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2.
Cancer Discov ; : OF1-OF24, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38593348

RESUMEN

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors.

3.
Proc Natl Acad Sci U S A ; 121(19): e2318413121, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38683993

RESUMEN

Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the ß-myosin heavy chain (MYH7) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant MYH7 G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure-function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the MYH7 G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype-phenotype relationships underlying other genetic cardiovascular diseases.


Asunto(s)
Miosinas Cardíacas , Cardiomiopatía Hipertrófica , Células Madre Pluripotentes Inducidas , Contracción Miocárdica , Miocitos Cardíacos , Cadenas Pesadas de Miosina , Humanos , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismo , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Contracción Miocárdica/genética , Mutación , Mitocondrias/metabolismo , Mitocondrias/genética , Miofibrillas/metabolismo , Respiración de la Célula/genética
4.
Vet Med Sci ; 10(2): e1388, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38379342

RESUMEN

BACKGROUND: Being able to model a growth curve using three or four non-linear functional parameters could help explain the growth phenomenon in a precise way and would allow the comparison of an animal's development rate, optimize management and feeding strategies and guide animal production strategies. OBJECTIVE: The goal of this study was to estimate the genetic parameters of growth traits of Isfahan indigenous chicken in Iran and to determine the best non-linear model describing the growth curve. METHODS: The prediction of additive genetic parameters was performed using the REML method by WOMBAT. Direct heritability of the studied traits and genetic correlations between them were obtained. The Logistic, Gompertz, von Bertalanffy, Brody, Negative exponential, Weibull, Janoschek and Bridges models were compared based on the coefficient of determination (R2 ), mean square error (MSE) and akaike information criterion. RESULTS: The Gompertz model was identified as the best model for describing the growth curve for Isfahan native chicken. The heritability of maturity weights (A), initial weight (B) and maturity rate (K) parameters were 0.223 ± 0.002, 0.016 ± 0.005 and 0.087 ± 0.001, respectively. CONCLUSION: This study shows that Isfahan indigenous chicken has the genetic potential for improving growth and reproduction based on their desirable heritabilities and correlations using appropriate models.


Asunto(s)
Pollos , Reproducción , Animales , Pollos/genética , Peso Corporal/genética , Fenotipo , Irán
5.
BMC Biol ; 22(1): 31, 2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38317190

RESUMEN

BACKGROUND: The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A virus (IAV), harbors almost all subtypes of IAVs and resists to many IAVs which cause extreme virulence in chicken and human. However, the response of duck's adaptive immune system to IAV infection is poorly characterized due to lack of a detailed gene map of the major histocompatibility complex (MHC). RESULTS: We herein reported a chromosome-scale Beijing duck assembly by integrating Nanopore, Bionano, and Hi-C data. This new reference genome SKLA1.0 covers 40 chromosomes, improves the contig N50 of the previous duck assembly with highest contiguity (ZJU1.0) of more than a 5.79-fold, surpasses the chicken and zebra finch references in sequence contiguity and contains a complete genomic map of the MHC. Our 3D MHC genomic map demonstrated that gene family arrangement in this region was primordial; however, families such as AnplMHCI, AnplMHCIIß, AnplDMB, NKRL (NK cell receptor-like genes) and BTN underwent gene expansion events making this area complex. These gene families are distributed in two TADs and genes sharing the same TAD may work in a co-regulated model. CONCLUSIONS: These observations supported the hypothesis that duck's adaptive immunity had been optimized with expanded and diversified key immune genes which might help duck to combat influenza virus. This work provided a high-quality Beijing duck genome for biological research and shed light on new strategies for AIV control.


Asunto(s)
Patos , Genoma , Animales , Humanos , Patos/genética , Complejo Mayor de Histocompatibilidad/genética , Cromosomas/genética , Familia de Multigenes
6.
Sci Data ; 11(1): 86, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38238322

RESUMEN

The white-crowned sparrow, Zonotrichia leucophrys, is a passerine bird with a wide distribution and it is extensively adapted to environmental changes. It has historically acted as a model species in studies on avian ecology, physiology and behaviour. Here, we present a high-quality chromosome-level genome of Zonotrichia leucophrys using PacBio and OmniC sequencing data. Gene models were constructed by combining RNA-seq and Iso-seq data from liver, hypothalamus, and ovary. In total a 1,123,996,003 bp genome was generated, including 31 chromosomes assembled in complete scaffolds along with other, unplaced scaffolds. This high-quality genome assembly offers an important genomic resource for the research community using the white-crowned sparrow as a model for understanding avian genome biology and development, and provides a genomic basis for future studies, both fundamental and applied.


