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1.
Mol Cell ; 81(16): 3368-3385.e9, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34375583

RESUMO

The mechanistic understanding of nascent RNAs in transcriptional control remains limited. Here, by a high sensitivity method methylation-inscribed nascent transcripts sequencing (MINT-seq), we characterized the landscapes of N6-methyladenosine (m6A) on nascent RNAs. We uncover heavy but selective m6A deposition on nascent RNAs produced by transcription regulatory elements, including promoter upstream antisense RNAs and enhancer RNAs (eRNAs), which positively correlates with their length, inclusion of m6A motif, and RNA abundances. m6A-eRNAs mark highly active enhancers, where they recruit nuclear m6A reader YTHDC1 to phase separate into liquid-like condensates, in a manner dependent on its C terminus intrinsically disordered region and arginine residues. The m6A-eRNA/YTHDC1 condensate co-mixes with and facilitates the formation of BRD4 coactivator condensate. Consequently, YTHDC1 depletion diminished BRD4 condensate and its recruitment to enhancers, resulting in inhibited enhancer and gene activation. We propose that chemical modifications of eRNAs together with reader proteins play broad roles in enhancer activation and gene transcriptional control.


Assuntos
Adenosina/análogos & derivados , Proteínas de Ciclo Celular/genética , Proteínas do Tecido Nervoso/genética , Fatores de Processamento de RNA/genética , RNA/genética , Fatores de Transcrição/genética , Adenosina/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica/genética , Humanos , Metilação , Elementos Reguladores de Transcrição/genética , Ativação Transcricional/genética
2.
Immunity ; 50(3): 576-590.e6, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30770249

RESUMO

Elevated glucose metabolism in immune cells represents a hallmark feature of many inflammatory diseases, such as sepsis. However, the role of individual glucose metabolic pathways during immune cell activation and inflammation remains incompletely understood. Here, we demonstrate a previously unrecognized anti-inflammatory function of the O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling associated with the hexosamine biosynthesis pathway (HBP). Despite elevated activities of glycolysis and the pentose phosphate pathway, activation of macrophages with lipopolysaccharide (LPS) resulted in attenuated HBP activity and protein O-GlcNAcylation. Deletion of O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, led to enhanced innate immune activation and exacerbated septic inflammation. Mechanistically, OGT-mediated O-GlcNAcylation of the serine-threonine kinase RIPK3 on threonine 467 (T467) prevented RIPK3-RIPK1 hetero- and RIPK3-RIPK3 homo-interaction and inhibited downstream innate immunity and necroptosis signaling. Thus, our study identifies an immuno-metabolic crosstalk essential for fine-tuning innate immune cell activation and highlights the importance of glucose metabolism in septic inflammation.


Assuntos
Apoptose/fisiologia , Inflamação/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Necrose/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Linhagem Celular , Glucose/metabolismo , Humanos , Imunidade Inata/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Serina/metabolismo , Transdução de Sinais/fisiologia , Treonina/metabolismo
3.
Proc Natl Acad Sci U S A ; 121(14): e2315509121, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38547055

RESUMO

Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism of polyamine dysregulation in cancer is not fully understood. In this study, we investigated the role of MUC1, a mucin protein overexpressed in pancreatic cancer, in regulating polyamine metabolism. Utilizing pancreatic cancer patient data, we noted a positive correlation between MUC1 expression and the expression of key polyamine metabolism pathway genes. Functional studies revealed that knockdown of spermidine/spermine N1-acetyltransferase 1 (SAT1), a key enzyme involved in polyamine catabolism, attenuated the oncogenic functions of MUC1, including cell survival and proliferation. We further identified a regulatory axis whereby MUC1 stabilized hypoxia-inducible factor (HIF-1α), leading to increased SAT1 expression, which in turn induced carbon flux into the tricarboxylic acid cycle. MUC1-mediated stabilization of HIF-1α enhanced the promoter occupancy of the latter on SAT1 promoter and corresponding transcriptional activation of SAT1, which could be abrogated by pharmacological inhibition of HIF-1α or CRISPR/Cas9-mediated knockout of HIF1A. MUC1 knockdown caused a significant reduction in the levels of SAT1-generated metabolites, N1-acetylspermidine and N8-acetylspermidine. Given the known role of MUC1 in therapy resistance, we also investigated whether inhibiting SAT1 would enhance the efficacy of FOLFIRINOX chemotherapy. By utilizing organoid and orthotopic pancreatic cancer mouse models, we observed that targeting SAT1 with pentamidine improved the efficacy of FOLFIRINOX, suggesting that the combination may represent a promising therapeutic strategy against pancreatic cancer. This study provides insights into the interplay between MUC1 and polyamine metabolism, offering potential avenues for the development of treatments against pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poliaminas/metabolismo , Transdução de Sinais , Acetiltransferases/genética , Acetiltransferases/metabolismo , Mucina-1
4.
Trends Immunol ; 43(1): 78-92, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34942082

