This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart ...Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.
Light plays a critical role in the regulation of numerous aspects of physiology and behaviour, including the entrainment of circadian rhythms and the regulation of sleep. These responses involve ...melanopsin (OPN4)-expressing photosensitive retinal ganglion cells (pRGCs) in addition to rods and cones. Nocturnal light exposure in rodents has been shown to result in rapid sleep induction, in which melanopsin plays a key role. However, studies have also shown that light exposure can result in elevated corticosterone, a response that is not compatible with sleep. To investigate these contradictory findings and to dissect the relative contribution of pRGCs and rods/cones, we assessed the effects of light of different wavelengths on behaviourally defined sleep. Here, we show that blue light (470 nm) causes behavioural arousal, elevating corticosterone and delaying sleep onset. By contrast, green light (530 nm) produces rapid sleep induction. Compared to wildtype mice, these responses are altered in melanopsin-deficient mice (Opn4-/-), resulting in enhanced sleep in response to blue light but delayed sleep induction in response to green or white light. We go on to show that blue light evokes higher Fos induction in the SCN compared to the sleep-promoting ventrolateral preoptic area (VLPO), whereas green light produced greater responses in the VLPO. Collectively, our data demonstrates that nocturnal light exposure can have either an arousal- or sleep-promoting effect, and that these responses are melanopsin-mediated via different neural pathways with different spectral sensitivities. These findings raise important questions relating to how artificial light may alter behaviour in both the work and domestic setting.
Field theoretic simulations are used to predict the equilibrium phase diagram of symmetric blends of AB diblock copolymer with A- and B-type homopolymers. Experiments generally observe a channel of ...bicontinuous microemulsion (BμE) separating the ordered lamellar (LAM) phase from coexisting homopolymer-rich (A+B) phases. However, our simulations find that the channel is unstable with respect to macrophase separation, in particular, A+B+BμE coexistence at high T and A+B+LAM coexistence at low T. The preference for three-phase coexistence is attributed to a weak attractive interaction between diblock monolayers.
Retinal photoreceptors entrain the circadian system to the solar day. This photic resetting involves cAMP response element binding protein (CREB)-mediated upregulation of Per genes within individual ...cells of the suprachiasmatic nuclei (SCN). Our detailed understanding of this pathway is poor, and it remains unclear why entrainment to a new time zone takes several days. By analyzing the light-regulated transcriptome of the SCN, we have identified a key role for salt inducible kinase 1 (SIK1) and CREB-regulated transcription coactivator 1 (CRTC1) in clock re-setting. An entrainment stimulus causes CRTC1 to coactivate CREB, inducing the expression of Per1 and Sik1. SIK1 then inhibits further shifts of the clock by phosphorylation and deactivation of CRTC1. Knockdown of Sik1 within the SCN results in increased behavioral phase shifts and rapid re-entrainment following experimental jet lag. Thus SIK1 provides negative feedback, acting to suppress the effects of light on the clock. This pathway provides a potential target for the regulation of circadian rhythms.
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•Nocturnal light induces widespread transcriptional changes in the SCN•The CRTC1-SIK1 cascade regulates entrainment of the circadian clock•Negative feedback by SIK1 limits the effects of light on the clock•Homeostatic regulation of entrainment ensures gradual adaptation to a new time zone
A negative-feedback loop involving the kinase SIK1 and the transcriptional coactivator CRTC1 delays re-entrainment of the circadian clock to new time zones, causing jet lag. Remarkably, inhibition of SIK1 allows rapid re-entrainment after an experimental jet lag protocol in mice.
The angiosome is a three-dimensional block of tissue supplied by a source vessel with its boundary outlined either by an anastomotic perimeter of reduced-caliber choke vessels or by true anastomoses ...with no reduction of vessel caliber. This article focuses on the role of these anastomotic vessels in defining flap survival or the necrotic pattern seen in fulminating meningococcal septicemia.
Experiments in pigs, dogs, guinea pigs, and rabbits over the past 46 years were reviewed, focusing on the necrosis line of flaps, the effects of various toxins in vivo, and correlating these results in the clinical setting.
Experimentally, choke anastomoses are functional and control flow between perforator angiosomes. They (1) permit capture of an adjacent angiosome when the flap is raised on a cutaneous perforator in 100 percent of cases, with the necrosis line occurring usually in the next interperforator connection; (2) confine flow to the territory of the involved artery when a toxin is introduced by spasm around its perimeter; and (3) lose this property of spasm when choke vessels are converted to true anastomoses following surgical delay, or where true anastomoses occur naturally, thereby allowing unimpeded blood flow and capture of additional angiosome territories. Clinical experience supports these observations.
The functional angiosome is the volume of tissue that clinically can be isolated on a source vessel. The area extends beyond its anatomical territory to capture an adjacent territory if connections are by choke anastomoses, or more if they are by true anastomoses.
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, ...implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
Recent field-theoretic simulations of symmetric ternary blends of A- and B-type homopolymers with AB diblock copolymer Vorselaars, B. ; Phys. Rev. Lett., 2020, 125, 117801predicted three-phase ...coexistence between bicontinuous microemulsion (BμE) and two homopolymer-rich phases. The present study begins by repeating their grand-canonical simulations over longer durations in simulation boxes of different sizes to ensure that the prediction was not an artifact of nonequilibrium effects or finite system sizes. The coexistence is then demonstrated in canonical simulations, where the three phases are explicitly separated by interfaces. From those simulations, we extract the interfacial widths, the interfacial tensions, the domain size in the BμE phase, and the copolymer concentration in each phase. The latter results are used to improve the accuracy of the previous phase diagram.
The performance of thermoplastic elastomers composed of block copolymers is dependent upon the molecular bridges linking together the discrete minority domains. Here we devise a strategy for ...calculating the bridging statistics for complex block copolymer architectures, using self-consistent field theory. The method is demonstrated on (AB) M stars with M identical diblock arms. The fraction of molecules forming bridges, νb, is found to increase rapidly with M to values well beyond that of conventional ABA triblock copolymers. Once M is of order 10, virtually all molecules form bridges, and furthermore their arms tend to be distributed equally among neighboring minority domains. These high bridging fractions combined with the tendency of single molecules to bridge multiple domains make diblock-arm stars an excellent candidate for improved thermoplastic elastomers.
We reexamine off-lattice Monte Carlo simulations for athermal blends of stiff and flexible polymers next to a hard wall. The original simulations Kumar et al. J. Chem. Phys. 1995, 103, 10332, which ...were supported by wall-PRISM calculations, predicted a short-range preference for the stiff polymers at the wall, which contradicts experiments as well as alternative calculations. On this basis, Kumar et al. asserted that the true entropic preference in the experiments was masked by enthalpic interactions and that the other calculations were incorrect because they did not account for local packing effects at the wall. However, with vastly improved equilibration and statistics, we now find that the simulations actually predict a long-range surface preference for the flexible polymers, which resolves a controversy that has existed for over 25 years. Furthermore, we show that the excess of flexible polymer adopts a universal concentration profile, as predicted by mean-field theory Wu et al. J. Chem. Phys. 1996, 104, 6387.
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