Conflict of Interest: None declared
Many pregnant women around the world eat diets that are nutritionally inadequate, and result in undernourished infants who are at greater risk for health problems later in life. Adequate nutrition during infancy is essential for lifelong health and well-being. Infants should be exclusively breastfed for the first six months of life to achieve optimal growth, development and health. Thereafter, to meet their evolving nutritional requirements, infants should receive nutritionally adequate and safe complementary foods, while continue to be breastfed for up to two years or more. The 2006-2007 Pakistan Demographic

Inhibitors,research,lifescience,medical and Health survey (PDHS) was designed to provide data for monitoring the Inhibitors,research,lifescience,medical health situation in . The survey,1 showed that the infant mortality rate in Pakistan was 78 deaths per 1,000 live births, which was higher than those in Nepal (48 in 1,000 live births), India (57 in 1,000 live births) and Bangladesh (65 in 1,000 live births). The leading causes of infant

death were sepsis and infections (38%) followed by asphyxia Inhibitors,research,lifescience,medical (22%).1 Breast feeding plays an important role in the life of an infant as it is not only a source of nutrition, but also derives and strengthens the baby’s immunity and response. The survey,1 also highlighted that in Pakistan exclusive breast feeding for 6 months was only 37% of which only 55% continue to breast feed for 2 years. World Health Organization stresses the need of breast

Inhibitors,research,lifescience,medical feeding by reiterating that about 33% of infant deaths are preventable with the introduction of exclusive breast feeding initiated within an hour of delivery and continued for at least 6 months.2 With improvement in neonatal survival, the age of viability is being pushed back to 24 weeks. Due to obstetricians’ Inhibitors,research,lifescience,medical choice and failure of induction at early gestations the common mode of delivery at these gestations is cesarean. These factors along with newer surgical and anesthetic skills have made cesarean to be a safer method of delivery than previously thought. The safety of cesarean has resulted in a rise in the rates of cesarean delivery, and more and more patients and doctors feel more comfortable with the it.3 Operative delivery has great psychological impact, and not only the patient and her family, but sometimes even the doctor becomes less motivated to initiate breast feeding. Prolonged periods of separation between babies and mothers, which are due to anesthesia, baby being kept in nursery, or mother being selleck compound sedated for pain and unable to feed can lead to poor maternal milk surge. Poor maternal milk surge results in a vicious cycle of less milk, baby being hungry and irritable, and mother too exhausted to put in an extra effort. These factors lead to the failure of breast feeding rates, and in a larger perspective, result in infant morbidity, mortality and malnutrition.

Treatment details listed by disease site are described in Table 1. Prior radiation therapy was delivered to the treated area in 40% of patients, and 30% of patients received post-SBRT chemotherapy for at least one cycle. The target volume for radiotherapy was delineated by the fusion of the simulation CT scan with pre-treatment diagnostic CT or CT/FDG-PET imaging, to encompass the gross tumor volume (GTV) on CT or volume with SUV > 3.5 units (body weight) on FDG-PET. A planning target volume (PTV) was constructed by adding a custom 2-5mm margin radially around the GTV. Respiratory gating with a 4-D CT simulation Inhibitors,research,lifescience,medical was performed with 9 treated

sites (39%). Radiation was delivered in a single fraction (87% sites), or fractionated over 2 to 3 treatments, each Inhibitors,research,lifescience,medical at least 3 days apart. Isodose lines of typical treatment

plan for a metastatic colon adenocarcinoma lymph node treated with one fraction is depicted in Figure 1. Table 1 Patient characteristics Figure 1 Isodose lines of typical treatment plan for a metastatic colon adenocarcinoma lymph node treated with one fraction For image guidance, the interventional radiology service implanted radio-opaque fiducial markers in close proximity to the tumor target in 18 (78%) sites. At the time of treatment, these markers were utilized as on-board imaging targets for kv-kv image matching, incorporating Inhibitors,research,lifescience,medical respiratory gating as appropriate. Of the remaining 5 treated sites, image guidance was performed by cone beam CT at the time of treatment in 3 cases. Treatment setup was confirmed in the final 2 sites

