bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Principles and Technologies in the Study of Immune Disorders
Authors: Puck Jennifer M , Nussbaum Robert L 
Published: November 2023

Abstract
Medical genetics is the subspecialty of medicine concerned with the investigation, diagnosis, treatment, counseling, and management of patients and families with inherited disease. Research in medical genetics focuses on identifying the genes involved in human hereditary diseases and the changes in DNA sequence that cause or predispose to these diseases; elucidating disease pathogenesis, including both genetic and environmental factors; understanding the inheritance patterns of diseases in families; developing new treatments or cures for hereditary disorders; and helping patients and families make reproductive decisions and cope with the impact of genetic disorders on the health of family members. Although a complete discussion of medical genetics is beyond the scope of this book and can be reviewed in several texts (Vogel and Motulsky, 1996; Scriver et al., 2001; Nussbaum et al., 2006), it is essential to present here an overview of the terminology, concepts, and methods of modern molecular genetics. This introduction will outline the approaches that have led to the identification of the genes involved in over 140 specific disorders of the immune system. These findings should make possible further revolutionary changes, not only in the discovery of additional disease genes, but also in understanding the pathogenesis of defects in host defenses. Using this understanding, we may create effective new therapies.
X-Linked Severe Combined Immunodeficiency
Authors: Puck Jennifer M 
Published: November 2023

Abstract
Severe combined immunodeficiency (SCID) comprises a collection of genetic defects that involve both humoral and cellular immunity. A profound lack of immune function leads to infections that are generally fatal in infancy unless the immune system can be reconstituted. X-linked SCID (XSCID, SCIDX1, MIM #300400) is caused by defects in IL2RG (MIM *308380), the gene encoding the interleukin-2 (IL-2) receptor γ chain (Online Mendelian Inheritance in Man [OMIM], 2000), also known as the common γ chain. XSCID is the most frequent genetic form of SCID. Its incidence is unknown, although it has been estimated to occur in at least 1 per 100,000 births. Males, who have a single X chromosome, are affected with XSCID. Female carriers, who have a mutated copy of the gene on one of their two X chromosomes and a normal copy on the other, remain healthy. However, carrier females can pass on the disease to their male offspring and the carrier state to their female offspring. XSCID appears to occur equally in all ethnic groups.
V(D)J Recombination Defects
Authors: Villartay Jean-Pierre De , Schwarz Klaus , Villa Anna 
Published: November 2023

Abstract
The vertebrate cognate immune system recognizes and responds to a virtually infinite number of foreign antigens via antigen specific immunoglobulin (Ig) or T cell receptor (TCR) molecules expressed on the cell surface of B and T lymphocytes, respectively. While the Ig receptor of B cells binds to soluble antigens, the TCR receptor recognizes peptide antigens presented by human leukocyte antigen (HLA) molecules. In general, allelic exclusion prevents expression by a single lymphocyte of two different receptors encoded by homologous alleles. The expression of each distinct receptor is maintained in the clonal progeny of a lymphocyte. Immunoglobulin and TCR chains consist of two structural domains: the constant regions mediate effector functions, while the variable part of the receptor chains forms the antigen-binding pocket. A site-specific recombination event (VDJ recombination) leads to generation of the variable domains of mature antigen receptor genes from a set of subgenic segments classified as variable (V), diversity (D), and joining (J) elements (for review see Schlissel and Stanhope-Baker, 1997; Nemazee 2000). In principle, each of the V elements can join to any of the D and J modules, thus a finite number of subgenes can establish the enormous antigen receptor diversity.
Severe Combined Immunodeficiency Due to Defects in T Cell Receptor–Associated Protein Tyrosine Kinases
Authors: Elder Melissa E 
Published: November 2023

