bluuebunny/crossref_metadata_2025 huggingface dataset:
Sickle Cell A Disease of Molecules and a Disease of Race
Authors: Shaiova Lauren , Blinderman Craig , Brookoff Daniel
Published: November 2023

It is a sad and shameful fact that ... this disease has been largely neglected throughout our history. We can’t re-write this record of neglect but we can reverse it. —President Richard M. Nixon, 1971, discussing sickle cell disease in a televised speech to the nation. Many credit this speech with triggering a burst of interest in sickle cell disease across the nation and prompting congressional passage of the National Sickle Cell Control Act, which greatly increased funding for research, community service and education about sickle cell disease (Scott, 1983).
Global Gene Expression Assays: Quantitative Noise Analysis
Authors: Held G A , Stolovitzky Gustavo , Tu Yuhai
Published: November 2023

The last decade has witnessed a shift in molecular biology from methods that probe hypotheses a few molecules at a time toward whole genome measurements. Global gene expression assays have enabled the monitoring of the transcription levels of tens of thousands of genes simultaneously [1–3]. In the near future, it will be possible to profile all of the nonrepetitive sequences in the genomes of higher organisms [4], including H. sapiens, with only a few DNA gene chips. This will allow one to obtain a global view of the transcriptomes corresponding to different cell phenotypes. Such capability will greatly accelerate and perhaps fundamentally change biomedical research and development in many areas, ranging from developing advanced diagnostics to unraveling complex biological pathways and networks, to eventually facilitating individual-based medicine [1,2]. Interestingly, the power of global gene expression assays brings along its own drawbacks—useful information is typically measured amidst high levels of noise. In general, the changes in the measured transcript values between different experiments are due to both biological variations (corresponding to real differences between different cell types and tissues) and experimental noise. To correctly interpret this data, it is crucial to understand the sources of the experimental noise. As will be demonstrated, systematic study of the noise in such data enables one to assign a meaningful statistical significance to observed transcriptional changes. In addition, understanding the sources of noise provides a useful guide in attempting to improve the technologies.
Mapping the Genotype–Phenotype Relationship in Cellular Signaling Networks: Building Bridges Over the Unknown
Authors: Papin Jason A , Gianchandani Erwin P , Subramaniam Shankar
Published: November 2023

The central challenge in postgenomic biology is the mapping of the genotype–phenotype relationship. For cellular signaling networks, the functional connections between genotype and phenotype are deciphered through an ever-growing toolbox of high-throughput experimental technologies. Each technology can be used to generate a vast amount of data particular to some aspect of a given cellular signaling network. However, despite this growing experimental toolbox and the associated repositories of data, there remains the challenge to connect these disparate data points to reconstruct the continuum from genotype to phenotype. Cellular signaling network functions can be discretized into three tiers (see figure 5.1). The first tier involves the transcriptional activity of a genome. The proteins that result from the transcription and translation of genes orchestrate the responses to a signaling event. The second tier is composed of the chemical transformations in which these proteins are involved. This set of chemical reactions and cellular events are here called “intermediate phenotypes.” The third tier is composed of the subsequent cellular behaviors that are a function of the given genotype and collection of intermediate phenotypes.
Biophysical Models of the Cardiovascular System
Authors: Winslow Raimond L , Greenstein Joseph. L , Helm Patrick A
Published: November 2023

Cardiac electrophysiology is a field with an extensive history of integrative modeling that is closely coupled with both the design and interpretation of experiments. The first models of the cardiac action potential (AP) were developed shortly after the Hodgkin–Huxley model of the squid AP, and were formulated in order to explain the experimental observation that, unlike the neuronal AP, cardiac APs exhibit a long duration plateau phase. It was not long after the formulation of these early myocyte models that initial models of electrical conduction in cardiac tissue were formulated and applied to yield clinically useful insights into mechanisms of arrhythmia. This close interplay between experiment and integrative modeling continues today, with new model components and applications being developed in close coordination with the emergence of new subcellular, cellular, and whole-heart data describing cardiac function in health and disease. This chapter reviews the current state of integrative modeling of the heart, focusing on three topics: (a) review of the anatomical and biophysical properties of cardiac muscle cells and how key processes may be modeled; (b) use of diffusion tensor magnetic resonance imaging for rapid acquisition of geometric and microanatomic data on cardiac ventricular structure at high spatial resolution; and (c) the integration of cellular models with this imaging to formulate computational models of cardiac ventricular electrical conduction.
Shotgun Fragment Assembly
Authors: Sutton Granger , Dew Ian
Published: November 2023

From a computational standpoint, a genome (or DNA target sequence) can be viewed as a string, or small set of strings, constructed from the alphabet {A,C,G,T}. The shotgun fragment assembly problem is to reconstruct the DNA target sequence as completely and accurately as possible given a set of randomly selected substrings. In practice these substrings, referred to as reads or fragments, are sequenced from multiple copies of larger substrings called clones. A carefully controlled random shearing process is applied to the DNA target sequence to produce libraries of clones whose lengths are approximately normally distributed and at least one order of magnitude shorter than the target sequence (see figure 3.1). The core challenge of the fragment assembly problem is to identify fragments that share some subsequence of the target sequence and merge them together. Consequently, a fundamental determination must be made for each pair of fragments, which is whether they share a subsequence of the target sequence. If they do, the fragments are said to overlap or have an overlap.
Complete Prokaryotic Genomes: Reading and Comprehension
Authors: Galperin Michael Y , Koonin Eugene V
Published: November 2023

