to determine the localized surface plasmon resonance (LSPR) wavelength and amplitude. Here, how the sulfur precursor reactivity in the synthesis of Cu2-x S NPs affects the resulting crystal phase and morphology is examined. Djurleite Cu1.94 S, roxbyite Cu1.8 S, digenite Cu1.8 S as well as covellite CuS nanodisks were synthesized by using 1-dodecanethiol, N,N-dibutylthiourea, and crystal sulfur 1-octadecene/oleylamine solutions and their crystal phase dependent LSPR properties were exhaustively discussed. In addition, crystal phase interconversion between covellite CuS and djurleite/roxbyite Cu2-x S was realized in the presence of the above sulfur precursors. On the other hand, djurleite Cu1.94 S nanorods rather than nanodisks were prepared by replacing 1-dodecanethiol with more reactive tert-dodecanethiol. The structural and morphological Cu2-x S NPs here holds great promise in the application of photothermal therapy, photocatalysis, surface-enhanced Raman scattering (SERS), and many others.

12.
Chemistry ; 27(26): 7444-7452, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33686735

RESUMO

A crucial parameter in the design of semiconductor nanoparticles (NPs) with controllable optical, magnetic, electronic, and catalytic properties is the morphology. Herein, we demonstrate the potential of additive metal cations with variable valency to direct the morphology evolution of copper-deficient Cu2-x S nanoparticles in the process of seed-mediated growth. In particular, the djurleite Cu1.94 S seed could evolve from disk into tetradecahedron in the presence of tin(IV) cations, whereas they merely formed sharp hexagonal nanodisks with tin(II) cations. In addition to djurleite Cu1.94 S, the tin(IV) cations could be generalized to direct the growth of roxbyite Cu1.8 S and covellite CuS nanodisk seeds into tetradecahedra. We further perform pseudomorphic cation exchanges of Cu1.94 S tetradecahedra with Zn2+ and Cd2+ to produce polyhedral zinc sulfide (ZnS) and cadmium sulfide (CdS) NPs. Moreover, we achieve Cu1.8 S/ZnS and Cu1.94 S/CdS tetradecahedral heterostructures via partial cation exchange, which are otherwise inaccessible by traditional synthetic approaches.

13.
Knee Surg Sports Traumatol Arthrosc ; 27(12): 4014-4020, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31451843

RESUMO

PURPOSE: To assess patients with and without postoperative residual pain and to compare clinical function and magnetic resonance imaging (MRI) appearance of the repaired supraspinatus tendon between patients with and without pain. METHODS: One-hundred and seventeen patients with supraspinatus tear were included in this study. Visual Analog Scale (VAS) scores for pain were assessed at a follow-up of at least 1 year. Patients with residual shoulder pain were enrolled in the residual pain group (RP group) and patients without pain enrolled in the no pain group (NP group). The American Shoulder and Elbow Surgeons (ASES) shoulder evaluation form, the modified University of California at Los Angeles (UCLA) score and the Fudan University Shoulder Score (FUSS) were also used to evaluate shoulder function. MRI examinations were performed to evaluate rotator cuff integrity according to the Sugaya method, and muscular hypotrophy, fatty infiltration, and signal/noise quotient (SNQ) of the rotator cuff tendon. RESULTS: Thirty-five patients had residual pain (RP group) and 82 patients had no pain (NR group). At the final follow-up, there was a significant difference in ASES (92 ± 8 points vs 76 ± 10 points; p < 0.001), UCLA (32 ± 3 points vs 28 ± 3 points; p < 0.001), FUSS (90 ± 7 points vs 80 ± 9 points; p < 0.001) and strength (9 ± 3 kg vs 6 ± 2 kg; p < 0.001) between the NP group and the RP group, respectively. Postoperative MRI revealed that there was no significant difference in the retear rate (9.8% vs 8.6%; ns), the muscular hypotrophy (ns), and the fatty infiltration index (0.9 ± 0.2 vs 0.9 ± 0.2; ns) between the NP and the RP groups, respectively. The postoperative tendon SNQ of the RP group was significantly higher than that of the NP group (4.6 ± 2.5 vs 3 ± 1.7; p < 0.001). There was a significant association between tendon SNQ and VAS for this cohort ([Formula: see text] = 0.29; p = 0.003). CONCLUSION: Postoperative residual pain is associated with a high MRI signal intensity of the repaired supraspinatus tendon. Since high signal intensity of tendon tissue indicates degenerated tendon tissue quality, it highlighted the necessity of debriding the degenerated rotator cuff tendon tissue. LEVEL OF EVIDENCE: III.


