Farmers' perceived risks of climate change and influencing factors: a study in the Mekong Delta, Vietnam.

Many countries are confronting climate change that threatens agricultural production and farmers' lives. Farmers' perceived risks of climate change and factors influencing those perceived risks are critical to their adaptive behavior and well-planned adaptation strategies. However, there is limited understanding of these issues. In this paper, we attempt to quantitatively measure farmers' perceived risks of climate change and explore the influences of risk experience, information, belief in climate change, and trust in public adaptation to those perceived risks. Data are from structured interviews with 598 farmers in the Mekong Delta. The study shows that perceived risks to production, physical health, and income dimensions receive greater priority while farmers pay less attention to risks to happiness and social relationships. Experiences of the events that can be attributed to climate change increase farmers' perceived risks. Information variables can increase or decrease perceived risks, depending on the sources of information. Farmers who believe that climate change is actually happening and influencing their family's lives, perceive higher risks in most dimensions. Farmers who think that climate change is not their concern but the government's, perceive lower risks to physical health, finance, and production. As to trust in public adaptation, farmers who believe that public adaptive measures are well co-ordinated, perceive lower risks to production and psychology. Interestingly, those who believe that the disaster warning system is working well, perceive higher risks to finance, production, and social relationships. Further attention is suggested for the quality, timing, and channels of information about climate change and adaptation.

The solitary wasp genus Orancistrocerus from Vietnam, with descriptions of two new species (Hymenoptera, Vespidae, Eumeninae).

New data are presented for the potter wasp genus Orancistrocerus van der Vecht (Eumeninae, Odynerini) occurring in Vietnam. Two species are described as new to science: Orancistrocerusthanhnhatsp. nov. and O.thanghensp. nov.Orancistrocerusaterrimuserythropus van der Vecht is synonymized with Orancistrocerusaterrimusaterrimus (de Saussure); the male genitalia of this species are described for the first time. An updated key is presented to all species of the genus.

Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 10(6) cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs. unvaccinated MPTP-treated mice, but without a significant increase in substantia nigra tyrosine hydroxylase-staining neurons. Previous studies showed that BCG can induce regulatory T cells (Tregs) and that Tregs are neuroprotective in models of neurodegenerative diseases. However, MPTP is lymphotoxic, so it was unclear whether Tregs were maintained after MPTP treatment and whether a relationship existed between Tregs and the preservation of striatal DA system integrity. We found that, 21 days post-MPTP treatment, Treg levels in mice that had received BCG prior to MPTP were threefold greater than those in MPTP-only-treated mice and elevated above those in saline-only-treated mice, suggesting that the persistent BCG infection continually promoted Treg responses. Notably, the magnitude of the Treg response correlated positively with both striatal DA levels and DAT ligand binding. Therefore, BCG vaccine-mediated neuroprotection is associated with Treg levels in this mouse model. Our results suggest that BCG-induced Tregs could provide a new adjunctive therapeutic approach to ameliorating pathology associated with PD and other neurodegenerative diseases.

Parasitoid Wasp Acerophagus papayae: A Promising Solution for the Control of Papaya Mealybug Paracoccus marginatus in Cassava Fields in Vietnam.

Cassava is a valuable export commodity crop that is often attacked by pests, causing economic losses for this crop. The papaya mealybug Paracoccus marginatus has become a major pest of cassava in Vietnam. The parasitoid wasp Acerophagus papayae has been demonstrated to be the most efficient parasitoid wasp for controlling P. marginatus in many regions. We observed the occurrence of A. papayae in Vietnam, studied the biological characteristics of A. papayae, and investigated its parasitic activity on P. marginatus. The results showed that A. papayae occurred more frequently than Anagyrus loecki, another known parasitoid of P. marginatus. The lifespan of A. papayae was approximately 16 days. In the absence of hosts, a 50% honey solution was an essential diet to increase the longevity of both female and male of A. papayae. The second instar of P. marginatus was a suitable host stage for parasitism by A. papayae. Female A. papayae laid approximately 60.8 eggs within 17 days, mostly during the first 6 to 7 days. These findings suggest that A. papayae has the potential to control P. marginatus, and could inform the development of more effective pest management strategies for cassava crops in Vietnam and other regions affected by this pest.