The windfall of complete genomic sequences in the past ten years has dramatically changed the face of biology, which has started to lose its purely descriptive character. Instead, biology is gradually becoming a quantitative discipline that deals with firmly established numerical values and can be realistically described by mathematical models. Indeed, we now know that, for example, the bacteriumMycoplasma genitalium has a single chromosome which consists of 580,074 base pairs and carries genes for three ribosomal RNAs (5S, 16S, and 23S), 36 tRNAs, and 478 proteins [1,2]. We also know that about a hundred of the protein-coding genes can be disrupted without impairing the ability of this bacterium to grow on a synthetic peptide-rich broth containing the necessary nutrients [3], suggesting that the truly minimal gene set necessary for the cell life might be even smaller, in the 300–350 gene range [4–6]. Furthermore, we know that the cell ofAquifex aeolicus with its 1521 protein-coding genes is capable of autonomous, autotrophic existence in the environment, requiring for growth only hydrogen, oxygen, carbon dioxide, and mineral salts [7]. These observations bring us to the brink of finally answering the 60-year-old question posed by Erwin Schrödinger’s “What is Life?” Furthermore, although the descriptions of greatly degraded organelle-like cells likeBuchnera aphidicola[8,9] and giant cell-like mimiviruses [10] necessarily complicate the picture, analysis of these genomes allows an even better understanding of what is necessary and what is dispensable for cellular life.
Artistic Leadership
Authors: Wittry Diane
Published: November 2023

Leadership requires two things: someone to lead and someone to follow. Just be- cause you want to be a leader and think that you have good ideas does not mean that anyone will automatically follow you. The art of leadership is an art of per- suasion. All great leaders know where they are going and they are able to persuade others to follow them. They can do this through two different types of leadership power: the power of position, or the power of trust.

Unfortunately, examples of this type of leadership are still present in our field, and some conductors are taught early on that this is the means to their greatness. Although this type of leadership has worked in the past, due to the restructuring of unions and the structure of most orchestras’ administrative staffs, this is no longer a viable way to move one’s career, or an organization, forward.
Congruence and the Good of Justice
Authors: Freeman Samuel
Published: November 2023

One of Rawls’s guiding aims in the development and revision of his work has been to show how a well-ordered society of justice as fairness is realistically possible. Rawls thinks establishing the “stability” of a conception of justice and the enduring feasibility of a society patterned upon it is essential to justifying a conception of justice. My aim is to discuss the role and import of Rawls’s stability argument. To do so, I will concentrate primarily on the second part of Rawls’s discussion of stability in Theory of Justice, the argument for the “congruence of the right and the good.”1 This argument particularly exhibits Rawls’s indebtedness to Kant in the justification of his view. After discussing the purpose of congruence (in secs. I and II), I outline in detail what the argument is (secs. III and IV), emphasizing the role of the Kantian interpretation of justice as fairness. Then (in sec. V), I discuss how problems with the Kantian congruence argument led Rawls to political liberalism.
Political Liberalism and the Possibility of a Just Democratic Constitution
Authors: Freeman Samuel
Published: November 2023

Introduction

My aim in this paper is to provide an overview of John Rawls’s project in Political Liberalism.1 I sketch how this book is designed to respond to certain problems internal to Rawls’s argument in A Theory of Justice.2 Political Liberalism is a development and extension of Rawls’s original project, as stated in A Theory of Justice, to work out “the most appropriate moral basis for a democratic society” (TJ, viii/ xviii rev.). A Theory of Justice itself invokes assumptions and arguments that are at odds with Rawls’s egalitarian liberalism. It is to respond to these internal tensions that Rawls recasts not the substantive content of justice as fairness or its principles but how we are to conceive of their justification.

To say this recasting is internal to Rawls’s original project means that Political Liberalism is not motivated by external criticisms.3 There is a widespread perception that the revisions Rawls has made to A Theory of Justice leading up to Political Liberalism have come largely in response to communitarian criticisms.4
Distributive Justice and the Law of Peoples
Authors: Freeman Samuel
Published: November 2023

I. Introduction: Justice and the Division of Institutional Labor

In A Theory of Justice, Rawls says that the distribution of income and wealth within a society is just when laws and economic institutions are designed so as to maximally benefit the least advantaged members of that same society.1 This standard for domestic distributive justice is to apply worldwide, to determine just distributions in every society in the world. In this regard, Rawls has an account of global distributive justice. But he does not have, and he does not endorse, a global distribution principle. The difference principle applies globally, within each society, but it is not global in reach.

