Single-cell analysis of the T-cell receptor repertoire in untreated myeloma patients suggests potential myeloma-reactive CD8+ T-cells are shared between blood and marrow.

Not available.

The Parasite-Derived Peptide, FhHDM-1, Selectively Modulates miRNA Expression in ß-Cells to Prevent Apoptotic Pathways Induced by Proinflammatory Cytokines.

We have previously identified a parasite-derived peptide, FhHDM-1, that prevented the progression of diabetes in nonobese diabetic (NOD) mice. Disease prevention was mediated by the activation of the PI3K/Akt pathway to promote ß-cell survival and metabolism without inducing proliferation. To determine the molecular mechanisms driving the antidiabetogenic effects of FhHDM-1, miRNA:mRNA interactions and in silico predictions of the gene networks were characterised in ß-cells, which were exposed to the proinflammatory cytokines that mediate ß-cell destruction in Type 1 diabetes (T1D), in the presence and absence of FhHDM-1. The predicted gene targets of miRNAs differentially regulated by FhHDM-1 mapped to the biological pathways that regulate ß-cell biology. Six miRNAs were identified as important nodes in the regulation of PI3K/Akt signaling. Additionally, IGF-2 was identified as a miRNA gene target that mediated the beneficial effects of FhHDM-1 on ß-cells. The findings provide a putative mechanism by which FhHDM-1 positively impacts ß-cells to permanently prevent diabetes. As ß-cell death/dysfunction underlies diabetes development, FhHDM-1 opens new therapeutic avenues.

Who feels happier right now?: The impact of temporal distance on children's judgements of emotional intensity.

Do children consider temporal distance in their reasoning about the world? Using a novel method that relied minimally on verbal ability, we asked N = 106 3- to 6-year-olds to judge which of two characters felt more 'happy'/'sad' right now: one engaging in a pleasant/unpleasant activity tomorrow or another engaging in this same activity when they are a year older. That is, we examined whether children understood that the closer in time a future event, the more intense the currently felt emotion. Starting at age 4, children correctly judged which child was more 'happy'/'sad' right now. However, 4- to 6-year-olds tended not to explain their judgements by referring to temporal distance, per se. Results suggest that children are sensitive to temporal distance early in development, but do not yet verbally express this understanding. Implications for theories about children's future thinking and future areas of research are discussed.

The helminth-derived peptide, FhHDM-1, reverses the trained phenotype of NOD bone-marrow-derived macrophages and regulates proinflammatory responses.

We implicate a phenotype of trained immunity in bone-marrow-derived macrophages in the onset and progression of type 1 diabetes in nonobese diabetic mice. Treatment with FhHDM-1 reversed immune training, reducing histone methylation and glycolysis, and decreasing proinflammatory cytokine production to the same level as macrophages from nondiabetic immune-competent BALB/c mice.

Tomorrow versus a year from now: Do children represent the near and distant future differently?

Adults represent the near future more concretely and vividly than the distant future, with important implications for future-oriented behavior (e.g., planning, self-control). Although children are adept at describing future events at around 5 years of age, we know little about how temporal distance (i.e., "near" vs "distant") affects their future event representations. In a series of three experiments, we sought to determine the effects of temporal distance, age, and event frequency on children's future event representations. Participants, 5- to 9-year-olds, were asked to describe frequent (e.g., snack) and infrequent (e.g., party) events, with half of children imagining that these events would happen in the near future and the other half imagining that they would happen in the distant future. We investigated the effect of temporal distance on numerous event representation indicators (e.g., clarity, details, pronouns), all theoretically grounded in previous literature. Although children perceived near events as closer in time than distant events (Experiments 2 and 2b) and temporal distance affected the clarity of event representations (Experiment 2), most indicators were not affected by temporal distance. In contrast, event frequency (examined in Experiment 1) played an important role in children's event representations, with infrequent events being described more concretely than frequent events. Results suggest that young children may begin perceiving differences in temporal distance but that this does not translate to their event representations (e.g., clarity, pronouns) until later in development. Implications for children's future thinking and future research are discussed.

How do parasitic worms prevent diabetes? An exploration of their influence on macrophage and ß-cell crosstalk.

