Mortality after non-surgically treated acute type A aortic dissection is higher than previously reported.

OBJECTIVES: It has been commonly accepted that untreated acute type A aortic dissection (ATAAD) results in an hourly mortality rate of 1-2% during the 1st 24 h after symptom onset. The data to support this statement rely solely on patients who have been denied surgical treatment after reaching surgical centres. The objective was to perform a total review of non-surgically treated (NST) ATAAD and provide contemporary mortality data. METHODS: This was a regional, retrospective, observational study. All patients receiving one of the following diagnoses: International Classification of Diseases (ICD)-9 4410, 4411, 4415, 4416 or ICD-10 I710, I711, I715, I718 in an area of 1.9 million inhabitants in Southern Sweden during a period of 23 years (January 1998 to November 2021) were retrospectively screened. The search was conducted using all available medical registries so that every patient diagnosed with ATAAD in our region was identified. The charts and imaging of each screened patient were subsequently reviewed to confirm or discard the diagnosis of ATAAD. RESULTS: Screening identified 2325 patients, of whom 184 NST ATAAD patients were included. The mortality of NST ATAAD was 47.3 ± 4.4%, 55.0 ± 4.4%, 76.7 ± 3.7% and 83.9 ± 4.3% at 24 h, 48 h, 14 days and 1 year, respectively. The hourly mortality rate during the 1st 24 h after symptom onset was 2.6%. CONCLUSIONS: This study observed higher mortality than has previously been reported. It emphasizes the need for timely diagnosis, swift management and emergent surgical treatment for patients suffering an acute type A aortic dissection.

Radiological properties of neurological injury following acute type A aortic dissection repair.

Objective: The study objective was to assess the radiological properties of acute type A aortic dissection-related neurological injuries and identify predictors of neurological injury. Methods: Our single-center, retrospective, observational study included all patients who underwent acute type A aortic dissection repair between January 1998 and December 2021. Multivariable analyses and Cox regression were performed to identify predictors of embolic lesions, watershed lesions, neurological injury, 30-day mortality, and late mortality. Results: A total of 538 patients were included. Of these, 120 patients (22.3%) experienced postoperative neurological injury; 74 patients (13.8%) had postoperative stroke, and 36 patients (6.8%) had postoperative coma. The 30-day mortality was 22.7% in the neurological injury group versus 5.8% in the no neurological injury group (P < .001). We identified several independent predictors of neurological injury. Cerebral malperfusion (odds ratio, 2.77; 95% confidence interval, 1.53-5.00), systemic hypotensive shock (odds ratio, 1.97; 95% confidence interval, 1.13-3.43), and aortic arch replacement (odds ratio, 3.08; 95% confidence interval, 1.17-8.08) predicted embolic lesions. Diabetes mellitus (odds ratio, 5.35; 95% confidence interval, 1.85-15.42), previous cardiac surgery (odds ratio, 8.62; 95% confidence interval, 1.47-50.43), duration of hypothermic circulatory arrest (odds ratio, 1.05; 95% confidence interval, 1.01-1.08), cardiopulmonary bypass time (odds ratio, 1.01; 95% confidence interval, 1.00-1.01), ascending aortic/arch cannulation (odds ratio, 5.68; 95% confidence interval, 1.88-17.12), and left ventricular cannulation (odds ratio, 17.81; 95% confidence interval, 1.69-188.01) predicted watershed lesions. Retrograde cerebral perfusion (odds ratio, 0.28; 95% confidence interval, 0.01-0.84) had a protective effect against watershed lesions. Conclusions: In this study, we demonstrated that the radiological features of neurological injury may be as important as clinical characteristics in understanding the pathophysiology and causality behind neurological injury related to acute type A aortic dissection repair.

The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts.

Nuclear mRNA metabolism is regulated by multiple proteins, which either directly bind to RNA or form multiprotein complexes. The RNA-binding protein ZC3H11A is involved in nuclear mRNA export, NF-κB signaling, and is essential during mouse embryo development. Furthermore, previous studies have shown that ZC3H11A is important for nuclear-replicating viruses. However, detailed biochemical characterization of the ZC3H11A protein has been lacking. In this study, we established the ZC3H11A protein interactome in human and mouse cells. We demonstrate that the nuclear poly(A)-binding protein PABPN1 interacts specifically with the ZC3H11A protein and controls ZC3H11A localization into nuclear speckles. We report that ZC3H11A specifically interacts with the human adenovirus type 5 (HAdV-5) capsid mRNA in a PABPN1-dependent manner. Notably, ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and viral mRNA. Further, we demonstrate that the lack of ZC3H11A alters the polyadenylation of HAdV-5 capsid mRNA. Taken together, our results suggest that the ZC3H11A protein may act as a novel regulator of polyadenylation of nuclear mRNA.

Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes.

ZC3H11A (zinc finger CCCH domain-containing protein 11A) is a stress-induced mRNA-binding protein required for efficient growth of nuclear-replicating viruses. The cellular functions of ZC3H11A during embryonic development are unknown. Here, we report the generation and phenotypic characterization of Zc3h11a knockout (KO) mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type mice. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a -/- embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a -/- embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a-/- embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Furthermore, embryonic stem cells with an induced deletion of Zc3h11a display an impaired differentiation toward epiblast-like cells and impaired mitochondrial membrane potential. Altogether, the results show that ZC3H11A is participating in export and posttranscriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional KO did not lead to obvious phenotypic defects.

Carbon dioxide flooding to reduce postoperative neurological injury following surgery for acute type A aortic dissection: a prospective, randomised, blinded, controlled clinical trial, CARTA study protocol - objectives and design.

INTRODUCTION: Neurological complications after surgery for acute type A aortic dissection (ATAAD) increase patient morbidity and mortality. Carbon dioxide flooding is commonly used in open-heart surgery to reduce the risk of air embolism and neurological impairment, but it has not been evaluated in the setting of ATAAD surgery. This report describes the objectives and design of the CARTA trial, investigating whether carbon dioxide flooding reduces neurological injury following surgery for ATAAD. METHODS AND ANALYSIS: The CARTA trial is a single-centre, prospective, randomised, blinded, controlled clinical trial of ATAAD surgery with carbon dioxide flooding of the surgical field. Eighty consecutive patients undergoing repair of ATAAD, and who do not have previous neurological injuries or ongoing neurological symptoms, will be randomised (1:1) to either receive carbon dioxide flooding of the surgical field or not. Routine repair will be performed regardless of the intervention. The primary endpoints are size and number of ischaemic lesions on brain MRI performed after surgery. Secondary endpoints are clinical neurological deficit according to the National Institutes of Health Stroke Scale, level of consciousness using the Glasgow Coma Scale motor score, brain injury markers in blood after surgery, neurological function according to the modified Rankin Scale and postoperative recovery 3 months after surgery. ETHICS AND DISSEMINATION: Ethical approval has been granted by Swedish Ethical Review Agency for this study. Results will be disseminated through peer-reviewed media. TRIAL REGISTRATION NUMBER: NCT04962646.

A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken.

The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5th exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.

Rescue of Escherichia coli auxotrophy by de novo small proteins.

Increasing numbers of small proteins with diverse physiological roles are being identified and characterized in both prokaryotic and eukaryotic systems, but the origins and evolution of these proteins remain unclear. Recent genomic sequence analyses in several organisms suggest that new functions encoded by small open reading frames (sORFs) may emerge de novo from noncoding sequences. However, experimental data demonstrating if and how randomly generated sORFs can confer beneficial effects to cells are limited. Here, we show that by upregulating hisB expression, de novo small proteins (≤50 amino acids in length) selected from random sequence libraries can rescue Escherichia coli cells that lack the conditionally essential SerB enzyme. The recovered small proteins are hydrophobic and confer their rescue effect by binding to the 5' end regulatory region of the his operon mRNA, suggesting that protein binding promotes structural rearrangements of the RNA that allow increased hisB expression. This study adds RNA regulatory elements as another interacting partner for de novo proteins isolated from random sequence libraries and provides further experimental evidence that small proteins with selective benefits can originate from the expression of nonfunctional sequences.

S100B predicts neurological injury and 30-day mortality following surgery for acute type A aortic dissection: an observational cohort study.