Neither Political Liberalism nor The Law of Peoples retracts or alters this position. The primary focus of political liberalism is not ideal justice but liberal legitimacy. It implies that laws regulating distributions in a democratic society can be legitimate, hence, worthy of respect, even if they are not wholly just.2 Unlike the basic liberties and their priority, the difference principle is not required by liberal legitimacy; for legitimacy, it suffices that a liberal society provide an adequate social minimum (adequate to enable free and equal persons to realize the moral powers and effectively exercise equal basic liberties). The difference principle is one among several standards that satisfy the legitimacy test, all of which meet the criterion of reciprocity and the requirements of public reason.
Two Alternate Conclusions to The Curse of Caste
Authors: Collins Julia C
Published: November 2023

After her tearful but joyous reunion with her father, Claire learns from him that her mother was a noble, refined, and pure woman, as Claire had always hoped would be true. Although the story of her mother’s death moves Claire deeply, she is inspired by the knowledge that Lina Tracy was a loyal and faithful wife. When her father tells her about her mother’s enslavement and African American heritage, Claire is shocked to think that such an injustice could occur, but she is not horrified at the realization that she too is mixed race. The “darkly beautiful” Claire reveals to her father that even in girlhood, her color had given her intimations of a difference from other children, that Juno, her nurse, never tried to deny. Arriving at the Tracys’ New Orleans estate and finding herself to be “an object of curiosity even to the negroes,” Claire could not help but ponder her mysterious origins of “poverty and misfortune.”
The Essays of Julia C. Collins, 1864–1865
Authors: Collins Julia C
Published: November 2023

It is a faulty and indolent humility that makes some of our people sit still and learn nothing, because they cannot learn everything. We are born with faculties and power, capable of almost anything. Who can measure our capacity, or set bounds to our progression in knowledge? Destitute alike of knowledge, the children of the white race have, in this respect, no advantage over the black; both have everything to learn. All must begin with the simplest elements of knowledge, and advance from step to step, in nearly the same manner. Much time and skill are requisite to mould the mind in strength and beauty, by proper exercise of its faculties. The mind is formed, gradually expanded and strengthened into vigorous action. We must subject ourselves to severe, and sometimes painful discipline, for this very exercise will enrich and embellish the mind with new and important ideas. We must feel that there is nothing too hard for industry and perseverance to accomplish. We must scale the rugged hill of science, by dint of powerful effort and great self-reliance, and at last reward ourselves by drinking at the richest streams of science and literature.
The Moral Significance of Early Human Embryos in Religious Thought
Authors: Cohen Cynthia B
Published: November 2023

In a pluralistic democratic society such as that in the United States, no exploration of the moral significance of early human embryos would be complete it if were to consider only secular views of this matter. The views of those who adhere to religious traditions within that polity also need to be taken into account if we are to gain a more complete picture of the reasoning of many citizens about contentious issues as we develop public policy. That is especially the case today, when the views of active and influential religious adherents about whether stem cells derived from human embryos should be used in research have been playing a prominent role in public policy decisions about this research.
Sleep In The Medical Disorders
Authors: Lee-Chiong Teofilo
Published: November 2023

Many medical disorders can give rise to disturbances of sleep and alter sleep architecture. Sleep can be impaired by the medical conditions themselves or by the medications used to treat them. Several symptoms associated with medical disorders, such as pain, dyspnea, nocturia, and pruritus can potentially disturb sleep, with the severity of sleep complaints waxing and waning in relation to the course of the medical illness. More than one sleep pathology may be present in a particular patient. The sleep disturbance causes distress and functional impairment, and requires independent clinical management. Conversely, sleep impairment can alter the presentation and adversely affect the symptoms of a variety of medical conditions, including respiratory, cardiac, gastrointestinal, renal, rheumatologic and infectious disorders.

Asthma is a disease characterized by episodic dyspnea and wheezing, reversible episodes of bronchoconstriction, and airway hyperreactivity to a variety of specific and nonspecific stimuli.

Sleep disturbance in patients with asthma can result in complaints of insomnia (including early morning awakenings) or excessive sleepiness. In one study, three of every four asthmatics reported nocturnal awakenings occurring at least once weekly, whereas two-thirds had nocturnal awakenings at least three times a week. Sleep in patients with nocturnal asthma is characterized by poor sleep quality with frequent arousals. They may awaken repeatedly due to coughing, dyspnea, wheezing, and chest discomfort. Complaints of insomnia and/or excessive daytime sleepiness are not infrequent.
Sleep in Neurologic Disorders
Authors: Lee-Chiong Teofilo
Published: November 2023

Alzheimer disease is the most common degenerative disorder of the central nervous system that causes dementia. Fragmentation and repetitive arousals/awakenings characterize the sleep of persons with dementia. Confusion, agitation, and wandering can occur at night (“sun downing”), further contributing to sleep disruption (Box 10–1). Sleep complaints may be due primarily to the underlying dementia or to related sleep-disordered breathing, periodic limb movements of sleep, or secondary depression. Reversal of the sleep-wake rhythms can be seen with patients complaining of nocturnal insomnia and excessive daytime sleepiness. Polysomnography may demonstrate decreases in rapid eye movement (REM) sleep time and REM density. Sleep efficiency is reduced.

