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PHD finger protein 7 (Phf7) is a member of the PHF family proteins, which plays important roles in spermiogenesis. Phf7 is expressed in the adult testes and its deficiency causes male infertility. In this study, we tried to find the causal relationship between Phf7 deficiency and reduced growth retardation which were found in null knock-out (Phf7-/-) mice. Phf7-/- mice were born normally in the Mendelian ratio. However, the Phf7-/- males showed decreased body weight gain, bone mineral density, and bone mineral content compared to those in wild-type (WT) mice. Histological analysis for tibia revealed increased number of osteoclast cells in Phf7-/- mice compared with that in WT mice. When we analyzed the expressions for marker genes for the initial stage of osteoclastogenesis, such as receptor activator of nuclear factor kappa B (Rank) in tibia, there was no difference in the mRNA levels between Phf7-/- and WT mice. However, the expression of tartrate-resistant acid phosphatase (Trap), a mature stage marker gene, was significantly higher in Phf7-/- mice than in WT mice. In addition, the levels of testosterone and dihydrotestosterone (DHT), more potent and active form of testosterone, were significantly reduced in the testes of Phf7-/- mice compared to those in WT mice. Furthermore, testicular mRNA levels for steroidogenesis marker genes, namely Star, Cyp11a1, Cyp17a1 and 17ß-hsd, were significantly lower in Phf7-/- mice than in WT mice. In conclusion, these results suggest that Phf7 deficiency reduces the production of male sex hormones and thereby impairs associated bone remodeling.
Assuntos
Hormônios Testiculares , Animais , Masculino , Camundongos , Remodelação Óssea , Osteoclastos/metabolismo , RNA Mensageiro/metabolismo , Hormônios Testiculares/metabolismo , Testosterona/metabolismoRESUMO
This study employed a longitudinal analysis to evaluate the association between the coronavirus disease 2019 pandemic and neurodevelopment by analyzing over 1.8 million children from the Korean Developmental Screening Test for Infants and Children included in South Korea's National Health Screening Program. We compared the developmental outcomes in five age groups-9-17 months, 18-29 months, 30-41 months, 42-53 months, and 54-65 months-between the pre-pandemic (2018-2019) and pandemic (2020-2021) periods. Significant increases in potential developmental delays were observed during the pandemic in communication, cognitive, social interaction, self-care, and fine motor skills across most age groups. All five age groups experienced notable disruptions in communication and fine motor skills. Children from socioeconomically disadvantaged backgrounds faced higher risks across all domains. These findings highlight the need for targeted interventions and continuous monitoring to support the developmental needs of children affected by pandemic-related disruptions.
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COVID-19 , Desenvolvimento Infantil , Deficiências do Desenvolvimento , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , República da Coreia/epidemiologia , Pré-Escolar , Estudos Longitudinais , Lactente , Feminino , Masculino , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/diagnóstico , SARS-CoV-2/isolamento & purificação , Criança , Destreza Motora , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/diagnósticoRESUMO
BACKGROUND: Vancomycin (VCM) is a widely used antibiotic for the treatment of gram-positive microorganisms, with some nephrotoxic effects. Recent studies have suggested that piperacillin-tazobactam (TZP) aggravates VCM-induced nephrotoxicity in adults and adolescents. However, there is a lack of research investigating these effects in the newborn population. Therefore, this study investigates whether the concomitant use of TZP with VCM use increases the risk of acute kidney injury (AKI) and to explore the factors associated with AKI in preterm infants treated with VCM. METHODS: This retrospective study included preterm infants with birth weight < 1,500 g in a single tertiary center who were born between 2018 and 2021 and received VCM for a minimum of 3 days. AKI was defined as an increase in serum creatinine (SCr) of at least 0.3 mg/dL and an increase in SCr of at least 1.5 times baseline during and up to 1 week after discontinuation of VCM. The study population was categorized as those with or without concomitant use of TZP. Data on perinatal and postnatal factors associated with AKI were collected and analyzed. RESULTS: Of the 70 infants, 17 died before 7 postnatal days or antecedent AKI and were excluded, while among the remaining participants, 25 received VCM with TZP (VCM + TZP) and 28 VCM without TZP (VCM-TZP). Gestational age (GA) at birth (26.4 ± 2.8 weeks vs. 26.5 ± 2.6 weeks, p = 0.859) and birthweight (750.4 ± 232.2 g vs. 838.1 ± 268.7 g, p = 0.212) were comparable between the two groups. There were no significant differences in the incidence of AKI between groups. Multivariate analysis showed that GA (adjusted OR: 0.58, 95% CI: 0.35-0.98, p = 0.042), patent ductus arteriosus (PDA) (adjusted OR: 5.23, 95% CI: 0.67-41.05, p = 0.115), and necrotizing enterocolitis (NEC) (adjusted OR: 37.65, 95% CI: 3.08-459.96, p = 0.005) were associated with AKI in the study population. CONCLUSIONS: In very low birthweight infants, concomitant use of TZP did not increase the risk of AKI during VCM administration. Instead, a lower GA, and NEC were associated with AKI in this population.
