Homology-a similar trait shared by different species and derived from common ancestry, such as a seal's fin and a bird's wing-is one of the most fundamental yet challenging concepts in evolutionary ...biology. This groundbreaking book provides the first mechanistically based theory of what homology is and how it arises in evolution.
Günter Wagner, one of the preeminent researchers in the field, argues that homology, or character identity, can be explained through the historical continuity of character identity networks-that is, the gene regulatory networks that enable differential gene expression. He shows how character identity is independent of the form and function of the character itself because the same network can activate different effector genes and thus control the development of different shapes, sizes, and qualities of the character. Demonstrating how this theoretical model can provide a foundation for understanding the evolutionary origin of novel characters, Wagner applies it to the origin and evolution of specific systems, such as cell types; skin, hair, and feathers; limbs and digits; and flowers.
The first major synthesis of homology to be published in decades,Homology, Genes, and Evolutionary Innovationreveals how a mechanistically based theory can serve as a unifying concept for any branch of science concerned with the structure and development of organisms, and how it can help explain major transitions in evolution and broad patterns of biological diversity.
Hereditary angioedema (HAE) is a rare genetic disorder with substantial morbidity and mortality. Despite expanded choices for effective acute treatment, prophylactic options are more limited. ...Intravenous C1 esterase inhibitor (C1-INHIV) is licensed and used to prevent HAE symptoms.
To better understand patient experiences with using C1-INH(IV), including level of satisfaction and types and frequency of complications.
Fifty adult members (≥18 years of age) of the US HAE Association who had HAE type I or II completed a self-administered internet survey. Eligible participants were experiencing at least 1 HAE attack per month and must have been receiving treatment with C1-INH(IV) as prophylaxis or acute therapy.
Almost all respondents (n = 47; 94%) were using C1-INH(IV) for HAE prophylaxis. Most patients reported administration of C1-INH(IV) through a peripheral vein (n = 34) and 19 were currently (n = 17) or previously (n = 2) using a central venous port. Most respondents (62%) who used a peripheral vein to administer treatment reported having difficulty finding a usable vein or getting the infusion to work properly at least some of the time. Issues accessing veins, exhausted veins, and frequency of attacks were the main reasons physicians recommended ports to respondents. Although ports allow easier administration of therapy, 47% of respondents with ports experienced problems such as occlusion, thrombosis, and infection. Respondents using C1-INH prophylaxis reported a mean of 2.3 attacks per month during the previous 6 months.
The survey results identified clinical challenges with IV HAE medication use, including venous access issues and ongoing monthly attack occurrence despite prophylactic C1-INH(IV) administration.
Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that ...encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.
Niemann‐Pick disease Types A and B (NPA/B) are autosomal recessive disorders caused by variants in the sphingomyelin phosphodiesterase‐1 (SMPD1) gene. This study aimed to describe and characterize a ...cohort of 118 patients diagnosed with NPA/B based on clinical, biochemical, and molecular findings, and to identify sound correlations between laboratory findings and clinical presentations. Decreased peripheral leukocyte acid sphingomyelinase activity levels and increased plasma 7‐ketocholesterol levels were significantly correlated with disease onset and severity of the clinical course. We identified 92 different sequence SMPD1 variants, including 41 novel variants, in 118 NPA/B patients (19 NPA, 24 intermediate type, 75 NPB). The most prevalent mutation was p.Arg602His, which accounted for 9.3% of the alleles. Patients homozygous for p.Arg602His or p.Asn522Ser showed a late‐onset form of the NPB phenotype. The homozygous SMPD1 variant p.Tyr500His correlated with the early‐onset NPB clinical form. Additionally, homozygous variants p.His284SerfsX18, p.Phe465Ser, and p.Ser486Arg were associated with the neuronopathic NPA clinical form. The homozygous variant p.Arg3AlafsX74 was associated with the intermediate clinical form. Our study contributes to the understanding of the natural history of NPA/B and assists in the development of efficacious treatments for patients afflicted with this devastating lysosomal storage disorder.
Graphical
Decreased peripheral leukocyte ASM activity levels and increased plasma 7‐ketocholesterol levels showed significant correlations with disease onset and severity of the clinical course.
We present the first installment of a massive spectroscopic survey of Galactic O stars, based on new, high signal-to-noise ratio, R ~ 2500 digital observations from both hemispheres selected from the ...Galactic O-Star Catalog of Maiz Apellaniz et al. and Sota et al. The spectral classification system is rediscussed and a new atlas is presented, which supersedes previous versions. Extensive sequences of exceptional objects are given, including types Ofc, ON/OC, Onfp, Of?p, Oe, and double-lined spectroscopic binaries. The remaining normal spectra bring this first sample to 184 stars, which is close to complete to B = 8 and north of Delta *d = --20? and includes all of the northern objects in Maiz Apellaniz et al. that are still classified as O stars. The systematic and random accuracies of these classifications are substantially higher than previously attainable, because of the quality, quantity, and homogeneity of the data and analysis procedures. These results will enhance subsequent investigations in Galactic astronomy and stellar astrophysics. In the future, we will publish the rest of the survey, beginning with a second paper that will include most of the southern stars in Maiz Apellaniz et al.
Weather types (WTs) are common atmospheric patterns that shape weather and climate characteristics. While an improved understanding of WTs can provide insights into seasonal predictions, few studies ...have investigated WT transitions and their impacts on temperature and precipitation across the continental United States (U.S.). This study focuses on 23 WT scenarios, involving five weather type classifications evaluated over the years 1979–2018 derived from 500-hPa geopotential height anomaly. There are five persistent WT scenarios with the same WT on back-to-back days and 18 non-persistent transition scenarios. Two additional non-persistent scenarios had no occurrences during this time. Persistent WT/non-persistent transition scenarios account for ~ 70%/30% of total transition cases, respectively. The weather regime transitions exhibit distinct impacts on temperature and precipitation across the U.S. The impacts of WT transitions on precipitation can be explained by changes in moisture flux and vertical pressure velocity. WT transitions show strong seasonality, with stronger impacts in winter months than summer months, leading to larger temperature and precipitation anomalies. Persistent scenarios of WT transitions account for the vast majority of transition cases and contribute more to individual WT trends. Our results suggest WT transitions play a crucial role in modulating temperature and precipitation anomalies. An improved understanding of WT transitions sets the stage for improving seasonal to sub-seasonal forecasts of the U.S. climate.
Summary
The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme ...system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1‐INH) deficiency. C1‐INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1‐INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.
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