RESUMO

Cholesterol is a multifaceted metabolite that is known to modulate processes in cancer, atherosclerosis, and autoimmunity. A common denominator between these diseases appears to be the immune system, in which many cholesterol-associated metabolites impact both adaptive and innate immunity. Many cancers display altered cholesterol metabolism, and recent studies demonstrate that manipulating systemic cholesterol metabolism may be useful in improving immunotherapy responses. However, cholesterol can have both proinflammatory and anti-inflammatory roles in mammals, acting via multiple immune cell types, and depending on context. Gaining mechanistic insights into various cholesterol-related metabolites can improve our understanding of their functions and extensive effects on the immune system, and ideally will inform the design of future therapeutic strategies against cancer and/or other pathologies.


Assuntos
Aterosclerose , Neoplasias , Animais , Anti-Inflamatórios , Colesterol/metabolismo , Humanos , Imunidade Inata , Mamíferos , Neoplasias/tratamento farmacológico
5.
PLoS Biol ; 20(5): e3001634, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35584084

RESUMO

Therapeutic methods to modulate skin pigmentation has important implications for skin cancer prevention and for treating cutaneous hyperpigmentary conditions. Towards defining new potential targets, we followed temporal dynamics of melanogenesis using a cell-autonomous pigmentation model. Our study elucidates 3 dominant phases of synchronized metabolic and transcriptional reprogramming. The melanogenic trigger is associated with high MITF levels along with rapid uptake of glucose. The transition to pigmented state is accompanied by increased glucose channelisation to anabolic pathways that support melanosome biogenesis. SREBF1-mediated up-regulation of fatty acid synthesis results in a transient accumulation of lipid droplets and enhancement of fatty acids oxidation through mitochondrial respiration. While this heightened bioenergetic activity is important to sustain melanogenesis, it impairs mitochondria lately, shifting the metabolism towards glycolysis. This recovery phase is accompanied by activation of the NRF2 detoxication pathway. Finally, we show that inhibitors of lipid metabolism can resolve hyperpigmentary conditions in a guinea pig UV-tanning model. Our study reveals rewiring of the metabolic circuit during melanogenesis, and fatty acid metabolism as a potential therapeutic target in a variety of cutaneous diseases manifesting hyperpigmentary phenotype.


Assuntos
Metabolismo dos Lipídeos , Melaninas , Pigmentação da Pele , Animais , Ácidos Graxos , Glucose , Cobaias , Melaninas/metabolismo
6.
J Biol Chem ; 299(7): 104865, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37268160