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Injúria Renal Aguda , Vancomicina , Adulto , Lactente , Humanos , Recém-Nascido , Adolescente , Vancomicina/efeitos adversos , Estudos Retrospectivos , Recém-Nascido Prematuro , Antibacterianos/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Peso ao Nascer , Quimioterapia Combinada , Recém-Nascido de muito Baixo PesoRESUMO
The placenta regulates maternal-fetal communication, and its defect leads to significant pregnancy complications. The maternal and embryonic circulations are primitively connected in early placentation, but the function of the placenta during this developmentally essential period is relatively unknown. We thus performed a comparative proteomic analysis of the placenta before and after primary placentation and found that the metabolism and transport of lipids were characteristically activated in this period. The placental fatty acid (FA) carriers in specific placental compartments were upregulated according to gestational age, and metabolomic analysis also showed that the placental transport of FAs increased in a time-dependent manner. Further analysis of two mutant mice models with embryonic lethality revealed that lipid-related signatures could reflect the functional state of the placenta. Our findings highlight the importance of the nutrient transport function of the primary placenta in the early gestational period and the role of lipids in embryonic development. SUMMARY SENTENCE: The placenta is activated characteristically in terms of lipid transport during primary placentation, and the lipid-related signatures closely reflect the functional state of the placenta.
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Placenta , Placentação , Animais , Ácidos Graxos/metabolismo , Feminino , Idade Gestacional , Camundongos , Placenta/metabolismo , Gravidez , ProteômicaRESUMO
Topoisomerase IIIß (Top3ß), the only dual-activity topoisomerase in mammals that can change topology of both DNA and RNA, is known to be associated with neurodevelopment and mental dysfunction in humans. However, there is no report showing clear associations of Top3ß with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3ß on neuro-behavior using newly generated Top3ß deficient (Top3ß-/-) mice. We found that Top3ß-/- mice showed decreased anxiety and depression-like behaviors. The lack of Top3ß was also associated with changes in circadian rhythm. In addition, a clear expression of Top3ß was demonstrated in the central nervous system of mice. Positron emission tomography/computed tomography (PET/CT) analysis revealed significantly altered connectivity between many brain regions in Top3ß-/- mice, including the connectivity between the olfactory bulb and the cerebellum, the connectivity between the amygdala and the olfactory bulb, and the connectivity between the globus pallidus and the optic nerve. These connectivity alterations in brain regions are known to be linked to neurodevelopmental as well as psychiatric and behavioral disorders in humans. Therefore, we conclude that Top3ß is essential for normal brain function and behavior in mice and that Top3ß could be an interesting target to study neuropsychiatric disorders in humans.