Asunto(s)
Genoma , Gorriones , Animales , Femenino , Hipotálamo , Ovario , Gorriones/genética , Masculino
7.
Sci Rep ; 14(1): 2209, 2024 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-38278850

RESUMEN

Indigenous poultry breeds from Africa can survive in harsh tropical environments (such as long arid seasons, excessive rain and humidity, and extreme heat) and are resilient to disease challenges, but they are not productive compared to their commercial counterparts. Their adaptive characteristics are in response to natural selection or to artificial selection for production traits that have left selection signatures in the genome. Identifying these signatures of positive selection can provide insight into the genetic bases of tropical adaptations observed in indigenous poultry and thereby help to develop robust and high-performing breeds for extreme tropical climates. Here, we present the first large-scale whole-genome sequencing analysis of Nigerian indigenous chickens from different agro-climatic conditions, investigating their genetic diversity and adaptation to tropical hot climates (extreme arid and extreme humid conditions). The study shows a large extant genetic diversity but low level of population differentiation. Using different selection signature analyses, several candidate genes for adaptation were detected, especially in relation to thermotolerance and immune response (e.g., cytochrome P450 2B4-like, TSHR, HSF1, CDC37, SFTPB, HIF3A, SLC44A2, and ILF3 genes). These results have important implications for conserving valuable genetic resources and breeding improvement of chickens for thermotolerance.


Asunto(s)
Pollos , Calor , Animales , Pollos/genética , Genoma , Genómica/métodos , Selección Genética , Variación Genética , Polimorfismo de Nucleótido Simple
8.
Exp Clin Psychopharmacol ; 32(1): 35-44, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37523300

RESUMEN

Little is known about the naturalistic use of cannabis oil vaporization, a high-potency product with the ability to be administered discreetly. This pilot study evaluated the feasibility of utilizing a "smart" vaporizer and application to assess the timing, frequency, socioenvironmental factors, and substance use involved in cannabis oil vaporization. Adults with a medical cannabis registration card were recruited from a dispensary in Rhode Island and completed a 2-week study monitoring period using the Gram1 vaporizer, followed by a poststudy qualitative interview. The sample included nine adults who were predominantly male (89%), 100% White, and 100% non-Hispanic. The Gram1 collected topographical vaping data, and the cellphone application utilized ecological momentary assessment (EMA) to assess socioenvironmental factors and other substance use. Qualitative interview data were coded, and illustrative quotations were selected to support quantitative findings. A total of 224 vaping sessions were recorded reflecting 76.4% of the study monitoring period. There was an average of 1.79 vaping sessions per day across all days. Participants took 8.76 puffs on average (SD = 8.23) per vaping session, and the session lasted 2.59 min on average (SD = 4.19). Regular vaporization was exhibited across days of the week and hours of the day. EMA reports indicated that smoking cannabis flower was the most common additional mode of cannabis administration. This study utilized a naturalistic design with novel topographical data and EMA to characterize cannabis oil vaporization. These findings establish the feasibility of collecting objective, momentary data to better understand use behaviors which are critical to informing safe consumption. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Asunto(s)
Cannabis , Alucinógenos , Fumar Marihuana , Trastornos Relacionados con Sustancias , Adulto , Humanos , Masculino , Femenino , Proyectos Piloto , Volatilización , Agonistas de Receptores de Cannabinoides
9.
Proc Natl Acad Sci U S A ; 121(1): e2307086120, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38147543

RESUMEN

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Proteínas Serina-Treonina Quinasas , Ratones , Humanos , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Citocinas , Inflamación/tratamiento farmacológico , Isoformas de Proteínas , Antiinflamatorios/farmacología , Inmunidad Innata , Factores de Transcripción
10.
Front Psychiatry ; 14: 1267753, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38076702

