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1.  Contribution of B-1a cells to systemic lupus erythematosus in the NZM2410 mouse model 
Systemic lupus erythematosus (SLE) is an autoimmune disease of complex etiology in which B cells play a central role. An expanded number of B-1a cells have been consistently associated with murine lupus, and more recently with human SLE. We have identified CdKn2c, a gene that controls cell cycle progression, as a key regulator of B-1a cell numbers, and have associated Cdkn2c deficiency with autoimmune pathology, including the production of autoantibodies and the skewing of CD4+ T cells toward inflammatory effector functions. We review the genetic studies that have led to these findings, as well as the possible mechanisms by which B-1a cell expansion and Cdkn2c deficiency are related to SLE pathogenesis.
PMCID: PMC4550580  PMID: 25728381
systemic lupus erythematosus; B-1a cell; NZM2410 mice
2.  Endosymbiont evolution: Predictions from theory and surprises from genomes 
Genome data has created new opportunities to untangle evolutionary processes shaping microbial variation. Among bacteria, long-term mutualists of insects represent the smallest and (typically) most AT-rich genomes. Evolutionary theory provides a context to predict how an endosymbiotic lifestyle may alter fundamental evolutionary processes - mutation, selection, genetic drift, and recombination - and thus contribute to extreme genomic outcomes. These predictions can then be explored by comparing evolutionary rates, genome size and stability, and base compositional biases across endosymbiotic and free-living bacteria. Recent surprises from such comparisons include genome reduction among uncultured, free-living species. Some studies suggest that selection generally drives this streamlining, while drift drives genome reduction in endosymbionts; however, this remains an hypothesis requiring additional data. Unexpected evidence of selection acting on endosymbiont GC content hints that even weak selection may be effective in some long-term mutualists. Moving forward, intraspecific analysis offers a promising approach to distinguish underlying mechanisms, by testing the null hypothesis of neutrality and by quantifying mutational spectra. Such analyses may clarify whether endosymbionts and free-living bacteria occupy distinct evolutionary trajectories or alternatively, represent varied outcomes of similar underlying forces.
PMCID: PMC4600008  PMID: 25866055
genome reduction; endosymbiosis; mutualism; molecular evolution; neutrality; population genetics
3.  B-1 lymphocytes in mice and non-human primates 
B-1 cells comprise subpopulations of B lymphocytes in mice that display developmental, phenotypic, and functional characteristics that are distinct from that of conventional B cell populations (often referred to as “B-2” cells). Despite the known importance of murine B-1a (CD5+) and B-1b (CD5−) cells in the production of natural antibodies and rapid antigen-specific humoral responses to infection, evidence for B-1 cells in primates, including humans, is very limited. Identifying these cells in humans proves challenging given the limited number of cells that can be obtained from sites expected to harbor increased frequencies of these cells (ie., peritoneal and pleural cavities) and the need to perform functional analyses on these cells, which in the case of B-1b cells must be carried out in vivo. The use of cynomolgus macaques and African Green monkeys has enabled us to bypass these limitations and to identify and extensively analyze primate B cell populations with the phenotypic and functional characteristics of mouse B-1a and B-1b cells. Our results reveal striking similarities between primate and murine B-1 cells, including a conserved functional role for primate B-1b–like cells in immunity to T cell independent type 2 antigens.
PMCID: PMC4627897  PMID: 25930711
Non-human primates; B-1a cells; B-1b cells; T cell independent type 2 antigens
4.  Protective natural autoantibodies to apoptotic cells: evidence of convergent selection of recurrent innate-like clones 
During murine immune development, recurrent B cell clones arise in a predictable fashion. Among these B cells, an archetypical clonotypic set that recognizes phosphorylcholine (PC) antigens and produces anti-PC IgM, first implicated for roles in microbial protection, was later found to become expanded in hyperlipidemic mice and in response to an increased in vivo burden of apoptotic cells. These IgM natural antibodies can enhance clearance of damaged cells and induce intracellular blockade of inflammatory signaling cascades. In clinical populations, raised levels of anti-PC IgM correlate with protection from atherosclerosis and may also down-modulate the severity of autoimmune disease. Human anti-PC-producing clones without hypermutation have been isolated that can similarly discriminate apoptotic from healthy cells. An independent report on unrelated adults has described anti-PC-producing B cells with IgM genes that have conserved CDR3 motifs, similar to stereotypic clonal sets of B cell chronic lymphocytic leukemia (CLL). Taken together, emerging evidence suggests that, despite the capacity to form an effectively limitless range of Ig receptors, the human immune system may often recurrently generate lymphocytes expressing structurally convergent BCRs with protective and homeostatic roles.