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Transtornos de Ansiedade/patologia , Comportamento Animal , Ritmo Circadiano , Conectoma , DNA Topoisomerases Tipo I/fisiologia , Depressão/patologia , Animais , Transtornos de Ansiedade/etiologia , Depressão/etiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos KnockoutRESUMO
BACKGROUND: Community acquired-methicillin resistant Staphylococcus aureus (MRSA) clones, including ST1, ST8, and ST30 are reported worldwide. However, data among Korean children are limited. Thus, we investigated the molecular characteristics of S. aureus among children in Korea. METHODS: S. aureus isolated from Korean children diagnosed with skin and soft tissue infection (SSTI) or bone and joint infection due to S. aureus infection at Seoul National University Bundang Hospital, from August 2010 to November 2016, were analyzed for multilocus sequence type (ST) and SCCmec typing. Polymerase chain reaction of Panton-Valentine leukocidin (PVL), qac A/B, smr and mupA genes were also performed. Electronic medical records were reviewed for clinical data and antibiotic susceptibility results. Cases were classified into three groups: health care-associated community-onset (HACO) infections, hospital-onset (HO) infections, and community-acquired (CA) infections. RESULTS: A total of 67 strains from children with SSTI (41/67, 61.2%) and bone and joint infection (26/67, 38.8%) were included. Among all isolates, 29.9% (20/67) were MRSA, and 70% (14/20) were classified as CA, 20% (4/20) as HACO and 10% (2/20) as HO infections. MRSA rate according to disease was 34.1% (14/41) for SSTI and 23.1% (6/26) for bone and joint infection. MRSA strains included ST72-SCCmec IV (14/20, 70.0%), ST5-SCCmec II (3/20, 15.0%) and ST1-SCCmec IV (2/20, 10.0%). ST30 was the most common cause of SSTI and bone and joint infections and 96.6% (28/29) were methicillin-susceptible Staphylococcus aureus (MSSA). PVL genes were detected in 3 strains (3.8%, ST30-SCCmec IV n = 1, MSSA ST30 n = 2), qac A/B in 3 (MRSA = 3), smr in 3 (MSSA = 1, MRSA = 2) and mupA in 7 (MRSA = 5, MSSA = 2). CONCLUSION: Molecular epidemiology of S. aureus in Korean children with SSTI and bone and joint infection showed that ST30 was predominant and mostly MSSA. Among MRSA, ST72-SCCmec type IV was the most common strain.
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Doenças Ósseas/diagnóstico , Artropatias/diagnóstico , Infecções dos Tecidos Moles/diagnóstico , Infecções Cutâneas Estafilocócicas/diagnóstico , Adolescente , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Doenças Ósseas/epidemiologia , Doenças Ósseas/microbiologia , Criança , Pré-Escolar , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/epidemiologia , Farmacorresistência Bacteriana/genética , Feminino , Humanos , Lactente , Recém-Nascido , Artropatias/epidemiologia , Artropatias/microbiologia , Masculino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Tipagem de Sequências Multilocus , República da Coreia/epidemiologia , Infecções dos Tecidos Moles/epidemiologia , Infecções dos Tecidos Moles/microbiologia , Infecções Cutâneas Estafilocócicas/epidemiologia , Infecções Cutâneas Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificaçãoRESUMO
BACKGROUND: Nontuberculous mycobacteria (NTM) lymphadenitis is an under-recognized entity, and data of the true burden in children are limited. Without a high index of suspicion, diagnosis may be delayed and microbiological detection is challenging. Here, we report a cluster of NTM lymphadenitis experienced in Korean children. METHODS: Subjects under 19 years of age diagnosed with NTM lymphadenitis during November 2016-April 2017 and April 2018 were included. Electronic medical records were reviewed for clinical, laboratory and pathological findings. Information regarding underlying health conditions and environmental exposure factors was obtained through interview and questionnaires. RESULTS: A total of ten subjects were diagnosed during 18 months. All subjects were 8-15 years of age, previously healthy, male and had unilateral, nontender, cervicofacial lymphadenitis for more than 3 weeks with no significant systemic symptoms and no response to empirical antibiotics. Lymph nodes involved were submandibular (n = 8), preauricular (n = 6) and submental (n = 1). Five patients had two infected nodes and violaceous discoloration was seen in seven subjects. Biopsy specimens revealed chronic granulomatous inflammation and acid-fast bacteria culture identified Mycobacterium haemophilum in two cases and NTM polymerase chain reaction was positive in two cases. Survey revealed various common exposure sources. CONCLUSION: NTM lymphadenitis is rare but increasing in detection and it may occur in children and adolescents. Diagnosis requires high index of suspicion and communication between clinicians and the laboratory is essential for identification of NTM.