Management includes proper sleep hygiene practices (eg, avoiding caffeine, maintaining a regular sleep schedule, and eliminating daytime naps), and treatment of concurrent depression and medical disorders, including pain syndromes, that might contribute to sleep disturbance. Short-term use of hypnotics, such as zolpidem, zaleplon, or eszopiclone, may be tried for insomnia.
Psychiatric and Behavioral Disorders
Authors: Lee-Chiong Teofilo
Published: November 2023

Acomplicated interface exists between psychiatric and sleep disorders—psychiatric symptoms are amplified and aggravated by sleep disruption, and the pathology of psychiatric disorders may contribute to worsening sleep quality. In addition, persons with insomnia are at higher risk of developing a new psychiatric disorder, particularly major depression, within a year of the onset of insomnia.

Psychiatric disorders can give rise to insomnia, excessive sleepiness, or parasomnias (eg, nightmares or sleep terrors) (Boxes 11–1 and 11–2).. It has been estimated that a third to a half of cases of chronic insomnia are associated with a psychiatric condition. Changes in sleep architecture include a decrease in rapid eye movement (REM) sleep latency that is seen with depressive episodes, schizophrenia, and borderline personality disorder.

Schizophrenia (psychosis) is a chronic psychiatric disorder characterized by both “positive symptoms” (eg, hallucinations, delusions, and disorganized speech and behavior) and “negative symptoms” (eg, affective flattening, avolition [limited goal-directed behavior], and alogia [restricted thought and speech production]). This disabling condition has a median age of onset between 15 and 25 years of age. Course is chronic with significant impairments in self-care, interpersonal interactions, and work performance.
First Steps
Authors: Shuy Roger W
Published: November 2023

As obvious as this may sound, somehow the fact that one first has to become a linguist seems to get lost on some aspiring forensic linguists. There’s no need to try to apply linguistics to any other area of life before you’ve first learned what it is that you have to apply.
Doing Business
Authors: Shuy Roger W
Published: November 2023

So the phone finally rings, and the lawyer on the other end asks you to work on a case. You’ll need to take a few precautions before leaping into it. Beware of calls from the clients themselves, however, because it is always better (and safer) to work with their attorneys.
Being Deposed
Authors: Shuy Roger W
Published: November 2023

After the report is submitted, American linguistic expert witnesses can expect to be deposed by the other side, whose lawyers will go through each point with a finetoothed comb. (The deposition does not exist in the United Kingdom, where experts can be questioned at trial about their written reports.) The U.S. deposition is structured so that the opposing lawyers can try to find out (discover) what you will say at trial and to provide a record of your work that can be addressed if you do testify. Their third agenda is to discover what kind of witness you’ll be, whether you can be rattled, how well you handle tough questions, and how the jury or judge may regard you as an expert. The deposition is taken under oath and is usually held in the office of the opposing attorney. The attorney you work with will be there to object whenever necessary. Depositions are recorded by a court reporter, often with an accompanying videotape recording.
Giving Testimony in the Direct Examination
Authors: Shuy Roger W
Published: November 2023

Most civil and criminal cases never go to trial. It is estimated, in fact, that some 90 percent of criminal and criminal cases end before any testimony has to be given. Criminal cases can end with a plea of guilty, a negotiated plea agreement, or a dismissal of charges. Civil cases are often settled with agreements by both parties, often involving the exchange of sums of money. My own experience bears this out. I have testified in only 10 percent of all the cases I’ve worked on over the past 30 years.
Muscle and Somite Development
Authors: anderson Douglas , Rhee, jerry m. , rawls alan
Published: November 2023

Vertebrate skeletal muscle is derived from paraxial and head mesoderm that appears on either side of the neural tube during gastrulation. A fundamental understanding of the cellular events associated with myogenesis has been well established through classic embryological studies in the chicken and mouse model systems. The 7rst appearance of myogenic cells is within individual somites derived from paraxial mesoderm. During embryonic development, these cells must undergo rapid expansion, migration, differentiation, and remodeling in order to generate the morphologically and functionally diverse perinatal muscles groups. Myogenic cells must also respond to spatial and temporal cues that lead to differences in cell fate along the anterior/posterior (A/P) and dorsal/ventral (D/V) axes. In addition, development of the skeletal muscle must be coordinated with the development of bone and cartilage, tendon, the peripheral nerves, and vasculature. During the past 15 years, gain-of-function and loss-of-function approaches have been used to reveal the complex genetic network that integrates these processes. In this chapter, we will review the embryonic development of somites and muscle and focus on our current understanding of the genetic regulation of somitogenesis and skeletal muscle development.
IHH and Acrocapitofemoral Dysplasia and Brachydactyly A1
Authors: Hellemans Jan , Mortier Geert R
Published: November 2023