RESUMO

Spleen tyrosine kinase (Syk) is expressed in a variety of hemopoietic cells. Upon phosphorylation of the platelet immunoreceptor-based activation motif of the glycoprotein VI (GPVI)/Fc receptor gamma chain collagen receptor, both the tyrosine phosphorylation and activity of Syk are increased leading to downstream signaling events. Although it has been established that the activity of Syk is regulated by tyrosine phosphorylation, the specific roles of individual phosphorylation sites remain to be elucidated. We observed that Syk Y346 in mouse platelets was still phosphorylated when GPVI-induced Syk activity was inhibited. We then generated Syk Y346F mice and analyzed the effect this mutation exerts on platelet responses. Syk Y346F mice bred normally, and their blood cell count was unaltered. We did observe potentiation of GPVI-induced platelet aggregation and ATP secretion as well as increased phosphorylation of other tyrosines on Syk in the Syk Y346F mouse platelets when compared to WT littermates. This phenotype was specific for GPVI-dependent activation, since it was not seen when AYPGKF, a PAR4 agonist, or 2-MeSADP, a purinergic receptor agonist, was used to activate platelets. Despite a clear effect of Syk Y346F on GPVI-mediated signaling and cellular responses, there was no effect of this mutation on hemostasis as measured by tail-bleeding times, although the time to thrombus formation determined using the ferric chloride injury model was reduced. Thus, our results indicate a significant effect of Syk Y346F on platelet activation and responses in vitro and reveal its complex nature manifesting itself by the diversified translation of platelet activation into physiological responses.


Assuntos
Plaquetas , Agregação Plaquetária , Quinase Syk , Animais , Camundongos , Fosforilação , Ativação Plaquetária , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quinase Syk/genética , Quinase Syk/metabolismo , Tirosina
7.
Stroke ; 55(5): 1218-1226, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38572636

RESUMO

BACKGROUND: Decompressive neurosurgery is recommended for patients with cerebral venous thrombosis (CVT) who have large parenchymal lesions and impending brain herniation. This recommendation is based on limited evidence. We report long-term outcomes of patients with CVT treated by decompressive neurosurgery in an international cohort. METHODS: DECOMPRESS2 (Decompressive Surgery for Patients With Cerebral Venous Thrombosis, Part 2) was a prospective, international cohort study. Consecutive patients with CVT treated by decompressive neurosurgery were evaluated at admission, discharge, 6 months, and 12 months. The primary outcome was death or severe disability (modified Rankin Scale scores, 5-6) at 12 months. The secondary outcomes included patient and caregiver opinions on the benefits of surgery. The association between baseline variables before surgery and the primary outcome was assessed by multivariable logistic regression. RESULTS: A total of 118 patients (80 women; median age, 38 years) were included from 15 centers in 10 countries from December 2011 to December 2019. Surgery (115 craniectomies and 37 hematoma evacuations) was performed within a median of 1 day after diagnosis. At last assessment before surgery, 68 (57.6%) patients were comatose, fixed dilated pupils were found unilaterally in 27 (22.9%) and bilaterally in 9 (7.6%). Twelve-month follow-up data were available for 113 (95.8%) patients. Forty-six (39%) patients were dead or severely disabled (modified Rankin Scale scores, 5-6), of whom 40 (33.9%) patients had died. Forty-two (35.6%) patients were independent (modified Rankin Scale scores, 0-2). Coma (odds ratio, 2.39 [95% CI, 1.03-5.56]) and fixed dilated pupil (odds ratio, 2.22 [95% CI, 0.90-4.92]) were predictors of death or severe disability. Of the survivors, 56 (78.9%) patients and 61 (87.1%) caregivers expressed a positive opinion on surgery. CONCLUSIONS: Two-thirds of patients with severe CVT were alive and more than one-third were independent 1 year after decompressive surgery. Among survivors, surgery was judged as worthwhile by 4 out of 5 patients and caregivers. These results support the recommendation to perform decompressive neurosurgery in patients with CVT with impending brain herniation.

8.
Opt Express ; 32(3): 4668-4683, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38297662

RESUMO

Display field communication (DFC) is an unobtrusive display-to-camera technology that transmits data within the frequency domain of images, ensuring that the embedded data are hidden and do not disrupt the viewing experience. The display embeds data into image frames, while the receiver captures the display and extracts it. Two-dimensional DFC (2D-DFC) focuses on embedding data in the width and height of an image. This study explores two methods to minimize the error rate in 2D-DFC without affecting the quality of the displayed image. The orthogonal method embeds data in the orthogonal direction of an image. On the other hand, the diagonal embedding method strategically embeds the data in the diagonal direction. Experiments show the diagonal method maintains a higher peak signal-to-noise ratio and surpasses the orthogonal embedding method in terms of bit error rate. 2D-DFC is expected to have practical applications in digital signage, advertising and informational displays at airports and train stations, as well as at large-scale displays for events, sports arenas, and performance venues.

