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1.
Nature ; 583(7818): 768-770, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32728241

RESUMEN

Globular clusters are some of the oldest bound stellar structures observed in the Universe1. They are ubiquitous in large galaxies and are believed to trace intense star-formation events and the hierarchical build-up of structure2,3. Observations of globular clusters in the Milky Way, and a wide variety of other galaxies, have found evidence for a 'metallicity floor', whereby no globular clusters are found with chemical (metal) abundances below approximately 0.3 to 0.4 per cent of that of the Sun4-6. The existence of this metallicity floor may reflect a minimum mass and a maximum redshift for surviving globular clusters to form-both critical components for understanding the build-up of mass in the Universe7. Here we report measurements from the Southern Stellar Streams Spectroscopic Survey of the spatially thin, dynamically cold Phoenix stellar stream in the halo of the Milky Way. The properties of the Phoenix stream are consistent with it being the tidally disrupted remains of a globular cluster. However, its metal abundance ([Fe/H] = -2.7) is substantially below the empirical metallicity floor. The Phoenix stream thus represents the debris of the most metal-poor globular clusters discovered so far, and its progenitor is distinct from the present-day globular cluster population in the local Universe. Its existence implies that globular clusters below the metallicity floor have probably existed, but were destroyed during Galactic evolution.

2.
Proc Natl Acad Sci U S A ; 120(21): e2301897120, 2023 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-37186861

RESUMEN

The peptidoglycan (PG) cell wall produced by the bacterial division machinery is initially shared between the daughters and must be split to promote cell separation and complete division. In gram-negative bacteria, enzymes that cleave PG called amidases play major roles in the separation process. To prevent spurious cell wall cleavage that can lead to cell lysis, amidases like AmiB are autoinhibited by a regulatory helix. Autoinhibition is relieved at the division site by the activator EnvC, which is in turn regulated by the ATP-binding cassette (ABC) transporter-like complex called FtsEX. EnvC is also known to be autoinhibited by a regulatory helix (RH), but how its activity is modulated by FtsEX and the mechanism by which it activates the amidases have remained unclear. Here, we investigated this regulation by determining the structure of Pseudomonas aeruginosa FtsEX alone with or without bound ATP, in complex with EnvC, and in a FtsEX-EnvC-AmiB supercomplex. In combination with biochemical studies, the structures reveal that ATP binding is likely to activate FtsEX-EnvC and promote its association with AmiB. Furthermore, the AmiB activation mechanism is shown to involve a RH rearrangement. In the activated state of the complex, the inhibitory helix of EnvC is released, freeing it to associate with the RH of AmiB, which liberates its active site for PG cleavage. These regulatory helices are found in many EnvC proteins and amidases throughout gram-negative bacteria, suggesting that the activation mechanism is broadly conserved and a potential target for lysis-inducing antibiotics that misregulate the complex.


Asunto(s)
Proteínas de Escherichia coli , Escherichia coli , Hidrólisis , N-Acetil Muramoil-L-Alanina Amidasa/metabolismo , Amidohidrolasas/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Pared Celular/metabolismo , Adenosina Trifosfato/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Peptidoglicano/metabolismo , Endopeptidasas/metabolismo , Proteínas de Escherichia coli/metabolismo
3.
Proc Natl Acad Sci U S A ; 120(13): e2213584120, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36943879

RESUMEN

Virtually all living cells are encased in glycans. They perform key cellular functions such as immunomodulation and cell-cell recognition. Yet, how their composition and configuration affect their functions remains enigmatic. Here, we constructed isogenic capsule-switch mutants harboring 84 types of capsular polysaccharides (CPSs) in Streptococcus pneumoniae. This collection enables us to systematically measure the affinity of structurally related CPSs to primary human nasal and bronchial epithelial cells. Contrary to the paradigm, the surface charge does not appreciably affect epithelial cell binding. Factors that affect adhesion to respiratory cells include the number of rhamnose residues and the presence of human-like glycomotifs in CPS. Besides, pneumococcal colonization stimulated the production of interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractantprotein-1 (MCP-1) in nasal epithelial cells, which also appears to be dependent on the serotype. Together, our results reveal glycomotifs of surface polysaccharides that are likely to be important for colonization and survival in the human airway.