The 7rst steps in skeletal morphogenesis involve the induction of undifferentiated mesenchyme and its differentiation into condensed mesenchyme. In the human skeleton, only the membranous bones of the skull and part of the clavicle are formed by direct ossi7cation of condensed mesenchyme (intramembranous ossi7cation). For the large majority of bones, bone formation and growth proceed through an intermediate cartilaginous template or anlage in a process called endochondral ossi7cation. These cartilaginous models are formed by further differentiation of condensed mesenchymal cells into chondrocytes that produce hyaline cartilage instead of mesenchymal matrix. In the center of these cartilaginous templates, chondrocytes will form columns of proliferating cells and subsequently enlarge to become hypertrophic chondrocytes, producing type X collagen. In parallel with the cellular differentiation, the extracellular cartilage matrix will be altered through the actions of carbonic anhydrase and alkaline phosphatase. Finally, the hypertrophic chondrocytes disintegrate and die with simultaneous calci7cation of the modi7ed matrix. The newly formed spaces with calci7ed cartilage are invaded by periosteal blood vessels and osteogenic cells, which soon differentiate into osteoblasts. The latter deposit a bony matrix on the calci7ed cartilage, resulting in the formation of the primary center of ossi7cation. This ossi7cation center is formed within the central portion of the cartilage template and will expand both proximally and distally toward the ends (epiphyses) of the developing bone. Also, secondary ossi7cation centers start appearing in the epiphyseal regions. As these ossi7cation centers enlarge, they replace almost all the cartilage by bone except, 7rstly, for a layer of specialized hyaline cartilage at the joint surfaces (articular cartilage) and, secondly, a thicker zone between the diaphysis and the epiphysis, representing the growth plate.
An Introduction to TGF-J3-related Signaling
Authors: Descotte Veronica , O’connor, Michael B , Jadrich Joy
Published: November 2023

Members of the transforming growth factor-β (TGF-β) superfamily of secreted polypeptides play diverse roles in regulating numerous biological processes in a wide variety of organisms. These factors have been implicated in mediating embryonic development, cell proliferation and differentiation, apoptosis, organogenesis, and wound healing; and when misregulated, they can contribute to the etiology of disease. Phylogenetic considerations suggest that this family is one of the oldest signaling pathways, having arisen before the divergence of a common ancestor of arthropods and vertebrates approximately 1.3 billion years ago (Newfeld et al., 1999). In this chapter, we will provide an overview of the signal-transduction pathway utilized by these factors and the mechanisms by which the activities of these pathways are regulated. Much of our understanding of the biology of these factors derives from a multidisciplinary experimental approach using biochemical, genetic, and embryological methods as well as numerous model systems such as Drosophila, Caenorhabditis elegans, Xenopus, zebrafish, and mice. We will give only selected examples here, and the reader is encouraged to examine other reviews (Shi and Massagué, 2003; Massagué et al., 2005; Moustakas and Heldin, 2005) for supplementary information on specific aspects of the biology of these factors. In addition, other chapters in this volume will focus on various human pathologies and developmental disorders that have been linked to defects in different components of this pathway (see Chapters 32–40).
GDF5 (CDMP1) and Chondrodysplasia (Grebe, Hunter–Thompson, and Du Pan Types), and Brachydactyly, Type C
Authors: Kilpatrick Michael W , Tsipouras Petros
Published: November 2023

The human osteochondrodysplasias comprise a large and heterogeneous group of inherited disorders affecting skeletal morphogenesis. Grebe-type chondrodysplasia (OMIM 200700) is characterized by a normal axial skeleton and severely shortened and deformed extremities exhibiting a proximo-distal gradient of severity. This condition is classi%ed as a form of acromesomelic dysplasia. Two other phenotypically similar conditions are the Hunter–Thompson (OMIM 201250) and Du Pan (OMIM 228900) types of chondrodysplasia. Brachydactyly type C (BTC) (OMIM 113100) is characterized primarily by shortening and hypersegmentation of phalangeal and metacarpal bones, and occasionally polydactyly and other skeletal abnormalities. In contrast to the autosomal recessive Grebe, Hunter– Thompson, and Du Pan types of chondrodysplasia, BTC is inherited as autosomal dominant. These conditions are caused by mutations in the gene encoding growth differentiation factor 5 (GDF5), otherwise known as cartilage-derived morphogenetic protein-1 (CDMP1) (OMIM 601146), and they together comprise the spectrum of CDMP1 morphopathies. CDMP1 encodes a signaling molecule, which is a member of the transforming growth factor-β (TGF-β) superfamily.
ENG, ACVRL1, and SMAD4 and Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)
Authors: Srinivasan Sudha , Berg, Jonathan N , Marchuk Douglas A
Published: November 2023

Hereditary hemorrhagic telangiectasia (HHT) or Osler–Weber–Rendu syndrome is an autosomal-dominant vascular disorder characterized by the presence of focal arteriovenous malformations (AVMs) and telangiectases. AVMs are direct communications between arteries and veins without an intervening capillary bed. Telangiectases are clusters of abnormally dilated thin-walled vessels. Penetrance of HHT is age dependent and nearly complete by age 50. There is a high variability of symptoms among affected individuals even in the same family with respect to the age of onset, severity, and organs affected (reviewed in Guttmacher et al., 1995; Marchuk et al., 2003; Abdalla and Letarte, 2006). Symptoms include recurrent epistaxis (nosebleeds), mucocutaneous telangiectases, and AVMs, particularly in the lung, brain, and liver. The primary symptoms can lead to secondary complications such as high-output cardiac failure and stroke.
RUNX2 and Cleidocranial Dysplasia
Authors: Fonseca Patricia , Lee, Brendan , Napierala Dobrawa
Published: November 2023

