bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOXC1 and FOXL2 and the Axenfeld–Rieger Malformations and the Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome
Authors: Saleem Ramsey A , Berry Fred B , Huang, Lijia , Walter Michael A 
Published: November 2023

Abstract
The complex process of embryogenesis proceeds through molecular signaling and regulation by developmentally important transcription factors. Of the regulatory molecules known, members of the evergrowing forkhead family of transcription factors are known to play key roles in the development of a wide range of organisms (Kaufmann and Knochel, 1996). Forkhead transcription factors are characterized by the presence of a conserved, 110-amino acid, DNA-binding domain; the forkhead domain (FHD). This DNA-binding motif is a variant of the helix–turn–helix motif, consisting of one minor and three major α-helices, two β-sheets, and two large loops that form “wing-like” structures. Consequently, FHDs are often referred to as winged-helix domains. Increasingly, winged-helix or FOX (Forkhead Box) genes have been shown to be involved in human heritable disorders. FOXC1 and FOXL2 are two of four FOX genes known to be involved with diseases possessing an ocular phenotype. FOXC1 mutations underlie ocular anterior segment dysgenesis with an increased risk of glaucoma and systemic defects, while FOXL2 mutations cause blepharophimosis ptosis and epicanthus inversus syndrome (BPES) (MIM 110100), an autosomal dominant disorder affecting the eyelids and tissues surrounding the eye. In this chapter, we discuss the involvement of FOXC1 and FOXL2 in development as well as describe the pathology when alterations to these genes are present.
TBX3 and TBX5 and the Ulnar–Mammary and Holt–Oram Syndromes
Authors: Bamshad Michael J , Jorde Lynn B 
Published: November 2023

Abstract
Ulnar–mammary syndrome (UMS) and Holt–Oram syndrome (HOS) are rare, autosomal dominant, multiple malformation disorders. UMS is characterized by apocrine abnormalities including breast defects and malformations of the posterior elements of the upper limb. In contrast, HOS is typi)ed by heart malformations, most commonly an atrial septal defect (ASD) or ventricular septal defect (VSD), conduction abnormalities, and defects of the anterior elements of the upper limb. UMS and HOS are caused by myriad mutations in TBX3 and TBX5, respectively, two members of the T-box gene family linked together on chromosome 12q24. There is little evidence to support a genotype–phenotype correlation for either condition. The long-term care of patients with UMS or HOS can be challenging, but in general, most patients do well. In the heart, TBX5 physically activates atrial natriuretic factor (ANF), connexin-40 (cx40), and GATA4 to play an important role in formation of the septa, chambers, and conduction system. In the limb, Tbx5 appears to activate )broblast growth factor-10 (Fgf10) directly to initiate forelimb bud outgrowth and to in%uence, in part, forelimb identity. Tbx3 acts as a negative repressor of p19ARF and p53 and interferes with apoptosis. Tbx3 is essential for formation of the mammary glands and plays multiple roles in limb development including the speci)cation of digit identity. In vitro studies demonstrate that substitutions in the DNA-binding domain of TBX3 and TBX5 or truncations in the C terminus of the TBX3 and TBX5 proteins fail to bind DNA and lose their transcriptional properties. Loss of Tbx3 repressor activity may promote a pro-apoptotic path that results in a diminished number of mesodermal cells in the developing limb and breast. Loss of Tbx5 activity appears to result in the down-regulation of several genes critical for normal heart development.
SOX2 and Malformations of the Eye, Brain, Foregut, and Male Genital Tract
Authors: Fitzpatrick David R 
Published: November 2023

Abstract
Heterozygous loss-of-function mutations in the high mobility group (HMG) domain-containing transcription factor SOX2 are associated with a complex spectrum of malformations. The most characteristic malformations are absent (anophthalmia) or small (microphthalmia) eyes, which are usually bilateral, severe, and apparent at birth or by prenatal ultrasound examination. Other commonly associated malformations involve the brain, pituitary gland, trachea, esophagus, and male genital tract (hypospadias, cryptorchidism, and micropenis). Postnatal growth failure, delayed motor development, seizures, and learning disability are other common associations. SOX2 mutations are usually de novo although parental germline mosaicism has been seen. SOX2 appears to function as a transcriptional regulator of developmentally critical genes both in vivo and in embryonic stem (ES) cell culture. Homozygous loss of Sox2 in mouse embryos results in early lethality and failure to establish any of the normal early cell lineages. In contrast to humans, the heterozygous null mice show no major malformations.
SOX9 and Campomelic Dysplasia and Sex Reversal
Authors: Mansour Sahar 
Published: November 2023