Diabetes is the fastest growing chronic disease globally, with prevalence increasing at a faster rate than heart disease and cancer. While the disease presents clinically as chronic hyperglycaemia, two distinct subtypes have been recognised. Type 1 diabetes (T1D) is characterised as an autoimmune disease in which the insulin-producing pancreatic ß-cells are destroyed, and type 2 diabetes (T2D) arises due to metabolic insufficiency, in which inadequate amounts of insulin are produced, and/or the actions of insulin are diminished. It is now apparent that pro-inflammatory responses cause a loss of functional ß-cell mass, and this is the common underlying mechanism of both T1D and T2D. Macrophages are the central immune cells in the pathogenesis of both diseases and play a major role in the initiation and perpetuation of the proinflammatory responses that compromise ß-cell function. Furthermore, it is the crosstalk between macrophages and ß-cells that orchestrates the inflammatory response and ensuing ß-cell dysfunction/destruction. Conversely, this crosstalk can induce immune tolerance and preservation of ß-cell mass and function. Thus, specifically targeting the intercellular communication between macrophages and ß-cells offers a unique strategy to prevent/halt the islet inflammatory events underpinning T1D and T2D. Due to their potent ability to regulate mammalian immune responses, parasitic worms (helminths), and their excretory/secretory products, have been examined for their potential as therapeutic agents for both T1D and T2D. This research has yielded positive results in disease prevention, both clinically and in animal models. However, the focus of research has been on the modulation of immune cells and their effectors. This approach has ignored the direct effects of helminths and their products on ß-cells, and the modulation of signal exchange between macrophages and ß-cells. This review explores how the alterations to macrophages induced by helminths, and their products, influence the crosstalk with ß-cells to promote their function and survival. In addition, the evidence that parasite-derived products interact directly with endocrine cells to influence their communication with macrophages to prevent ß-cell death and enhance function is discussed. This new paradigm of two-way metabolic conversations between endocrine cells and macrophages opens new avenues for the treatment of immune-mediated metabolic disease.

The helminth derived peptide FhHDM-1 redirects macrophage metabolism towards glutaminolysis to regulate the pro-inflammatory response.

We have previously identified an immune modulating peptide, termed FhHDM-1, within the secretions of the liver fluke, Fasciola hepatica, which is sufficiently potent to prevent the progression of type 1 diabetes and multiple sclerosis in murine models of disease. Here, we have determined that the FhHDM-1 peptide regulates inflammation by reprogramming macrophage metabolism. Specifically, FhHDM-1 switched macrophage metabolism to a dependence on oxidative phosphorylation fuelled by fatty acids and supported by the induction of glutaminolysis. The catabolism of glutamine also resulted in an accumulation of alpha ketoglutarate (α-KG). These changes in metabolic activity were associated with a concomitant reduction in glycolytic flux, and the subsequent decrease in TNF and IL-6 production at the protein level. Interestingly, FhHDM-1 treated macrophages did not express the characteristic genes of an M2 phenotype, thereby indicating the specific regulation of inflammation, as opposed to the induction of an anti-inflammatory phenotype per se. Use of an inactive derivative of FhHDM-1, which did not modulate macrophage responses, revealed that the regulation of immune responses was dependent on the ability of FhHDM-1 to modulate lysosomal pH. These results identify a novel functional association between the lysosome and mitochondrial metabolism in macrophages, and further highlight the significant therapeutic potential of FhHDM-1 to prevent inflammation.

Pancreatic Transdifferentiation Using ß-Cell Transcription Factors for Type 1 Diabetes Treatment.

Type 1 diabetes is a chronic illness in which the native beta (ß)-cell population responsible for insulin release has been the subject of autoimmune destruction. This condition requires patients to frequently measure their blood glucose concentration and administer multiple daily exogenous insulin injections accordingly. Current treatments fail to effectively treat the disease without significant side effects, and this has led to the exploration of different approaches for its treatment. Gene therapy and the use of viral vectors has been explored extensively and has been successful in treating a range of diseases. The use of viral vectors to deliver ß-cell transcription factors has been researched in the context of type 1 diabetes to induce the pancreatic transdifferentiation of cells to replace the ß-cell population destroyed in patients. Studies have used various combinations of pancreatic and ß-cell transcription factors in order to induce pancreatic transdifferentiation and have achieved varying levels of success. This review will outline why pancreatic transcription factors have been utilised and how their application can allow the development of insulin-producing cells from non ß-cells and potentially act as a cure for type 1 diabetes.

Exploring the role of macrophages in determining the pathogenesis of liver fluke infection.