Abstract
The processes involved in CD4 vs. CD8 selection during T cell ontogeny are not fully understood, but are known to require intact signal transduction through the TCR of the differentiating thymocyte (Pfeffer and Mak, 1994; Robey and Fowlkes, 1994). The signal transduction events mediated by the TCR on thymocytes are thought to be similar to those responsible for the activation of mature T cells. Propagation of antigen-binding signals from the TCR to the nucleus is dependent on the activation of the PTKs Lck and ZAP-70 (reviewed in Chan et al., 1994a; Weiss and Littman, 1994; Cantrell, 1996; Wange and Samelson, 1996; Kane et al., 2000). PTK activation is a rapid and critical event that results in phosphorylation of numerous downstream molecules, including phospholipase Cδ1 (PLCδ1), linker for activation of T cells (LAT), Src homology 2 (SH2) domain–containing 76 kDa leukocyte protein (SLP-76), and the Vav guanine nucleotide exchange factor (reviewed in Wange and Samelson, 1996; Qian and Weiss, 1997; Rudd, 1999; van Leeuwen and Samelson, 1999; van Oers, 1999; Kane et al., 2000). These tyrosine phosphorylation events are required for mobilization of intracellular free calcium ([Ca2+]i) and activation of the Ras/mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 (PI3) kinase pathways. These downstream reactions culminate in activation of T cells and initiation of T cell–specific responses, described in more detail in Chapter 6.
Human Interleukin-2 Receptor α Deficiency
Authors: Roifman Chaim M 
Published: November 2023

Abstract
Regulation of the immune system requires communication among its cellular components. Such cell-to-cell interplay occurs in microenvironments in the lymphoid organs and sites of in?ammation. A major mechanism of communication includes the secretion of a vast number of soluble mediators, of which the most extensively studied is interleukin-2 (IL-2). Originally identified as a T cell growth factor (Gillis and Smith, 1977a, 1977b) IL-2 was also later implicated in promoting growth of natural killer (NK) cells and B cells.
Autosomal Recessive Agammaglobulinemia
Authors: Conley Mary Ellen 
Published: November 2023

Abstract
Normal development of the B cell lineage is dependent on appropriate expression and extinction of a panoply of genes, some of which are B cell–specific and some of which are more broadly expressed (Billips et al., 1995; Rajewsky, 1996; Yankee and Clark, 2000; Rolink et al., 2001). These genes encode B cell–specific transcription factors, proteins required for the rearrangement of the immunoglobulin gene segments, signal transduction molecules, receptors for growth factors and adhesion molecules, and many others. The immunoglobulin genes and proteins encoded by these genes obviously play a central role. The classic disorder of B cell development, X-linked agammaglobulinemia (XLA), was first described in the 1950s (Bruton, 1952; Janeway et al., 1953; Good, 1954a, 1954b). It is characterized by the early onset of bacterial infections, profound hypogammaglobulinemia, and markedly reduced numbers of B cells (Ochs and Winkelstein, 1996; Conley et al., 2000a). The defective gene in this disorder encodes a cytoplasmic tyrosine kinase, Btk, that is involved in signal transduction (Tsukada et al., 1993; Vetrie et al., 1993). It is not yet clear, however, how defects in this protein result in impaired B cell proliferation, differentiation, or survival.
Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dystrophy
Authors: Peltonen-Palotie Leena , Halonen Maria , Perheentupa Jaakko 
Published: November 2023

Abstract
Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED; OMIM 240300), an autosomal recessive disease, provides a unique model for molecular studies of auto-immunity because of the monogenic inheritance of this disorder, characterized by multiple features of abnormal immunological tolerance. APECED was first mentioned in the literature by Thorpe and Handley in 1929, and since then it has been given several names, such as APS1 or Whitaker’s syndrome (Leonard, 1946; Whitaker et al., 1956; Neufeld et al., 1981; Ahonen, 1985). Patients with APECED have been identified in numerous populations and among multiple ethnicities. The disease occurs more frequently in isolated populations, the lifetime prevalence being rather high among the Finns, Iranian Jews, and Sardinians (1/25,000, 1/9000, and 1/14,500, respectively) (Zlotogora and Shapiro, 1992; Rosatelli et al., 1998).
Inherited Disorders of the Interleukin-12/23–Interferon Gamma Axis
Authors: Newport Melanie J , Holland Steven M , Levin Michael , Casanova Jean-Laurent 
Published: November 2023