Abstract
Campomelic dysplasia (also known as camptomelic dysplasia) (CMD) is a rare, usually lethal skeletal dysplasia. Unlike other forms of skeletal dysplasia, it is frequently associated with XY sex reversal. The gene for this condition, SOX9, was identified in 1994. As suggested by the phenotype in CMD, SOX9 is an important gene, not only in the sex determination pathway but also in chondrogenesis. In this chapter, I discuss SOX9 and its role in both the sex determination pathway and the cartilage and collagen pathway. The clinical and radiological features of CMD are described, including the phenotype and complications in survivors with this condition.
MITF and the Waardenburg Type II and Albinism–Deafness (Tietz) Syndromes
Authors: Hornyak Thomas J , Chung, Nancy M , Tachibana Masayoshi 
Published: November 2023

Abstract
Microphthalmia-associated transcription factor (MITF) is a member of a large family of proteins with basic helix–loop–helix leucine zipper (bHLHZip) domains. Mutations in this transcription factor initially have been described in mice showing microphthalmia, variable pigmentary loss, and hearing deficit. Similar phenotypes can be seen in humans with Waardenburg Type II Syndrome (WS2) and Albinism–Deafness (Tietz) Syndrome with mutations in MITF. The manifestations of MITF mutations result from loss of melanocytes in the eyes, skin, and cochlea emphasizing the importance of this protein in the differentiation and maintenance of melanocytes.
SALL4 and the Okihiro/Duane Radial-Ray and Acro–Renal–Ocular Syndromes
Authors: BI WEIMIN , LUPSKI JAMES R 
Published: November 2023

Abstract
Okihiro/Duane-radial-ray syndrome (DRRS) is a rare autosomal dominant condition characterized by radial-ray defects and Duane anomaly (a form of strabismus). Other abnormalities recognized in this condition are anal, renal, cardiac, ear and foot malformations, hearing loss, postnatal growth retardation, and facial asymmetry. The disease is caused by a mutation in SAL-like 4 ( SALL4) a human gene related to the developmental regulator sal of Drosophila melanogaster. SALL4 mutations may also cause acro–renal–ocular syndrome (AROS), which differs from DRRS by the presence of structural eye anomalies, and phenotypes similar to thalidomide embryopathy and Holt–Oram syndrome (HOS). The SALL4 gene product is a zinc-)nger protein thought to act as a transcription factor. It contains three highly conserved C2H2 double zinc-)nger domains, which are evenly distributed. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL4 contains a C2HC motif. Of the SALL4 mutations known to date, 20 out of 27 are located in exon 2 and 7 in exon 3; and unlike SALL1 mutations causing Townes–Brocks syndrome (see Chapter 25), the mutations do not cluster in a hotspot region. These are nonsense mutations, short insertions/duplications, and short deletions, as well as one missense mutation. All truncating mutations lead to preterminal stop codons and are thought to cause the phenotype via haploinsuf)ciency with the exception of one nonsense mutation, which is associated with a striking intrafamilial phenotypic variability and predicted to escape nonsense-mediated messenger RNA (mRNA) decay. The missense mutation is associated with cranial midline defects, in addition to Okihiro syndrome (OS) features, and predicted to result in an increased DNA-binding af)nity of the mutated zinc-)nger domain. The detection of larger deletions involving the whole SALL4 gene or single exons in patients with OS or AROS provided proof for haploinsuf)ciency as the cause of the malformations.
TCF2 (HNF-1_) and MODY5 and Urogenital Malformations
Authors: BI WEIMIN , LUPSKI JAMES R 
Published: November 2023

Abstract
The clinical entity discussed here was recognized in the early 1970s in a Norwegian family, with the combination of congenital renal disease and glucose intolerance in infancy. Mutations in hepatocyte nuclear factor (HNF)-1, encoded by the transcription factor-2 (TCF2) gene, were demonstrated in Japanese patients with cystic renal disease and early onset diabetes mellitus (Horikawa et al., 1997; Nishigori et al., 1998).
RECQL4 and the Rothmund–Thomson, RAPADILINO, and Baller–Gerold Syndromes
Authors: Maldergem Lionel Van , Siitonen H Annika , Jabs, Ethylin Wang , Gordillo Miriam 
Published: November 2023

