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1.
BMC Public Health ; 22(1): 495, 2022 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-35287656

RESUMEN

Food insecurity is associated with increased risk of chronic disease and poor dietary intake. The United States charitable food system, a complex network of food banks, pantries and congregate meal sites, provides food for millions of low-income households each year. Food banks and pantries play a critical role in supporting food security and are an important contributor to dietary intake for its clients. In recent years, there has been an increased focus on sourcing and supplying more nutritious foods within the charitable food system. Despite this, there is a lack of alignment in how the charitable food system defines and tracks the nutritional quality of food.In 2019, Healthy Eating Research convened a panel of nutrition, charitable food system and food policy experts to create a set of evidence-based nutrition standards. Standards were developed based on a review of the literature and existing nutrition ranking systems, while also considering the operational needs and capacity of the charitable food system. The panel provided recommendations for eleven distinct food categories: fruits and vegetables, grains, protein, dairy, non-dairy alternatives, beverages, mixed dishes, processed and packaged snacks, desserts, condiments and cooking staples, and other miscellaneous items. Products are ranked into three tiers, choose often (green), choose sometimes (yellow) or choose rarely (red), based on designated saturated fat, sodium, and added sugar thresholds. This paper outlines the expert panel's approach and summarizes the barriers and opportunities for implementing these standards across the charitable food system.


Asunto(s)
Asistencia Alimentaria , Verduras , Abastecimiento de Alimentos , Humanos , Política Nutricional , Estado Nutricional , Valor Nutritivo , Estados Unidos
2.
Gen Dent ; 70(6): 52-58, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36288076

RESUMEN

Periodontal disease affects 42% of adults in the United States. Both the periodontal microbiome and the host immune inflammatory response may be influenced by overweight/obesity status. This retrospective analysis sought to determine the associations of periodontal disease parameters with body mass index (BMI) and obesity status in patients undergoing periodontal maintenance therapy. The records of 418 patients who were undergoing periodontal maintenance after periodontitis treatment were examined, and the patients' demographic characteristics (sex, age, and race/ethnicity), self-reported BMI, periodontal disease condition, number of sites with probing depth ≥ 4 mm, missing teeth, and sites with bleeding on probing (BOP) were recorded. Patients were determined to have active moderate to severe periodontitis if they presented with 2 or more sites in 2 different quadrants with clinical attachment loss ≥ 5 mm and probing depth ≥ 5 mm. Individuals were also categorized into 3 groups: underweight/normoweight, BMI < 25; overweight, BMI 25 ≤ 30; or obese, BMI ≥ 30. In the study population, BMI ranged from 16.827 to 51.389. The periodontitis status was not significantly associated with a BMI status of overweight (odds ratio [OR] = 1.388 [95% CI, 0.961- 2.006]) or obese (OR = 1.168 [95% CI, 0.77-1.757]). Female sex (OR = 0.561 [95% CI, 0.343-0.918]) and age (OR = 0.983 [95% CI, 0.967-0.999]) were negatively associated with active periodontitis status. Obese patients demonstrated significantly more sites with BOP than either underweight/normoweight or overweight patients, and a BMI indicating obesity was associated with increasing age (P < 0.001) and higher number of missing teeth (P = 0.0064). In a population of patients undergoing periodontal maintenance therapy, BMI was associated with age and missing teeth, and obese status was associated with a significantly higher number of sites with BOP.


Asunto(s)
Enfermedades Periodontales , Periodontitis , Pérdida de Diente , Adulto , Humanos , Femenino , Índice de Masa Corporal , Sobrepeso/complicaciones , Índice Periodontal , Estudios Retrospectivos , Delgadez , Periodontitis/complicaciones , Periodontitis/terapia , Obesidad/complicaciones , Enfermedades Periodontales/complicaciones , Pérdida de la Inserción Periodontal/complicaciones , Pérdida de la Inserción Periodontal/epidemiología
3.
J Sleep Res ; 30(3): e13130, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-32567219