PMCID: PMC4651665  PMID: 25990717
natural antibody; apoptotic cell; immunoregulation; B cell; apoptotic clearance
5.  New insights into heterogeneity of peritoneal B-1a cells 
Peritoneal B-1a cells are characterized by their expression of CD5 and enrichment for germ line–encoded IgM B cell receptors (BCRs). Early studies showing expression of a diverse array of VDJ sequences among purified B-1a cells provided a molecular basis for understanding the heterogeneity of the B-1a cell repertoire. Antigen-driven positive selection and the identification of B-1a specific progenitors suggest multiple origins of B-1a cells. The introduction of new markers such as PD-L2, CD25, CD73, and PC1 (plasma cell alloantigen 1, also known as ectonucleotide phosphodiesterase/pyrophosphatase 1 (ENPP1)) further helped to identify phenotypically and functionally distinct B-1a subsets. Among many B-1a subsets defined by these new markers, PC1 is unique in that it subdivides B-1a cells into PC1hi and PC1lo subpopulations with distinct functions, such as production of natural IgM and gut IgA, response to the pneumococcal antigen PPS-3, secretion of interleukin (IL)-10, and support for T helper 1 (TH1) cell differentiation. RNA sequencing (RNA-seq) of these subsets revealed differential expression of genes involved in cellular movement and immune cell trafficking. We will discuss these new insights underlying the heterogeneous nature of the B-1a cell repertoire.
PMCID: PMC4651667  PMID: 25988856
B-1a; PC1; IL-10; lymphocyte trafficking
6.  Role of B cell receptor signaling in IL-10 production by normal and malignant B-1 cells 
B-1 cells are considered innate immune cells that produce the majority of natural antibodies. B-1 cell responses to B cell receptor (BCR) and Toll-like receptor (TLR) ligation are tightly regulated owing to the cross-reactivity to self-antigens. CD5 has been shown to play a major role in down regulation of BCR responses in B-1 cells. Here, we provide evidence for another mechanism by which BCR response is regulated in B-1 cells. B-1 cells, as well as their malignant counterpart B cell chronic lymphocytic leukemia (CLL) cells, produce interleukin-10 (IL-10) constitutively. IL-10 secretion by normal B-1 cells downregulates their proliferation responses to BCR ligation. However, we found that CLL cells appear to be unique in not responding to IL-10–mediated feedback-suppressive effects in comparison to normal B-1 cells. In addition, we describe a novel role of the B cell receptor signaling pathway in constitutive IL-10 secretion by normal and malignant B-1 cells. We found that inhibition of Src family kinases, spleen tyrosine kinase, Syk, or Bruton's tyrosine kinase (Btk) reduces constitutive IL-10 production by both normal and malignant B-1 cells.
PMCID: PMC4676736  PMID: 26096907
B-1 cell; B cell receptor; Toll-like receptor; chronic lymphocytic leukemia; IL-10
7.  B cells in the aging immune system: time to consider B-1 cells 
The investigation of immune senescence has uncovered many changes in B cell development, maintenance, and function with increasing age. However, most of these studies have focused on conventional B cell subsets in the spleen. The B-1 cell subset is an essential arm of the innate immune system, which in general has been understudied in terms of immune senescence. Here, we review what is currently known about B cells during aging and go on to describe why B-1 cell biology is an important component of the aging immune system in the context of diseases that most affect the aged population.