Abstract
Over the past 50 years there have been a number of reported cases of severe disseminated infection with weakly virulent mycobacteria in individuals without recognized predisposing immunodeficiency. Mycobacterial species included various environmental mycobacteria (EM) and several Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine substrains. High rates of affected siblings and parental consanguinity suggested the existence of a novel primary immunodeficiency syndrome, subsequently named Mendelian susceptibility to mycobacterial disease (MSMD, MIM 209950). Molecular investigation of these families has identified mutations in five genes in the interleukin (IL)-12/23–dependent interferon-gamma (IFN-γ) axis, highlighting the importance of this pathway in human immunity to mycobacteria. There remain a number of patients for whom a genetic etiology has yet to be identified; mutations in other genes await discovery.
Chromosomal Instability Syndromes Other Than Ataxia-Telangiectasia
Authors: Wegner Rolf-Dieter , German James J , Chrzanowska Krystyna H , Digweed Martin , Stumm Markus 
Published: November 2023

Abstract
A number of syndromes exist in which an increased incidence of spontaneous and/or induced chromosomal aberrations is the unifying diagnostic criterion. These disorders, called chromosomal instability syndromes, include the classical chromosomal instability syndromes—namely, ataxia-telangiectasia (A-T), Fanconi anemia (FA), and Bloom syndrome (BS). On the basis of this definition, Nijmegen breakage syndrome (NBS) and A-T-like disorder (A-TLD) must also be added to this group. More recently, case reports of patients with ligase I (LIG1) deficiency, ligase IV (LIG4) deficiency, NHEJ1, and RAD50 deficiency have provided evidence for the existence of a long list of diseases belonging to this group.
X-Linked Lymphoproliferative Disease Due to Defects of SH2D1A
Authors: Schuster Volker , Terhorst Cox 
Published: November 2023

Abstract
X-linked lymphoproliferative disease (XLP; MIM 308240) is an inherited immunodeficiency involving primarily T, natural killer (NK) and natural killer T (NKT) cells that in most cases is exacerbated following exposure to Epstein-Barr virus (EBV). In older children and adults, EBV, one of the eight known human herpesviruses, is the causative agent of infectious mononucleosis (Henle and Henle, 1979). This is usually a self-limiting polyclonal lymphoproliferative disease with an excellent prognosis. In immunosuppressed individuals, EBV infection may lead to life-threatening lymphoproliferative disorders and lymphoma (Hanto et al., 1985). Moreover, EBV has been associated with certain malignancies, such as endemic Burkitt lymphoma, nasopharyngeal carcinoma, certain B and T cell lymphomas, and approximately 50% of Hodgkin disease (Zur Hausen et al., 1970; Ott et al., 1992; Weiss et al., 1989). In 1969 a family was described with two brothers suffering from hypogammaglobulinemia and malignant lymphoma following infectious mononucleosis (Hambleton and Cottom, 1969). This was the first report of XLP in the medical literature. In 1975, Purtilo et al. reported a large family, the Duncan kindred, in which multiple male members had died from fulminant infectious mononucleosis in early life, whereas others developed hypogammaglobulinemia after infectious mononucleosis or ex tranodal ileocecal malignant lymphoma during the next years of life. This apparently X-chromosomally inherited syndrome with a high vulnerability to EBV infection was classified as Duncan disease (in reference to the first described XLP family).
Genetically Determined Deficiencies of the Complement System
Authors: Sullivan Kathleen E , Winkelstein Jerry A 
Published: November 2023

Abstract
The complement system is composed of a series of plasma proteins that play a critical role in host defense and in?ammation. The first patient with a genetically determined deficiency of an individual component of the complement system was described in 1960 (Silverstein, 1960). Since then, inherited deficiencies of nearly all of the individual components of complement have been identified (Ross and Densen, 1984; Figueroa and Densen, 1991). In this chapter, we review the biochemistry and biology of the normal complement system and relate them to the clinical presentation of complement deficiency diseases and their molecular genetic basis.
Conventional Therapy of Primary Immunodeficiency Diseases
Authors: Stiehm E Richard , Chapel Helen M 
Published: November 2023