by bony kv-kv image matching. A summary of treatment characteristics is listed in Table 2. Table 2 Treatment characteristics Treatment response and local control Treatment response based on CT & Inhibitors,research,lifescience,medical FDG-PET imaging at 1 month, 3 months, and last follow-up is presented in Table 3, with a median follow-up of 6.3 months after SBRT (range Inhibitors,research,lifescience,medical 1.5-12.2 months). The overall response rate (the sum of complete responses and partial responses) by treated site was noted in 36% (1 month), 47% (3 months) and 48% (final). A complete response was achieved in 13% (3 sites). At last follow-up, local control (sum of response rate and stable disease) Org 27569 was 74% (Tab 3, Fig 2). Table 4 lists local control by specifically RG7204 research buy grouped treatment sites. Table 3 Overall response Figure 2 Local control Table 4 Local control by site Metabolic response Pre-and post-SBRT evaluable CT/FDG-PET scans were available for review in 39% of treated sites. Based on maximum reported SUV, the metabolic response rate (sum of partial and complete responders) was 85% on final analysis (Tab 5, Fig 3). 23% of sites achieved a complete response. Two treated sites (13%) did show evidence of progression at 3 months, but subsequent CT/FDG-PET scans showed a decrease in maximum SUV; no patients suffered progressive disease based on metabolic imaging at last follow-up.

Jayanthi N. Koneru, Department of Internal Medicine, Division of Cardiology and Cardiac Electrophysiology, Virginia Commonwealth University, Richmond, Virginia, USA. Christopher Kogut, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA. Ericka L. Breden Crouse, Department of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, Inhibitors,research,lifescience,medical USA. Jules C. Hancox, School of Physiology

and Pharmacology and Cardiovascular Research Laboratories, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK. Antony Fernandez, Departments of Psychiatry and Virginia Commonwealth University and Mental Health Service Line, Veterans Administration Medical Center, Inhibitors,research,lifescience,medical Richmond, Virginia, USA. Ananda K. Pandurangi, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.

It has been over 50 years since Cade first described this simple cation’s therapeutic role in manic illness [Cade, 1949]. Since this discovery, our understanding of its mechanisms of action have developed significantly [Lenox and Hahn, 2000], although the full nature of its effects are yet to be elucidated. Lithium is primarily used in the recovery of bipolar affective disorder, with evidence supporting its role in both Inhibitors,research,lifescience,medical acute mania [Gershon and Soares,

1997; Soares and Gershon, 1998, 2000; Bowden, 2000; Poolsup et al. 2000; Shafti, 2010] and prophylactic treatment [Soares and Gershon, 1998, 2000; Burgess et al. 2001; Geddes et al. 2004, 2010]. It is also efficacious

in the treatment Inhibitors,research,lifescience,medical of unipolar depression [Coppen, 2000], particularly as augmentation therapy in severe refractory depression [Bauer et al. 2003b; Kennedy and Paykel, 2004], and bipolar depression [Lloyd et al. 2011]. In addition, it has been noted to effect aggressiveness [Jones et al. 2011], Akt inhibitor reduce suicide rates in affective disorders [Tondo and Baldessarini, 2000; Cipriani et al. Inhibitors,research,lifescience,medical 2005] and, more speculatively, has been considered as a possible therapeutic agent for treating chronic neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases [Marmol, 2008; Dudev and Lim, 2011]. Yet, despite no lithium’s extensive clinical applications and its ability to provide potentially lifesaving treatment to patients [Nemeroff, 2000; Jope, 2003], the exact mechanisms by which it exerts its therapeutic effects remain incompletely understood [Phiel and Klein, 2001; Gould and Manji, 2005; Haimovich et al. 2012]. Further exploration is required, to determine more fully why lithium provides effective mood stabilisation for patients and allow clearer insight into mood disorder pathophysiology. In addition, lithium’s usage is limited by its narrow therapeutic window and significant range of adverse side effects [Livingstone and Rampes, 2006; McKnight et al.