9.
Microb Cell Fact ; 23(1): 187, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951813

RESUMO

BACKGROUND: Plastic is widely utilized in packaging, frameworks, and as coverings material. Its overconsumption and slow degradation, pose threats to ecosystems due to its toxic effects. While polyhydroxyalkanoates (PHA) offer a sustainable alternative to petroleum-based plastics, their production costs present significant obstacles to global adoption. On the other side, a multitude of household and industrial activities generate substantial volumes of wastewater containing both organic and inorganic contaminants. This not only poses a threat to ecosystems but also presents opportunities to get benefits from the circular economy. Production of bioplastics may be improved by using the nutrients and minerals in wastewater as a feedstock for microbial fermentation. Strategies like feast-famine culture, mixed-consortia culture, and integrated processes have been developed for PHA production from highly polluted wastewater with high organic loads. Various process parameters like organic loading rate, organic content (volatile fatty acids), dissolved oxygen, operating pH, and temperature also have critical roles in PHA accumulation in microbial biomass. Research advances are also going on in downstream and recovery of PHA utilizing a combination of physical and chemical (halogenated solvents, surfactants, green solvents) methods. This review highlights recent developments in upcycling wastewater resources into PHA, encompassing various production strategies, downstream processing methodologies, and techno-economic analyses. SHORT CONCLUSION: Organic carbon and nitrogen present in wastewater offer a promising, cost-effective source for producing bioplastic. Previous attempts have focused on enhancing productivity through optimizing culture systems and growth conditions. However, despite technological progress, significant challenges persist, such as low productivity, intricate downstream processing, scalability issues, and the properties of resulting PHA.


Assuntos
Poli-Hidroxialcanoatos , Águas Residuárias , Poli-Hidroxialcanoatos/biossíntese , Poli-Hidroxialcanoatos/metabolismo , Águas Residuárias/microbiologia , Águas Residuárias/química , Fermentação , Bactérias/metabolismo , Biodegradação Ambiental
10.
Mol Cell ; 63(4): 608-620, 2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27499294

RESUMO

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.


Assuntos
Comportamento Animal , Ataxia Cerebelar/enzimologia , Cerebelo/enzimologia , Proteínas Mitocondriais/deficiência , Músculo Esquelético/enzimologia , Ubiquinona/deficiência , Animais , Células COS , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Ataxia Cerebelar/psicologia , Cerebelo/fisiopatologia , Cerebelo/ultraestrutura , Chlorocebus aethiops , Modelos Animais de Doenças , Tolerância ao Exercício , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Metabolismo dos Lipídeos , Masculino , Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Modelos Moleculares , Atividade Motora , Força Muscular , Músculo Esquelético/fisiopatologia , Fenótipo , Ligação Proteica , Conformação Proteica , Proteômica/métodos , Reconhecimento Psicológico , Teste de Desempenho do Rota-Rod , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Convulsões/enzimologia , Convulsões/genética , Convulsões/fisiopatologia , Relação Estrutura-Atividade , Fatores de Tempo , Transfecção , Ubiquinona/química , Ubiquinona/genética
11.
Nucleic Acids Res ; 50(6): 3394-3412, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35286386

RESUMO

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive types of cancer, is characterized by aberrant activity of oncogenic KRAS. A nuclease-hypersensitive GC-rich region in KRAS promoter can fold into a four-stranded DNA secondary structure called G-quadruplex (G4), known to regulate KRAS expression. However, the factors that regulate stable G4 formation in the genome and KRAS expression in PDAC are largely unknown. Here, we show that APE1 (apurinic/apyrimidinic endonuclease 1), a multifunctional DNA repair enzyme, is a G4-binding protein, and loss of APE1 abrogates the formation of stable G4 structures in cells. Recombinant APE1 binds to KRAS promoter G4 structure with high affinity and promotes G4 folding in vitro. Knockdown of APE1 reduces MAZ transcription factor loading onto the KRAS promoter, thus reducing KRAS expression in PDAC cells. Moreover, downregulation of APE1 sensitizes PDAC cells to chemotherapeutic drugs in vitro and in vivo. We also demonstrate that PDAC patients' tissue samples have elevated levels of both APE1 and G4 DNA. Our findings unravel a critical role of APE1 in regulating stable G4 formation and KRAS expression in PDAC and highlight G4 structures as genomic features with potential application as a novel prognostic marker and therapeutic target in PDAC.