Abstract
Long-term care of patients with primary immunodeficiencies is aimed at prevention of infections and their long-term sequelae as well as treatment of breakthrough infections. The extent of both the protection required and the appropriate prophylaxis depends on the nature of the immune deficiency. For this reason, this chapter is divided into two sections: the first describes general measures applicable to all forms of immune deficiency, and the second details specific measures for patients with individual diseases. The management of all forms of immunodeficiency disease requires interaction between generalists and specialists with experience and expertise in primary immune deficiencies. This usually requires a team of a primary care pediatrician or internist and an immunologist with assistance and advice from other specialists (e.g., dermatologists, pulmonologists, gastroenterologists, and radiologists) as necessary, since it is important that patients continue to have the benefit of optimal diagnostic procedures and new drugs for all organ-based complications they may develop.
Gene Therapy
Authors: Candotti Fabio , Fischer Alain 
Published: November 2023

Abstract
As currently practiced, gene therapy can be defined as the transfer of exogenous genes to somatic cells of a patient in order to correct an inherited or acquired gene defect, or to introduce a new function or trait. In the last 15 years, gene therapy has moved from the speculative stage to clinical applications as clinical gene transfer protocols have been applied to inherited genetic defects, malignancies, and infectious diseases. Primary immunodeficiciency diseases (PIDs), especially severe combined immunodeficiency (SCID) disorders, have played a major role in this process as they have provided a proving ground for the first therapeutic applications (Blaese et al., 1995) as well as the first evidence that gene therapy can be curative (CavazzanaCalvo et al., 2000; Hacein-Bey-Abina et al., 2002). Several advantageous characteristics have made PIDs attractive candidate diseases for gene therapy. First, PIDs are often curable by allogeneic hematopoietic stem cell transplantation (HSCT), which translates into the possibility that they should also be treatable with procedures combining ex vivo manipulation and reinfusion of autologous, gene-corrected hematopoietic stem cells. Second, the target cells reside in the bone marrow, a readily accessible tissue, which makes them amenable to harvest for ex vivo gene transfer, the procedure that currently offers the best success. In addition, the regulation of genes responsible for many PIDs (i.e., adenosine deaminase deficiency, chronic granulomatous disease, X-linked severe combined immunodeficiency, leukocyte adhesion deficiency) appears relatively simple and, while currently available technology does not allow reproducing the physiological control mechanisms of gene expression, the available gene transfer vectors are more than adequate to provide expression of these genes at levels required for clinical benefit. Finally, for several PIDs, gene-corrected progenitors and mature cells have a survival advantage over the unmodified, affected cell populations. This selective survival translates into the very advantageous circumstance that even low gene transfer efficiency can have therapeutic effects.
Modernists vs. Traditionalists: Competition and Legitimacy within American Conservative Judaism
Authors: Silverstein Alan 
Published: November 2023

Abstract
Assessments of contemporary Conservative Judaism have been colored by memories of strife regarding women’s ritual participation within the movement during the 1970s and early 1980s. Rabbis and ritual committees, men and women, the Jewish Theological Seminary (JTS) and its alumni-all were often at odds. Describing that period of time, the provost of JTS, Jack Wertheimer, posited that, “far more than the other denominations, Conservative Judaism experienced severe turbulence and even demoralization.”1 Ought this assessment be extended as well to the final decades of the 20th century? During the 1980s and 1990s, virtually all denominations within America’s religious landscape experienced turmoil in which “modernists” and “traditionalists” were pitted against one another.2 The modernists claimed that religious belief and practice ought to change in accordance with evolving mores, whereas traditionalists asserted that religion offered timeless truths that were meant to withstand the ever-changing tide of moral relativism.
Uzi Meshulam’s “Mishkan Ohalim”: A Contemporary Apocalyptic Messianic Sect in Israel
Authors: Inbari Motti 
Published: November 2023

Abstract
The phenomenon of recurrent and active messianism has been part of Jewish history for 2,000 years. Appearing first among the Dead Sea sects before the destruction of the Second Temple, it continued through the Bar-Kokhba revolt, the Middle Ages, the aftermath of the expulsion from Spain, the Sabbetai Zevi episode, and up to the present day, with the emergence of a number of apocalyptic messianic cults in the modern state of Israel. Given the incessant failures, disappointments, and chagrin over erroneous calculations of the End, what accounts for the resilience of active messianism is the utopian vision it affords to its believers, most of whom have low material or spiritual status. The cycles of war, destruction, and persecution that were endured by the Jewish people resulted in yearning for the homeland and anticipation of a messiah who would redeem them from their travails.
Introduction: Opening Remarks and Motivation
Authors: Goetzmann William N , Ibbotson Roger G 
Published: November 2023