Lee12 calculated that infants born at 22–25 weeks and who are in the highest-risk category (male gender, no antenatal steroids, multiple birth, and lower weight percentile) have a mortality rate of over 80%, while for the lower-risk infants it is less than 20%. Given all the above data, what is one to do when confronted with an impending delivery at the limits of viability, i.e. 22–24 weeks? Whose data should serve as the reference point

for discussions with the parents? Whose Inhibitors,research,lifescience,medical data are so biased by a self-fulfilling prophesy of poor survival that they reflect an arbitrary decision not to initiate intensive care in infants born earlier than a given gestational age? Whose data have not factored in weight, gender, or administration of antenatal steroids Inhibitors,research,lifescience,medical in the decision-making process?4,13 In fact, careful perusal of the published reports does not allow one to conclude that we have

reached the biologic end of the line and that there is no more room for further improvement in the survival rate of these extremely immature infants, as in essence we have become prisoners of our own expectations. LONG-TERM MORBIDITY OUTCOME To many, the decision-making in this moral gray zone has been primarily influenced by the published Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical data as to the long-term neurodevelopmental outcome of the surviving infants and not mortality rates. Reports on follow-up data from the NICHD Network14 from two treatment epochs (E1: 1999–2001 and E2: 2002–2004) have noted that there was no improvement in early childhood outcome between the two periods (mirroring Inhibitors,research,lifescience,medical the lack of improvement in survival rates). In both periods

there was comparable use of prenatal steroids (approximately 80%), and there was no significant difference in the percentage of multiple births or female infants. The rate of significant neurodevelopmental impairment at 18–22 Selleckchem OSI-027 months in surviving infants born at 23 weeks or less was similar in both epochs, 23.6% in E1 and 26.5% in E2, and at 24 weeks it was 14.6% in E1 and 14.2% in E2. Most importantly, the percentage of the surviving infants born at 24 weeks or less who were unimpaired or only minimally impaired was no unless different in both epochs and was only 22%. As such, these data highlighting such a poor outcome have served for many as the basis for the global recommendation of restrictive care for the infant born before 24 weeks of gestation, i.e. limiting care to non-treatment and comfort care only. Unfortunately, the fact that such recommendations are unrelated to the various factors that significantly modify survival rates speaks of poor ethical reasoning.

Meehl suggested that individuals with schizotaxia would develop either schizotypy or schizophrenia, depending on the protection or liability afforded by environmental circumstances, although he later proposed that schizotaxia need not progress into either of these more overt conditions.42 Given current data showing that, in addition to genes, environmental events (eg, obstetric complications, viruses) augment susceptibility to schizophrenia, Faraone ct al43 proposed that we use the term schizotaxia to indicate the

premorbid, neurobiological substrate of schizophrenia. Now, almost 40 years after the idea of schizotaxia was first advanced, a preponderance Inhibitors,research,lifescience,medical of evidence shows it to be a clinically meaningful AZD1480 cost condition. In fact, studies of nonschizotypal, nonpsychotic relatives of schizophrenic patients show that schizotaxia is not merely a theoretical construct, but has distinct psychiatric and neurobiological features. These include negative symptoms, neuropsychological impairment, impaired eye-tracking, and structural brain abnormalities.43 Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical Schizotaxia is a broader construct than schizophrenia. Our empirical studies suggest that the basic symptoms of schizotaxia occurs in 20% to 50% of first-degree relatives

of schizophrenic patients.40,44 In comparison, only about 10% of relatives will become psychotic, and less than 10% will develop schizotypal personality disorder.45,46 These figures suggest that schizotaxia does not

lead inevitably to schizotypal personality or schizophrenia, but in most cases is a long-term condition. This leads to the question of what type of etiological model accounts best for a long-term biological vulnerability (schizotaxia) that, under some circumstances, leads to more serious conditions (schizophrenia). Inhibitors,research,lifescience,medical Diagnostic criteria for schizophrenia ignore its etiology and pathophysiology DSM-III (and later versions) explicitly dissociated diagnostic criteria from speculation about Inhibitors,research,lifescience,medical etiology to avoid incorporating theories of etiology that were not subjected to empirical tests. At this point, however, DSM-III’s rejection of theoretical speculation about etiology should not lead us to reject empirical facts about over etiology as being relevant to diagnosis or conceptualization. Moreover, such a view risks a continuing disconnection of treatment from etiology. Since the introduction of antipsychotic medications, pharmacological treatments have focused on alleviating the most acute, florid symptoms of schizophrenia, ie, those related to psychosis. Although several newer antipsychotic medications also alleviate selected negative symptoms and cognitive deficits, treatment remains symptomatic. It is not aimed at correcting specific causes of the disorder, nor is it aimed at preventing its onset. We recognize how counterintuitive it is to think of psychosis as a somewhat nonspecific end state of schizophrenia.