Assuntos
Carcinoma Ductal Pancreático , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Quadruplex G , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Carcinoma Ductal Pancreático/genética , DNA/química , Endonucleases/metabolismo , Humanos , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Pancreáticas
12.
Childs Nerv Syst ; 40(2): 495-502, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37391518

RESUMO

BACKGROUND: Spinal deformities are common in Marfan syndrome (MFS). They usually involve the thoraco-lumbar spine but rarely involves the cervical spine. Kyphosis is the common spine deformity of the cervical spine and mandates surgical correction as they are at risk of neurological deterioration since they are refractory to conservative management. Few studies of surgical correction of spine deformity included cervical deformity. OBJECTIVES: To analyze the challenges faced during surgery, clinical and radiological outcome, and complications following surgical correction for cervical kyphosis in Marfan syndrome. METHODS: We identified that 5 patients with a diagnosis of MFS with cervical kyphosis who underwent fusion surgery between the years 2010 and 2022 were reviewed, retrospectively. We analyzed the demographic details, radiological parameters, operative variables (blood loss and nuances), perioperative complications, length of stay, clinical and radiological outcome, and complications following fusion surgery for cervical kyphosis in MFS. RESULTS: The mean age of patients was 16.6 ± 4.72 years (range, 12-23 years). The average kyphotic vertebra involved is 3 ± 0.7 bodies (range 2-4) with 2 patients with thoracic deformity. All patients underwent surgical deformity correction. All patients improved clinically with Nurick grade (pre vs. post: 3.4 vs. 2.2) and mJOA (pre vs. post: 8.2 vs. 12.6). There was significant deformity correction from 37.48° to 9.1°. Mean blood loss encountered was 900 ± 173.2 ml. Perioperative complications: wound complication with CSF leak (1). Late complications: ventilator dependence (1) and junctional kyphosis (1). Mean length of hospital stay was 103 ± 178.9 days. All patients were doing symptomatically better after mean follow-up of 58 ± 28.32 months. One patient is bedridden and hospitalized. CONCLUSION: Cervical kyphosis is a rare spine deformity in patients with MFS, and they usually present with neurological deterioration mandating surgical correction. Multidisciplinary approach (pediatrics, genetics and cardiology) is required for systematic evaluation of these patients. They should be evaluated with necessary imaging to rule out associated spinal deformity (atlanto-axial subluxation, scoliosis, and intraspinal pathology like ductal ectasia). Our results suggest better surgical outcome in terms of low operative complications with neurologic improvement in MFS patients. These patients require regular follow-up to identify late complications (instrument failure, non-union, and pseudarthrosis).


Assuntos
Cifose , Síndrome de Marfan , Fusão Vertebral , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Síndrome de Marfan/complicações , Síndrome de Marfan/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Cifose/diagnóstico por imagem , Cifose/etiologia , Cifose/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Fusão Vertebral/métodos
13.
Childs Nerv Syst ; 40(4): 1065-1077, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38051310