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Linfadenite/diagnóstico , Infecções por Mycobacterium não Tuberculosas/patologia , Adolescente , Antibacterianos/uso terapêutico , Criança , Humanos , Linfadenite/tratamento farmacológico , Linfadenite/etiologia , Masculino , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium haemophilum/genética , Mycobacterium haemophilum/isolamento & purificação , Micobactérias não Tuberculosas/genética , Micobactérias não Tuberculosas/isolamento & purificação , RNA Bacteriano/metabolismoRESUMO
Protein tyrosine phosphatase 1B (PTP1B) plays a specific role as a negative regulator of insulin signaling pathways and is a validated therapeutic target for Type 2 diabetes. Previously, arylbenzofurans were reported to have inhibitory activity against PTP1B. However, detailed investigation regarding their structure activity relationship (SAR) has not been elucidated. The main aim of this work was to investigate the PTP1B inhibitory activity of 2-arylbenzofuran analogs (sanggenofuran A (SA), mulberrofuran D2 (MD2), mulberrofuran D (MD), morusalfuran B (MB), mulberrofuran H (MH)) isolated from the root bark of Morus alba. All compounds demonstrated potent inhibitory activity with IC50 values ranging from 3.11 to 53.47 µM. Among the tested compounds, MD2 showed the strongest activity (IC50, 3.11 µM), followed by MD and MB, while SA and MH demonstrated the lowest activity. Lineweaver-Burk and Dixon plots were used for the determination of inhibition type whereas ligand and receptor interactions were investigated in modeled complexes via molecular docking. Our study clearly supports 2-arylbenzofuran analogs as a promising class of PTP1B inhibitors and illustrates the key positions responsible for the inhibitory activity, their correlation, the effect of prenyl/geranyl groups, and the influence of resorcinol scaffold, which can be further explored in-depth to develop therapeutic agents against T2DM.
Assuntos
Benzofuranos/química , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Morus/química , Raízes de Plantas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Benzofuranos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/químicaRESUMO
BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the most common postsurgical complications. Palonosetron, a 5-hydroxytryptamine receptor antagonist, is effective for PONV prevention. Herein, we compared palonosetron and aprepitant (a neurokinin-1 receptor antagonist) for PONV prevention in patients indicated for laparoscopic gynaecologic surgery. METHODS: Ninety-three patients who were scheduled to undergo laparoscopic gynaecologic surgery under general anaesthesia were assigned to receive either a single intravenous injection of 0.075-mg palonosetron or 40-mg oral aprepitant in a double-blind randomised trial. The primary efficacy end points included complete response (visual analogue scale [VAS] nausea score <4 and no use of rescue therapy) 0-48 h after surgery. Nausea severity (0-10) and use of rescue therapy were monitored for 0-48 h. The secondary efficacy end points were the effect of aprepitant quantified using a 10-point VAS for pain, consumption of intravenous patient-controlled analgesia, and use of rescue analgesics. RESULTS: Aprepitant was non-inferior to palonosetron in terms of complete response 0-48 hours after surgery (74% vs. 77%). At 0 and 2 h after administration, the nausea severity with 40-mg aprepitant was significantly lesser than that with 0.075-mg palonosetron (P < 0.05). At 6 and 24 h after administration, fentanyl consumption with 40-mg aprepitant was significantly lower than that with 0.075-mg palonosetron. Greater amounts of rescue analgesics were required in the aprepitant group. CONCLUSIONS: Palonosetron and aprepitant were both effective for PONV prevention in the patients indicated for laparoscopic gynaecologic surgery. The drugs can be used in combination for multimodal therapy because they bind to different receptors. More research is needed to evaluate the effects of aprepitant on pain management in humans.