PMCID: PMC4679494  PMID: 26194480
B cells; aging; B-1 cells; senescence
8.  Fluorescence tagging and inducible depletion of PD-L2–expressing B-1 B cells in vivo 
L2pB1 cells are a subpopulation of B-1a B cells that express PD-L2 (programmed death ligand 2) as their unique cell surface marker. In mice, about 50% of peritoneal B-1a cells are L2pB1 cells. The remaining B-1a cells are L2nB1 (PD-L2−) B-1a cells. L2pB1 cells differ from L2nB1 cells in their immunoglobulin repertoire, expression of interleukin 10, and their capacity to phagocytose phosphatidylcholine (PtC). The physiological roles of L2pB1 cells have not been investigated owing to the lack of an animal model that allows for specific depletion of L2pB1 cells. Our data showed that depletion of L2pB1 cells significantly reduces serum anti-phosphorylcholine (PC) IgM level as well as IL-10 expression in the peritoneal cavity. This animal model provides an unequivocal tool for the study of the immune regulatory functions of L2pB1 cells in health and diseases.
PMCID: PMC4679664  PMID: 26291441
L2pB1 cells; monoallelic expression; ZsGreen; TdTomato; diphtheria toxin receptor
9.  The role of evolutionary conserved germline DH sequence in B-1 cell development and natural antibody production 
Due to N addition and variation in the site of V–D–J joining, the third complementarity-determining region of the heavy chain (CDR-H3) is the most diverse component of the initial immunoglobulin antigen-binding site repertoire. A large component of the peritoneal cavity B-1 cell component is the product of fetal and perinatal B cell production. The CDR-H3 repertoire is thus depleted of N addition, which increases dependency on germ-line sequence. Cross-species comparisons have shown that DH gene sequence demonstrates conservation of amino acid preferences by reading frame. Preference for reading frame 1, which is enriched for tyrosine and glycine, is created both by rearrangement patterns and by pre-BCR and BCR selection. In previous studies, we have assessed the role of conserved DH sequence by examining peritoneal cavity B-1 cell numbers and antibody production in BALB/c mice with altered DH loci. Here, we review our finding that changes in the constraints normally imposed by germ line–encoded amino acids within the CDR-H3 repertoire profoundly affect B-1 cell development, especially B-1a cells, and thus natural antibody immunity. Our studies suggest that both natural and somatic selection operate to create a restricted B-1 cell CDR-H3 repertoire.
PMCID: PMC4679679  PMID: 26104486
10.  Characteristics of natural antibody–secreting cells 
Natural IgM plays a critical role in protection from pathogens and the prevention of autoimmunity. While its importance has been shown in many different settings, its origins are incompletely understood. This review focuses on the properties of the natural IgM antibody-secreting cells (ASCs), which arise mainly from the B-1 cell lineage. B-1 cells are generated in multiple waves during development, mostly in the fetal and early postfetal periods. The developmental time points can affect their repertoire: prenatal B-1 cells express a mainly germ line–encoded repertoire, while postnatally developing B-1 cells can express Ig with a greater degree of variation. Spleen and bone marrow, but not the body cavities, are primary sites of natural IgM secretion. Within these tissues heterogeneous populations of IgM ASCs can be found. While some ASCs express classical markers of B-1 lymphocytes, others express those of terminally differentiated plasma cells. A better understanding of the properties of these different natural IgM ASCs could aid their future therapeutic exploitation.
PMCID: PMC4679694  PMID: 26104151
B-1 cells; B-1 cell development; Blimp-1; natural IgM
11.  A subset of AID-dependent B-1a cells initiates hypersensitivity and pneumococcal pneumonia resistance 
We propose that there is a special B-1a B cell subset (“sB-1a” cells) that mediates linked processes very early after immunization to initiate cutaneous contact sensitivity (CS), delayed-type hypersensitivity (DTH), and immune resistance to pneumococcal pneumonia. Our published data indicate that in CS and DTH these initiating processes are required for elicitation of the delayed onset and late-occurring classical T cell–mediated responses. sB-1a cells resemble memory B2 cells, as they are stimulated within 1-hour of immunization and depend on T helper cytokines—uniquely IL-4 from hepatic iNKT cells–for activation and rapid migration from the peritoneal cavity to the spleen to secrete IgM antibody (Ab) and Ab-derived free light chains (FLC) by only one day after immunization. Unlike conventional B-1a (cB-1a) cell–produced IgM natural Ab, IgM Ab produced by sB-1a cells has high Ag affinity owing to immunoglobulin V-region mutations induced by activation-induced cytidine deaminase (AID). The dominant cB-1a cells are increased in immunized AID-deficient mice but do not mediate initiation, CS, or pneumonia resistance because natural Ab has relatively low Ag-affinity because of unmutated germ line V-regions. In CS and DTH, sB-1a IgM Ag affinity is sufficiently high to mediate complement activation for generation of C5a that, together with vasoactive mediators such as TNF-α released by FLC-sensitized mast cells activate local endothelium for extravascular recruitment of effector T cells. We conclude by discussing the possibility of functional sB-1 cells in humans.