Asunto(s)
Células Epiteliales , Streptococcus pneumoniae , Humanos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/metabolismo , Sistema Respiratorio , Polisacáridos/metabolismo , Nariz
4.
Nature ; 574(7776): 69-71, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31578482

RESUMEN

Large galaxies grow through the accumulation of dwarf galaxies1,2. In principle it is possible to trace this growth history via the properties of a galaxy's stellar halo3-5. Previous investigations of the galaxy Messier 31 (M31, Andromeda) have shown that outside a galactocentric radius of 25 kiloparsecs the population of halo globular clusters is rotating in alignment with the stellar disk6,7, as are more centrally located clusters8,9. The M31 halo also contains coherent stellar substructures, along with a smoothly distributed stellar component10-12. Many of the globular clusters outside a radius of 25 kiloparsecs are associated with the most prominent substructures, but some are part of the smooth halo13. Here we report an analysis of the kinematics of these globular clusters. We find two distinct populations rotating perpendicular to each other. The rotation axis for the population associated with the smooth halo is aligned with the rotation axis for the plane of dwarf galaxies14 that encircles M31. We interpret these separate cluster populations as arising from two major accretion epochs, probably separated by billions of years. Stellar substructures from the first epoch are gone, but those from the more recent second epoch still remain.

5.
Nano Lett ; 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38619329

RESUMEN

Excessive accumulation of reduced nicotinamide adenine dinucleotide (NADH) within biological organisms is closely associated with many diseases. It remains a challenge to efficiently convert superfluous and detrimental NADH to NAD+. NADH oxidase (NOX) is a crucial oxidoreductase that catalyzes the oxidation of NADH to NAD+. Herein, M1M2 (Mi=V/Mn/Fe/Co/Cu/Mo/Rh/Ru/Pd, i = 1 or 2) mated-atom nanozymes (MANs) are designed by mimicking natural enzymes with polymetallic active centers. Excitingly, RhCo MAN possesses excellent and sustainable NOX-like activity, with Km-NADH (16.11 µM) being lower than that of NOX-mimics reported so far. Thus, RhCo MAN can significantly promote the regeneration of NAD+ and regulate macrophage polarization toward the M2 phenotype through down-regulation of TLR4 expression, which may help to recover skin regeneration. However, RhRu MAN with peroxidase-like activity and RhMn MAN with superoxide dismutase-like activity exhibit little modulating effects on eczema. This work provides a new strategy to inhibit skin inflammation and promote skin regeneration.

6.
Opt Lett ; 49(7): 1790-1793, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38560864

RESUMEN

This study proposes a high-sensitivity resonant graphene accelerometer based on a pressure-induced sensing mechanism. The accelerometer design encompasses an optical fiber and a vacuum-sealed graphene resonator affixed to a silicon sensitive film, incorporating a proof mass. This indirect sensing mechanism effectively mitigates the vibration mode aliasing of graphene and the proof mass while ensuring a minimal energy loss in the operating resonator. The mechanical vibration of graphene is excited and detected through an all-fiber optical system. Notably, the proposed sensor demonstrates a sensitivity of 34.3 kHz/g within the range of 0-3.5 g, which is eight times higher than comparable accelerometers utilizing a proof mass on a graphene membrane. This work exhibits a novel, to the best of our knowledge, approach to an acceleration measurement using 2D resonators, exhibiting distinct advantages in terms of compact size and heightened sensitivity.

