Understanding growth regulatory pathways is important in aquaculture, fisheries, and vertebrate physiology generally. Machine learning pattern recognition and sensitivity analysis were employed to ...examine metabolomic small molecule profiles and transcriptomic gene expression data generated from liver and white skeletal muscle of hybrid striped bass (white bass Morone chrysops x striped bass M. saxatilis) representative of the top and bottom 10 % by body size of a production cohort. Larger fish (good-growth) had significantly greater weight, total length, hepatosomatic index, and specific growth rate compared to smaller fish (poor-growth) and also had significantly more muscle fibers of smaller diameter (less than or equal to 20 microm diameter), indicating active hyperplasia. Differences in metabolomic pathways included enhanced energetics (glycolysis, citric acid cycle) and amino acid metabolism in good-growth fish, and enhanced stress, muscle inflammation (cortisol, eicosanoids) and dysfunctional liver cholesterol metabolism in poor-growth fish. The majority of gene transcripts identified as differentially expressed between groups were down-regulated in good-growth fish. Several molecules associated with important growth-regulatory pathways were up-regulated in muscle of fish that grew poorly: growth factors including agt and agtr2 (angiotensins), nicotinic acid (which stimulates growth hormone production), gadd45b, rgl1, zfp36, cebpb, and hmgb1; insulin-like growth factor signaling (igfbp1 and igf1); cytokine signaling (socs3, cxcr4); cell signaling (rgs13, rundc3a), and differentiation (rhou, mmp17, cd22, msi1); mitochondrial uncoupling proteins (ucp3, ucp2); and regulators of lipid metabolism (apoa1, ldlr). Growth factors pttg1, egfr, myc, notch1, and sirt1 were notably up-regulated in muscle of good-growing fish. A combinatorial pathway analysis using metabolomic and transcriptomic data collectively suggested promotion of cell signaling, proliferation, and differentiation in muscle of good-growth fish, whereas muscle inflammation and apoptosis was observed in poor-growth fish, along with elevated cortisol (an anti-inflammatory hormone), perhaps related to muscle wasting, hypertrophy, and inferior growth. These findings provide important biomarkers and mechanisms by which growth is regulated in fishes and other vertebrates as well.
Striped bass, Morone saxatilis, is an anadromous fish native to the North American Atlantic Coast and is well recognized as one of the most important and highly regarded recreational fisheries in the ...United States. Decades of research have been conducted on striped bass and its hybrid (striped bass × white bass Morone chrysops) and culture methods have been established, particularly for the hybrid striped bass, the fourth largest finfish aquaculture industry in the United States (US $50 million). Domesticated striped bass have been developed since the 1990s and broodstock are available from the government for commercial fry production using novel hormone‐free methods along with traditional hormone‐induced tank and strip spawning. No commercial‐scale intensive larval rearing technologies have been developed at present and current fingerling production is conducted in fertilized freshwater ponds. Larval diets have not been successfully used as first feeds; however, they have been used for weaning from live feeds prior to metamorphosis. Striped bass can be grown out in marine (32 ppt) or freshwater (<5 ppt); however, they require high hardness (200+ ppm) and some salinity (8–10 ppt) to offset handling stress. Juveniles must be 1–10 g/fish prior to stocking into marine water. Commercially available fingerling, growout, and broodstock feeds are available from several vendors. Striped bass may reach 1.36 kg/fish in recirculating aquaculture by 18 months and as much as 2.27 kg/fish by 24 months. Farm gate value of striped bass has not been determined, although seasonally available wild‐harvested striped bass are valued at about US $6.50 to US $10.14 per kg and cultured hybrid striped bass are valued at about US $8.45 to US $9.25 per kg whole; the farm gate value for cultured striped bass may be as much as US $10.00 or more per kg depending on demand and market. The ideal market size is between 1.36 and 2.72 kg/fish, which is considerably larger than the traditional 0.68 to 0.90 kg/fish for the hybrid striped bass market.