While the correlation effect may be partially related to the larger range of spikes seen at this concentration, both the significant correlation and the leftward shift can be parsimoniously accounted for by a β-adrenoceptor-mediated increase in granule cell membrane resistance (Lacaille and Schwartzkroin 1988). β-adrenoceptor effects as related to locus coeruleus Inhibitors,research,lifescience,medical activation The present results suggest that the β-adrenoceptor effects on long-term plasticity of either the fEPSP or the population spike are not linearly related to dose. Intermediate, rather than maximal, doses

appear to provide the clearest effects. This is consistent with a reported inverted U-curve for norepinephrine-associated arousal on neuronal activity and/or behavior and may provide an underpinning

of such effects in the dentate gyrus. In previous in vivo work all of the plasticity effects of locus coeruleus activation on the dentate gyrus-perforant path-evoked potential, whether in urethane-anesthetized (Harley and Inhibitors,research,lifescience,medical Milway 1986; Harley et al. 1989) or awake rats (Kitchigina et al. 1997; Walling and Harley 2004) could be blocked by the β-adrenoceptor antagonist propranolol. Inhibitors,research,lifescience,medical Future studies will be required to delineate the substrates of the buy TW-37 concentration effects observed. Varying concentrations of ISO may recruit differing proportions of β-adrenoceptor subtypes and the predominant localization of the β-adrenoceptor subtypes recruited may also differ. Higher concentrations may also be less selective for β-adrenoceptors. The main point of interest of the present experiments is that enduring, and differing, plasticity effects are recruited

by different levels and/or patterns Inhibitors,research,lifescience,medical of β-adrenoceptor activation. The local modulation of norepinephrine levels is likely to play a critical role in recruitment of plasticity, Inhibitors,research,lifescience,medical at least within the dentate gyrus. Naturalistic modulation of dentate gyrus plasticity The present patterns of results are consistent with independent β-adrenoceptor modulation of both synaptic input and cell excitability. Previous naturalistic investigations of novelty exploration, which activates the locus coeruleus (Vankov et al. 1995), together with monitoring of the perforant path-evoked potential, have revealed both an increase in cell DNA ligase excitability (Kitchigina et al. 1997) and a decrease in synaptic input (Moser 1996). A β-adrenoceptor antagonist prevented the increase in cell excitability (Kitchigina et al. 1997). The depression of synaptic input was not assessed pharmacologically (Moser 1996). Both forms of plasticity can be input selective (see for example Frick and Johnston 2005). Selective dendritic excitability changes have been proposed as another potential underpinning of learning and memory circuit changes (Frick and Johnston 2005; Reid and Harley 2010).

In contrast, Hinderlich et al. demonstrated that in lymphoblastoid cell lines expressing M712T, the membrane-bound sialic acid levels in patients did not differ from control (17). Salama et al. compared the sialylation status of cultured muscle cells from patients harboring M712T mutation with other patients having mutations in the epimerase domain (19). They have found that all patients have lower membrane-bound sialic acid levels but with overlapping values with control cells; M712T cells have lower sialic acid levels

but no statistical significance was seen. Other groups analyzed Inhibitors,research,lifescience,medical muscle glycoproteins and revealed that sialic acid levels are reduced (19–21). Nevertheless, it is still unclear why this disease should involve

primarily the skeletal muscle, while GNE is ubiquitously expressed, and sialic acid is involved in various physiologic processes in various organs. Functions of GNE beyond sialic acid synthesis Although Inhibitors,research,lifescience,medical GNE has been believed to be present in cytosol, it was surprising Inhibitors,research,lifescience,medical that it was also localized within the Golgi apparatus, as it colocalizes with golgin-97, a Golgi-specific protein (22). One possible explanation offered by the authors is the fact that sialylation of glycoconjugates occur in the Golgi complex. In addition, GNE was also detected in the nucleus, although this is controversial at present. These results Inhibitors,research,lifescience,medical suggested that GNE, apart from its role in sialic acid synthesis, might influence gene expression modulation when targeted to the nucleus. This observation also led to the hypothesis that GNE can act as a nucleocytoplasmic shuttling protein (22), but proving this would necessitate in vivo labeling of GNE to determine its precise subcellular targeting. Nonetheless, in a more recent paper, the subcellular distribution of GNE in skeletal muscles and primary myoblasts/myotubes