Assuntos
Artroscopia , Imageamento por Ressonância Magnética , Dor Pós-Operatória/etiologia , Lesões do Manguito Rotador/cirurgia , Manguito Rotador/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Escala Visual Analógica
14.
Knee Surg Sports Traumatol Arthrosc ; 27(10): 3180-3187, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30683950

RESUMO

PURPOSE: The purpose of this study is to compare pain patterns and identify factors associated with residual shoulder pain after rotator cuff repairs using double-row and single-row techniques. METHODS: A cohort study was performed using patients who underwent arthroscopic rotator cuff repairs at our center in 2015. Patients were allocated according to the repair technique into an single-row (SR) group or a double-row (DR) group. Visual Analog Scale (VAS) scores for pain were assessed at 1 week, 3 months, 6 months, 12 months and 24 months after surgery. Functional and radiographic assessments were performed at least 24 months postoperatively. The proportion of patients with residual pain and factors associated with residual shoulder pain (VAS > 0 at the final follow-up) were analyzed in both groups. RESULTS: Fifty-two patients were enrolled in the SR group, and 53 were enrolled in the DR group. The DR group appeared to have higher levels of pain 1 week (P < 0.001) and 3 months (P = 0.041) postoperatively, while at other time points, the pain intensity of the two groups was comparable. Fourteen (26.4%) and 25 (48.1%) patients in the DR and the SR groups, respectively, developed residual shoulder pain, (P = 0.022; RR 1.82). The univariate analysis and multiple regression revealed that a poorer quality of tendon tissue is related to residual pain in the SR group, whereas tendon retraction is associated with residual pain in the DR group. The rate of re-tear was similar between the two groups and between patients with and without residual pain. CONCLUSIONS: The DR repair technique results in a greater intensity of pain than that of SR repair during the first 3 months after surgery; however, patients who underwent DR repair presented a significantly lower proportion of residual shoulder pain and better tendon quality after 2 years. Poorer tendon quality and larger tendon retraction as determined intraoperatively were risk factors for residual pain. These results highlight the necessity of promoting healing on the grounds of residual pain prevention. LEVEL OF EVIDENCE: II.


Assuntos
Dor Pós-Operatória/etiologia , Lesões do Manguito Rotador/cirurgia , Manguito Rotador/cirurgia , Dor de Ombro/etiologia , Técnicas de Sutura , Artroscopia/métodos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Escala Visual Analógica
15.
AAPS PharmSciTech ; 20(1): 12, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30560388

RESUMO

The collective impact of cellulosic polymers on the dissolution, solubility, and crystallization inhibition of amorphous active pharmaceutical ingredients (APIs) is still far from being adequately understood. The goal of this research was to explore the influence of cellulosic polymers and incubation conditions on enhancement of solubility and dissolution of amorphous felodipine, while inhibiting crystallization of the drug from a supersaturated state. Variables, including cellulosic polymer type, amount, ionic strength, and viscosity, were evaluated for effects on API dissolution/solubility and crystallization processes. Water-soluble cellulosic polymers, including HPMC E15, HPMC E5, HPMC K100-LV, L-HPC, and MC, were studied. All cellulosic polymers could extend API dissolution and solubility to various extents by delaying crystallization and prolonging supersaturation duration, with their effectiveness ranked from greatest to least as HPMC E15 > HPMC E5 > HPMC K100-LV > L-HPC > MC. Decreased polymer amount, lower ionic strength, or higher polymer viscosity tended to decrease dissolution/solubility and promote crystal growth to accelerate crystallization. HPMC E15 achieved greatest extended API dissolution and maintenance of supersaturation from a supersaturated state; this polymer thus had the greatest potential for maintaining sustainable API absorption within biologically relevant time frames.


Assuntos
Felodipino/química , Cristalização , Polímeros/química , Solubilidade , Viscosidade
16.
Org Biomol Chem ; 15(36): 7584-7593, 2017 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-28861587

RESUMO

A three-step domino reaction between 1-aryl-3-hexyne-2,6-diol derivatives and aldehydes is used to construct tricyclic 1,4-dihydro-2H-benzo[f]isochromenes. The cascade is initiated by BF3·OEt2 and involves alkynyl-Prins cyclization, Friedel-Crafts alkenylation, and dehydration/aromatization to create a new, central aromatic ring and eliminate 2 equiv. of water. Electron-donating substituents on the aryl ring of the 1-aryl-3-hexyne-2,6-diols significantly increase overall yields as do electron-rich aldehyde reaction partners. For 2,4-disubstituted 2H-benzo[f]isochromene products, diastereoselectivities in the alkynyl-Prins reaction are ∼1.4 : 1 in favor of the cis-diastereomer. The stereochemistry of one cis-product was verified by X-ray crystallographic analysis and a second structure was also verified by X-ray analysis.