An aquaculture research facility experienced high mortality rates in white bass Morone chrysops associated with a monogenean infestation of the gills, but not in striped bass Morone saxatilis in the ...same facility. All mortalities had pale gills. Monogeneans, identified as Gamacallum macroura (MacCallum and MacCallum 1913) Unnithan 1971, were found on the gills. Pale-gilled and healthy white bass were selected with no particular attention to condition for venipuncture and euthanasia for postmortem examination, including parasite counts from gills. The median packed cell volume (PCV) of fish with gill pallor was 12.5% (range 9–37%) while PVC of fish with more normal color was 30% (27–33%). Association between the PCV and gill pallor score was statistically significant, as was the association between PCV and the number of monogeneans found on the gills of each fish. Median estimated white blood cell count of fish with gill pallor, at 12.05 × 10 ³/μL (range 3.8–24.7), was significantly lower than of apparently healthy fish: 24.7 × 10 ³/μL (17.3–31.5). Histopathology of the gill arches of pale-gilled fish revealed multifocal moderate to severe branchitis, focal areas of dilated hyperplastic lamellae occluded by fibrin, and monogeneans attached to the lamellae. Fish that were apparently healthy had grossly similar histologic lesions, but at lower frequency and severity.
Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory ...diseases, and cancer. By contrast, cGAS reactivity against self-DNA in the nucleus is suppressed by chromatin tethering. We report a 3.3-angstrom-resolution cryo-electron microscopy structure of cGAS in complex with the nucleosome core particle. The structure reveals that cGAS uses two conserved arginines to anchor to the nucleosome acidic patch. The nucleosome-binding interface exclusively occupies the strong double-stranded DNA (dsDNA)-binding surface on cGAS and sterically prevents cGAS from oligomerizing into the functionally active 2:2 cGAS-dsDNA state. These findings provide a structural basis for how cGAS maintains an inhibited state in the nucleus and further exemplify the role of the nucleosome in regulating diverse nuclear protein functions.
Attenuated familial adenomatous polyposis is characterised by low number (≤100) and delayed development of colorectal adenomas. Various definitions have been used, and genotype-phenotype correlations ...have been suggested.
We aimed to evaluate phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and assess familial variability.
This is a retrospective study.
This study was conducted at a tertiary polyposis registry.
Individuals with attenuated familial adenomatous polyposis were identified. Phenotypic group was defined as 100 or fewer adenomas at age 25 years and genotypic group was defined as a variant in the adenomatous polyposis coli region associated with attenuated familial adenomatous polyposis. Pathology polyp count was used for patients who had undergone surgery and endoscopic polyp count for those with intact colon.
We evaluated phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and familial variability.
A total of 69 patients were identified in the phenotypic group, of whom 54 (78%) had a pathogenic variant in the attenuated regions of the adenomatous polyposis coli gene. Forty-eight (70%) had intact colon (median age at last colonoscopy 43 25-73 years; median endoscopic polyp count 20 0-100) and 21 (30%) had undergone colectomy (median age at surgery 45 25-54 years; median pathology polyp count 43 3-100). Eighty-three patients were identified in the genotypic group of which 54 (65%) had attenuated phenotype. Inter- and intrafamilial variability were observed.
This study was limited by its retrospective nature and single-center experience.
Phenotype in familial adenomatous polyposis lies on a spectrum and is determined in part by genotype and age at adenoma count. Diagnosis of attenuated familial adenomatous polyposis should be based on phenotype; genotype is not a reliable indicator. Management should be personalized according to the phenotype of each individual. See Video Abstract at http://links.lww.com/DCR/B775.