from DMRV patients remain unaltered Inhibitors,research,lifescience,medical (23), suggesting that other pathomechanistic factors await further elucidation to explain how GNE mutations contribute to no the phenotype of DMRV. Because hyposialylation in DMRV is not fully agreed upon, other authors consider a disparate between a low GNE enzymatic levels and variable reduction of sialic acid as reported by several groups. Thus they believed that there should be a role of GNE in addition to the already-established role of GNE in sialic acid synthesis. Wang et al. demonstrated that GNE controlled selleck chemicals sialyltransferase expression, ganglioside production (GM3 and GD3), and the subsequent modulation of proliferation and apoptosis, independent of sialic acid production (24). However, although the influence of GNE on sialyltranferase expression is far from being understood and may pose a challenge for further studies, this is not actually totally out of the context in the role of GNE in sialic acid synthesis.

Importantly, they were also able to demonstrate the persistence of these beneficial effects 5 years after the procedure. Furthermore, they showed the 5-year survival of patients who received stem cells was significantly better than that of controls (96% vs. 84%, P <0.01). The results of clinical trials in ischemic heart failure are difficult to compare since stem cell types,

their amount, and delivery routes were different. Inhibitors,research,lifescience,medical Based on available preclinical and clinical data, however, it seems that bone marrow stem cells (CD34+, mesenchymal stem cells) delivered intramyocardially yielded the best results. Although a significant step forward was made in stem Inhibitors,research,lifescience,medical cell therapy for ischemic heart failure, several important questions regarding

stem cell type, delivery method, amount of cells to be transplanted, and, above all, timing of stem cell transplantation in patients with ischemic heart disease remain unanswered and represent a focus of future research in this field. Stem Cell Therapy for Nonischemic Heart Failure Stem Cells and Inhibitors,research,lifescience,medical Remodelling in Nonischemic Heart Failure learn more One-third of heart failure patients have a diagnosis of dilated cardiomyopathy (DCM).28 DCM is thought to result from various pathogenic mechanisms including genetic factors, mechanical stress, and intoxication. However, about two-thirds of DCM patients show evidence of a myocardial viral genomic persistence, indicating that inflammation may be the most prevalent cause for DCM development.29 The progression to DCM may be caused by the direct Inhibitors,research,lifescience,medical adverse effects of

the pathogen upon the myocardial tissue or by activation of autoreactive lymphocytes via molecular mimicry, which leads to unfavorable changes in ventricular myocytes and extracellular matrix. Changes in cardiac myocytes after viral infections result from direct infection-dependent injury and by infection-induced autoimmune response. Besides their potential Inhibitors,research,lifescience,medical effects on cardiac myocyte regeneration, stem cells could improve cardiac function in DCM through potential paracrine effects, which include: (1) secretion of factors that attenuate apoptosis of endogenous cardiomyocytes unless and endothelial cells;30 (2) promotion of angiogenesis; (3) activation of resident cardiac stem cells;31 or (4) supplying large amounts of anti-inflammatory factors.32 Alternatively, stem cell transplantation may neutralize circulating autoantibodies that are present in DCM via similar mechanisms that are thought to be responsible for the effects of CD34+ cell transplantation in the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis.33 According to this postulate, stem cells might be able to limit the overactivated immune response in DCM by tolerization of autoreactive T and B cells.

The last two lectures were dedicated to the description of LMNA prevalence in two different realities: the Sardinia isle in Italy and the Poland country. N. Carboni showed his database including 46 subjects with LMNA gene mutations, all but 1 familial cases. He presented one of the families showing familial dilated cardiomyopathy with conduction defects due to mutation in Lamin A/C gene (28). Patients with overlapping syndromes, obtained by the concomitant presence of cardiac compromise,