7.
Artículo en Inglés | MEDLINE | ID: mdl-38670871

RESUMEN

BACKGROUND: Normal bile is sterile. Studies have shown that cholangitis after liver transplantation (LT) was associated with a relatively poor prognosis. It remains unclear whether the bacteriobilia or fungibilia impact the patient outcomes in LT recipients, especially with donation after circulatory death (DCD) allografts, which was correlated with a higher risk of allograft failure. METHODS: This retrospective study included 139 LT recipients of DCD grafts from 2019 to 2021. All patients were divided into two groups according to the presence or absence of bacteriobilia or fungibilia. The prevalence and microbial spectrum of postoperative bacteriobilia or fungibilia and its possible association with outcomes, especially hospital stay were analyzed. RESULTS: Totally 135 and 171 organisms were isolated at weeks 1 and 2, respectively. Among all patients included in this analysis, 83 (59.7%) developed bacteriobilia or fungibilia within 2 weeks post-transplantation. The occurrence of bacteriobilia or fungibilia (ß = 7.43, 95% CI: 0.02 to 14.82, P = 0.049), particularly the detection of Pseudomonas (ß = 18.84, 95% CI: 6.51 to 31.07, P = 0.003) within 2 weeks post-transplantation was associated with a longer hospital stay. However, it did not affect the graft and patient survival. CONCLUSIONS: The occurrence of bacteriobilia or fungibilia, particularly Pseudomonas within 2 weeks post-transplantation, could influence the recovery of liver function and was associated with prolonged hospital stay but not the graft and patient survival.

8.
Medicina (Kaunas) ; 60(2)2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38399588

RESUMEN

Background and Objectives: This study examined whether the decline in people's adoption of personal NPIs (e.g., mask wearing) results from the preclusion by vaccination. This study also incorporates the concepts of risk perception and the risk-as-feelings model to elucidate the possible mechanisms behind this preclusion. Materials and Methods: Two cross-sectional surveys (N = 462 in Survey 1 and N = 505 in Survey 2) were administered before and during the first outbreak of COVID-19 in Taiwan. The survey items were designed to measure participants' perceived severity of COVID-19, worry about COVID-19, intention to adopt personal NPIs, and attitudes toward COVID-19 vaccines. Utilizing the risk perception framework, we conducted multigroup SEM (Structural Equation Modeling) to construct the optimal structural model for both samples. Results and Conclusions: The multigroup SEM results showed that worry (i.e., the emotional component of risk perception) fully mediates the influence of the perceived severity of COVID-19 (i.e., the cognitive component of risk perception) on the intention to adopt NPIs in both surveys [z = 4.03, p < 0.001 for Survey 1 and z = 2.49, p < 0.050 for Survey 2]. Before the outbreak (i.e., Survey 1), people's attitudes toward COVID-19 vaccines showed no significant association with their worry about COVID-19 [z = 0.66, p = 0.508]. However, in Survey 2, following the real outbreak of COVID-19, people's attitudes toward COVID-19 vaccines negatively predicts their worry about COVID-19 [z = -4.31, p < 0.001], indirectly resulting in a negative effect on their intention to adopt personal NPIs. This suggests the occurrence of the Peltzman effect. That is, vaccination fosters a sense of safety, subsequently diminishing alertness to COVID-19, and thus reducing the intention to adopt personal NPIs.


Asunto(s)
COVID-19 , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , Vacunas contra la COVID-19/uso terapéutico , Máscaras , Estudios Transversales , Vacunación
9.
J Clin Immunol ; 43(4): 835-845, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36807221

RESUMEN

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.


Asunto(s)
Adenosina Desaminasa , Péptidos y Proteínas de Señalización Intercelular , Humanos , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Estudios de Cohortes , Estudios Retrospectivos , Mutación
10.
Nutr Metab Cardiovasc Dis ; 33(5): 1087-1092, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36958971

RESUMEN

BACKGROUND AND AIMS: In observational studies, statins have been suggested to have protective effects on venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). To this aim, we performed a two-sample mendelian randomization (MR) analysis to determine whether these associations were causal. METHODS AND RESULTS: Data on the single nucleotide polymorphisms (SNPs) related to statin medication were obtained from the FinnGen study, and data for VTE, PE and DVT of lower extremities (LEDVT) were from the UK Biobank study, respectively. Inverse variance weighted (IVW) method was used as the principal analysis of MR, and sensitivity analysis was performed to detect horizontal pleiotropy and heterogeneity. MR estimates showed an inverse causal association between statin medication and the risk of VTE (odds ratio [OR]: 0.999, 95% CI: 0.998-1.000, P = 0.004), PE (OR: 0.999, 95% CI: 0.999-1.000, P = 0.011) and LEDVT (OR: 0.999, 95% CI: 0.999-1.000, P = 0.008). CONCLUSION: Our findings provide direct evidence that statins might decrease the risk of VTE, PE and LEDVT in agreement with observational studies. The specific mechanism of statin therapy for venous thromboembolism needs to be further studied.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Embolia Pulmonar , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Análisis de la Aleatorización Mendeliana , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/epidemiología , Trombosis de la Vena/genética , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiología , Embolia Pulmonar/genética
11.
Diabetologia ; 65(12): 2044-2055, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36102938