Abstract
Disease-causingmutationsinthe RECQL4 genehavebeenassociated with three apparently distinct clinical entities: Rothmund– Thomson syndrome (RTS, OMIM 268400), RAPADILINO syndrome (OMIM 266280) and Baller–Gerold syndrome (BGS, OMIM 218600). RECQL4 belongs to the highly conserved RecQ helicase family com- posed of five members in humans. It has an important role in genomic stability and functions at the interface of DNA replication and DNA repair. Mutations in two other human RecQ helicases, WRN and BLM are implicated in Werner syndrome (WS; OMIM 277700) and Bloom syndrome (BS; OMIM 210900), respectively. RTS, BLM, and BS are associated in varying degrees to premature aging, skin and skeletal abnormalities, and cancer predisposition. All the RECQL4-related syndromes are rare autosomal recessive disorders that have in common growth retardation, radial ray hypo/aplasia, patellar hypo/aplasia, and infantile diarrhea. Poikilodermatous skin change with a characteristic pattern is the hallmark of RTS while craniosynostosis is associated more frequently with BGS. Predisposition to osteosarcoma is also a feature of RTS. The specific function of RECQL4 and mechanism by which it induces pleiotropic manifestations in these syndromes are largely unknown. However, recent studies support its role in initiation of DNA replication and in cell proliferation. In addition, the expression pattern of mouse Recql4 during embryo development and findings relating RECQL4 to osteoprogenitor proliferation suggest a role for RECQL4 during skeleton development.
GPC3 and the Simpson–Golabi–Behmel Syndrome
Authors: Saunders Scott , Martin, Rick A , Debaun Michael R 
Published: November 2023

Abstract
Most genetically characterized cases of Simpson–Golabi–Behmel syndrome (SGBS) in humans have been linked with mutations in the GPC3 gene located at Xq26 (Pilia et al., 1996), a gene encoding for glypican-3, a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan (Fig. 164–1). However, a severe form of SGBS has also been reported that maps to Xp22 (Brzustowicz et al., 1999), and many patients with the clinical diagnosis of SGBS have as yet no detectable mutations identified within their GPC3 gene. These data suggest that not all cases of SGBS result solely from GPC3 mutations. Six distinct glypican genes have been identified in vertebrates, all encoding heparan sulfate proteoglycans with structural features similar to those shown in Figure 164–1 (Paine-Saunders et al., 1999; Veugelers et al., 1999). Interestingly, the GPC4 gene is located immediately centromeric to GPC3 in both humans (Huber et al., 1998; Veugelers et al., 1998) and mice (Matsuki et al., 1998), and at least one patient with SGBS has been identi2ed with a deletion involving both GPC3 and GPC4 (Veugelers et al., 1998). However, isolated GPC4 mutations have not been identi2ed in any patients with SGBS, and there is no evidence to suggest that patients with mutations involving both GPC3 and GPC4 have any distinct alteration or enhancement of their phenotype. Furthermore, none of the remaining glypican genes have been mapped to loci linked either specifically with SGBS or, more generally, with overgrowth phenotypes in humans, and mutant alleles of other glypican genes in mice do not seem to phenocopy SGBS (S. Saunders, unpublished data). Therefore, cases of SGBS not arising from GPC3 mutations are unlikely to be due to mutations in genes encoding other members of the glypican gene family.
TRPS1 and the Tricho-rhino-phalangeal Syndromes*
Authors: Lüdecke Hermann-Josef , Horsthemke Bernhard 
Published: November 2023

Abstract
Tricho-rhino-phalangeal syndromes (TRPSs) is an autosomal dominant malformation syndrome which is characterized by craniofacial and skeletal abnormalities. The main features of all three subtypes, TRPS I, II, and III, are caused by mutations in or deletions of the TRPS1 gene on human chromosome 8. TRPS1 encodes a protein featuring an unusual combination of different zinc finger motifs, including GATA-type and IKAROS-like domains. The protein is a potent repressor of GATA-mediated gene expression.
Physiological Bonds
Authors: Lab Mullers 
Published: November 2023