Inhibitors,research,lifescience,medical late lipodystrophy of the Dunnigan type, diabetes and axonal neuropathy (34) and a series of pictures of lower limbs muscle MRI were shown. Despite the different (prevalently cardiac or muscle) phenotype, all patients had a similar pattern of posterior leg’s muscles involvement, affecting medial head of gastrocnemius, sartorius and lateral head of gastrocnemius (35). Follow

up studies on larger cohorts of patients are to be encouraged and the experience of the Italian Centre for Laminopathies taken as an example of Inhibitors,research,lifescience,medical a fruitful collaboration (36, 37). Irena Hausmanowa-Petrusewicz concluded the congress reporting various aspects of laminopathies Inhibitors,research,lifescience,medical in Poland. She said: “Our adventure with laminopathies started long time ago when we, by IKK Inhibitor VII in vivo chance, got for consultation the patient whom we were unable to recognize as were also same with local doctors. The diagnosis in this patient was made by British colleagues, who recognized laminopathy, which was a terminology unknown to us. In spite of this we

began fascinated by this problem. We started and still are working on laminopathies Inhibitors,research,lifescience,medical (38, 39). The historic patient was a member of huge family P., affected by emerinopathy (mutation in EMD gene). We had access many members of this family. The patients were only males, and we checked carriers, who were mostly fifty or sixty year old females, developing at this age cardiac symptoms. Such cardiac symptoms became clear to us as a part of clinical picture, following muscle involvement and joint contractures. Quite soon after identification of Inhibitors,research,lifescience,medical the second gene associated with similar clinical presentation we found also in Poland many cases which had the same phenotype, resulting from mutations in another gene, LMNA, encoding lamin A/C. The most fascinating through problem became to us the striking variability (inter- and intrafamiliar) of phenotype in laminopathic disorders. Our clinical activity was concentrated on therapy, provided by the Department of cardiology, chaired by prof. Opolski (39). In the following years we started to look for patients in the clinical centers of our country and as a result we became still modest, but anyway leading center of laminopathies in Poland. We recognized better the pathology of nuclear proteins i.a. that expressed in other tissues, manifesting as lipodystrophy, peripheral neuropathy, isolated cardiomyopathy and progeria.

Contributor Information Francesco Urciuolo, Center for Advanced Microbiology inhibitor Biomaterials for HealthCare at CRIB Istituto Italiano di Tecnologia, Naples, Italy; Interdisciplinary Research Center on Biomaterials (CRIB), University of Naples Federico II, Naples, Italy. Giorgia Imparato, Center for Advanced Biomaterials for HealthCare at CRIB Istituto Italiano di Tecnologia, Naples, Italy; Interdisciplinary Inhibitors,research,lifescience,medical Research Center on Biomaterials (CRIB),

University of Naples Federico II, Naples, Italy. Alessandra Totaro, Center for Advanced Biomaterials for HealthCare at CRIB Istituto Italiano di Tecnologia, Naples, Italy; Interdisciplinary Research Center on Biomaterials (CRIB), University of Naples Federico II, Naples, Italy. Paolo A. Netti, Center for Advanced Biomaterials for HealthCare at CRIB Istituto Italiano di Tecnologia, Inhibitors,research,lifescience,medical Naples, Italy; Interdisciplinary Research Center on Biomaterials (CRIB), University of Naples Federico II, Naples, Italy.
Introduction Inhibitors,research,lifescience,medical In 2012, the Nobel Prize in Medicine or Physiology was awarded jointly to Dr. Shinya Yamanaka and Sir John B. Gurdon “for the discovery that mature cells can be reprogrammed to become

pluripotent.” The work of these scientists has opened our eyes to the plasticity of cells and to the possibilities for true regeneration. As described below, the development of iPSCs will soon change the way we practice medicine. Dr. Gurdon was the first to show that cell fate was fluid and that pluripotency could be restored in somatic cells. In 1962, he revealed that when the nucleus from Inhibitors,research,lifescience,medical a mature somatic cell (a frog intestinal cell) was Inhibitors,research,lifescience,medical placed into an enucleated egg cell, it could be reprogrammed. Specifically, the modified egg cell containing the nucleus from the frog intestinal cell developed into

a normal tadpole. Thus, factors within the enucleated egg cell could act on the nucleus of the somatic cell, reprogramming its chromatin to express the genes required for pluripotency. Four decades later, Dr. Yamanaka embarked upon a heroic project to determine which factors were responsible Ribonucleotide reductase for pluripotency. He focused on transcriptional proteins that were known to be expressed by pluripotent stem cells in mice. Remarkably, he discovered that a small set of factors could reprogram mature cells to become pluripotent stem cells. Specifically, by overexpressing the genes encoding just four transcriptional proteins, he could induce mouse fibroblasts to become pluripotent stem cells. These iPSCs could generate any tissue in the mouse. In 2007, he showed that the same four genes, when overexpressed in human fibroblasts, could also generate iPSCs. Dr.