RESUMEN

Prolonged viewing of screen-based media is associated with poor sleep in children. Previous systematic reviews have analysed the effectiveness of interventions that aim to limit children's screen use; however, none have evaluated its effect on sleep. The aim of this systematic review was to evaluate the effect of interventions that incorporate strategies to control children's screen use on screen use and sleep. The databases Pubmed, Embase, Eric, Scopus and PsycInfo were searched during October 2017 and updated in February 2019 for experimental studies with a control that assessed interventions to control screen use in children aged 2-14 years and reported both screen use and sleep outcomes. From 3,872 initial records, 11 studies (six randomized control [RCT], four cluster RCT and one cluster, quasi-experimental) were eligible for inclusion. A total of 4,656 children aged 2-13 years were included in the studies. The mean reduction in screen time was 0.56 hr (33 min)/day (95% confidence interval [CI], 0.92, 0.20) and the mean sleep duration increased by 0.19 hr (11 min)/day (95% CI, 0.05, 0.33). Bedtime was advanced by 0.16 hr (10 min) on weekdays and by 1.0 hr at the weekend. Subgroup analyses indicated stronger intervention effects for interventions of shorter duration (<3 months), which specifically targeted screen use or sleep, and those with direct participant contact. In conclusion, small improvements in screen time and sleep duration can be achieved in children. It is not possible to determine if a reduction in screen time directly improves sleep, due to the limited number of studies, the presence of co-interventions, issues with studies' methodological quality and heterogeneity.


Asunto(s)
Sueño/fisiología , Televisión/instrumentación , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Factores de Tiempo
4.
J Hered ; 112(5): 447-451, 2021 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-34223905

RESUMEN

Over 30 polymorphisms in the KIT Proto-Oncogene Receptor Tyrosine Kinase (KIT) gene have been implicated in white spotting patterns ranging from small areas to full dermal depigmentation in the horse. We performed a candidate-gene exon sequencing approach on KIT and MITF, 2 known causatives of white spotting patterns, within 2 families of horses of unknown white spotting. Family 1 (Fam1, N = 5) consisted of a Quarter Horse stallion and 4 offspring with white spotting pattern ranging from legs, lower ventral, and head regions with jagged borders, to almost complete white. The second family (Fam2, N = 7) consisted of 6 half-sibling American Paint Horse/Quarter Horse and their dam, demonstrating unpigmented limbs with belly spots and an extensive white patterning on the face. This approach resulted in 2 variants significantly associated with familial phenotypes, where Fam1 variant is an indel leading to a frameshift mutation, and Fam2 a non-synonymous SNP. We validated the variants within an unrelated population of horses (Fam2 variant, P = 0.00271944) as well as for protein functional impact with ExPASy, Protter, Phyre2, SMART, PROVEAN, SIFT, and I-TASSER, confirming the reported associations. Fam1 associated variant, deemed W31, alters the protein sequence, leading to an early stop codon truncating the normal amino acid sequence from 972 to just 115 amino acids. Fam2 associated variant, deemed W32, may have a subtle impact on receptor function or could be in linkage with a non-coding or regulatory change creating the mild spotting pattern observed in this family.


Asunto(s)
Color del Cabello , Proteínas Proto-Oncogénicas c-kit , Animales , Exones , Ligamiento Genético , Caballos/genética , Masculino , Fenotipo , Proteínas Proto-Oncogénicas c-kit/genética
5.
Public Health Nutr ; 24(15): 5066-5073, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33243307

RESUMEN

OBJECTIVE: In the USA, community-based food pantries provide free groceries to people struggling with food insecurity. Many pantries obtain food from regional food banks using an online shopping platform. A food bank introduced a visible nutrition rank (i.e. green, yellow or red) onto its platform. The hypothesis was that pantry orders would increase for the healthiest options (green) and decrease for the least healthy options (red). DESIGN: Interrupted time series (ITS) analysis of a natural experiment. Monthly data included nutrition ranks of available inventory and itemised records of all products ordered during the 15-month baseline period and 14-month intervention. SETTING: A New England food bank. PARTICIPANTS: The twenty-five largest food pantries in the network based on pounds of food ordered. RESULTS: Descriptive analyses of 63 922 pantry ordering records before and after the visible ranks identified an increase in the proportion of green items ordered (39·3-45·4 %) and a decrease in the proportion of red items ordered (10·5-5·1 %). ITS analyses controlling for monthly changes in inventory available and pantry variables indicated that average monthly orders of green items increased by 1286 pounds (P < 0·001) and red orders decreased by 631 pounds (P = 0·045). Among the largest changes were increases in orders of fresh produce, brown rice, low-fat dairy and low-fat meats and decreases in orders of sugary juice drinks, canned fruit with added sugar, higher fat dairy and higher fat meats. CONCLUSIONS: This promising practice can support system-wide efforts to promote healthier foods within the food banking network.