Abstract
Like Müller, du Bois-Reymond spent much of his life longing for friends who shared his scientific outlook. In his twenties, he was far luckier than his mentor, finding in Berlin a group of talented physicists and physiologists with whom he could work. Among them was Ernst Brücke (1819–1892), a painter’s son who had hoped to become an artist but after meeting Müller had shifted his allegiance to experimental physiology.1 In March 1841, du Bois-Reymond organized a group of several young scientists who supported active experimentation and opposed the notion of life force. In January 1845, this group became the Berlin Physical Society, meeting weekly at the physicist Gustav Magnus’s house to exchange ideas about experiments.2 Later that year, they were joined by Hermann von Helmholtz and the engineer Werner von Siemens (1816–1892), who designed Prussia’s telegraph network. Because all of these scientists built their own innovative equipment, the Physical Society provided a forum for technical discussions among physicists, physiologists, and mechanics. In addition to university lecturers, the society included instrument makers and technicians from the Prussian military who wanted to collaborate with physicists.3 As they shared technical tips, these young experimenters inspired each other and formed passionate scientific bonds.
A Boy and His Books
Authors: Hayes Kevin J 
Published: November 2023

Abstract
The chapman was a familiar figure along the byways of colonial America. With a pack on his back filled with a variety of inexpensive goods both useful and entertaining, the chapman crisscrossed the colonies selling his wares. Men and women, boys and girls, all came to know the chapman and eagerly anticipated his visits. Among his wares, he usually kept a stock of books. They were known not only as Chapman’s books, but also as “little books,” “small books,” or, regardless of their largely fictional nature, “small histories.” Some people just called them “histories.” The most ambitious chapmen stocked a good selection of titles. Chapbook texts popular in eighteenth-century America included Dr. Faustus, The Famous History of the Seven Champions of Christendom, The History of Fortunatus, The History of Parismus, The History of Tom Thumb, Jack the Giant Killer, Reynard the Fox, Valentin and Orson, and The Wise Men of Gotham. These entertaining storybooks captured the attention of numerous young readers in colonial America—Thomas Jefferson included.
The Pen and the Tomahawk
Authors: Hayes Kevin J 
Published: November 2023

Abstract
As the mild winter came to a close in March 1775—”the most favorable winter ever known in the memory of man,” Jefferson called it—men from all parts of Virginia began wending their way toward Richmond, where they would gather at St. John’s Church for the second Virginia Convention, rather than at Williamsburg. As the colonial capital, Williamsburg was becoming increasingly uncomfortable for local citizens who were challenging the British administration. Delegates to the Virginia Convention had been elected by voters across the colony from the counties or corporations where they made their homes. This group of over a hundred men included nearly all of Virginia’s foremost leaders. Some, like Peyton Randolph, were old hands at Virginia governance, while others were fairly green. Their youth fueled their enthusiasm and their ardor.
“Life of Captain Lewis”
Authors: Hayes Kevin J 
Published: November 2023

Abstract
History of the Expedition under the Command of Captains Lewis and Clark, the most substantial work of American literature to appear in the first two decades of the nineteenth century, was based on journals Meriwether Lewis and William Clark kept during their transcontinental expedition. Eight years would pass between their return in 1806 and the publication of History of the Expedition. During that time Nicholas Biddle began preparing their unwieldy journals for publication but wearied of the task before its completion. Paul Allen took over as editor and saw the work through the press.
The University of Virginia from Dream to Reality
Authors: Hayes Kevin J 
Published: November 2023

Abstract
The last week of November 1821, Jefferson wrote an eloquent letter to William Short, conveying his hopes for the University of Virginia: “It will be a splendid establishment, would be thought so in Europe, and for the chastity of its architecture and classical taste leaves everything in America far behind it.” These words convey the profound satisfaction Jefferson felt at the moment. Finally, his dream of the ideal university was becoming a reality. It had been a long time coming. Construction of the Rotunda had yet to begin, but the rest of the campus was definitely showing signs of progress. Six pavilions, eighty-two dormitories, and two hotels had been completed. Once built, the Rotunda would be the university’s centerpiece. It would unify the campus in terms of both its architecture and its function: Jefferson had designed the Rotunda as the library. Just as he had imagined how Monticello would appear before it was finished, he could now imagine how the University of Virginia would appear when it welcomed its first class of students. Maybe not the next year and maybe not even the year after that, but soon it would open, soon it would emerge as a great university.
Letters to Doubting Thomas
Authors: Layman C Stephen 
Published: November 2023