BACKGROUND: Neurological injuries are frequent following Acute Type A Aortic Dissection (ATAAD) repair occurring in 4-30% of all patients. Our objective was to study whether S100B can predict neurological injury following ATAAD repair. METHODS: This was a single-center, retrospective, observational study. The study included all patients that underwent ATAAD repair at our institution between Jan 1998 and Dec 2021 and had recorded S100B-values. The primary outcome measure was neurological injury, defined as focal neurological deficit or coma diagnosed by clinical assessment with or without radiological confirmation and with a symptom duration of more than 24 h. Secondary outcome measure was 30-day mortality. RESULTS: 538 patients underwent surgery during the study period and 393 patients, had recorded S100B-values. The patients had a mean age of 64.4 ± 11.1 years and 34% were female. Receiver operating characteristic curve for S100B 24 h postoperatively yielded area under the curve 0.687 (95% CI 0.615-0.759) and best Youden's index corresponded to S100B 0.225 which gave a sensitivity of 60% and specificity of 75%. Multivariable logistic regression identified S100B ≥ 0.23 µg/l at 24 h as an independent predictor for neurological injury (OR 4.71, 95% CI 2.59-8.57; p < 0.01) along with preoperative cerebral malperfusion (OR 4.23, 95% CI 2.03-8.84; p < 0.01) as well as an independent predictor for 30-day mortality (OR 4.57, 95% CI 1.18-11.70; p < 0.01). CONCLUSIONS: We demonstrated that S100B, 24 h after surgery is a strong independent predictor for neurological injury and 30-day mortality after ATAAD repair. TRIAL REGISTRATION: As this was a retrospective observational study it was not registered.

Limited Distal Repair Results in Low Rates of Distal Events Following Surgery for Acute Type A Aortic Dissection.

To investigate mortality and reoperation rates following limited distal repair after acute type A aortic dissection (ATAAD) at a single medium volume institution. We analyzed all patients that underwent limited distal repair (ascending aortic or hemiarch replacement) following ATAAD between January 1998 and April 2020 at our institution. During the study period, 489 patients underwent ATAAD surgery, of which 457 (94%) underwent limited distal repair with a 30-day mortality of 12.9%. Among 30-day survivors, late follow-up was 97.7% complete with a mean follow-up of 6.0 ± 5.5 years. In all, 50 patients (11%) required a reoperation during the study period at a mean of 3.4 ± 3.4 years after initial repair, with a 30-day mortality of 12%. An aortic reoperation was required in 4.1 (2.0-6.1)%, 10.3 (7.1-13.6)%, 15.1 (10.9-19.4)%, and 18.0 (13.0-22.9)% of patients at 1, 5, 10, and 15 years. A distal reoperation was required in 3.0 (1.2-4.7)%, 8.0 (5.1-10.9)%, 10.3 (6.8-13.8)%, and 12.4 (8.2-16.5)% of patients and 4.4 (2.3-6.4)%, 10.4 (7.1-13.7)%, 13.9 (9.8-18.0)%, and 16.9 (12.0-21.9)% of patents had a distal event at 1, 5, 10, and 15 years, respectively. Limited distal repair with an ascending aortic or hemiarch replacement was associated with acceptable survival and rates of reoperations and distal events. Limited distal repair is a safe and feasible standard approach to ATAAD surgery at a medium-volume center.

A prospective, controlled study on the utility of rotational thromboelastometry in surgery for acute type A aortic dissection.

To evaluate the hemostatic system with ROTEM in patients undergoing surgery for acute type aortic dissection (ATAAD) using elective aortic procedures as controls. This was a prospective, controlled, observational study. The study was performed at a tertiary referral center and university hospital. Twenty-three patients with ATAAD were compared to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM (INTEM, EXTEM, HEPTEM and FIBTEM) was tested at 6 points in time before, during and after surgery for ATAAD or elective aortic surgery. The ATAAD group had an activated coagulation coming into the surgical theatre. The two groups showed activation of both major coagulation pathways during surgery, but the ATAAD group consistently had larger deficiencies. Reversal of the coagulopathy was successful, although none of the groups reached elective baseline until postoperative day 1. ROTEM did not detect low levels of clotting factors at heparin reversal nor low levels of platelets. This study demonstrated that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients as well as in patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM does not adequately catch the full coagulopathy in ATAAD. A transfusion protocol in ATAAD should be specifically created to target this complex coagulopathic state and ROTEM does not negate the need for routine laboratory tests.

Oxygen saturation after birth in resuscitated neonates in Uganda: a video-based observational study.