Assuntos
Antieméticos/uso terapêutico , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Isoquinolinas/uso terapêutico , Laparoscopia/efeitos adversos , Morfolinas/uso terapêutico , Náusea e Vômito Pós-Operatórios/prevenção & controle , Quinuclidinas/uso terapêutico , Adulto , Analgesia Controlada pelo Paciente , Aprepitanto , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/prevenção & controle , Palonossetrom , Adulto JovemRESUMO
BACKGROUND: This study aimed to determine whether self-regulation acts as a mediating factor in the relationship between obesity-related stress and weight control behavior, targeting Korean female college students. Obesity-related stress and weight control behaviors are important factors affecting an individual's health and well-being, and self-control, a psychological trait, can play a pivotal role in regulating how individuals respond to stress and engage in weight management behaviors. METHODS: This study employed a descriptive correlational design. A total of 109 female college students with overweight and obesity participated in the study. We used a self-report questionnaire to measure obesity-related stress, self-control, and degree of weight control behavior. Data were analyzed using descriptive statistics, Pearson's correlation coefficient analysis, and bootstrapping using Hayes' PROCESS macro for mediation. RESULTS: Significant relationships between obesity-related stress and weight control behavior (r = 0.25, p < 0.001), obesity-related stress and self-control (r = -0.36, p < 0.001), and weight control behavior and self-control (r = 0.26, p < 0.001) were observed. Self-control showed an indirect mediating effect on the relationship between obesity-related stress and weight control behavior (Β = 0.37, p = 0.001). CONCLUSIONS: Through the research results, it was confirmed that self-control is a factor that has a mediating effect in the relationship between obesity-related stress and weight control behavior among female college students with overweight and obesity. These results underscore the importance of addressing self-control strategies in interventions aimed at promoting healthy weight management among female college students with overweight or obesity.
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Perinatal outcomes of twin pregnancies are determined by several factors, such as gestational age (GA), chorionicity, and discordance at birth. This retrospective study aimed to investigate the association of chorionicity and discordance with neonatal and neurodevelopmental outcomes in preterm twin infants from uncomplicated pregnancy. Data of very preterm twin infants who were both live-born between 2014 and 2019 on the chorionicity of the twin, diagnosis of the twin-to-twin syndrome (TTTS), weight discordance at birth, and neonatal and neurodevelopmental outcomes at 24 months of corrected age (CA) were collected. Of the 204 twin infants analyzed, 136 were dichorionic (DC) and 68 were monochorionic (MC), including 15 pairs with TTTS. After adjusting for GA, brain injury, including severe intraventricular hemorrhage and periventricular leukomalacia, was mostly found in the MC with TTTS group, with a higher incidence of cerebral palsy and motor delay at CA 24 months. After excluding TTTS, multivariable analysis showed no association between chorionicity and neonatal and developmental outcomes, whereas small infants among co-twins (adjusted odds ratio (aOR) 3.33, 95% confidence interval 1.03-10.74) and greater discordance (%) of weight at birth (aOR 1.04, 1.00-1.07) were associated with neurodevelopmental impairment. Monochorionicity might not determine adverse outcomes among very preterm twins from uncomplicated pregnancy.
Assuntos
Lactente Extremamente Prematuro , Gêmeos , Gravidez , Recém-Nascido , Lactente , Feminino , Humanos , Estudos Retrospectivos , Gravidez de Gêmeos , Idade Gestacional , Retardo do Crescimento Fetal/epidemiologia , Resultado da Gravidez , Gêmeos MonozigóticosRESUMO
BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase. The gene encoding BAP1 is mutated in various human cancers, including mesothelioma, uveal melanoma and renal cell carcinoma. BAP1 plays roles in many cancer-related cellular functions, including cell proliferation, cell death, and nuclear processes crucial for genome stability, such as DNA repair and replication. While these findings suggest that BAP1 functions as a tumor suppressor, recent data also suggest that BAP1 might play tumor-promoting roles in certain cancers, such as breast cancer and hematopoietic malignancies. Here, we show that BAP1 is upregulated in colon cancer cells and tissues and that BAP1 depletion reduces colon cancer cell proliferation and tumor growth. BAP1 contributes to colon cancer cell proliferation by accelerating DNA replication and suppressing replication stress and concomitant apoptosis. A recently identified BAP1 inhibitor, TG2-179-1, which seems to covalently bind to the active site of BAP1, exhibits potent cytotoxic activity against colon cancer cells, with half-maximal inhibitory concentrations of less than 10 µM, and inhibits colon tumor growth. TG2-179-1 exerts cytotoxic activity by targeting BAP1, leading to defective replication and increased apoptosis. This work therefore shows that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target for this cancer. Our work also suggests that TG2-179-1 can be developed as a potential therapeutic agent for colon cancer.