PMCID: PMC4681304  PMID: 26662721
activation-induced-deaminase; AID; free antibody light-chains; contact sensitivity; delayed-type hypersensitivity; DTH; pneumococcal pneumonia: B cell; IL-4
12.  Layered evolution in the immune system: a view from history 
Although much had still to be learned, evidence indicating that B-1a lymphocytes very likely belonged to a distinct lineage was largely in place by the time of the first large B-1a conference in 1991. The widely respected group of immunologists attending that meeting (including Tasuko Honjo and Klaus Rajewsky) developed and ultimately published the B-1a notation still in use today. Here, I briefly review some of the early B-1a findings that underlie current studies. I close with a brief summary of recent studies, mainly from my laboratory, showing that the hematopoietic stem cell (HSC) we all know and love as the origin of the cells that populate the adult lymphoid and myeloid system today is nonetheless not the origin of the B-1a lymphocytes with which most of us work today.
PMCID: PMC4761344  PMID: 26096553
HSC; B lineages; B-1a antibody responses; vaccine development
13.  Natural and induced B-1 cell immunity to infections raises questions of nature versus nurture 
Mouse B-1 cells are major producers of steady-state natural antibodies but also rapid responders to infections and inflammation. These discrete functions may be the outcomes of distinct environmental or developmental triggers that drive B-1 cells toward IgM production or an effector cell fate. Alternatively, distinct B-1 cell subsets may exist, which differ in their functional plasticity. In this paper, we summarize existing data suggesting that B-1 cells form a heterogeneous group of cells with distinct developmental requirements and non-overlapping functions. Most spleen B-1 cells differ in development from that of bone marrow and peritoneal cavity B-1 cells, in that they develop in the absence of natural IgM. Functional heterogeneity is revealed by findings that B-1 cells in the bone marrow and spleen, but not the peritoneal cavity, generate natural serum IgM, while the latter are rapid responders to inflammatory and infectious insults, resulting in their relocation to secondary lymphoid tissues. A clearer understanding of the developmental and functional differences within the B-1 cell pool may reveal how they might be harnessed for prophylaxis or therapy.
PMCID: PMC4881423  PMID: 26060895
B cell subsets; IgM; influenza virus infections; natural antibodies
14.  Acute hydrogen sulfide–induced neuropathology and neurological sequelae: challenges for translational neuroprotective research 
Hydrogen sulfide (H2S), the gas with the odor of rotten eggs, was formally discovered in 1777, over 239 years ago. For many years, it was considered an environmental pollutant and a health concern only in occupational settings. Recently, however, it was discovered that H2S is produced endogenously and plays critical physiological roles as a gasotransmitter. Although at low physiological concentrations it is physiologically beneficial, exposure to high concentrations of H2S is known to cause brain damage, leading to neurodegeneration and long‐term neurological sequelae or death. Neurological sequelae include motor, behavioral, and cognitive deficits, which are incapacitating. Currently, there are concerns about accidental or malicious acute mass civilian exposure to H2S. There is a major unmet need for an ideal neuroprotective treatment, for use in the field, in the event of mass civilian exposure to high H2S concentrations. This review focuses on the neuropathology of high acute H2S exposure, knowledge gaps, and the challenges associated with development of effective neuroprotective therapy to counteract H2S‐induced neurodegeneration.