Asunto(s)
Asistencia Alimentaria , Alimentos Especializados , Inseguridad Alimentaria , Abastecimiento de Alimentos , Humanos , Estado Nutricional
6.
Mycorrhiza ; 30(4): 491-501, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32506172

RESUMEN

The arbuscular mycorrhizal symbiosis is a very common association between plant roots and soil fungi, which greatly contributes to plant nutrition. Root-exuded compounds known as strigolactones act as symbiotic signals stimulating the fungus prior to root colonization. Strigolactones also play an endogenous role in planta as phytohormones and contribute to the regulation of various developmental traits. Structure-activity relationship studies have revealed both similarities and differences between the structural features required for bioactivity in plants and arbuscular mycorrhizal fungi. In the latter case, bioassays usually measured a stimulation of hyphal branching on isolated fungi of the Gigaspora genus, grown in vitro. Here, we extended these investigations with a bioassay that evaluates the bioactivity of strigolactone analogs in a symbiotic situation and the use of the model mycorrhizal fungus Rhizophagus irregularis. Some general structural requirements for bioactivity reported previously for Gigaspora were confirmed. We also tested additional strigolactone analogs bearing modifications on the conserved methylbutenolide ring, a key element of strigolactone perception by plants. A strigolactone analog with an unmethylated butenolide ring could enhance the ability of R. irregularis to colonize host roots. Surprisingly, when applied to the isolated fungus in vitro, this compound stimulated germ tube elongation but inhibited hyphal branching. Therefore, this compound was able to act on the fungal and/or plant partner to facilitate initiation of the arbuscular mycorrhizal symbiosis, independently from hyphal branching and possibly from the strigolactone pathway.


Asunto(s)
Glomeromycota , Micorrizas , Hifa , Raíces de Plantas , Simbiosis
7.
J Clin Gastroenterol ; 51(7): e60-e67, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27661969

RESUMEN

GOALS: To further characterize the gastrointestinal manifestations of Cowden syndrome in clinically well-annotated patients to improve the diagnosis of this syndrome. BACKGROUND: The gastrointestinal manifestations of Cowden Syndrome, an important heritable and multiorgan cancer syndrome, are not well defined. Proper diagnosis is essential for effective cancer surveillance and prevention in these patients. STUDY: Cowden patients with gastrointestinal polyps were selected for medical record and pathologic slide review. RESULTS: Of 19 total patients, genetic testing revealed pathogenic PTEN mutations in 12. Pan-colonic (11-patients, 58%) and pan-gastrointestinal (8-patients, 42%) polyp distributions were common. Inflammatory (juvenile) polyps were the most common of the hamartomatous polyp (18 patients, 95%), along with expansive lymphoid follicle polyps (12 patients, 63%), ganglioneuromatous polyps (10 patients, 53%), and intramucosal lipomas (5 patients, 26%). The findings of 2 or more hamartomatous polyp types per patient emerged as a newly described and highly prevalent (79%) feature of Cowden syndrome. Ganglioneuromatous polyps, rare in the general population, and intramucosal lipomas, which may be unique to Cowden syndrome, should both prompt further evaluation. Colonic adenomas and adenocarcinomas were common; 10 patients (53%) had single and 3 (16%) had ≥3 adenomas, whereas 2 (11%) had colonic adenocarcinoma, strengthening the emerging association of colorectal cancer with Cowden syndrome. CONCLUSIONS: The clinical phenotypes and gastrointestinal manifestations in Cowden syndrome are quite variable but this series adds the following new considerations for this syndromic diagnosis: multiple gastrointestinal hamartomas, especially 2 or more hamartoma types, and any intramucosal lipomas or ganglioneuromas. These features should warrant consideration of Cowden syndrome.