The food-borne trematodes, Opisthorchis viverrini and Clonorchis sinensis, are classified as group 1 biological carcinogens: definitive causes of cancer. By contrast, infections with Fasciola hepatica, also a food-borne trematode of the phylum Platyhelminthes, are not carcinogenic. This review explores the premise that the differential activation of macrophages during infection with these food-borne trematodes is a major determinant of the pathological outcome of infection. Like most helminths, the latter stages of infection with all 3 flukes induce M2 macrophages, a phenotype that mediates the functional repair of tissue damaged by the feeding and migratory activities of the parasites. However, there is a critical difference in how the development of pro-inflammatory M1 macrophages is regulated during infection with these parasites. While the activation of the M1 macrophage phenotype is largely suppressed during the early stages of infection with F. hepatica, M1 macrophages predominate in the bile ducts following infection with O. viverrini and C. sinensis. The anti-microbial factors released by M1 macrophages create an environment conducive to mutagenesis, and hence the initiation of tumour formation. Subsequently, the tissue remodelling processes induced by the M2 macrophages promote the proliferation of mutated cells, and the expansion of cancerous tissue. This review will also explore the interactions between macrophages and parasite-derived signals, and their contributions to the stark differences in the innate immune responses to infection with these parasites.

Targeting the PI3K/Akt signaling pathway in pancreatic ß-cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin-producing ß-cells within the pancreas. Islet transplantation represents one cure; however, during islet preparation and post transplantation significant amounts of ß-cell death occur. Therefore, prevention and cure of T1D is dependent upon the preservation of ß-cell function and the prevention of ß-cell death. Phosphoinositide 3-kinase (PI3K)/Akt signaling represents a promising therapeutic target for T1D due to its pronounced effects on cellular survival, proliferation, and metabolism. A growing amount of evidence indicates that PI3K/Akt signaling is a critical determinant of ß-cell mass and function. Modulation of the PI3K/Akt pathway, directly (via the use of highly specific protein and peptide-based biologics, excretory/secretory products of parasitic worms, and complex constituents of plant extracts) or indirectly (through microRNA interactions) can regulate the ß-cell processes to ultimately determine the fate of ß-cell mass. An important consideration is the identification of the specific PI3K/Akt pathway modulators that enhance ß-cell function and prevent ß-cell death without inducing excessive ß-cell proliferation, which may carry carcinogenic side effects. Among potential PI3K/Akt pathway agonists, we have identified a novel parasite-derived protein, termed FhHDM-1 (Fasciola hepatica helminth defense molecule 1), which efficiently stimulates the PI3K/Akt pathway in ß-cells to enhance function and prevent death without concomitantly inducing proliferation unlike several other identified stimulators of PI3K/Akt signaling . As such, FhHDM-1 will inform the design of biologics aimed at targeting the PI3K/Akt pathway to prevent/ameliorate not only T1D but also T2D, which is now widely recognized as an inflammatory disease characterized by ß-cell dysfunction and death. This review will explore the modulation of the PI3K/Akt signaling pathway as a novel strategy to enhance ß-cell function and survival.

Recall, response bias and recognition are differentially impacted by social anxiety irrespective of feedback modality.

BACKGROUND AND OBJECTIVES: This study replicates and extends Houle-Johnson et al.'s (2019) findings to better understand the role of feedback modality, ambiguity and social anxiety in the recognition and recall of self-relevant feedback. METHODS: Participants gave a speech and were provided with positive, negative, and ambiguous feedback via written text, (n = 33) or recorded sentences (n = 31) and later completed a recognition and recall task for the feedback. RESULTS: Recognition (p = .80, ηp2 = 0) and recall (p = .09, ηp2 = 0.08) did not differ between written or recorded feedback. All participants demonstrated a negative response bias (p < .001, ηp2 = 0.22) and recalled more negative than positive feedback (p = .02, ηp2 = 0.10) but were no more accurate in recognizing negative compared to positive feedback (p = .08, ηp2 = 0). Although social anxiety did not impact recognition accuracy (p = .94, ηp2 = 0), participants with high social anxiety demonstrated a more pronounced negative response bias (p < .01, ηp2 = 0.11) and negative recall bias (p = .02, SE = 1.12) than low social anxiety participants. Moreover, the more negatively ambiguous items were perceived, the more likely they were identified old in the high social anxiety group, whereas the opposite was true for the low social anxiety group (B = .13, p < .10). LIMITATIONS: Task believability was relatively low across all participants. CONCLUSIONS: Our findings suggest that modality does not influence memory for feedback. Moreover, social anxiety might be characterized by a negative bias in recall and response bias, but not necessarily increased accuracy in recognition of negative feedback.