PMCID: PMC5063677  PMID: 27442775
brain; hydrogen sulfide; neuropathology; neurodegeneration; neuroprotection
15.  Tear gas: an epidemiological and mechanistic reassessment 
Deployments of tear gas and pepper spray have rapidly increased worldwide. Large amounts of tear gas have been used in densely populated cities, including Cairo, Istanbul, Rio de Janeiro, Manama (Bahrain), and Hong Kong. In the United States, tear gas was used extensively during recent riots in Ferguson, Missouri. Whereas tear gas deployment systems have rapidly improved—with aerial drone systems tested and requested by law enforcement—epidemiological and mechanistic research have lagged behind and have received little attention. Case studies and recent epidemiological studies revealed that tear gas agents can cause lung, cutaneous, and ocular injuries, with individuals affected by chronic morbidities at high risk for complications. Mechanistic studies identified the ion channels TRPV1 and TRPA1 as targets of capsaicin in pepper spray, and of the tear gas agents chloroacetophenone, CS, and CR. TRPV1 and TRPA1 localize to pain‐sensing peripheral sensory neurons and have been linked to acute and chronic pain, cough, asthma, lung injury, dermatitis, itch, and neurodegeneration. In animal models, transient receptor potential inhibitors show promising effects as potential countermeasures against tear gas injuries. On the basis of the available data, a reassessment of the health risks of tear gas exposures in the civilian population is advised, and development of new countermeasures is proposed.
PMCID: PMC5096012  PMID: 27391380
tear gas; pepper spray; capsaicin; chlorobenzalmalononitrile; CS; CN; CR; TRPV1; TRPA1
16.  Toll-like receptor signaling in primary immune deficiencies 
Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are specific for susceptibility to herpes simplex virus type 1 (HSV-1) encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell (pDC) defects enhance defective responses of B cells to shared TLR agonists. Dampening of TLR responses is seen for TLRs 2 and 4 in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome, and for most TLRs in adenosine deaminase deficiency.
PMCID: PMC4629506  PMID: 25930993
Toll-like receptors; primary immune deficiency; human immunology; infection
17.  Central tolerance to self revealed by the autoimmune regulator 
The autoimmune regulator (Aire) was initially identified as the gene causing multiorgan system autoimmunity in humans, and deletion of this gene in mice also resulted in organ-specific autoimmunity. Aire regulates the expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), which play a critical role in the negative selection of autoreactive T cells and the generation of regulatory T cells. More recently, the role of Aire in the development of mTECs have helped elucidate its ability to present the spectrum of TSAs needed to prevent autoimmunity. Molecular characterization of the functional domains of Aire have revealed multiple binding partners that assist Aire’s function in altering gene transcription and chromatin remodeling. These recent advances have further highlighted the importance of Aire in central tolerance.
PMCID: PMC4654700  PMID: 26579596
Aire; mTEC; APS-1; autoimmunity
18.  Diseases caused by mutations in ORAI1 and STIM1 
Ca2+ release-activated Ca2+ (CRAC) channels mediate a specific form of Ca2+ influx called store-operated Ca2+ entry (SOCE) that contributes to the function of many cell types. CRAC channels are formed by ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in dental enamel. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in these genes result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca2+ levels that are associated with an overlapping spectrum of diseases, including non-syndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes, two syndromes defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca2+ homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology.
PMCID: PMC4692058  PMID: 26469693
CRAC channel; channelopathy; STIM1; ORAI1; SOCE; calcium; Ca2+; disease; muscular hypotonia; tubular aggregate myopathy; skeletal muscle; Stormorken syndrome; York platelet syndrome; autoimmunity; platelets; thrombocytopenia; mutation; enamel; ameloblast
19.  Behavioral and brain asymmetries in primates: a preliminary evaluation of two evolutionary hypotheses 
Contrary to many historical views, recent evidence suggest that species-level behavioral and brain asymmetries are evident in nonhuman species. Here, we briefly present evidence of behavioral, perceptual, cognitive, functional, and neuroanatomical asymmetries in nonhuman primates. In addition, we describe two historical accounts of the evolutionary origins of hemispheric specialization and present data from nonhuman primates that address these specific theories. Specifically, we first discuss the evidence of that genes play specific roles in determining left–right differences in anatomical and functional asymmetries in primates. We next consider and present data on the hypothesis that hemispheric specialization evolved as a by-product of increasing brain size relative to the size of the corpus callosum in different primate species. Lastly, we discuss some of the challenges in the study of hemispheric specialization in primates and offer some suggestions on how to advance the field.