RESUMEN

AIMS/HYPOTHESIS: Cancer has contributed to an increasing proportion of diabetes-related deaths, while lifestyle management is the cornerstone of both diabetes care and cancer prevention. We aimed to evaluate the associations of combined healthy lifestyles with total and site-specific cancer risks among individuals with diabetes. METHODS: We included 92,239 individuals with diabetes but without cancer at baseline from five population-based cohorts in the USA (National Health and Nutrition Examination Survey and National Institutes of Health [NIH]-AARP Diet and Health Study), the UK (UK Biobank study) and China (Dongfeng-Tongji cohort and Kailuan study). Healthy lifestyle scores (range 0-5) were constructed based on current nonsmoking, low-to-moderate alcohol drinking, adequate physical activity, healthy diet and optimal bodyweight. Cox regressions were used to calculate HRs for cancer morbidity and mortality, adjusting for sociodemographic, medical and diabetes-related factors. RESULTS: During 376,354 person-years of follow-up from UK Biobank and the two Chinese cohorts, 3229 incident cancer cases were documented, and 6682 cancer deaths were documented during 1,089,987 person-years of follow-up in the five cohorts. The pooled multivariable-adjusted HRs (95% CIs) comparing participants with 4-5 vs 0-1 healthy lifestyle factors were 0.73 (0.61, 0.88) for incident cancer and 0.55 (0.46, 0.67) for cancer mortality, and ranged between 0.41 and 0.63 for oesophagus, lung, liver, colorectum, breast and kidney cancers. Findings remained consistent across different cohorts and subgroups. CONCLUSIONS/INTERPRETATION: This international cohort study found that adherence to combined healthy lifestyles was associated with lower risks of total cancer morbidity and mortality as well as several subtypes (oesophagus, lung, liver, colorectum, breast and kidney cancers) among individuals with diabetes.


Asunto(s)
Diabetes Mellitus , Neoplasias Renales , Humanos , Estudios de Cohortes , Encuestas Nutricionales , Estudios Prospectivos , Estilo de Vida Saludable , Morbilidad , China/epidemiología , Reino Unido/epidemiología , Factores de Riesgo
12.
FASEB J ; 35(2): e21187, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33197070

RESUMEN

Spermatogenesis is an important biological process in male reproduction. The interaction between male germ cells and somatic cells during spermatogenesis, is necessary for male reproductive activities. This cellular heterogeneity has made it difficult to profile distinct cell types at different stages of development. Here, we present the first comprehensive, unbiased single-cell transcriptomic study of sheep spermatogenesis using 10× genomics single cell sequencing (scRNA-seq). We collected scRNA-seq data from 11 772 cells from the adult sheep testis and identified all known germ cells (including early primary spermatocytes, late primary spermatocytes, round spermatids, elongated spermatids, and sperm), and somatic cells (Sertoli cells and Leydig cells), as well as one somatic cell that unexpectedly contained leukocytes. The functional enrichment analysis indicated that several pathways of cell cycle, gamete generation, protein processing, and mRNA surveillance pathways were significantly enriched in testicular germ cell types, and ribosome pathway was significantly enriched in testicular somatic cell types. Further analysis identified several stage-specific marker genes of sheep germ cells, such as EZH2, SOX18, SCP2, PCNA, and PRKCD. Our research explored for the first time of the changes in the transcription level of various cell types during the process of sheep spermatogenesis, providing new insights for sheep spermatogenesis and spermatogenic cell development.