Assuntos
Antineoplásicos , Neoplasias do Colo , Ubiquitina Tiolesterase , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/genéticaRESUMO
The structure-activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-4-[(methylsulfonylamino)benzyl] thioureas, which represent simplified RTX-based vanilloids, were investigated by varying the distances between the four principal pharmacophores and assessing binding and antagonistic activity on rTRPV1. The analysis indicated that a 3-pivaloyloxy-2-benzylpropyl C-region conferred the best potency in binding affinity and antagonism. The molecular modeling of this best template with the tetrameric homology model of rTRPV1 was performed to identify its binding interactions with the receptor.
Assuntos
Simulação de Dinâmica Molecular , Canais de Cátion TRPV/antagonistas & inibidores , Tioureia/química , Animais , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo , Tioureia/síntese químicaRESUMO
Multifocal colorectal cancer (CRC) comprises both clonally independent primary tumors caused by inherited predisposition and clonally related tumors mainly due to intraluminal spreading along an intact basement membrane. The distinction between these multifocal CRCs is essential because therapeutic strategies vary according to the clonal association of multiple tumor masses. Here, we report one unique case of synchronous intestinal cancer (SIC) with tumors occurring along the entire bowel tract, including the small intestine. We established six patient-derived organoids (PDOs), and patient-derived cell lines (PDCs) from each site of the SIC, which were subjected to extensive genomic, transcriptomic, and epigenomic sequencing. We also estimated the drug responses of each multifocal SIC to 25 clinically relevant therapeutic compounds to validate how the clinically actionable alternations between SICs were associated with drug sensitivity. Our data demonstrated distinct clonal associations across different organs, which were consistently supported by multi-omics analysis, as well as the accordant responses to various therapeutic compounds. Our results indicated the imminent drawback of a single tumor-based diagnosis of multifocal CRC and suggested the necessity of an in-depth molecular analysis of all tumor regions to avoid unexpected resistance to the currently available targeted therapies.
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Background: Cerebellar hemorrhage (CBH) is a major form of cerebellar injury in preterm infants. We aimed to investigate the risk factors and neurodevelopmental outcomes of isolated CBH and performed volumetric analysis at term-equivalent age. Methods: This single-centered nested case-control study included 26 preterm infants with isolated CBH and 52 infants without isolated CBH and any significant supratentorial injury. Results: Isolated CBH was associated with PCO2 fluctuation within 72 h after birth (adjusted odds ratio 1.007, 95% confidence interval 1.000-1.014). The composite score in the motor domain of the Bayley Scales of Infant and Toddler Development at 24 month of corrected age was lower in the punctate isolated CBH group than that in the control group (85.3 vs. 94.5, P = 0.023). Preterm infants with isolated CBH had smaller cerebellum and pons at term-equivalent age compared to the control group. Isolated CBH with adverse neurodevelopment had a smaller ventral diencephalon and midbrain compared to isolated CBH without adverse neurodevelopmental outcomes. Conclusions: In preterm infants, isolated CBH with punctate lesions were associated with abnormal motor development at 24 months of corrected age. Isolated CBH accompanied by a smaller ventral diencephalon and midbrain at term equivalent had adverse neurodevelopmental outcomes.