The parasite-derived peptide FhHDM-1 activates the PI3K/Akt pathway to prevent cytokine-induced apoptosis of ß-cells.

Type 1 diabetes (T1D) is an autoimmune disease characterised by the destruction of the insulin-producing beta (ß)-cells within the pancreatic islets. We have previously identified a novel parasite-derived molecule, termed Fasciola hepatica helminth defence molecule 1 (FhHDM-1), that prevents T1D development in non-obese diabetic (NOD) mice. In this study, proteomic analyses of pancreas tissue from NOD mice suggested that FhHDM-1 activated the PI3K/Akt signalling pathway, which is associated with ß-cell metabolism, survival and proliferation. Consistent with this finding, FhHDM-1 preserved ß-cell mass in NOD mice. Examination of the biodistribution of FhHDM-1 after intraperitoneal administration in NOD mice revealed that the parasite peptide localised to the pancreas, suggesting that it exerted a direct effect on the survival/function of ß-cells. This was confirmed in vitro, as the interaction of FhHDM-1 with the NOD-derived ß-cell line, NIT-1, resulted in increased levels of phosphorylated Akt, increased NADH and NADPH and reduced activity of the NAD-dependent DNA nick sensor, poly(ADP-ribose) polymerase (PARP-1). As a consequence, ß-cell survival was enhanced and apoptosis was prevented in the presence of the pro-inflammatory cytokines that destroy ß-cells during T1D pathogenesis. Similarly, FhHDM-1 protected primary human islets from cytokine-induced apoptosis. Importantly, while FhHDM-1 promoted ß-cell survival, it did not induce proliferation. Collectively, these data indicate that FhHDM-1 has significant therapeutic applications to promote ß-cell survival, which is required for T1D and T2D prevention and islet transplantation. KEY MESSAGES: FhHDM-1 preserves ß-cell mass in NOD mice and prevents the development of T1D. FhHDM-1 enhances phosphorylation of Akt in mouse ß-cell lines. FhHDM-1 increases levels of NADH/NADPH in mouse ß-cell lines in vitro. FhHDM-1 prevents cytokine-induced cell death of mouse ß-cell lines and primary human ß-cells in vitro via activation of the PI3K/Akt pathway.

Neonatal Rats Exhibit a Predominantly Anti-Inflammatory Response following Spinal Cord Injury.

It has been reported that children may respond better than adults to a spinal cord injury (SCI) of similar severity. There are known biomechanical differences in the developing spinal cord that may contribute to this "infant lesion effect," but the underlying mechanisms are unknown. Using immunohistochemistry, we have previously demonstrated a different injury progression and immune cell response after a mild thoracic contusion SCI in infant rats, as compared to adult rats. Here, we investigated the acute inflammatory responses using flow cytometry and ELISA at 1 h, 24 h, and 1 week after SCI in neonatal (P7) and adult (9 weeks) rats, and locomotor recovery was examined for 6 weeks after injury. Adult rats exhibited a pronounced pro-inflammatory response characterized by neutrophils and M1-like macrophage infiltration and Th1 cytokine secretion. Neonatal rats exhibited a decreased pro-inflammatory response characterized by a higher proportion of M2-like macrophages and reduced Th1 cytokine responses, as compared to adults. These results suggest that the initial inflammatory response to SCI is predominantly anti-inflammatory in very young animals.

Tomorrow will be different: Children's ability to incorporate an intervening event when thinking about the future.

Future-oriented thought is ubiquitous in humans but challenging to study in children. Adults not only think about the future but can also represent a future state of the world that differs from the present. However, behavioral tasks to assess the development of future thought have not traditionally required children to do so as most can be solved based solely on representations of the present. To overcome this limitation, we modified an existing task such that children could not simply rely on a representation of the present to succeed (i.e., the correct answer for "right now" was different than the correct answer for "tomorrow"). A sample of 117 4- to 7-year-olds (64 girls and 53 boys) from Ottawa, Canada, and surrounding area, who were predominantly European Canadian (78.6% of sample) and had a family income of over $100,000 CAN (66.1% of sample) participated. Children remembered the information required to solve our task, and there were age-related changes in performance, but only 7-year-olds made an adaptive future-oriented decision significantly more often than chance. With the task modification removed (so the correct answer for the present and the future was the same), even 4-year-olds were above chance. Our work challenges the notion that starting at age 4, children solve behavioral tasks of future thinking by acting on their representations of the future. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Use of a Hybrid Adeno-Associated Viral Vector Transposon System to Deliver the Insulin Gene to Diabetic NOD Mice.