PMCID: PMC4715693  PMID: 26426409
hemispheric specialization; primates; brain asymmetry; handedness; corpus callosum
20.  Fertility potential in thalassemia major women: current findings and future diagnostic tools 
Issues of preserving fertility, preventing early menopause, and predicting reproductive ability have become crucial for many adult thalassemia major females.
LH/FSH and estardiol, commonly used for assessment of fertility potential in thalassemia, have a poor predictive value. Current reproductive practice utilizes markers of ovarian reserve testing (ORT), which were not yet studied in thalassemia women. We explored the relationship between liver iron concentration (LIC) and fertility status in 26 females (mean 30 years old). Seventeen (65%) of them experienced primary or secondary amenorrhea. Levels of LH/FSH and estradiol were low or undetectable in 48% and 35% of patients, respectively and did not correlate with age, presence of amenorrhea and LIC. This further addresses the need for utilization of current available methods for assessment of fertility capacity in thalassemia, which will also allow future correlation with pituitary iron measures by MRI as well as early intervention for fertility preservation.
PMCID: PMC5074539  PMID: 20712797
Thalassemia major; infertility in thalassemia; ovarian reserve testing (ORT)
21.  Visualizing Myeloarchitecture With Magnetic Resonance Imaging in Primates 
Annals of the New York Academy of Sciences  2011;1225(Suppl 1):E171-E181.
The pattern of myelination over the cerebral cortex, termed myeloarchitecture, is an established and often-used feature to visualize cortical organization with histology in a variety of primate species. In this paper, we use in vivo magnetic resonance imaging (MRI) and advanced image processing using surface rendering to visualize and characterize myeloarchitecture in a small non-human primate, the common marmoset (Callithrix jacchus). Through images made in four female adult marmosets, we produce a representative 3D map of marmoset myeloarchitecture and flatten and annotate this map to show the location and extent of a variety of major areas of the cortex, including the primary visual, auditory, and somatosensory areas. By treating our MRI data as a surface, we can measure the surface area of cortical areas and we present these measurements here to summarize cortical organization in the marmoset.
PMCID: PMC5027904  PMID: 21599695
magnetic resonance imaging; brain mapping; cortex; myelin; primate
22.  Bioavailability of iron, vitamin A, zinc, and folic acid when added to condiments and seasonings 
Seasonings and condiments can be candidate vehicles for micronutrient fortification if consumed consistently and if dietary practices ensure bioavailability of the nutrient. In this review, we identify factors that may affect the bioavailability of iron, vitamin A, zinc, and folic acid when added to seasonings and condiments and evaluate their effects on micronutrient status. We take into consideration the chemical and physical properties of different forms of the micronutrients, the influence of the physical and chemical properties of foods and meals to which fortified seasonings and condiments are typically added, and interactions between micronutrients and the physiological and nutritional status of the target population. Bioavailable fortificants of iron have been developed for use in dry or fluid vehicles. For example, sodium iron ethylenediaminetetraacetic acid (NaFeEDTA) and ferrous sulfate with citric acid are options for iron fortification of fish and soy sauce. Furthermore, NaFeEDTA, microencapsulated ferrous fumarate, and micronized elemental iron are potential fortificants in curry powder and salt. Dry forms of retinyl acetate or palmitate are bioavailable fortificants of vitamin A in dry candidate vehicles, but there are no published studies of these fortificants in fluid vehicles. Studies of zinc and folic acid bioavailability in seasonings and condiments are also lacking.