RESUMO

BACKGROUND: Non-chordomatous bony tumors of the clivus are extremely rare. Site, extent, and aggressiveness of tumor limits the extent of resection. It poses challenge to the neurosurgeons due to the complexity of anatomy. There is paucity of literature exclusively on non-chordomatous bone tumors of the clivus in young adults. OBJECTIVES: To analyze the clinical presentation, imaging findings, surgical approach, complications, and outcome of primary clival bony tumors in young adults. METHODS: We retrospectively reviewed children and young adults with primary clival bony tumors excluding chordoma who underwent surgical resection between years 2010 and 2023 in our center. We analyzed the demographic details, imaging findings, operative variables, perioperative complications, length of stay, complications, and outcome at latest follow-up. RESULTS: The mean age was 17.5 ± 1.73 years (range 16 to 19 years). Headache was the presenting complaint in all four patients (100%). The mean duration of symptom was 7.25 ± 3.2 months (range 5 to 12 months). The tumor was localized in clivus in all four patients (100%). The mean length of stay in hospital was 30.5 ± 13.48 days (range 11 to 40 days). All patients underwent surgical treatment. Surgical approaches used were anterior approach in four patients (100%). Gross total excision was performed in one patient (25%), sub-total excision was performed in two patients (50%), and tumor decompression was performed in one patient (25%). Of these, three were designated as having benign tumors and one had a malignant tumor. There was no perioperative mortality. There was one mortality (25%) on 2 months follow-up due to tumor progression. Three patients (75%) had improved symptomatically at latest follow-up. Two patients (50%) received adjuvant chemoradiotherapy. The mean follow-up was 38 ± 39.29 months (range 2 to 72 months). CONCLUSION: Non-chordomatous bony tumors of the clivus are rare and often underestimated. Surgery is the treatment of choice. Tumor consistency and adhesion to critical neurovascular structures precludes gross total resection. Various approaches are in the armamentarium. Approach to be decided based on the expertise of the neurosurgeon to achieve safe maximal resection. Multidisciplinary approach is mandatory for streamlined management. Adjuvant therapy is decided based on the residual tumor following surgery.


Assuntos
Neoplasias Ósseas , Cordoma , Neoplasias da Base do Crânio , Adulto Jovem , Criança , Humanos , Adolescente , Adulto , Seguimentos , Estudos Retrospectivos , Cordoma/cirurgia , Neoplasias Ósseas/patologia , Fossa Craniana Posterior/cirurgia , Neoplasias da Base do Crânio/cirurgia , Resultado do Tratamento
14.
AAPS PharmSciTech ; 25(5): 130, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844611

RESUMO

Naringenin (NRG) inhibits the fungal 17ß-hydroxysteroid dehydrogenase accountable for ergosterol synthesis in Candida albicans (C. albicans), a causative agent for cutaneous candidiasis. In present research, NRG was complexed with ZnO nanomaterial (NRG-Zn2+) to synthesize NRG-Zn2+ nanocomposites. The particle size and ζ-potential of NRG-Zn2+ nanocomposites were respectively estimated to be 180.33 ± 1.22-nm and - 3.92 ± 0.35-mV. In silico data predicted the greater affinity of NRG-Zn2+ nanocomposite for 14α-demethylase and ceramide in comparison to NRG alone. Later, NRG-Zn2+ nanocomposites solution was transformed in to naringenin-zinc oxide nanocomposites loaded chitosan gel (NRG-Zn-CS-Gel) with viscosity and firmness of 854806.7 ± 52386.43 cP and 698.27 ± 10.35 g, respectively. The ex-vivo skin permeation demonstrated 70.49 ± 5.22% skin retention, significantly greater (P < 0.05) than 44.48 ± 3.06% of naringenin loaded chitosan gel (NRG-CS-Gel) and 31.24 ± 3.28% of naringenin solution (NRG Solution). NRG-Zn-CS-Gel demonstrated 6.71 ± 0.84% permeation of NRG with a flux value of 0.046 ± 0.01-µg/cm2/h. The MIC50 of NRG-Zn-CS-Gel against C. albicans was estimated to be 0.156-µg/mL with FICI (fractional inhibitory concentration index) of 0.018 that consequently exhibited synergistic efficacy. Further, NRG-Zn-CS-Gel demonstrated superior antifungal efficacy in C. albicans induced cutaneous candidiasis infection in Balb/c mice. The fungal burden in NRG-Zn-CS-Gel treated group was 109 ± 25 CFU/mL, significantly lower (P < 0.05) than positive control (2260 ± 446 CFU/mL), naringenin loaded chitosan gel (NRG-CS-Gel; 928 ± 127 CFU/mL) and chitosan gel (CS-Gel; 2116 ± 186 CFU/mL) treated mice. Further, histopathology examination and cytokine profiling of TNF-α, IL-1ß and IL-10 revealed the healing of skin and inflammation associated with cutaneous candidiasis infection. In conclusion, NRG-Zn-CS-Gel may be a potential candidate for translating in to a clinical viable topical nanotherapeutic.