Previously, we used a lentiviral vector to deliver furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes using intervallic infusion in full flow occlusion (FFO), with resultant reversal of diabetes, restoration of glucose tolerance and pancreatic transdifferentiation (PT), due to the expression of beta (ß)-cell transcription factors (ß-TFs). The present study aimed to determine whether we could similarly reverse diabetes in the non-obese diabetic (NOD) mouse using an adeno-associated viral vector (AAV) to deliver INS-FUR ± the ß-TF Pdx1 to the livers of diabetic mice. The traditional AAV8, which provides episomal expression, and the hybrid AAV8/piggyBac that results in transgene integration were used. Diabetic mice that received AAV8-INS-FUR became hypoglycaemic with abnormal intraperitoneal glucose tolerance tests (IPGTTs). Expression of ß-TFs was not detected in the livers. Reversal of diabetes was not achieved in mice that received AAV8-INS-FUR and AAV8-Pdx1 and IPGTTs were abnormal. Normoglycaemia and glucose tolerance were achieved in mice that received AAV8/piggyBac-INS-FUR/FFO. Definitive evidence of PT was not observed. This is the first in vivo study using the hybrid AAV8/piggyBac system to treat Type 1 diabetes (T1D). However, further development is required before the system can be used for gene therapy of T1D.

Are all distances created equal? Insights from developmental psychology.

Gilead et al.'s theory presupposes that traversing temporal, spatial, social, and hypothetical distances are largely interchangeable acts of mental travel that co-occur in human ontogeny. Yet, this claim is at odds with recent developmental data suggesting that children's reasoning is differentially affected by the dimension which they must traverse, and that different representational abilities underlie travel across different dimensions.

The roles of perspective and language in children's ability to delay gratification.

Increasing psychological distance is an established method for improving children's performance in a number of self-regulation tasks. For example, using a delay of gratification (DoG) task, Prencipe and Zelazo (Psychological Science, 2005, Vol. 16, pp. 501-505) showed that 3-year-olds delay more for "other" than they do for "self," whereas 4-year-olds make similar choices for self and other. However, to our knowledge, no work has manipulated language to increase psychological distance in children. In two experiments, we sought to manipulate psychological distance by replicating Prencipe and Zelazo's age-related findings and extending them to older children (Experiment 1) and also sought to manipulate psychological distance using the auxiliary verbs "want" and "should" to prime more impulsive preference-based decisions or more normative optimal decisions (Experiment 2). In Experiment 1, 96 3- to 7-year-olds showed age-related improvements and interactive effects between age and perspective on DoG performance. In Experiment 2, 132 3- to 7-year-olds showed age-related improvements and a marginal interaction between age and perspective on DoG performance, but no effect of auxiliary verbs was detected. Results are discussed in terms of differing developmental trajectories of DoG for self and other due to psychological distancing, and how taking another's perspective may boost DoG in younger children but not older children.

Ex Vivo Expansion of Murine MSC Impairs Transcription Factor-Induced Differentiation into Pancreatic ß-Cells.