Asunto(s)
Enfermedades Gastrointestinales/patología , Síndrome de Hamartoma Múltiple/patología , Pólipos/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenoma/diagnóstico , Adenoma/genética , Adenoma/patología , Adolescente , Adulto , Anciano , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Estudios de Seguimiento , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/genética , Marcadores Genéticos , Síndrome de Hamartoma Múltiple/diagnóstico , Síndrome de Hamartoma Múltiple/genética , Humanos , Poliposis Intestinal/diagnóstico , Poliposis Intestinal/genética , Poliposis Intestinal/patología , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/genética , Pólipos/diagnóstico , Pólipos/genética , Estudios Retrospectivos , Adulto Joven
12.
Methods ; 65(2): 219-28, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23969317

RESUMEN

Protein tyrosine phosphatases (PTPs) represent an important class of enzymes that mediate signal transduction and control diverse aspects of cell behavior. The importance of their activity is exemplified by their significant contribution to disease etiology with over half of all human PTP genes implicated in at least one disease. Small molecule inhibitors targeting individual PTPs are important biological tools, and are needed to fully characterize the function of these enzymes. Moreover, potent and selective PTP inhibitors hold the promise to transform the treatment of many diseases. While numerous methods exist to develop PTP-directed small molecules, we have found that complimentary use of both virtual (in silico) and biochemical (in vitro) screening approaches expedite compound identification and drug development. Here, we summarize methods pertinent to our work and others. Focusing on specific challenges and successes we have experienced, we discuss the considerable caution that must be taken to avoid enrichment of inhibitors that function by non-selective oxidation. We also discuss the utility of using "open" PTP structures to identify active-site directed compounds, a rather unconventional choice for virtual screening. When integrated closely, virtual and biochemical screening can be used in a productive workflow to identify small molecules targeting PTPs.


Asunto(s)
Bioensayo/métodos , Simulación por Computador , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Proteínas Tirosina Fosfatasas/metabolismo , Bibliotecas de Moléculas Pequeñas , Bioensayo/instrumentación , Dominio Catalítico , Inhibidores Enzimáticos/farmacología , Humanos , Proteínas Tirosina Fosfatasas/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
14.
Matern Child Health J ; 18(1): 326-332, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23417212

RESUMEN

Both the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and Head Start/Early Head Start (HS/EHS) Programs serve low-income women and children at high risk for health disparities, yet they do not have a formal state-level partnership in Connecticut. Both programs serve children up to age five, yet children's participation in the WIC Program declines sharply after 2 years of age, limiting the potential benefits of cross-program participation. The goal of this study is to examine current and prospective collaboration efforts among the WIC and HS/EHS Programs in Connecticut and identify barriers to collaboration. An online survey was administered to staff from both programs. Six focus groups were held in January, 2012 with staff and participants from both programs. Results showed areas of existing collaboration between local WIC and HS/EHS Programs, yet also identified many areas where relationships could be strengthened or established. Common themes that were identified included a need for more knowledge among staff about the other program, collaboration involving sharing of client information, and improving referral procedures. Staff from both programs strongly expressed interest in a cross-program collaboration (73 % of HS staff and 86 % of WIC staff). This research serves as a framework for how a state-level collaboration could be established in Connecticut, to enable these two programs to work together more efficiently and effectively for the benefit of mothers and children. Results can provide other State WIC Programs with a blueprint for collaborating with HS/EHS.