Asunto(s)
RNA-Seq/métodos , Análisis de la Célula Individual/métodos , Espermatogénesis , Transcriptoma , Animales , Perfilación de la Expresión Génica/métodos , Células Intersticiales del Testículo/metabolismo , Masculino , Células de Sertoli/metabolismo , Ovinos , Espermatozoides/metabolismo , Factores de Transcripción
13.
J Org Chem ; 87(17): 11491-11502, 2022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-35951357

RESUMEN

A convenient synthesis of methylene-bridged pyrrolo[2,1-a]isoquinolines has been developed. Treatment of pyrroloisoquinolines with acetyl chloride and dimethylsulfoxide (DMSO) at ambient temperature afforded bispyrroloisoquinolylmethanes in 17-85% yields. This reaction system can also be expanded to the synthesis of bispyrrolylmethanes (34-94% yields). Easy chemical transformation of methylene-bridged pyrroloisoquinoline provided an unsymmetric acid and amide possessing a privileged framework.


Asunto(s)
Isoquinolinas , Pirroles , Acetatos , Cloruros , Dimetilsulfóxido
14.
J Reprod Dev ; 68(3): 198-208, 2022 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-35228412

RESUMEN

Spermatozoa acquire fertilization ability through post-translational modifications. These membrane surface alterations occur in various segments of the epididymis. Quiescin sulfhydryl oxidases, which catalyze thiol-oxidation reactions, are involved in disulfide bond formation, which is essential for sperm maturation, upon transition and migration in the epididymis. Using castration and azoospermia transgenic mouse models, in the present study, we showed that quiescin sulfhydryl oxidase 1 (QSOX1) protein expression and secretion are positively correlated with the presence of testosterone and sperm cells. A two-dimensional in vitro epithelium-sperm co-culture system provided further evidence in support of the notion that both testosterone and its dominant metabolite, 5α-dihydrotestosterone, promote epididymal QSOX1 secretion. We also demonstrated that immature caput spermatozoa, but not mature cauda sperm cells, exhibited great potential to stimulate QSOX1 secretion in vitro, suggesting that sperm maturation is a key regulatory factor for mouse epididymal QSOX1 secretion. Proteomic analysis identified 582 secretory proteins from the co-culture supernatant, of which 258 were sperm-specific and 154 were of epididymal epithelium-origin. Gene Ontology analysis indicated that these secreted proteins exhibit functions known to facilitate sperm membrane organization, cellular activity, and sperm-egg recognition. Taken together, our data demonstrated that testosterone and sperm maturation status are key regulators of mouse epididymal QSOX1 protein expression and secretion.


Asunto(s)
Epidídimo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Espermatozoides , Animales , Técnicas de Cocultivo , Epidídimo/citología , Epidídimo/enzimología , Epidídimo/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Masculino , Ratones , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Proteómica , Espermatozoides/citología , Espermatozoides/enzimología , Espermatozoides/metabolismo , Testosterona/metabolismo
15.
Yi Chuan ; 44(12): 1141-1147, 2022 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-36927559

RESUMEN

Recently, several pedigree-based studies have shown that abnormal replication of an enhancer element regulatory region in the downstream of the bone morphogenetic protein 2 (BMP2) gene is the cause of brachydactyly type A2 (BDA2). However, the exact molecular function of this regulatory region is unclear, and even conflicting results have emerged. In this study, based on bioinformatics analysis, we amplified target fragments of different lengths in this regulatory region by PCR technology, including a highly conserved 2.1 kb core sequence and 3 fragments that can completely cover the core 2.1 kb fragment. Then, the gene recombination vectors were constructed, and the biological function of these fragments was analyzed by the dual-luciferase reporter gene technology system. We found that the highly conserved 2.1 kb fragment did not have enhancer activity, while all of three truncated fragments showed strong enhancer activity. The results suggest that the expression regulation mode of the BMP2 gene is very complex. For the downstream regulatory region, selecting fragments of different lengths may have different effects on the regulation of BMP2 expression, which may due to the fragments with different lengths carrying different regulatory elements in the number of types. In summary, this study revealed the complexity of BMP2 gene regulatory elements, and provided new clues and directions for the subsequent in-depth exploration of the molecular pathogenic mechanism of BDA2.


