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1.
BMC Endocr Disord ; 24(1): 127, 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39060948

RESUMEN

BACKGROUND: Prognosis of DKA has improved over time with the availability of evidence-based protocols and resources. However, in Kenya, there are limited resources for the appropriate diagnosis and management of DKA, mostly limited to tertiary-level referral facilities. This study aimed to review the clinical presentation, management, and outcomes of adult patients admitted with DKA and assess differences in these parameters before and during the COVID-19 pandemic. METHODS: This was a retrospective study of DKA admissions from January 2017 to December 2021. Patient data were retrieved from the medical records department using ICD-10 codes, and individual details were abstracted on clinical presentation, management, and outcomes of DKA. Comparisons were made between pre-COVID-19 and during COVID-19 durations. RESULTS: 150 patients admitted with DKA were included (n = 48 pre- COVID-19, n = 102 during COVID-19 (n = 23 COVID-19 positive, n = 79 COVID-19 negative)). Median age was 47 years (IQR 33.0, 59.0), median HbA1C was 12.4% [IQR 10.8, 14.6]), and most patients had severe DKA (46%). Most common DKA precipitants were infections (40.7%), newly diagnosed diabetes (33.3%) and missed medication (25.3%). There was a significant difference in pulmonary infections as a DKA precipitant, between the pre- COVID and during COVID-19 pandemic (21.6% during COVID-19 versus 6.3% pre- COVID-19; p = 0.012). Median total insulin dose used was 110.0 units [IQR 76.0, 173.0], and a 100% of patients received basal insulin. Median length of hospital stay was 4.0 days [IQR 3.0, 6.0] and time to DKA resolution was 30.0 h [IQR 24.0, 48.0]. There were 2 deaths (1.3%), none directly attributable to DKA. Severity of DKA significantly differed between pre- COVID-19, COVID-19 positive and COVID-19 negative DKA (52.2% of COVID-19 positive had moderate DKA compared to 26.6% of COVID-19 negative and 22.9% of Pre-COVID-19 (p = 0.006)). CONCLUSION: Even in developing regions, good outcomes can be achieved with the appropriate facilities for DKA management. Clinician and patient education is necessary to ensure early detection and prompt referral to avoid patients presenting with severe DKA. Exploratory studies are needed to assess reasons for prolonged time to DKA resolution found in this study.


Asunto(s)
COVID-19 , Cetoacidosis Diabética , Centros de Atención Terciaria , Humanos , COVID-19/epidemiología , COVID-19/complicaciones , COVID-19/terapia , Cetoacidosis Diabética/terapia , Cetoacidosis Diabética/epidemiología , Cetoacidosis Diabética/diagnóstico , Kenia/epidemiología , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , SARS-CoV-2 , Pronóstico , Hospitalización/estadística & datos numéricos
2.
Biochem J ; 473(18): 2783-98, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27371320

RESUMEN

Cyclin-dependent kinases (Cdks) control the eukaryotic cell cycle by phosphorylating serine and threonine residues in key regulatory proteins, but some Cdk family members may exert kinase-independent functions that cannot easily be assessed using gene knockout approaches. While Cdk2-deficient mice display near-normal mitotic cell proliferation due to the compensatory activities of Cdk1 and Cdk4, they are unable to undergo meiotic generation of gametes and are consequently sterile. To investigate whether Cdk2 regulates meiosis via protein phosphorylation or by alternative kinase-independent mechanisms, we generated two different knockin mouse strains in which Cdk2 point mutations ablated enzyme activity without altering protein expression levels. Mice homozygous for the mutations Cdk2(D145N/D145N) or Cdk2(T160A/T160A) expressed only 'kinase-dead' variants of Cdk2 under the control of the endogenous promoter, and despite exhibiting normal expression of cell cycle regulatory proteins and complexes, both mutations rendered mice sterile. Mouse cells that expressed only 'kinase-dead' variants of Cdk2 displayed normal mitotic cell cycle progression and proliferation both in vitro and in vivo, indicating that loss of Cdk2 kinase activity exerted little effect on this mode of cell division. In contrast, the reproductive organs of Cdk2 mutant mice exhibited abnormal morphology and impaired function associated with defective meiotic cell division and inability to produce gametes. Cdk2 mutant animals were therefore comparable to gene knockout mice, which completely lack the Cdk2 protein. Together, our data indicate that the essential meiotic functions of Cdk2 depend on its kinase activity, without which the generation of haploid cells is disrupted, resulting in sterility of otherwise healthy animals.