RESUMEN

Two primary ovarian hormones that fluctuate across the female menstrual cycle-estradiol and progesterone-have been independently linked in separate literatures to nicotine reinforcement and anxiety psychopathology. We identify existing methodological limitations in these literatures, describe an example protocol that was developed to address such limitations, highlight case examples, and offer insights on the resulting advantages and challenges. This protocol was an observational, prospective, within-subjects study of female cigarette smokers who were followed over the course of a complete menstrual cycle. Non-treatment seeking, female cigarette smokers (N = 50), between the ages of 18-40 who have a normal menstrual cycle (25-35 days in length) were recruited from the community. Females with anxiety or mood psychopathology represented 38.0% of the sample. Salivary progesterone and estradiol were assessed each morning via at-home saliva collection methods. Self-reported within-day momentary ratings of anxiety and nicotine reinforcement were collected using ecological momentary assessment (EMA) via a mobile app. Protocol compliance was >85%. Within- and between-subjects heterogeneity was observed in the progesterone and estradiol, anxiety, and nicotine craving measures, especially in the context of anxiety psychopathology. We aimed to integrate the anxiety and nicotine dependence literatures and advance the empirical study of the role of ovarian hormones. This protocol reflects an intensive, yet feasible approach to collecting daily-level naturalistic data related to estradiol, progesterone, anxiety, and nicotine reinforcement.

11.
Commun Biol ; 6(1): 1233, 2023 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-38057566

RESUMEN

A set of high-quality pan-genomes would help identify important genes that are still hidden/incomplete in bird reference genomes. In an attempt to address these issues, we have assembled a de novo chromosome-level reference genome of the Silkie (Gallus gallus domesticus), which is an important avian model for unique traits, like fibromelanosis, with unclear genetic foundation. This Silkie genome includes the complete genomic sequences of well-known, but unresolved, evolutionarily, endocrinologically, and immunologically important genes, including leptin, ovocleidin-17, and tumor-necrosis factor-α. The gap-less and manually annotated MHC (major histocompatibility complex) region possesses 38 recently identified genes, with differentially regulated genes recovered in response to pathogen challenges. We also provide whole-genome methylation and genetic variation maps, and resolve a complex genetic region that may contribute to fibromelanosis in these animals. Finally, we experimentally show leptin binding to the identified leptin receptor in chicken, confirming an active leptin ligand-receptor system. The Silkie genome assembly not only provides a rich data resource for avian genome studies, but also lays a foundation for further functional validation of resolved genes.


Asunto(s)
Pollos , Leptina , Animales , Pollos/genética , Leptina/genética , Genoma , Genómica , Cromosomas
12.
BMC Biol ; 21(1): 303, 2023 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-38129834

RESUMEN

BACKGROUND: Identifying the key factors that underlie complex traits during domestication is a great challenge for evolutionary and biological studies. In addition to the protein-coding region differences caused by variants, a large number of variants are located in the noncoding regions containing multiple types of regulatory elements. However, the roles of accumulated variants in gene regulatory elements during duck domestication and economic trait improvement are poorly understood. RESULTS: We constructed a genomics, transcriptomics, and epigenomics map of the duck genome and assessed the evolutionary forces that have been in play across the whole genome during domestication. In total, 304 (42.94%) gene promoters have been specifically selected in Pekin duck among all selected genes. Joint multi-omics analysis reveals that 218 genes (72.01%) with selected promoters are located in open and active chromatin, and 267 genes (87.83%) with selected promoters were highly and differentially expressed in domestic trait-related tissues. One important candidate gene ELOVL3, with a strong signature of differentiation on the core promoter region, is known to regulate fatty acid elongation. Functional experiments showed that the nearly fixed variants in the top selected ELOVL3 promoter in Pekin duck decreased binding ability with HLF and increased gene expression, with the overexpression of ELOVL3 able to increase lipid deposition and unsaturated fatty acid enrichment. CONCLUSIONS: This study presents genome resequencing, RNA-Seq, Hi-C, and ATAC-Seq data of mallard and Pekin duck, showing that selection of the gene promoter region plays an important role in gene expression and phenotypic changes during domestication and highlights that the variants of the ELOVL3 promoter may have multiple effects on fat and long-chain fatty acid content in ducks.