Runt-related transcription factor 2 (RUNX2) is a RUNT-domain transcription factor required for osteoblast cell fate commitment and chondrocyte maturation. Hence, it serves as a central regulator of intramembranous and endochondral ossification during embryonic skeletogenesis and during the postnatal development. Runx2 directs the expression of multiple genes, including matrix components of bone and hypertrophic cartilage, and regulates the transition of hypertrophic chondrocytes to primary spongiosa. It acts in a context-dependent fashion, specified by both upstream transcriptional regulators of Runx2 expression and direct protein–protein interactions regulating its transactivation of target genes. Haploinsufficiency of RUNX2 in humans causes a dominantly inherited skeletal disorder: cleidocranial dysplasia (CCD). CCD is characterized by delayed intramembranous ossification and defective chondrocyte maturation in some (but not all) skeletal elements. The classic form of CCD is characterized by the triad of delayed closure of the fontanel, hypoplastic clavicles, and dental anomalies. However, genotype–phenotype studies show that RUNX2 mutations can also result in a range of phenotypes from mild CCD predominated by dental features to severe CCD, complicated by significant osteoporosis. The clinical diagnosis can usually be confirmed by pathognomonic findings from radiographic studies. Management is conservative for the skeletal complications, but the significant morbidity associated with dental anomalies dictates an aggressive multidisciplinary approach. Both in vitro and mouse model studies have identified regulators of RUNX2 function, whereas the description of CCD-related conditions raises interesting questions about the potential relationship of these conditions to components of the RUNX2 transcriptional network.
FLT4 (VEGFR3) and Milroy Disease
Authors: Ferrell Robert E , Finegold David
Published: November 2023

The vascular endothelial growth factor receptor-3 (VEGFR3) is a member of the VEGF receptor family, which binds both vascular endothelial growth factors C and D. VEGFR3 is expressed on lymphatic endothelia, and is required for normal development of the lymphatic system. Mutations in VEGFR1 (now designated FLT4 for fms-related tyrosine kinase 4) have been found to cause Milroy disease, an inherited abnormality of the lymphatic system. This autosomal dominant disorder is characterized by swelling of the extremities, the lower usually being affected to a greater degree than the upper. Imaging studies reveal hypoplasia or aplasia of the lymphatics. The management is symptomatic, currently limited to manual massage and compression. Multiple, independent, nonconservative mutations in the tyrosine kinase domains of VEGFR3 have been identified, which segregate with the lymphedema phenotype in families, and show defective protein kinase activity and altered stability in in vitro expression studies. The Chy mouse, a chemically mutagenized model, demonstrates a comparable mutation in the kinase domain of the mouse homolog of VEGFR3, and the dermal lymphatic phenotype is corrected by VEGFC gene therapy. This and early human studies make VEGFR3 an attractive target for the treatment of human lymphedema.
Signaling Pathways of Glial Cell–Derived Neurotrophic Factor
Authors: Reichardt Louis F
Published: November 2023

Glial cell–derived neurotrophic factor (GDNF), a distant relative of transforming growth factor-β (TGF-β), was purified as a factor that promotes the survival and differentiation of embryonic mesencephalic dopaminergic neurons (Lin et al., 1993). A closely related protein, neurturin, was purified as a factor that promotes the survival of sympathetic neurons (Kotzbauer et al., 1996). Subsequently, two additional members of the GDNF family of ligands, artemin and persephin, were identified in expressed sequence tag (EST) databases (Baloh et al., 1998; Milbrandt et al., 1998; Masure et al., 1999). Each of these proteins has been shown to function as a survival and differentiation factor for subpopulations of cultured neurons (reviewed in Baloh et al., 2000a; Takahashi, 2001; Sariola and Saarma, 2003).
The PI3K-LKB1 Pathway
Authors: Shaw Reuben J , Cantley lewis C
Published: November 2023

Rrowth control in all metazoans is regulated by a number of conserved signal transduction pathways. These pathways govern the timing and developmental speci>city of cell growth and differentiation in response to external cues including presence and location of growth factors, morphogens, nutrients, and neighboring cells. The phosphoinositol 3-kinase (PI3K) pathway is one of the central signaling pathways governing cell growth, cell survival, and cell migration. Studies in the past few years have revealed that activation of PI3K underlies the development of a large number of human cancers. One of the main downstream targets of PI3K activity is the protein serine/ threonine kinase mTOR (mammalian target of rapamycin). Recent studies have revealed that hyperactivation of mTOR signaling is a common biochemical thread underlying a handful of inherited familial cancer syndromes including those with phosphatase and tensin homolog deleted on chromosome ten (PTEN), TSC1, TSC2, NF1, and LKB1 (STK11) mutations. Here we illuminate what is known about the detailed circuitry of these signaling pathways, and discuss potential points for therapeutic intervention (Fig. 57–1).
PTEN and the Cowden and Bannayan–Riley–Ruvalcaba Syndromes
Authors: Zbuk Kevin M , Eng Charis
Published: November 2023