BACKGROUND: Monitoring of peripheral capillary oxygen saturation (SpO2) during neonatal resuscitation is standard of care in high-resource settings, but seldom performed in low-resource settings. We aimed to measure SpO2 and heart rate during the first 10 min of life in neonates receiving positive pressure ventilation (PPV) according to the Helping Babies Breathe (HBB) protocol and compare results with SpO2 and heart rate targets set by the American Heart Association (AHA). METHODS: A cross-sectional study was conducted at Mulago National Referral Hospital, Kampala, Uganda, as a substudy of the NeoSupra Trial. SpO2 and heart rate were measured on apnoeic neonates (≥34 weeks) who received PPV according to HBB (room air). Those who remained distressed after PPV received supplemental oxygen (O2). All resuscitations were video recorded and data were extracted by video review at 1 min intervals until 10 min post partum. Data were analysed for all observations and separately for only observations before and during PPV. RESULTS: 49 neonates were analysed. Median SpO2 at 5 min (n=39) was 67% (49-88) with 59% of the observations below AHA target of 80%. At 10 min median SpO2 (n=44) was 93% (80-97) and 32% were below AHA target of 85%. When only observations before and during PPV were analysed, median SpO2 at 5 min (n=18) was 52% (34-66) and 83% were below AHA target. At 10 min (n=15), median SpO2 was 72% (57-89) and 67% were below AHA target. Median heart rates were above AHA target of 100 beats/min at all time intervals. CONCLUSIONS: A high proportion of neonates resuscitated with PPV after birth failed to reach the AHA SpO2 target in this small sample, implying an increased risk of hypoxic-ischaemic encephalopathy. Further studies in low-resource settings are needed to evaluate baseline data and the need for supplemental O2 and optimal SpO2 during PPV. TRIAL REGISTRATION NUMBER: This is a substudy to the trial 'Neonatal Resuscitation with Supraglottic Airway Trial (NeoSupra)'; ClinicalTrials.gov Registry (NCT03133572).

ZBED6 regulates Igf2 expression partially through its regulation of miR483 expression.

The expression of Igf2 in mammals shows a complex regulation involving multiple promoters and epigenetic mechanisms. We previously identified a novel regulatory mechanism based on the interaction between the transcriptional factor ZBED6 and Igf2 intron. Disruption of the ZBED6-Igf2 interaction leads to a dramatic up-regulation of IGF2 expression postnatally. In the current study we characterize an additional layer of regulation involving miR483 encoded by another Igf2 intron. We found a highly significant up-regulation of miR483 expression when the ZBED6-Igf2 axis is disrupted in transgenic mice. Furthermore, CRISPR/Cas9 mediated knock-out of miR483 in C2C12 myoblast cells, both wild-type and cells with disrupted ZBED6-Igf2 axis (Igf2dGGCT), resulted in down-regulation of Igf2 expression and a reduced proliferation rate. This was further validated using miR483 mimics and inhibitors. RNA-seq analysis revealed a significant enrichment of genes involved in the PI3K-Akt signaling pathway among genes down-regulated in miR483-/- cells, including Igf2 down-regulation. The opposite pattern was observed in Igf2dGGCT cells, where Igf2 is up-regulated. Our data suggest a positive feedback between miR483 and Igf2 promoter activity, strongly affecting how ZBED6 controls Igf2 expression in various cell types.

The effect of postoperative anticoagulation on false lumen patency after surgery for acute type A aortic dissection.

BACKGROUND: Patent false lumen has been shown to have a negative impact on prognosis after surgery for acute type A aortic dissection (ATAAD). We aimed to assess the effect of postoperative anticoagulation on false lumen patency and clinical outcomes in relation to false lumen status. METHODS: Postoperative computed tomographies of 156 patients undergoing ATAAD DeBakey type I surgery were retrospectively evaluated for false lumen patency. The patients were divided into groups determined by anticoagulation treatment at discharge. Uni- and multivariable logistic regression was used for analysing the effect of anticoagulation on the false lumen, and Kaplan-Meier estimates were used to assess the association of a patent false lumen with the incidence of reoperation and long-term survival. RESULTS: A patent false lumen was present in 81% of the patients. Postoperative anticoagulants were not associated with a patent false lumen (p = 0.48) in univariable analysis. In multivariable analysis, both hemiarch replacement (OR 0.15, CI95% 0.05-0.49, p = 0.001) and the use of betablockers had a protective effect (OR 0.29, CI95% 0.10-0.85, p = 0.023). The Kaplan-Meier estimates for survival and the composite endpoint of survival and freedom from distal reintervention indicated no difference in outcome between patients in regard to anticoagulation treatment (survival p = 0.43, composite p = 0.82) or false lumen status (survival p = 0.21, composite p = 0.09). CONCLUSION: This study could not show negative effects from the postoperative use of anticoagulants on false lumen status, nor that false lumen patency was associated with poorer prognosis. A hemiarch procedure was shown to be associated with reduced risk of false lumen patency.