Assuntos
Antifúngicos , Candida albicans , Quitosana , Flavanonas , Géis , Camundongos Endogâmicos BALB C , Nanocompostos , Óxido de Zinco , Animais , Flavanonas/administração & dosagem , Flavanonas/farmacologia , Camundongos , Candida albicans/efeitos dos fármacos , Quitosana/química , Quitosana/administração & dosagem , Nanocompostos/química , Nanocompostos/administração & dosagem , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/farmacocinética , Óxido de Zinco/administração & dosagem , Óxido de Zinco/farmacologia , Óxido de Zinco/química , Sistemas de Liberação de Medicamentos/métodos , Pele/metabolismo , Pele/efeitos dos fármacos , Pele/microbiologia , Candidíase/tratamento farmacológico , Polímeros/química , Absorção Cutânea/efeitos dos fármacos , Tamanho da Partícula , Administração Cutânea
16.
Platelets ; 34(1): 2249549, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37661351

RESUMO

Alternate splicing is among the regulatory mechanisms imparting functional diversity in proteins. Studying protein isoforms generated through alternative splicing is therefore critical for understanding protein functions in many biological systems. Spleen tyrosine kinase (Syk) plays an essential role in ITAM/hemITAM signaling in many cell types, including platelets. However, the spectrum of Syk isoforms expressed in platelets has not been characterized. Syk has been shown to have a full-length long isoform SykL and a shorter SykS lacking 23 amino acid residues within its interdomain B. Furthermore, putative isoforms lacking another 23 amino acid-long sequence or a combination of the two deletions have been postulated to exist. In this report, we demonstrate that mouse platelets express full-length SykL and the previously described shorter isoform SykS, but lack other shorter isoforms, whereas human platelets express predominantly SykL. These results both indicate a possible role of alternative Syk splicing in the regulation of receptor signaling in mouse platelets and a difference between signaling regulation in mouse and human platelets.


Platelets express two sizes of the Syk molecule with possible alternate functions in the cell. We need to understand how these two differ in their structure so that further studies can be developed by selectively deleting one of them to evaluate their function in platelets. This study shows that platelet Syk molecules differ in their structure with and without a linker region in the molecule.


Assuntos
Aminoácidos , Plaquetas , Humanos , Animais , Camundongos , Quinase Syk/genética , Isoformas de Proteínas/genética , Sequência de Aminoácidos
17.
Cell Biochem Funct ; 41(8): 996-1007, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37812062

RESUMO

Breast cancer is the most common cancer among women globally and presents a significant challenge due to its rising incidence and fatality rates. Factors such as cultural, socioeconomic, and educational barriers contribute to inadequate awareness and access to healthcare services, often leading to delayed diagnoses and poor patient outcomes. Furthermore, fostering a collaborative approach among healthcare providers, policymakers, and community leaders is crucial in addressing this critical women's health issue, reducing mortality rates, alleviating, and the overall burden of breast cancer. The main goal of this review is to explore various techniques of machine learning algorithms to examine high accuracy and early detection of breast cancer for the safe health of women.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/diagnóstico , Algoritmos , Aprendizado de Máquina
18.
Childs Nerv Syst ; 39(1): 239-247, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36220935