Asunto(s)
Braquidactilia , Secuencias Reguladoras de Ácidos Nucleicos , Humanos , Secuencias Reguladoras de Ácidos Nucleicos/genética , Proteína Morfogenética Ósea 2/genética
16.
Langmuir ; 37(24): 7565-7572, 2021 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-34110827

RESUMEN

Controlling droplet deposition with a minute amount of polymer additives is of profound practical importance in a wild range of applications. Previous work ascribed the relevant mechanisms to extensional viscosity, normal stress, wetting properties, etc., but the mechanism remains controversial. In this paper, we employ molecular dynamics simulations systematically for the first time to investigate the origin of rebound suppression for dilute polymer solution droplets on a flat superhydrophobic substrate. The results demonstrate that polymer-substrate interactions and impact velocities dominate the antirebound phenomenon. For low impact velocities, the dynamic characteristics of droplets are insensitive to polymer additives. However, large impact velocities will enhance the stretch behavior of polymer chains and make the chains closer to the substrate, increasing the probability of polymer molecules contacting the bottom substrate. With the cooperation of strong polymer-substrate interactions, polymer molecules can be absorbed easily by the bottom substrate, resisting the retraction process and leading to the onset of the antirebound behavior.

17.
Pharm Res ; 38(1): 79-87, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33496870

RESUMEN

PURPOSES: To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin. METHODS: Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (Css,avg) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model. RESULTS: The systemic exposure (AUC0-inf) of CMS were 59.49 ± 5.90 h·µg/mL and 51.09 ± 4.70 h·µg/mL, and the AUC0-inf of colistin were 15.39 ± 2.63 h·µg/mL and 12.36 ± 2.10 h·µg/mL for CTTQ and Parkedale, respectively. The ratios (90% CI) of geometric mean of AUC0-inf of CTTQ to Parkedale were 116.38% (112.95%, 119.91%) and 124.49% (120.76%, 128.35%) for CMS and colistin, respectively. The predicted Css,avg (95% CI) were 0.92 (0.85, 0.99) µg/mL and 0.74 (0.69, 0.79) µg/mL for CTTQ and Parkedale, respectively. CONCLUSION: The difference in component content in the two CMS formulas had a significant (P < 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.


Asunto(s)
Antibacterianos/farmacocinética , Colistina/farmacocinética , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/química , Colistina/administración & dosificación , Colistina/química , Estudios Cruzados , Composición de Medicamentos/métodos , Femenino , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Profármacos/administración & dosificación , Profármacos/química , Profármacos/farmacocinética , Adulto Joven
18.
Nanotechnology ; 32(29)2021 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-33711826

RESUMEN

Doxorubicin (DOX) is a commonly used anticancer drug, but it is inefficient as a therapeutic due to a lack of targeting. Peptide-tuned self-assembly of DOX offers a strategy to improve targeting for greater efficacy. In this work, we designed and prepared an amphiphilic tumor cell-targeting peptide, P14 (AAAAFFFHHHGRGD), able to encapsulate DOX by self-assembly to form tumor cell-targeting and pH-sensitive nano-micelles. The results showed a critical P14-micelle concentration of 1.758 mg l-1and an average particle size of micelles of 121.64 nm, with entrapment and drug-loading efficiencies of 28.02% ± 1.35% and 12.06% ± 0.59%, respectively. The prepared micelles can release 73.52 ± 1.27% DOX within 24 h in pH 4.5 medium, and the drug cumulative release profile of micelles can be described by the first-order model. Compared with free DOX, the micelles exhibited an increased ability to inhibit tumor cell growth and cause tumor apoptosisin vitro, with IC50values of DOX and P14-DOX micelles against human breast cancer cells (MCF-7) of 0.91 ± 0.07 and 0.75 ± 0.06µg ml-1, respectively, and cellular apoptotic rates of DOX and P14-DOX micelles of 70.3% and 42.4%, respectively. Cellular uptake experiments revealed high concentrations of micelles around and inside MCF-7 cells, demonstrating that micelles can target tumor cells. These results indicate the excellent potential for the application of this amphiphilic peptide as a carrier for small-molecule drugs and suggest a strategy for the design of effective anti-tumor drugs.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos , Nanoestructuras/química , Péptidos/metabolismo , Antibióticos Antineoplásicos/química , Apoptosis/efectos de los fármacos , Doxorrubicina/química , Composición de Medicamentos/métodos , Liberación de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Cinética , Células MCF-7 , Micelas , Terapia Molecular Dirigida , Nanoestructuras/ultraestructura , Péptidos/síntesis química
19.
BMC Surg ; 21(1): 54, 2021 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-33482805