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This study aimed to develop quantitative assessments of spontaneous movements in high-risk preterm infants based on a deep learning algorithm. Video images of spontaneous movements were recorded in very preterm infants at the term-equivalent age. The Hammersmith Infant Neurological Examination (HINE) was performed in infants at 4 months of corrected age. Joint positional data were extracted using a pretrained pose-estimation model. Complexity and similarity indices of joint angle and angular velocity in terms of sample entropy and Pearson correlation coefficient were compared between the infants with HINE < 60 and ≥ 60. Video images of spontaneous movements were recorded in 65 preterm infants at term-equivalent age. Complexity indices of joint angles and angular velocities differed between the infants with HINE < 60 and ≥ 60 and correlated positively with HINE scores in most of the joints at the upper and lower extremities (p < 0.05). Similarity indices between each joint angle or joint angular velocity did not differ between the two groups in most of the joints at the upper and lower extremities. Quantitative assessments of spontaneous movements in preterm infants are feasible using a deep learning algorithm and sample entropy. The results indicated that complexity indices of joint movements at both the upper and lower extremities can be potential candidates for detecting developmental outcomes in preterm infants.
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Aprendizado Profundo , Lactente Extremamente Prematuro , Aprendizagem , Movimento , Redes Neurais de Computação , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
We investigated how differences in age, sex, or vaccine type can affect humoral and cellular immune responses after vaccination with vector (ChAdOx1 nCoV-19), mix-and-match (first, ChAdOx1 nCoV-19, and second, BNT162b2), or mRNA (BNT162b2 or mRNA-1273) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Venous blood was collected from 573 subjects (vector, 396; mix-and-match, 96; and mRNA, 81) before the first vaccination (T0), 7 to 8 weeks (vector) or 3 to 4 weeks (mRNA) after the first vaccination (T1), and 3 to 4 weeks after the second vaccination (T2). The humoral and cellular immune responses were evaluated using Elecsys anti-SARS-CoV-2 (Roche), Alinity SARS-CoV-2 IgG II Quant (Abbott), cPass SARS-CoV-2 neutralization antibody detection (GenScript), and QuantiFERON SARS-CoV-2 (Qiagen) kits. At T1, the levels of the receptor-binding domain antibodies (RBD Ab) and neutralizing antibodies (NAb) decreased with aging, but interferon gamma release (IGR) levels increased. The RBD Ab, NAb, and IGR levels were higher in females than in males at T1 and T2. The NAb levels were higher in the mix-and-match and mRNA vaccine groups than in the vector vaccine group at T2. The RBD Ab and IGR levels were higher in the mRNA vaccine group than in the vector or mix-and-match vaccine groups at T2. The optimal cutoffs for RBD Ab and NAb, which were used to determine the presence of T cell responses, were 5.7 binding antibody units per milliliter (BAU mL-1) and 12.0 IU mL-1, respectively. Age, sex, and vaccine type affected the humoral and cellular immune responses, and T cell responses could be estimated from RBD Ab and NAb levels. IMPORTANCE There have been few studies that comprehensively evaluated factors affecting immune responses and the correlation between humoral and cellular immune responses after vector, mix-and-match, and mRNA vaccines against SARS-CoV-2. Therefore, we analyzed the effects of age, sex, and the different vaccine regimens on the immune responses to vaccination against SARS-CoV-2. The correlation between humoral and cellular immune responses and the cutoffs were derived for RBD antibodies and neutralizing antibodies to predict the presence of the cellular immune responses. In this comprehensive study, we demonstrated that there were differences in the immune responses induced after vaccination depending on the age and sex of an individual. Among the three vaccine regimens, the mix-and-match and mRNA vaccines induced the most robust immune responses. Finally, the proposed optimal cutoffs for RBD and neutralizing antibodies may be useful for predicting cellular immune responses when assays for cellular immune responses are not available.