ANTECEDENTES:La poliposis adenomatosa familiar atenuada se caracteriza por un número bajo (≤100) y desarrollo retardado de adenomas colorrectales. Se han utilizado varias definiciones y se han sugerido correlaciones genotipo-fenotipo.OBJETIVO:Nuestro objetivo es evaluar la correlación fenotípica y genotípica en pacientes con presunta poliposis adenomatosa familiar atenuada y evaluar la variabilidad familiar.DISEÑO:Este es un estudio retrospectivo.AJUSTE:Este estudio se realizó en un registro terciario de poliposis.PACIENTES:Se identificaron individuos con poliposis adenomatosa familiar atenuada. El grupo fenotípico se definió como ≤100 adenomas a la edad de 25 años y el grupo genotípico se definió como una variante en la región de poliposis coli adenomatosa asociada con poliposis adenomatosa familiar atenuada. Se utilizó el recuento de pólipos en patología para los pacientes que se habían sometido a cirugía y el recuento de pólipos endoscópico para los que tenían el colon intacto.PRINCIPALES MEDIDAS DE RESULTADO:Evaluamos la correlación fenotípica y genotípica en pacientes con presunta poliposis adenomatosa familiar atenuada y variabilidad familiar.RESULTADOS:Un total de 69 pacientes se identificaron en el grupo fenotípico de los cuales 54 (78%) tenían una variante patogénica en las regiones atenuadas del gen de la poliposis coli adenomatosa. Cuarenta y ocho (70%) tenían colon intacto (edad media en la última colonoscopia 43 25-73 años; mediana del recuento de pólipos endoscópicos 20 0-100) y 21 (30%) se habían sometido a colectomía (edad edia en el momento de la cirugía 45 25-54 años; mediana del recuento de pólipos patológicos 43 3-100). Se identificaron 83 pacientes en el grupo genotípico de los cuales 54 (65%) tenían fenotipo atenuado. Se observó variabilidad inter e intrafamiliar.LIMITACIONES:Este estudio estuvo limitado por su naturaleza retrospectiva y la experiencia de un solo centro.CONCLUSIÓNES:El fenotipo en la poliposis adenomatosa familiar se encuentra en un espectro, determinado en parte por el genotipo y la edad en el momento del recuento de adenomas. El diagnóstico de poliposis adenomatosa familiar atenuada debe basarse en el fenotipo; el genotipo no es un indicador confiable. El manejo debe personalizarse según el fenotipo de cada individuo. Consulte Video Resumen en http://links.lww.com/DCR/B775.
A key role of chromatin kinases is to phosphorylate histone tails during mitosis to spatiotemporally regulate cell division. Vaccinia-related kinase 1 (VRK1) is a serine-threonine kinase that ...phosphorylates histone H3 threonine 3 (H3T3) along with other chromatin-based targets. While structural studies have defined how several classes of histone-modifying enzymes bind to and function on nucleosomes, the mechanism of chromatin engagement by kinases is largely unclear. Here, we paired cryo-electron microscopy with biochemical and cellular assays to demonstrate that VRK1 interacts with both linker DNA and the nucleosome acidic patch to phosphorylate H3T3. Acidic patch binding by VRK1 is mediated by an arginine-rich flexible C-terminal tail. Homozygous missense and nonsense mutations of this acidic patch recognition motif in VRK1 are causative in rare adult-onset distal spinal muscular atrophy. We show that these VRK1 mutations interfere with nucleosome acidic patch binding, leading to mislocalization of VRK1 during mitosis, thus providing a potential new molecular mechanism for pathogenesis.
Single hepatocellular carcinoma (HCC) tumors can be successfully eradicated with thermal ablation (TA). We assessed the validity of the Liver Imaging Reporting and Data System Treatment Response ...(LR‐TR) criteria with a retrospective analysis of a single‐center database of patients with small HCC tumors (<3 cm in diameter) who underwent both laparoscopic TA and liver transplantation (LT) from 2004 to 2018. Postablation MRIs were assigned LR‐TR categories (nonviable, equivocal, and viable) for ablated lesions and Liver Imaging Reporting and Data System (LI‐RADS) categories (probable or definite HCC) for untreated lesions. Interpretations were compared with the histopathology of the post‐LT explanted liver. There were 45 patients with 81 tumors (59 ablated and 22 untreated; mean size, 2.2 cm), and 23 (39%) of the ablated tumors had viable HCC on histopathology. The sensitivity/specificity of LR‐TR categories (nonviable/equivocal versus viable) of ablated tumors was 30%/99%, with a positive predictive value (PPV)/negative predictive value (NPV) of 93%/69%. The sensitivity varied with residual tumor size. The sensitivity/specificity of LI‐RADS 4 and 5 diagnostic criteria at detecting new HCC was 65%/94%, respectively, with a PPV/NPV of 85%/84%. The interrater reliability (IRR) was high for LR‐TR categories (90% agreement, Cohen’s ĸ = 0.75) and for LI‐RADS LR‐4 and LR‐5 diagnostic categories (91% agreement, Cohen’s ĸ = 0.80). In patients with HCC <3 cm in diameter, LR‐TR criteria after TA had high IRR but low sensitivity, suggesting that the LR‐TR categories are precise but inaccurate. The low sensitivity may be secondary to TA’s disruption in the local blood flow of the tissue, which could affect the arterial enhancement phase on MRI. Additional investigation and new technologies may be necessary to improve imaging after ablation.
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