Abstract
When people encounter an argument for or against God's existence, it often raises more questions than it answers. In Letters to Doubting Thomas, C. Stephen Layman offers a fresh, insightful approach to the issue of God's existence--a way to organize what can seem like a blizzard of claims and concepts--bringing clarity to a debate often mired in confusion. Layman explores the evidence for the existence of God in a series of fictionalized letters between two characters--Zachary, a philosopher, and Thomas, an old college friend who appeals to Zach for help in sorting out his thoughts about God. As their correspondence grows, Zachary leads Thomas through an informal and highly readable comparison of Naturalism (the belief that there is no God and that ultimate reality is physical reality), and Theism (the idea that there is an almighty, perfectly good God). In engaging letters that break down complex philosophical arguments into easily digestible bits, the two friends delve into such weighty topics as the reliability of religious experience, various arguments for God's existence (such as the cosmological, design, and moral arguments), the question of free will, and the problem of evil. A piece at a time, they build an argument that shows that Theism, on balance, provides a better explanation of the world and human life than does Naturalism. Here then is a highly accessible account of the major arguments for and against the existence of God, capturing some of the best new insights of modern philosophy in a marvelously clear and engaging format.
Religious Experience and Interpretation
Authors: Layman C Stephen 
Published: November 2023

Abstract
Dear Thomas, Thanks for your recent post on religious traditions and religious experience. Agreed: Many horrible things have been done in the name of religion. Once you get large numbers of people living within a religious tradition-or claiming to do so, such things are likely to occur sooner or later, aren’t they? But I don’t see that this lamentable fact disproves the official teachings of the traditions.
Nutritional Interventions in Cancer
Authors: Block Keith I 
Published: November 2023

Abstract
Single vitamins, minerals, or antioxidants, in the absence of a comprehensive diet intervention, have very limited ability to prevent cancer or retard its progression. To control cancer-promoting inflammation, intake of animal fat andomega-6 fatty acidsshould belimited, whileintakeofomega-3 fatty acids and monounsaturated fats should be emphasized. To control insulin levels, carbohydrates should come from whole grain products, vegetables, and fruits, while refined flours and added sugars should be limited or eliminated. Plant proteins, egg whites, and fish are the safest protein sources for cancer patients.
The Antioxidant Debate
Authors: ladas Elena , Kelly kara M 
Published: November 2023

Abstract
Patients with cancer are taking antioxidant supplements in combination with conventional chemotherapy and radiotherapy to enhance the anticancer activity and to reduce the side effects of conventional treatment. Many oncologists are concerned that the protective mechanisms of antioxidants may not distinguish between normal and malignant cells, so that supplements may interfere with the anticancer activity of the conventional therapies. Not all antioxidant supplements are equivalent; antioxidants counteract free radical activity through multiple mechanisms of action.
Tending the Spirit in Cancer
Authors: Remen Rachel Naomi 
Published: November 2023

Abstract
Perhaps it is useful to say that spirit is accessed as often through life experience as it is through formal religion. Falling in love, marriage, the birth of a child; these moments may initiate a revolution in personal values and spiritual perspective. The spiritual is really a human birthright; it is the dimension of our being that is the meeting place which underlies human diversity and which creates a genuine connection among all people. Religion attempts to make this real for us through community, practice, and belief, and may become a bridge to the spiritual; but the lived experience of spiritual realities lies beyond all beliefs and practices; it is the all-inclusive ground of being.
Integrative Medicine in Colorectal Cancer
Authors: Jacobson Judith s. , Neugut Alfred I 
Published: November 2023

Abstract
Colorectal cancer may be especially well suited to an integrative approach, which may benefit patients with high risk or precursor conditions as well as those with the disease. A diet rich in fruits and vegetables and regular physical activity may help both to prevent colorectal cancer and to improve survival among patients with colorectal cancer. Two studies have found associations between adverse life events and increased risk of colorectal cancer. Although not conclusive, these data support exploration of stress management measures for individuals at risk.