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COVID-19 , Vacinas Virais , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , ChAdOx1 nCoV-19 , Feminino , Humanos , Imunidade Celular , Masculino , RNA Mensageiro , SARS-CoV-2/genética , Vacinação , Vacinas Sintéticas , Vacinas de mRNARESUMO
A series of 5'-halogenated resiniferatoxin analogs have been investigated in order to examine the effect of halogenation in the A-region on their binding and the functional pattern of agonism/antagonism for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Halogenation at the 5-position in the A-region of RTX and of 4-amino RTX shifted the agonism of parent compounds toward antagonism. The extent of antagonism was greater as the size of the halogen increased (I > Br > Cl > F) while the binding affinities were similar, as previously observed for our potent agonists. In this series, 5-bromo-4-amino RTX (39) showed very potent antagonism with K(i) (ant) = 2.81 nM, which was thus 4.5-fold more potent than 5'-iodo RTX, previously reported as a potent TRPV1 antagonist. Molecular modeling analyses with selected agonists and the corresponding halogenated antagonists revealed a striking conformational difference. The 3-methoxy of the A-region in the agonists remained free to interact with the receptor whereas in the case of the antagonists, the compounds assumed a bent conformation, permitting the 3-methoxy to instead form an internal hydrogen bond with the C4-hydroxyl of the diterpene.
Assuntos
Diterpenos/química , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Diterpenos/síntese química , Diterpenos/farmacologia , Halogenação , Ligantes , Modelos Moleculares , Ratos , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismoRESUMO
In the present study, a novel synthetic tissue adhesive material capable of sealing wounds without the use of any crosslinking agent was developed by conjugating thermosensitive hexanoyl glycol chitosan (HGC) with gallic acid (GA). The degree of N-gallylation was manipulated to prepare GA-HGCs with different GA contents. GA-HGCs demonstrated thermosensitive sol-gel transition behavior and formed irreversible hydrogels upon natural oxidation of the pyrogallol moieties in GA, possibly leading to GA-HGC crosslinks through intra/intermolecular hydrogen bonding and chemical bonds. The GA-HGC hydrogels exhibited self-healing properties, high compressive strength, strong tissue adhesive strength and biodegradability that were adjustable according to the GA content. GA-HGCs also presented excellent biocompatibility and wound healing effects. The results of in vivo wound healing efficacy studies on GA-HGC hydrogels indicated that they significantly promote wound closure and tissue regeneration by upregulating growth factors and recruiting fibroblasts compared to the untreated control group.
Assuntos
Materiais Biocompatíveis/química , Quitosana/química , Ácido Gálico/química , Animais , Materiais Biocompatíveis/farmacologia , Força Compressiva , Hidrogéis/química , Hidrogéis/farmacologia , Reologia , Suínos , Adesivos Teciduais/química , Cicatrização/efeitos dos fármacosRESUMO
Asb2, ankyrin repeat, and SOCS box protein 2 form an E3 ubiquitin ligase complex. Asb2 ubiquitin ligase activity drives the degradation of filamins, which have essential functions in humans. The placenta is a temporary organ that forms during pregnancy, and normal placentation is important for survival and growth of the fetus. Recent studies have shown that approximately 25-30% of knockout (KO) mice have non-viable offspring, and 68% of knockout lines exhibit placental dysmorphologies. There are very few studies on Asb2, with insufficient research on its role in placental development. Therefore, we generated Asb2 knockout mice and undertook to investigate Asb2 expression during organogenesis, and to identify its role in early embryonic and placental development. The external morphology of KO embryos revealed abnormal phenotypes including growth retardation, pericardial effusion, pale color, and especially heart beat defect from E 9.5. Furthermore, Asb2 expression was observed in the heart from E 9.5, indicating that it is specifically expressed during early heart formation, resulting in embryonic lethality. Histological analysis of E 10.5 KO heart showed malformations such as failure of chamber formation, reduction in trabeculated myocardium length, absence of mesenchymal cells, and destruction of myocardium wall. Moreover, the histological results of Asb2-deficient placenta showed abnormal phenotypes including small labyrinth and reduced vascular complexity, indicating that failure to establish mature circulatory pattern affects the embryonic development and results in early mortality. Collectively, our results demonstrate that Asb2 knockout mice have placental defects, that subsequently result in failure to form a normal cardiac septum, and thereby result in embryo mortality in utero at around E 9.5.