Asunto(s)
Domesticación , Patos , Animales , Patos/genética , Patos/metabolismo , Herencia Multifactorial , Regiones Promotoras Genéticas , Ácidos Grasos/metabolismo
13.
bioRxiv ; 2023 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-38105998

RESUMEN

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

14.
Front Immunol ; 14: 1235155, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37691939

RESUMEN

Background: Peri-implantitis is an infectious/inflammatory disease with similar clinical and radiographic features to periodontitis. Overwhelming evidence confirmed that periodontitis causes elevations in systemic inflammatory mediators; this is unclear for peri-implantitis. Hence, this study aimed to appraise all available evidence linking peri-implantitis with systemic inflammation. Methods: A systematic review was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eight electronic databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Web of Science, Dentistry & Oral Sciences Source, Scopus, LILACS, and China Online), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), and gray literature were searched up to February 9, 2023. Human studies of randomized controlled trials, non-randomized intervention studies, cohort studies, case-control, and cross-sectional studies were eligible for inclusion. Quantitative analyses were performed using random effects models. Results: A total of 27 full-text articles were retrieved, and 11 clinical studies were included in the final analyses. All evidence gathered demonstrated a consistent association between peri-implantitis and systemic inflammation. Patients with peri-implantitis exhibited higher levels of serum C-reactive protein (CRP) (standard mean difference (SMD): 4.68, 98.7% CI: 2.12 to 7.25), interleukin-6 (IL-6) (weighted mean difference (WMD): 6.27 pg/mL, 0% CI: 5.01 to 7.54), and white blood cell counts (WMD: 1.16 * 103/µL, 0% CI: 0.61 to 1.70) when compared to participants without peri-implantitis. Conclusion: Peri-implantitis is associated with higher systemic inflammation as assessed by serum CRP, IL-6, and white blood cell counts. Further research is needed to clarify the nature of this association. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=246837, identifier CRD42021246837.


Asunto(s)
Periimplantitis , Humanos , Proteína C-Reactiva , Estudios Transversales , Inflamación , Interleucina-6 , Periimplantitis/etiología
15.
Science ; 381(6659): 794-799, 2023 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-37590355

RESUMEN

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).


Asunto(s)
Productos Biológicos , Ciclofilina A , Inmunofilinas , Chaperonas Moleculares , Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Cisteína/química , Cisteína/genética , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal , Ciclofilina A/química , Ciclofilina A/metabolismo , Inmunofilinas/química , Inmunofilinas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética
16.
bioRxiv ; 2023 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-37333118

RESUMEN

Rationale: Over 200 mutations in the sarcomeric protein ß-myosin heavy chain (MYH7) have been linked to hypertrophic cardiomyopathy (HCM). However, different mutations in MYH7 lead to variable penetrance and clinical severity, and alter myosin function to varying degrees, making it difficult to determine genotype-phenotype relationships, especially when caused by rare gene variants such as the G256E mutation. Objective: This study aims to determine the effects of low penetrant MYH7 G256E mutation on myosin function. We hypothesize that the G256E mutation would alter myosin function, precipitating compensatory responses in cellular functions. Methods: We developed a collaborative pipeline to characterize myosin function at multiple scales (protein to myofibril to cell to tissue). We also used our previously published data on other mutations to compare the degree to which myosin function was altered. Results: At the protein level, the G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 50.9%, suggesting more myosins available for contraction. Myofibrils isolated from hiPSC-CMs CRISPR-edited with G256E (MYH7 WT/G256E ) generated greater tension, had faster tension development and slower early phase relaxation, suggesting altered myosin-actin crossbridge cycling kinetics. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. Single-cell transcriptomic and metabolic profiling demonstrated upregulation of mitochondrial genes and increased mitochondrial respiration, suggesting altered bioenergetics as an early feature of HCM. Conclusions: MYH7 G256E mutation causes structural instability in the transducer region, leading to hypercontractility across scales, perhaps from increased myosin recruitment and altered crossbridge cycling. Hypercontractile function of the mutant myosin was accompanied by increased mitochondrial respiration, while cellular hypertrophy was modest in the physiological stiffness environment. We believe that this multi-scale platform will be useful to elucidate genotype-phenotype relationships underlying other genetic cardiovascular diseases.