RESUMO

PURPOSE: To study clinical and radiological outcomes of pediatric cervical kyphosis correction with a standalone posterior cervical approach. Cervical spine kyphotic deformity in pediatric age group is a distinct entity and the management is challenging. Pediatric cervical kyphosis is less often encountered, and literature is sparse with only few case series. Management algorithms are devised keeping the flexibility of the deformity at the core of decision making. Circumferential fusion is mostly recommended for non-flexible (rigid) kyphosis. METHODS: Authors present a single center retrospective analysis of cases of pediatric cervical kyphosis managed by a standalone posterior approach. Pre- and post-operative clinical and radiological parameters were recorded and analyzed. Changes in neurological status, kyphosis correction and bony fusion were assessed. Surgical and implant related complications were noted. RESULTS: Seven cases (6 male, 1 female) were included. Mean age was 13.9±2.9 years, ranging from 8-17 years. Etiology was traumatic in 2 cases, developmental in 2, and syndromic, Hirayama disease and post-laminectomy in 1 case each. Mean kyphosis correction was 36.80±19.30 (87%±21%) with a mean pre-operative kyphosis angle of 37.80±15.30 and mean immediate post-operative kyphosis angle of 3.70±8.70. Mean hospital stay duration was 10±6 days. Median follow-up duration was 36 months. Myelopathy improved in 5 cases at last follow-up. Six cases demonstrated bony fusion at a mean follow-up of 8.4±1.5 months. CONCLUSION: Significant immediate correction in pediatric cervical kyphosis may be achieved with a standalone posterior approach with proper planning and technique in selected cases. Inserting pedicle screws at strategic locations of implant construct offer better corrections and pull-out strength and maintain long-term stability resulting in higher arthrodesis rates. Larger studies with longer follow up are needed to further ascertain the role of standalone posterior cervical approaches in pediatric cervical kyphosis.

19.
Genomics ; 114(5): 110436, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35902069

RESUMO

Black rice is famous for containing high anthocyanin while Joha rice is aromatic with low anthocyanin containing rice from the North-Eastern Region (NER) of India. However, there are limited reports on the anthocyanin biosynthesis in Manipur Black rice. Therefore, the present study was aimed to understand the origin, domestication and anthocyanin biosynthesis pathways in Black rice using the next generation sequencing approaches. With the sequencing data, various analyses were carried out for differential expression and construction of a pan-genome. Protein coding RNA and small RNA sequencing analysis aided in determining 7415 and 131 differentially expressed transcripts and miRNAs, respectively in NER rice. This is the first extensive study on identification and expression analysis of miRNAs and their target genes in regulating anthocyanin biosynthesis in NER rice. This study will aid in better understanding for decoding the theory of high or low anthocyanin content in different rice genotypes.


Assuntos
MicroRNAs , Oryza , Antocianinas , Regulação da Expressão Gênica de Plantas , Variação Genética , Genômica , Índia , MicroRNAs/genética , MicroRNAs/metabolismo , Oryza/genética , Oryza/metabolismo , Transcriptoma
20.
Sensors (Basel) ; 23(21)2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37960482

RESUMO

Road network extraction is a significant challenge in remote sensing (RS). Automated techniques for interpreting RS imagery offer a cost-effective solution for obtaining road network data quickly, surpassing traditional visual interpretation methods. However, the diverse characteristics of road networks, such as varying lengths, widths, materials, and geometries across different regions, pose a formidable obstacle for road extraction from RS imagery. The issue of road extraction can be defined as a task that involves capturing contextual and complex elements while also preserving boundary information and producing high-resolution road segmentation maps for RS data. The objective of the proposed Archimedes tuning process quantum dilated convolutional neural network for road Extraction (ATP-QDCNNRE) technology is to tackle the aforementioned issues by enhancing the efficacy of image segmentation outcomes that exploit remote sensing imagery, coupled with Archimedes optimization algorithm methods (AOA). The findings of this study demonstrate the enhanced road-extraction capabilities achieved by the ATP-QDCNNRE method when used with remote sensing imagery. The ATP-QDCNNRE method employs DL and a hyperparameter tuning process to generate high-resolution road segmentation maps. The basis of this approach lies in the QDCNN model, which incorporates quantum computing (QC) concepts and dilated convolutions to enhance the network's ability to capture both local and global contextual information. Dilated convolutions also enhance the receptive field while maintaining spatial resolution, allowing fine road features to be extracted. ATP-based hyperparameter modifications improve QDCNNRE road extraction. To evaluate the effectiveness of the ATP-QDCNNRE system, benchmark databases are used to assess its simulation results. The experimental results show that ATP-QDCNNRE performed with an intersection over union (IoU) of 75.28%, mean intersection over union (MIoU) of 95.19%, F1 of 90.85%, precision of 87.54%, and recall of 94.41% in the Massachusetts road dataset. These findings demonstrate the superior efficiency of this technique compared to more recent methods.

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