Abstract
The equity risk premium is commonly viewed as the extra return needed to induce investors to risk their money in the stock market, rather than opting for the safe haven of government bonds. It is simple theory based on common sense. Economic risk-taking must be rewarded, or else no rational person would prefer a gamble over a sure thing. Although reasonable people may disagree about whether equity investing is a gamble and whether government securities are a sure thing, the principle of the equity premium is the main reason to invest in the stock market.
Wealth: U.S. and Foreign Market Values and Returns
Authors: Ibbotson Roger G , Siegel Laurence B , Love Kathryn S 
Published: November 2023

Abstract
On two occasions in this journal,1 we have presented annual aggregate values and total returns for major asset classes in the U.S. and in foreign markets, and we have formed U.S., foreign, and world “market wealth portfolios.” The portfolios are composed of five major categories of assets: equities (stocks), bonds, cash equivalents, real estate, and monetary metals (gold and silver). With a quarter century now elapsed since the appearance of accurate foreign equity data, we are newly motivated to examine the aggregate values of and total returns on the components of world wealth
Predictions of the Past and Forecasts for the Future: 1976–2025
Authors: Ibbotson Roger G 
Published: November 2023

Abstract
In early 1973, Professor Roger Ibbotson and Rex Sinquefield partnered to research historical returns for common stocks, U.S. government and corporate bonds, U.S. Treasury bills, and inflation. At the time, Professor Ibbotson taught at the University of Chicago Graduate School of Business. Through their research, Ibbotson and Sinquefield hoped to provide an update to the historical performance study done years earlier by Lawrence Fisher and James Lorie,1 as well as present convincing evidence that common stocks were still appropriate for long-term investors. During the 21-month period between January 1973 and September 1974, investors suffered a 42% drop in the stock market. In order to win over skeptics, Professor Ibbotson believed there needed to be a forecast set in historical terms to convey his prediction that stocks would outperform bonds over long time periods.
Survival
Authors: Brown Stephen J , Goetzmann William N , Ross Stephen A 
Published: November 2023

Abstract
Much to our surprise, this article has caused a stir in academic and practitioner circles, almost certainly because of a section about the equity premium. The key contribution of the work (from the authors’ perspective, at least) is that it analyzes a few basic cases in which the survival of a market or a security might affect econometric analysis. In particular, we show how very simple rules can dramatically bias the measure of the equity risk premium, the measure of the autocorrelation of stock market returns, and the measurement of the significance of corporate events, such as earnings announcements and stock splits. Our analysis of the equity risk premium is the most controversial—we show that if the probability of a market failure is high enough, then a researcher measuring the equity premium ex post, using historical data from only a market that has survived, will overestimate the premium. Although we do not claim that this “solves” the equity premium puzzle, we believe it adds another dimension to consider.
The Dow Theory: William Peter Hamilton’s Track Record Reconsidered
Authors: Brown Stephen J , Goetzmann William N , Kumar Alok 
Published: November 2023

Abstract
Alfred Cowles’ test of the Dow Theory apparently provides strong evidence against the ability of Wall Street’s most famous chartist, William Peter Hamilton, to forecast the stock market. Cowles’ (1934) analysis is a landmark in the development of empirical evidence about the informational efficiency of the market. He claims that market timing based on the Dow Theory results in returns that lag the market. In this article, we review Cowles’ evidence and find that it supports the contrary conclusion—the Dow Theory, as applied by Hamilton over the period 1902 to 1929, yields positive risk-adjusted returns. The difference in the results is apparently due to the lack of adjustment for risk. Cowles compares the returns obtained from Hamilton’s market timing strategy to a benchmark of a fully invested stock portfolio. In fact, the Hamilton portfolio, as Cowles interprets it, is frequently out of the market. Adjustment for systematic risk appears to vindicate Hamilton as a market timer.