17.
Cells ; 12(8)2023 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-37190060

RESUMEN

Primordial germ cells (PGCs) are germline-restricted embryonic cells that form the functional gametes of the adult animal. The use of avian PGCs in biobanking and producing genetically modified birds has driven research on the in vitro propagation and manipulation of these embryonic cells. In avian species, PGCs are hypothesized to be sexually undetermined at an early embryonic stage and undergo differentiation into an oocyte or spermatogonial fate dictated by extrinsic factors present in the gonad. However, chicken male and female PGCs require different culture conditions, suggesting that there are sex-specific differences, even at early stages. To understand potential differences between male and female chicken PGCs during migratory stages, we studied the transcriptomes of circulatory stage male and female PGCs propagated in a serum-free medium. We found that in vitro cultured PGCs were transcriptionally similar to their in ovo counterparts, with differences in cell proliferation pathways. Our analysis also revealed sex-specific transcriptome differences between male and female cultured PGCs, with notable differences in Smad7 and NCAM2 expression. A comparison of chicken PGCs with pluripotent and somatic cell types identified a set of genes that are exclusive to germ cells, enriched in the germplasm, and associated with germ cell development.


Asunto(s)
Pollos , Transcriptoma , Animales , Femenino , Masculino , Pollos/genética , Transcriptoma/genética , Caracteres Sexuales , Bancos de Muestras Biológicas , Células Germinativas/metabolismo
18.
AIMS Public Health ; 10(1): 116-128, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37063359

RESUMEN

Obesity is a significant public health concern, especially in the Deep South and in Mississippi where prevalence is among the worst in the nation paired, with other poor health outcomes and socioeconomic conditions. Lifestyle management programs that address modifiable risk factors, such as nutrition and physical activity, can be effective mitigation strategies to halt weight accumulation patterns and ameliorate metabolic risk factors for some populations. However, there is limited evidence regarding the implementation of effective practice models to address obesity risk in underserved and underrepresented populations, such as African Americans, and people in the stage of earlier adulthood. Furthermore, there is growing evidence supporting the impact of the COVID-19 pandemic on lifestyle management programs that should be considered in these populations. The purpose of this manuscript was to describe the development and telehealth implementation of a weight management program during the COVID-19 pandemic and provide a preliminary examination of recruitment strategies and baseline characteristics for enrolled participants. Passive recruitment (social media, web, email, and other media advertisements) resulted in 157 screening initiations, and 79 of those participants met the study inclusion criteria. Further, of the 79 eligible participants, 38 completed all study enrollment requirements and presented with metabolic abnormalities. The study findings add to the emerging body of evidence for how the pandemic may have impacted lifestyle management programs and is representative of an understudied and underrepresented population.

19.
Genes (Basel) ; 14(4)2023 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-37107551

RESUMEN

The purpose of the current study was to examine transcriptomic-based profiling of differentially expressed innate immune genes between indigenous and commercial chickens. In order to compare the transcriptome profiles of the different chicken breeds, we extracted RNA from blood samples of the Isfahan indigenous chicken (as indigenous) and Ross broiler chicken (as commercial) breeds. RNA-Seq yielded totals of 36,763,939 and 31,545,002 reads for the indigenous and commercial breeds, respectively, with clean reads then aligned to the chicken reference genome (Galgal5). Overall, 1327 genes were significantly differentially expressed, of which 1013 genes were upregulated in the commercial versus the indigenous breed, while 314 were more highly expressed in the indigenous birds. Furthermore, our results demonstrated that the SPARC, ATP6V0D2, IL4I1, SMPDL3A, ADAM7, TMCC3, ULK2, MYO6, THG1L and IRG1 genes were the most significantly expressed genes in the commercial birds and the PAPPA, DUSP1, PSMD12, LHX8, IL8, TRPM2, GDAP1L1, FAM161A, ABCC2 and ASAH2 genes were the most significant in the indigenous chickens. Of notable finding in this study was that the high-level gene expressions of heat-shock proteins (HSPs) in the indigenous breeds could serve as a guideline for future genetic improvement. This study identified genes with breed-specific expression, and comparative transcriptome analysis helped understanding of the differences in underlying genetic mechanisms between commercial and local breeds. Therefore, the current results can be used to identify candidate genes for further breed improvement.


Asunto(s)
Pollos , Transcriptoma , Animales , Pollos/genética , RNA-Seq , Irán , Transcriptoma/genética , Inmunidad Innata/genética
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