Asunto(s)
Intervención Educativa Precoz/organización & administración , Asistencia Alimentaria/organización & administración , Preescolar , Connecticut , Conducta Cooperativa , Estudios de Evaluación como Asunto , Femenino , Grupos Focales , Investigación sobre Servicios de Salud/métodos , Humanos , Lactante , Relaciones Interinstitucionales , Investigación Cualitativa
15.
Animals (Basel) ; 14(3)2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38338094

RESUMEN

Traits such as shape, size, and color often influence the economic and sentimental value of a horse. Around the world, horses are bred and prized for the colors and markings that make their unique coat patterns stand out from the crowd. The underlying genetic mechanisms determining the color of a horse's coat can vary greatly in their complexity. For example, only two genetic markers are used to determine a horse's base coat color, whereas over 50 genetic variations have been discovered to cause white patterning in horses. Some of these white-causing mutations are benign and beautiful, while others have a notable impact on horse health. Negative effects range from slightly more innocuous defects, like deafness, to more pernicious defects, such as the lethal developmental defect incurred when a horse inherits two copies of the Lethal White Overo allele. In this review, we explore, in detail, the etiology of white spotting and its overall effect on the domestic horse to Spot the Pattern of these beautiful (and sometimes dangerous) white mutations.

16.
Animals (Basel) ; 14(3)2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38338160

RESUMEN

The influence of a horse's appearance on health, sentimental and monetary value has driven the desire to understand the etiology of coat color. White markings on the coat define inclusion for multiple horse breeds, but they may disqualify a horse from registration in other breeds. In domesticated horses (Equus caballus), 35 KIT alleles are associated with or cause depigmentation and white spotting. It is a common misconception among the general public that a horse can possess only two KIT variants. To correct this misconception, we used BEAGLE 5.4-phased NGS data to identify 15 haplotypes possessing two or more KIT variants previously associated with depigmentation phenotypes. We sourced photos for 161 horses comprising 12 compound genotypes with three or more KIT variants and employed a standardized method to grade depigmentation, yielding average white scores for each unique compound genotype. We found that 7 of the 12 multi-variant haplotypes resulted in significantly more depigmentation relative to the single-variant haplotypes (ANOVA). It is clear horses can possess more than two KIT variants, and future work aims to document phenotypic variations for each compound genotype.

17.
Chest ; 165(3): 590-600, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37813180

RESUMEN

BACKGROUND: Venous excess ultrasound (VExUS) is a novel ultrasound technique previously reported as a noninvasive measure of venous congestion and predictor of cardiorenal acute kidney injury. RESEARCH QUESTION: Are there associations between VExUS grade and cardiac pressures measured by right heart catheterization (RHC) and cardiac biomarkers and clinical outcomes in patients undergoing RHC? STUDY DESIGN AND METHODS: We conducted a prospective cohort study at the Denver Health Medical Center from December 20, 2022, to March 25, 2023. All patients undergoing RHC underwent a blinded VExUS assessment prior to their procedure. Multivariable regressions were conducted to assess relationships between VExUS grade and cardiac pressures, biomarkers, and changes in weight among patients with heart failure, a proxy for diuretic success. Receiver operating characteristic curve and area under the curve (AUC) were derived for VExUS, inferior vena cava (IVC) diameter, and IVC collapsibility index (ICI) to predict right atrial pressure (RAP) > 10 and < 7 mm Hg. RESULTS: Among 81 patients, 45 of whom were inpatients, after adjusting for age, sex, and Charlson Comorbidity Index, there were significant relationships between VexUS grade of 2 (ß = 4.8; 95% CI, 2.6-7.1; P < .01) and 3 (ß = 11; 95% CI, 8.9-14; P < .01) and RAP, VExUS grade of 2 (ß = 6.8; 95% CI, 0.16-13; P = .045) and 3 (ß = 15; 95% CI, 7.3-22; P < .01) and mean pulmonary artery pressure, and VExUS grade of 2 (ß = 7.0; 95% CI, 3.9-10; P < .01) and 3 (ß = 13; 95% CI, 9.5-17; P < .01) and pulmonary capillary wedge pressure. AUC values for VExUS, IVC diameter, and ICI as predictors of RAP > 10 mm Hg were 0.9 (95% CI, 0.83-0.97), 0.77 (95% CI, 0.68-0.88), and 0.65 (95% CI, 0.52-0.78), respectively. AUC values for VExUS, IVC diameter, and ICI as predictors of RAP < 7 mm Hg were 0.79 (95% CI, 0.70-0.87), 0.74 (95% CI, 0.64-0.84), and 0.62 (95% CI, 0.49-0.76), respectively. In a subset of 23 patients with heart failure undergoing diuresis, there was a significant association between VExUS grade 3 and change in weight between time of RHC and discharge (P = .025). INTERPRETATION: Although more research is required, VExUS has the potential to increase diagnostic and therapeutic capabilities of physicians at the bedside and increase our understanding of the underappreciated problem of venous congestion.