Impact of ABO blood group on bleeding complications after surgery for acute type A aortic dissection.

Excessive bleeding is a serious complication associated with impaired survival after surgery for acute type A aortic dissection (ATAAD). Different ABO blood groups are associated with variable levels of circulating von Willebrand factor and therefore potentially altered risks of surgical haemorrhage. The current study aimed to assess the impact of blood group on bleeding complications after ATAAD surgery. This was a retrospective cohort study including 336 patients surgically treated for ATAAD between January 2004 and January 2019. Patients with blood group O were compared with non-O patients. In total, 152 blood group O patients were compared with 184 non-O patients. There were no differences in rates of massive bleeding (27.0 vs. 25.5%, P = 0.767) or re-exploration for bleeding (16.4 vs. 13.0%, P = 0.379) in blood group O and non-O patients, respectively. Median chest tube output 12 h after surgery was 520 ml (350-815 ml) in blood group O and 490 ml (278-703 ml) in non-O patients (P = 0.229). Blood group O patients received more fibrinogen concentrate (6.1 ±â€Š4.0 vs. 4.9 ±â€Š3.3 g, P = 0.023) but administered units of packed red blood cells [5 (2-8) vs. 4 (2-9) U, P = 0.736], platelets [4 (2-4) vs. 3 (2-5) U, P = 0.521] or plasma [4 (1-7) vs. 4 (0-7) U, P = 0.562] were similar. This study could not demonstrate any association between blood group and bleeding after surgery for ATAAD. It cannot be ruled out that potential differences were levelled out by blood group O patients receiving significantly more fibrinogen concentrate.

Reconstruction of the birth of a male sex chromosome present in Atlantic herring.

The mechanisms underlying sex determination are astonishingly plastic. Particularly the triggers for the molecular machinery, which recalls either the male or female developmental program, are highly variable and have evolved independently and repeatedly. Fish show a huge variety of sex determination systems, including both genetic and environmental triggers. The advent of sex chromosomes is assumed to stabilize genetic sex determination. However, because sex chromosomes are notoriously cluttered with repetitive DNA and pseudogenes, the study of their evolution is hampered. Here we reconstruct the birth of a Y chromosome present in the Atlantic herring. The region is tiny (230 kb) and contains only three intact genes. The candidate male-determining gene BMPR1BBY encodes a truncated form of a BMP1B receptor, which originated by gene duplication and translocation and underwent rapid protein evolution. BMPR1BBY phosphorylates SMADs in the absence of ligand and thus has the potential to induce testis formation. The Y region also contains two genes encoding subunits of the sperm-specific Ca2+ channel CatSper required for male fertility. The herring Y chromosome conforms with a characteristic feature of many sex chromosomes, namely, suppressed recombination between a sex-determining factor and genes that are beneficial for the given sex. However, the herring Y differs from other sex chromosomes in that suppression of recombination is restricted to an ∼500-kb region harboring the male-specific and sex-associated regions. As a consequence, any degeneration on the herring Y chromosome is restricted to those genes located in the small region affected by suppressed recombination.

The importance of the ZBED6-IGF2 axis for metabolic regulation in mouse myoblast cells.

The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5'-GGCTCG-3' in intron 1 of Igf2. Deletion of this motif (Igf2ΔGGCT ) or complete ablation of Zbed6 leads to ~20-fold upregulation of the IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2ΔGGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2ΔGGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 upregulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with an enrichment of upregulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities, and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2ΔGGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study adds new insights how the ZBED6-Igf2 axis affects muscle metabolism.

A Discovery of a Genetic Mutation Causing Reduction of Atrogin-1 Expression in Broiler Chicken Muscle.