17.
Prog Neurobiol ; 234: 102588, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38378072

RESUMO

Demyelination stands out as a prominent feature in individuals with specific types of epilepsy. Concurrently, individuals with demyelinating diseases, such as multiple sclerosis (MS) are at a greater risk of developing epilepsy compared to non-MS individuals. These bidirectional connections raise the question of whether both pathological conditions share common pathogenic mechanisms. This review focuses on the reciprocal relationship between epilepsy and demyelination diseases. We commence with an overview of the neurological basis of epilepsy and demyelination diseases, followed by an exploration of how our comprehension of these two disorders has evolved in tandem. Additionally, we discuss the potential pathogenic mechanisms contributing to the interactive relationship between these two diseases. A more nuanced understanding of the interplay between epilepsy and demyelination diseases has the potential to unveiling the molecular intricacies of their pathological relationships, paving the way for innovative directions in future clinical management and treatment strategies for these diseases.


Assuntos
Doenças Desmielinizantes , Epilepsia , Esclerose Múltipla , Humanos , Doenças Desmielinizantes/patologia , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Epilepsia/complicações
18.
IEEE Trans Med Imaging ; PP2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38551825

RESUMO

Cross-modality data translation has attracted great interest in medical image computing. Deep generative models show performance improvement in addressing related challenges. Nevertheless, as a fundamental challenge in image translation, the problem of zero-shot learning cross-modality image translation with fidelity remains unanswered. To bridge this gap, we propose a novel unsupervised zero-shot learning method called Mutual Information guided Diffusion Model, which learns to translate an unseen source image to the target modality by leveraging the inherent statistical consistency of Mutual Information between different modalities. To overcome the prohibitive high dimensional Mutual Information calculation, we propose a differentiable local-wise mutual information layer for conditioning the iterative denoising process. The Local-wise-Mutual-Information-Layer captures identical cross-modality features in the statistical domain, offering diffusion guidance without relying on direct mappings between the source and target domains. This advantage allows our method to adapt to changing source domains without the need for retraining, making it highly practical when sufficient labeled source domain data is not available. We demonstrate the superior performance of MIDiffusion in zero-shot cross-modality translation tasks through empirical comparisons with other generative models, including adversarial-based and diffusion-based models. Finally, we showcase the real-world application of MIDiffusion in 3D zero-shot learning-based cross-modality image segmentation tasks.

19.
Oncogene ; 43(11): 789-803, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38273024

RESUMO

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.


Assuntos
Proteínas de Ciclo Celular , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Camundongos , Animais , Proteínas de Ciclo Celular/genética , Proteínas Tirosina Quinases/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Proteínas Nucleares/metabolismo , Pirimidinonas/farmacologia , Dano ao DNA , Linhagem Celular Tumoral
20.
Antibiotics (Basel) ; 13(4)2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38666996

RESUMO

Antimicrobial resistance is a global healthcare threat with significant clinical and economic consequences peaking at secondary and tertiary care hospitals where multidrug-resistant Gram-negative bacteria (MDR GNB) lead to poor outcomes. A prospective study was conducted between January and December 2019 for all invasive bloodstream infections (BSIs) secondary to MDR GNB in Qatar identified during routine microbiological service to examine their clinical, microbiological, and genomic characteristics. Out of 3238 episodes of GNB BSIs, the prevalence of MDR GNB was 13% (429/3238). The predominant MDR pathogens were Escherichia coli (62.7%), Klebsiella pneumoniae (20.4%), Salmonella species (6.6%), and Pseudomonas aeruginosa (5.3%), while out of 245 clinically evaluated patients, the majority were adult males, with the elderly constituting almost one-third of the cohort and with highest observed risk for prolonged hospital stays. The risk factors identified included multiple comorbidities, recent healthcare contact, previous antimicrobial therapy, and admission to critical care. The in-hospital mortality rate was recorded at 25.7%, associated with multiple comorbidities, admission to critical care, and the acquisition of MDR Pseudomonas aeruginosa. Resistant pathogens demonstrated high levels of antimicrobial resistance but noticeable susceptibility to amikacin and carbapenems. Genomic analysis revealed that Escherichia coli ST131 and Salmonella enterica ST1 were the predominant clones not observed with other pathogens.

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