The PTEN Hamartoma Tumor Syndrome (PHTS) includes not only the entities Cowden Syndrome (CS; MIM 158350) and Bannayan–Riley–Ruvalcaba syndrome (BRRS; MIM 153480), which are the focus of this chapter, but also Proteus syndrome (PS; MIM 176920), and Proteus-like syndrome (PSL), and perhaps other developmental disorders. These heterogeneous groups of disorders are all, to varying degrees, associated with germline mutations of the PTEN [for phosphatase and tensin homolog, deleted on chromosome 10 (ten)] tumor suppressor gene. PTEN, localized to 10q23.3 is a dual specicity phosphatase. Its lipid phosphatase is crucial in down-regulating the Akt pathway through dephosphorylation of phosphoinositol-3,4,5triphosphate (PIP3) thus facilitating G1 cell cycle arrest and/or apoptosis. It’s protein phosphatase down-regulates cyclin D1 and prevents the phosphorylation of mitogen-activated protein kinase (MAPK), playing important roles in inhibition of cell growth and spreading, in addition to mediating, cell cycle arrest. The importance of PTEN localization to different subcellular compartments is increasingly recognized and will undoubtedly offer insight into novel mechanisms of PTEN dysfunction. CS is an underrecognized and underdiagnosed autosomal dominant disorder. Patients with CS are at increased risk of developing breast, thyroid, and endometrial cancers, in addition to benign neoplasias of these same organs, and have characteristic cutaneous manifestations including papillomatous papules and trichilemmomas. BRRS is characterized by macrocephaly, lipomas, hemangiomas, and speckled penis.
The RAS/MAPK Pathway and the Cardio–Facio–Cutaneous Syndrome
Authors: Rauen Katherine A
Published: November 2023

Cardio facio cutaneous (CFC) syndrome (OMIM 115150) is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac defects, ectodermal anomalies, developmental delay, and hypotonia. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterogeneous de novo mutations in protein kinases B-Raf, mitogen-activated protein kinase kinase 1 (MEK1), and mitogenactivated protein kinase kinase 2 (MEK2). Activating mutations in K-Ras have also been implicated in causing CFC syndrome, yet its association has to be determined. CFC syndrome has a distinct phenotype, yet shares many overlapping features with other related Ras pathway syndromes, such as Noonan syndrome and Costello syndrome. CFC has characteristic craniofacial dysmorphia, cardiac anomalies, (pulmonic stenosis, atrial septal defects, and hypertropic cardiomyopathy being the most common) and ectodermal anomalies (sparse, curly hair, scant eyebrows and eyelashes, keratosis pilaris, ichthyosis, and nevi). Other features involve the musculoskeletal, ophthalmologic, gastrointestinal (GI), and lymphatic systems. Hypotonia is a consistent ending, and developmental delay ranges from mild to severe. Many patients have a seizure disorder and abnormal brain imaging. The clinical diagnosis of CFC is based on phenotypic /ndings, with molecular con/rmation of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), MEK1, kristen rat sarcoma viral oncogene homolog (MEK2), or KRAS by direct gene sequencing. Current medical management and therapy requires a multidisciplinary team of health care providers and is based on the symptomatology of the individual. Because the Ras/MAPK pathway has been studied intensively in the context of cancer, numerous therapeutics that speci/cally target this pathway may merit investigation in this population of patients.
HOXD13 and Synpolydactyly
Authors: Goodman Frances R , Scambler Peter J
Published: November 2023

OXD13 (homeobox D13), the most 5” member of the HOXD gene cluster, encodes a highly conserved transcription factor that plays a crucial role in the development of the autopod; but the molecular pathway in which it acts is poorly understood. Little is known about how its expression is regulated, and none of its target genes or transcriptional cofactors has yet been identified. Synpolydactyly (SPD), the first human birth defect found to be caused by mutations in a HOX gene, is a rare, dominantly inherited malformation of the hands and feet, characterized by soft tissue syndactyly between the third and fourth fingers and between the fourth and fifth toes, with variable digit duplication in the syndactylous web. Most cases result from different-sized expansions of a polyalanine tract in HOXD13”s N-terminal region, and both penetrance and phenotypic severity have been shown to correlate positively with expansion size. The mutant protein appears to interfere functionally with both the remaining wild-type HOXD13 and other 5” HOXD proteins expressed in the developing autopod, acting as a “super” dominant-negative protein. A milder atypical form of SPD, characterized by a distinctive foot phenotype, results from a variety of other HOXD13 mutations, all of which are likely to cause functional haploinsufficiency. In addition, two unusual forms of brachydactyly, distinct from SPD but exhibiting overlap with brachydactyly types D and E, result from specific missense mutations in the HOXD13 homeodomain, which alter rather than abolish DNA binding. The abnormalities in these conditions appear to reHect disturbances of patterning and growth both at the early stage of autopod development in undifferentiated mesenchyme and at a later stage in the chondrogenic cells of cartilaginous bone models. These observations suggest that downstream targets of HOXD13 are likely to include genes with important roles in cell sorting/boundary formation and cell cycle control.
EMX2 and HESX1 and Type I Schizencephaly and Septo-Optic Dysplasia
Authors: Kelberman Daniel , Dattani Mehul T
Published: November 2023