PMCID: PMC5019242  PMID: 26469774
seasonings; condiments; bioavailability; iron; zinc; folate; folic acid; vitamin A
23.  Dopaminergic and cholinergic learning mechanisms in nicotine addiction 
Nicotine addiction drives tobacco use by one billion people worldwide, causing nearly six million deaths a year. Nicotine binds to nicotinic acetylcholine receptors that are normally activated by the endogenous neurotransmitter acetylcholine. The widespread expression of nicotinic receptors throughout the nervous system accounts for the diverse physiological effects triggered by nicotine. A crucial influence of nicotine is on the synaptic mechanisms underlying learning that contribute to the addiction process. Here, we focus on the acquisition phase of smoking addiction and review animal model studies on how nicotine modifies dopaminergic and cholinergic signaling in key nodes of the reinforcement circuitry: ventral tegmental area, nucleus accumbens (NAc), amygdala, and hippocampus. Capitalizing on mechanisms that subserve natural rewards, nicotine activates midbrain dopamine neurons directly and indirectly, and nicotine causes dopamine release in very broad target areas throughout the brain, including the NAc, amygdala, and hippocampus. In addition, nicotine orchestrates local changes within those target structures, alters the release of virtually all major neurotransmitters, and primes the nervous system to the influence of other addictive drugs. Hence, understanding how nicotine affects the circuitry for synaptic plasticity and learning may aid in developing reasoned therapies to treat nicotine addiction.
PMCID: PMC4564314  PMID: 26301866
dopamine; acetylcholine; VTA; hippocampus; nucleus accumbens; memory
24.  Resting-state functional connectivity and nicotine addiction: prospects for biomarker development 
Given conceptual frameworks of addiction as a disease of intercommunicating brain networks, examinations of network interactions may provide a holistic characterization of addiction-related dysfunction. One such methodological approach is the examination of resting-state functional connectivity, which quantifies correlations in low frequency fluctuations of the blood oxygen level–dependent magnetic resonance imaging signal between disparate brain regions in the absence of task performance. Here, evidence of differentiated effects of chronic nicotine exposure, which reduces the efficiency of network communication across the brain, and acute nicotine exposure, which increases connectivity within specific limbic circuits, is discussed. Several large-scale resting networks, including the salience, default, and executive control networks, have also been implicated in nicotine addiction. The dynamics of connectivity changes among and between these large-scale networks during nicotine withdrawal and satiety provide a heuristic framework with which to characterize the neurobiological mechanism of addiction. The ability to simultaneously quantify effects of both chronic (trait) and acute (state) nicotine exposure provides a platform to develop a neuroimaging-based addiction biomarker. While such development remains in its early stages, evidence of coherent modulations in resting-state functional connectivity at various stages of nicotine addiction suggests potential network interactions on which to focus future addiction biomarker development.
PMCID: PMC4563817  PMID: 26348486
addiction; nicotine; resting-state functional connectivity; biomarkers
25.  Dopaminergic and cholinergic learning mechanisms in nicotine addiction 
Nicotine addiction drives tobacco use by 1 billion people worldwide, causing nearly 6 million deaths a year. Nicotine binds to nicotinic acetylcholine receptors that are normally activated by the endogenous neurotransmitter acetylcholine. The widespread expression of nicotinic receptors throughout the nervous system accounts for the diverse physiological effects triggered by nicotine. A crucial influence of nicotine is on the synaptic mechanisms underlying learning that contribute to the addiction process. Here we focus on the acquisition phase of smoking addiction and review animal model studies on how nicotine modifies dopaminergic and cholinergic signaling in key nodes of the reinforcement circuitry: ventral tegmental area, nucleus accumbens (NAc), amygdala, and hippocampus. Capitalizing on mechanisms that subserve natural rewards, nicotine activates midbrain dopamine neurons directly and indirectly, and causes dopamine release in very broad target areas throughout the brain, including the NAc, amygdala, and hippocampus. In addition, nicotine orchestrates local changes within those target structures, alters the release of virtually all major neurotransmitters, and primes the nervous system to the influence of other addictive drugs. Hence, understanding how nicotine affects the circuitry for synaptic plasticity and learning may aid in developing reasoned therapies to treat nicotine addiction.
PMCID: PMC4564314  PMID: 26301866
dopamine; acetylcholine; VTA; hippocampus; nucleus accumbens; memory

Results 1-25 (1023)