Combinatorial gene and cell therapy as a means of generating surrogate ß-cells has been investigated for the treatment of type 1 diabetes (T1D) for a number of years with varying success. One of the limitations of current cell therapies for T1D is the inability to generate sufficient quantities of functional transplantable insulin-producing cells. Due to their impressive immunomodulatory properties, in addition to their ease of expansion and genetic modification ex vivo, mesenchymal stem cells (MSCs) are an attractive alternative source of adult stem cells for regenerative medicine. To overcome the aforementioned limitation of current therapies, we assessed the utility of ex vivo expanded bone marrow-derived murine MSCs for their persistence in immune-competent and immune-deficient animal models and their ability to differentiate into surrogate ß-cells. CD45-/Ly6+ murine MSCs were isolated from the bone marrow of nonobese diabetic (NOD) mice and nucleofected to express the bioluminescent protein, Firefly luciferase (Luc2). The persistence of a subcutaneous (s.c.) transplant of Luc2-expressing MSCs was assessed in immune-competent (NOD) (n = 4) and immune-deficient (NOD/Scid) (n = 4) animal models of diabetes. Luc2-expressing MSCs persisted for 2 and 12 weeks, respectively, in NOD and NOD/Scid mice. Ex vivo expanded MSCs were transduced with the HMD lentiviral vector (MOI = 10) to express furin-cleavable human insulin (INS-FUR) and murine NeuroD1 and Pdx1. This was followed by the characterization of pancreatic transdifferentiation via reverse transcriptase polymerase chain reaction (RT-PCR) and static and glucose-stimulated insulin secretion (GSIS). INS-FUR-expressing MSCs were assessed for their ability to reverse diabetes after transplantation into streptozotocin- (STZ-) diabetic NOD/Scid mice (n = 5). Transduced MSCs did not undergo pancreatic transdifferentiation, as determined by RT-PCR analyses, lacked glucose responsiveness, and upon transplantation did not reverse diabetes. The data suggest that ex vivo expanded MSCs lose their multipotent differentiation potential and may be more useful as gene therapy targets prior to expansion.

Negative verbal self-relevant feedback is recognized with greater accuracy than facial feedback regardless of depression or social anxiety.

BACKGROUND AND OBJECTIVES: Self-referent information is critical for navigating the social realm, as we constantly use both verbal and non-verbal feedback in our interactions to understand ourselves and the world. In non-clinical samples, a memory bias for positive self-referent information has been observed, while a negativity bias has been observed among those with depression and anxiety. While research suggests that visual and auditory information is processed differently, no study has yet examined if memory biases persist for self-referent information presented by either means. We examined differences in memory for self-relevant social information presented as verbal or facial feedback, and whether symptoms of depression or anxiety influence memory for such information. We predicted that participants would remember more positive feedback overall, and that depression and anxiety would be positively related to memory for negative items. METHODS: Participants gave a speech, and were provided with positive and negative feedback via facial expressions, (n = 25) or verbal feedback presented aurally (n = 26). Participants then did a recognition test for the feedback they recieved. RESULTS: Recognition was higher for negative compared to positive feedback in the verbal condition, regardless of depression or anxiety. No memory biases were observed in the facial feedback condition. LIMITATIONS: No neutral stimuli was presented. CONCLUSIONS: Findings suggest that the type of social feedback one receives may influence how information is remembered, regardless of symptomatology. Future studies should examine the mechanisms by which memory biases exist for different types of self-relevant feedback.

Partial pancreatic transdifferentiation of primary human hepatocytes in the livers of a humanised mouse model.

BACKGROUND: Gene therapy is one treatment that may ultimately cure type 1 diabetes. We have previously shown that the introduction of furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes resulted in the reversal of diabetes and partial pancreatic transdifferentiation of liver cells. The present study investigated whether streptozotocin-diabetes could be reversed in FRG mice in which chimeric mouse-human livers can readily be established and, in addition, whether pancreatic transdifferentiation occurred in the engrafted human hepatocytes. METHODS: Engraftment of human hepatocytes was confirmed by measuring human albumin levels. Following delivery of the empty vector or the INS-FUR vector to diabetic FRG mice, mice were monitored for weight and blood glucose levels. Intraperitoneal glucose tolerance tests (IPGTTs) were performed. Expression levels of pancreatic hormones and transcription factors were determined by a reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Diabetes was reversed for a period of 60 days (experimental endpoint) after transduction with INS-FUR. IPGTTs of the insulin-transduced animals were not significantly different from nondiabetic animals. Immunofluorescence microscopy revealed the expression of human albumin and insulin in transduced liver samples. Quantitative RT-PCR showed expression of human and mouse endocrine hormones and ß-cell transcription factors, indicating partial pancreatic transdifferentiation of mouse and human hepatocytes. Nonfasting human C-peptide levels were significantly higher than mouse levels, suggesting that transdifferentiated human hepatocytes made a significant contribution to the reversal of diabetes. CONCLUSIONS: These data show that human hepatocytes can be induced to undergo partial pancreatic transdifferentiation in vivo, indicating that the technology holds promise for the treatment of type 1 diabetes.