Asunto(s)
Insuficiencia Cardíaca , Hiperemia , Humanos , Estudios Prospectivos , Hiperemia/diagnóstico por imagen , Ultrasonografía , Vena Cava Inferior/diagnóstico por imagen , Insuficiencia Cardíaca/diagnóstico por imagen , Biomarcadores
18.
Polymers (Basel) ; 16(13)2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-39000768

RESUMEN

Large-format additive manufacturing (LFAM) is used to print large-scale polymer structures. Understanding the thermal and mechanical properties of polymers suitable for large-scale extrusion is needed for design and production capabilities. An in-house-built LFAM printer was used to print polyethylene terephthalate glycol with 30% carbon fiber (PETG CF30%) samples for thermomechanical characterization. Thermogravimetric analysis (TGA) shows that the samples were 30% carbon fiber by weight. X-ray microscopy (XRM) and porosity studies find 25% voids/volume for undried material and 1.63% voids/volume for dry material. Differential scanning calorimetry (DSC) shows a glass transition temperature (Tg) of 66 °C, while dynamic mechanical analysis (DMA) found Tg as 82 °C. The rheology indicated that PETG CF30% is a good printing material at 220-250 °C. Bending experiments show an average of 48.5 MPa for flexure strength, while tensile experiments found an average tensile strength of 25.0 MPa at room temperature. Comparison with 3D-printed PLA and PETG from the literature demonstrated that LFAM-printed PETG CF30% had a comparative high Young's modulus and had similar tensile strength. For design purposes, prints from LFAM should consider both material choice and print parameters, especially when considering large layer heights.

19.
J Cell Sci ; 124(Pt 5): 812-9, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21303930

RESUMEN

Macroautophagy is a dynamic process whereby portions of the cytosol are encapsulated in double-membrane vesicles and delivered to the lysosome for degradation. Phosphatidylinositol-3-phosphate (PtdIns3P) is concentrated on autophagic vesicles and recruits effector proteins that are crucial for this process. The production of PtdIns3P by the class III phosphatidylinositol 3-kinase Vps34, has been well established; however, protein phosphatases that antagonize this early step in autophagy remain to be identified. To identify such enzymes, we screened human phosphatase genes by RNA interference and found that loss of PTPσ, a dual-domain protein tyrosine phosphatase (PTP), increases levels of cellular PtdIns3P. The abundant PtdIns3P-positive vesicles conferred by loss of PTPσ strikingly phenocopied those observed in cells starved of amino acids. Accordingly, we discovered that loss of PTPσ hyperactivates both constitutive and induced autophagy. Finally, we found that PTPσ localizes to PtdIns3P-positive membranes in cells, and this vesicular localization is enhanced during autophagy. We therefore describe a novel role for PTPσ and provide insight into the regulation of autophagy. Mechanistic knowledge of this process is crucial for understanding and targeting therapies for several human diseases, including cancer and Alzheimer's disease, in which abnormal autophagy might be pathological.


Asunto(s)
Autofagia/fisiología , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Línea Celular , Humanos , Fosfatidilinositol 3-Quinasa/metabolismo , Interferencia de ARN , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Sistemas de Mensajero Secundario/fisiología
20.
bioRxiv ; 2023 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-38077086

RESUMEN

Kinase domains are highly conserved within protein kinases in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. The serine/threonine kinases ULK1 and ULK2 are highly conserved with N- and C-terminal domains, phosphate-binding P-loops, αC-helix, regulatory and catalytic spines, and activation loop DFG and APE motifs. Here, we performed molecular dynamics (MD) simulations to understand better the potency and selectivity of the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the αC-helix. Large movements in the P-loop are also associated with ULK-101 inhibitor binding and exit from ULK2. Our data further suggests that ULK-101 could induce a folded P-loop conformation and hydrophobic pocket reflected in its nanomolar potency and kinome selectivity.

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