Chickens are bred all over the world and have significant economic value as one of the major agricultural animals. The growth rate of commercial broiler chickens is several times higher than its Red Jungle fowl (RJF) ancestor. To further improve the meat production of commercial chickens, it is quite important to decipher the genetic mechanism of chicken growth traits. In this study, we found that broiler chickens exhibited lower levels of E3 ubiquitin ligase muscle atrophy F-box (MAFbx or Atrogin-1) relative to its RJF ancestor. As a ubiquitin ligase, Atrogin-1 plays a crucial role in muscle development in which its up-regulation often indicates the activation of muscle atrophic pathways. Here, we showed that the Atrogin-1 expression variance partly affects chicken muscle growth rates among different breeds. Furthermore, we demonstrated that the reduced expression of Atrogin-1 in broiler chickens was ascribed to a single nucleotide polymorphism (SNP), which inhibited the binding of transcription regulators and attenuated the enhancer activity. The decreased Atrogin-1 in broiler chickens suppresses the catabolism of muscle protein and preserves muscle mass. Our study facilitates the understanding of the molecular mechanism of chicken muscle development and has a high translational impact in chicken breeding.

The role of gelsolin domain 3 in familial amyloidosis (Finnish type).

In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.

The role of von Willebrand factor in acute type A aortic dissection and aortic surgery.

INTRODUCTION: Massive bleeding is a serious complication associated with impaired survival after surgery for acute type A aortic dissection (ATAAD). There are no previous reports evaluating the effect of ATAAD and associated surgery on von Willebrand factor (VWF). The aim of the present study was to analyze VWF activity (VWF:GPIbM) and thus the potential of Factor (F) VIII/VWF concentrate as a treatment for refractory bleeding in surgery for acute type A aortic dissection. MATERIAL AND METHODS: We prospectively compared serial measurements of VWF:GPIbM in 25 patients with ATAAD to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. In 10 of the ATAAD patients, high molecular weight multimer distribution was measured. RESULTS: Preoperatively, ATAAD patients demonstrated significantly higher VWF:GPIbM (1.58 (1.40-2.05) kIU/L vs 1.25 (1.02-1.42) kIU/L, p = 0.003). In the ATAAD group, VWF:GPIbM significantly decreased to 1.24 (0.98-1.44) kIU/L at lowest core temperature (T0 vs T1 p < 0.001), but remained unchanged in the elective group (1.25 (1.04-1.43) kIU/L, T0 vs T1 p < 0.625). Neither aortic dissection nor hypothermia caused any changes to the proportion of high molecular weight multimers when compared to control patients. Both groups demonstrated supernormal VWF:GPIbM on the first and fifth day after surgery. CONCLUSIONS: This report showed that patients with acute aortic dissection had increased levels of VWF:GPIbM before surgery that decreased slightly during surgery. Our study could not provide evidence that would encourage administration of FVIII/VWF concentrate for major bleeding in patients undergoing surgery for ATAAD as well as elective aortic procedures.

The Coagulopathy of Acute Type A Aortic Dissection: A Prospective, Observational Study.

OBJECTIVE: To evaluate the hemostatic system in patients undergoing surgery for acute type A aortic dissection (ATAAD) compared with those undergoing elective aortic procedures. DESIGN: This was a prospective, observational study. SETTING: The study was performed at a single university hospital. PARTICIPANTS: Twenty-five patients with ATAAD were compared with 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Platelet count and levels of fibrinogen, D-dimer, prothrombin time/international normalized ratio, activated partial thromboplastin time, and antithrombin were analyzed perioperatively and compared between the 2 groups. Patients with ATAAD had lower preoperative levels of platelets (188 [156-217] × 109/L v 221 [196-240] × 109/L; p = 0.018), fibrinogen (1.9 [1.6-2.4] g/L v 2.8 [2.2-3.0] g/L; p = 0.003), and antithrombin (0.81 [0.73-0.94] kIU/L v 0.96 [0.92-1.00] kIU/L; p = 0.003) and significantly higher levels of D-dimer (2.9 [1.7-9.7] mg/L v 0.1 [0.1-0.2] mg/L; p < 0.001) and prothrombin time/international normalized ratio (1.15 [1.1-1.2] v 1.0 [0.93-1.0]; p = 0.001). Surgery caused significant changes of the coagulation system in both groups. Intraoperative bleeding volumes were larger in the ATAAD group (2,407 [1,804-3,209] mL v 1,212 [917-1,920] mL; p < 0.001), and patients undergoing ATAAD surgery received significantly more transfusions of red blood cells (2.5 [0.25-4.75] U v 0 [0-2.75] U; p = 0.022), platelets (4 [3.25-6] U v 2 [2-4] U; p = 0.002), and plasma (2 [0-4] U v 0 [0-0] U; p = 0.004) compared with the elective group. CONCLUSIONS: This study demonstrates that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients, but also in patients undergoing elective surgery of the ascending aorta or the aortic root.