Asunto(s)
Meiosis , Animales , Biocatálisis , Ciclo Celular , Células Cultivadas , Técnica del Anticuerpo Fluorescente , Infertilidad Masculina/genética , Masculino , Ratones , Mutación , Testículo/citología , Timo/citología
3.
Cell Mol Life Sci ; 69(22): 3835-50, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22763696

RESUMEN

Successful completion of the cell cycle relies on the precise activation and inactivation of cyclin-dependent kinases (Cdks) whose activity is mainly regulated by binding to cyclins. Recently, a new family of Cdk regulators termed Speedy/RINGO has been discovered, which can bind and activate Cdks but shares no apparent amino acid sequence homology with cyclins. All Speedy proteins share a conserved domain of approximately 140 amino acids called "Speedy Box", which is essential for Cdk binding. Speedy/RINGO proteins display an important role in oocyte maturation in Xenopus. Interestingly, a common feature of all Speedy genes is their predominant expression in testis suggesting that meiotic functions may be the most important physiological feature of Speedy genes. Speedy homologs have been reported in mammals and can be traced back to the most primitive clade of chordates (Ciona intestinalis). Here, we investigated the evolution of the Speedy genes and have identified a number of new Speedy/RINGO proteins. Through extensive analysis of numerous species, we discovered diverse evolutionary histories: the number of Speedy genes varies considerably among species, with evidence of substantial gains and losses. Despite the interspecies variation, Speedy is conserved among most species examined. Our results provide a complete picture of the Speedy gene family and its evolution.


Asunto(s)
Proteínas de Ciclo Celular/genética , Quinasas Ciclina-Dependientes/metabolismo , Evolución Molecular , Secuencia de Aminoácidos , Animales , Sitios de Unión , Evolución Biológica , Ciclo Celular/genética , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Pollos/genética , Pollos/metabolismo , Quinasas Ciclina-Dependientes/química , Humanos , Ratones , Datos de Secuencia Molecular , Pan troglodytes/genética , Pan troglodytes/metabolismo , Filogenia , Unión Proteica , Ratas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Tiburones/genética , Tiburones/metabolismo , Vertebrados/genética , Vertebrados/metabolismo , Proteínas de Xenopus/química , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismo , Xenopus laevis/genética , Xenopus laevis/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo
4.
Microbiol Spectr ; : e0433222, 2023 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-36946746

RESUMEN

Understanding the quality of immune repertoire triggered during natural infection can provide vital clues that form the basis for development of a humoral immune response in some individuals capable of broadly neutralizing pan-SARS-CoV-2 variants. In the present study, we report variations in neutralization potential against Omicron variants of two novel neutralizing monoclonal antibodies (MAbs), THSC20.HVTR11 and THSC20.HVTR55, isolated from an unvaccinated convalescent individual that represent distinct B cell lineage origins and epitope specificity compared to five MAbs we previously reported that were isolated from the same individual. In addition, we observed neutralization of Omicron variants by plasma antibodies obtained from this particular individual postvaccination with increased magnitude. Interestingly, this observation was found to be comparable with six additional individuals who initially were also infected with ancestral SARS-CoV-2 and then received vaccines, indicating that hybrid immunity can provide robust humoral immunity likely by antibody affinity maturation. Development of a distinct antigen-specific B cell repertoire capable of producing polyclonal antibodies with distinct affinity and specificities offers the highest probability of protecting against evolving SARS-CoV-2 variants. IMPORTANCE Development of robust neutralizing antibodies in SARS-CoV-2 convalescent individuals is known; however, it varies at the population level. We isolated monoclonal antibodies from an individual infected with ancestral SARS-CoV-2 in early 2020 that not only varied in their B cell lineage origin but also varied in their capability and potency to neutralize all the known variants of concern (VOCs) and currently circulating Omicron variants. This indicated establishment of unique lineages that contributed in forming a B cell repertoire in this particular individual immediately following infection, giving rise to diverse antibody responses that could complement each other in providing a broadly neutralizing polyclonal antibody response. Individuals who were able to produce polyclonal antibody responses with higher magnitude have a higher chance of being protected from evolving SARS-CoV-2 variants.

5.
Nat Cell Biol ; 13(8): 1004-9, 2011 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-21725316

RESUMEN

Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 (ref. 3) as its targeting subunit. Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles. We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 is a cell-cycle-regulated protein with expression levels peaking at the G1/S transition. We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. In summary, we show that a cell-cycle-regulated SCF complex is regulated by the kinase PLK4, and that this in turn restricts centrosome re-duplication through degradation of the centriolar protein HsSAS-6.


Asunto(s)
Proteínas de Ciclo Celular/fisiología , Centrosoma/fisiología , Proteínas F-Box/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Ligasas SKP Cullina F-box/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Ciclosoma-Complejo Promotor de la Anafase , Ciclo Celular/fisiología , Línea Celular , Centriolos/fisiología , Proteínas F-Box/antagonistas & inhibidores , Proteínas F-Box/genética , Células HeLa , Humanos , Modelos Biológicos , ARN Interferente Pequeño/genética , Especificidad por Sustrato , Complejos de Ubiquitina-Proteína Ligasa/fisiología
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