The pituitary gland is a central regulator of growth, reproduction, and homeostasis. During embryogenesis, complex molecular pathways are established to define the development of the pituitary. Given the close anatomical and developmental relationship between the forebrain and anterior pituitary any aberration in this process will impinge not only on the development of the anterior pituitary, but also on the development of other structures, particularly other forebrain structures, the developing eye, and the cerebellum. This suggestion has been borne out by descriptions of the genetic basis of syndromes affecting the pituitary, such as septo-optic dysplasia (SOD). Elucidation of the molecular basis of disorders affecting solely the pituitary and syndromes in which the pituitary is but one component can lead to a better understanding of the complex genetic pathways that result in normal patterning of the forebrain and structures such as the anterior pituitary.
PDX1 and Pancreatic Agenesis and Type 2 Diabetes
Authors: Thomas Melissa K , Habener Joel F
Published: November 2023

Pancreas duodenum homeobox-1 (PDX-1) is a pancreas-specific homeodomain transcription factor that regulates embryonic pancreas development, the expression of genes essential for glucose metabolism, and the differentiation, survival, and function of insulin-producing cells in the endocrine pancreas. Expression of PDX-1 is confined primarily to the developing embryonic pancreas and the adult pancreatic β cells, and PDX-1 function is essential for the proper development of both the endocrine and the exocrine pancreas and for normal metabolic function in the adult. Mutations in the PDX-1 gene are associated with multiple metabolic phenotypes in humans.
MSX1 and Partial Anodontia and the Witkop Syndrome
Authors: Boogaard Marie-Jos H Van Den
Published: November 2023

Msx1, isolated by homology to the Drosophila muscle-segment homeobox (msh) gene, is highly conserved; it plays an important role in inductive epithelial–mesenchymal interactions, leading to vertebrate organogenesis, and is involved in cell differentiation. During embryonic development, Msx1 is intensely expressed in the facial primordium and in a variety of embryonic tissues requiring epithelial– mesenchymal interactions for their morphogenesis, such as limb buds and tooth buds.
MSX2 and ALX4 and Craniosynostosis and Defects of Skull Ossification
Authors: Muller Ulrich
Published: November 2023

Mutations in the homeobox gene MSX2 can result in both craniosynostosis (premature fusion of the calvarial sutures) and its opposite, parietal foramina (PFM) (delayed ossification along the sagittal sutures). The one MSX2 mutation (Pro148His) described in craniosynostosis to date results in a gain of gene function due to increased binding to the consensus MSX binding site and the subsequent overstimulation of MSX2 target genes. Conversely, haploinsufficiency of MSX2 is the cause of PFM. Haploinsufficiency of another homeobox gene, ALX4, can also underlie PFM. No mutation has yet been discovered in this gene in craniosynostosis.
SHOX and Dyschondrosteosis and Turner Syndrome
Authors: Ellison Jay w.
Published: November 2023

The story of the short stature homeobox (SHOX) gene is an example of how observations of different clinical disorders can eventually converge on a single gene. The disorders in this case are dyschondrosteosis, a skeletal dysplasia; Turner syndrome, an aneuploid condition resulting from a missing sex chromosome; and idiopathic short stature (ISS). SHOX is implicated in each of these conditions, although its contribution to the phenotypes varies with respect to both level of involvement and level of experimental proof. The predicted nature of the gene product (as a DNA-binding transcriptional regulator), its abundant expression in bone, and the skeletal phenotypes of patients all point to the placement of SHOX in a developmental pathway of bone development. Details of this pathway are largely unknown, though preliminary studies suggest that SHOX may be important for proper chondrocyte differentiation in the relevant skeletal elements. This notion is supported by observations of a conditional knockout model of a mouse SHOX paralog (Shox2). Functional studies of SHOX have centered on in vitro systems that have identified functional domains of the SHOX gene, messenger RNA (mRNA), and protein. In addition, a cis-regulatory element has been inferred on the basis of deletions in a subset of patients. Continued work on these and other fronts will eventually lead to a better understanding of the role of SHOX in growth and skeletal development.
HLXB9 (MNX1) and Sacral Agenesis and the Currarino Syndrome
Authors: Scherer Stephen , Martucciello Guiseppe , Belloni, Elena , Torre Michele
Published: November 2023

Agenesis of the sacrum is a defect that involves the spinal column, with varying degrees of severity. It is usually sporadic in origin and associated with maternal diabetes. There are also familial forms, such as the Currarino syndrome (CS), in which the defects are transmitted through entire pedigrees, with reduced penetrance in some cases.