RESUMEN

BACKGROUND: Surgeons are likely to get progressively fatigued during the course of a normal workday. The objective of this study was to evaluate the impact of surgeon work duration prior to performing distal pancreatectomy (DP) on the perioperative outcome, especially frequency of grade II or higher grade postoperative complications. METHODS: Patients undergoing DP for all causes were divided into two groups according to surgeon work hours prior to performing DP: group A (less than 5 h) and group B (5-10 h). Propensity score matching (PSM) analysis (1:1) were performed to balance the baseline characteristics between the two groups. Intraoperative complications were compared between the two groups. Postoperative complications and their severity were followed up for 60 days and mortality for 90 days. The study was powdered to identify a 15% difference in the incidence of grade II or higher grade complications. RESULTS: By using PSM analysis, the patients in group A (N = 202) and group B (N = 202) were well matched regarding demographics, comorbidities, operative technique, pancreatic texture and pathology. There was no significant difference in the incidence of grade II or higher grade complications between the two groups. There was no difference in clinically relevant postoperative pancreatic fistula, percutaneous drainage, readmission, reoperation, or morality. Group B was associated with a higher incidence of intraoperative organ injury, which could be managed successfully during the operation. CONCLUSION: The retrospective study demonstrated that the surgeon work duration did not significantly affect the clinical outcome of DP.


Asunto(s)
Fatiga/complicaciones , Pancreatectomía/efectos adversos , Neoplasias Pancreáticas , Cirujanos , Rendimiento Laboral/normas , Anciano , Femenino , Humanos , Complicaciones Intraoperatorias/etiología , Masculino , Persona de Mediana Edad , Tempo Operativo , Pancreatectomía/normas , Enfermedades Pancreáticas/cirugía , Neoplasias Pancreáticas/cirugía , Complicaciones Posoperatorias/etiología , Puntaje de Propensión , Estudios Retrospectivos , Cirujanos/normas , Factores de Tiempo , Resultado del Tratamiento , Carga de Trabajo
20.
BMC Surg ; 21(1): 297, 2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34144694

RESUMEN

OBJECTIVE: This study aimed to investigate the prognostic value of CIP2A (cancerous inhibitor of protein phosphatase 2A) and the NLR (neutrophil-lymphocyte ratio) in the serum of patients with CRC (colorectal cancer) after resection. METHODS: The clinicopathological data of 61 patients who underwent resection between January 2012 and December 2013 were collected. The NLR and CIP2A were divided into low score groups (0) and high score groups (1) with 2.03 and 6.07 as the optimal cut-off value according to the receiver operating characteristic (ROC) curve analysis. To identify the COCN (combination of CIP2A and the NLR) score, we added CIP2A and NLR points together and categorized CRC patients into three groups. Kaplan-Meier curves were used to identify the overall survival (OS) rates of the different groups. Finally, a ROC curve was plotted to evaluate the prognostic efficacy of COCN. RESULTS: The CIP2A was associated with location (P = 0.046) and CEA (P = 0.037) in patients with CRC. Kaplan-Meier survival curves showed that the 5-year OS of patients with low level of serum CIP2A was better than that of high level. The 5-year OS of the patients in the low NLR group was better than that of those in the high NLR group. The COCN score was associated with CEA (P < 0.001) and CA19-9 (P = 0.001). The 5-year OS of the patients in the COCN 0 group was highest, followed by that of those in the COCN 1 and COCN 2 groups. Age, N stage and M stage were factors associated with 5-year OS according to the univariate and multivariate analyses (P < 0.05). The area under the curve (AUC) for COCN was largest, indicating that COCN has better prognostic power than CIP2A or the NLR alone. CONCLUSION: COCN could be used as a better prognostic biomarker for CRC than the NLR or CIP2A alone.


Asunto(s)
Neoplasias Colorrectales , Linfocitos , Neoplasias Colorrectales/diagnóstico , Humanos , Estimación de Kaplan-Meier , Neutrófilos , Pronóstico , Estudios Retrospectivos
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