Silver nanoparticle toxicity on Artemia parthenogenetica nauplii hatched on axenic tryptic soy agar solid medium.

The use of gnobiotic brine shrimp (Artemia spp.) for ecotoxicology and bacteria-host interaction studies is common. However, requirements for axenic culture and matrix effects of seawater media can be an obstacle. Thus, we investigated the hatching ability of Artemia cysts on a novel sterile Tryptic Soy Agar (TSA) medium. Herein, we demonstrate for the first time that Artemia cysts can hatch on a solid medium without liquid, which offers practical advantages. We further optimized the culture conditions for temperature and salinity and assessed this culture system for toxicity screening of silver nanoparticles (AgNPs) across multiple biological endpoints. Results revealed that maxima hatching (90%) of embryos occurred at 28 °C and without addition of sodium chloride. When capsulated cysts were cultured on TSA solid medium Artemia were negatively impacted by AgNPs at 30-50 mgL-1 in terms of the embryo hatching ratio (47-51%), umbrella- to nauplii-stage transformation ratio (54-57%), and a reduction in nauplii-stage growth (60-85% of normal body length). At 50-100 mgL-1 AgNPs and higher, evidence of damage to lysosomal storage was recorded. At 500 mgL-1 AgNPs, development of the eye was inhibited and locomotory behavior impeded. Our study reveals that this new hatching method has applications in ecotoxicology studies and provides an efficient means to control axenic requirements to produce gnotobiotic brine shrimp.

Neurons preferentially respond to self-MHC class I allele products regardless of peptide presented.

Studies of mice lacking MHC class I (MHC I)-associated proteins have demonstrated a role for MHC I in neurodevelopment. A central question arising from these observations is whether neuronal recognition of MHC I has specificity for the MHC I allele product and the peptide presented. Using a well-established embryonic retina explant system, we observed that picomolar levels of a recombinant self-MHC I molecule inhibited neurite outgrowth. We then assessed the neurobiological activity of a panel of recombinant soluble MHC Is, consisting of different MHC I heavy chains with a defined self- or nonself-peptide presented, on cultured embryonic retinas from mice with different MHC I haplotypes. We observed that self-MHC I allele products had greater inhibitory neuroactivity than nonself-MHC I molecules, regardless of the nature of the peptide presented, a pattern akin to MHC I recognition by some innate immune system receptors. However, self-MHC I molecules had no effect on retinas from MHC I-deficient mice. These observations suggest that neuronal recognition of MHC I may be coordinated with the inherited MHC I alleles, as occurs in the innate immune system. Consistent with this notion, we show that MHC I and MHC I receptors are coexpressed by precursor cells at the earliest stages of retina development, which could enable such coordination.

Automatic question answering for multiple stakeholders, the epidemic question answering dataset.

One of the effects of COVID-19 pandemic is a rapidly growing and changing stream of publications to inform clinicians, researchers, policy makers, and patients about the health, socio-economic, and cultural consequences of the pandemic. Managing this information stream manually is not feasible. Automatic Question Answering can quickly bring the most salient points to the user's attention. Leveraging a collection of scientific articles, government websites, relevant news articles, curated social media posts, and questions asked by researchers, clinicians, and the general public, we developed a dataset to explore automatic Question Answering for multiple stakeholders. Analysis of questions asked by various stakeholders shows that while information needs of experts and the public may overlap, satisfactory answers to these questions often originate from different information sources or benefit from different approaches to answer generation. We believe that this dataset has the potential to support the development of question answering systems not only for epidemic questions, but for other domains with varying expertise such as legal or finance.

Integration of lornoxicam nanocrystals into hydroxypropyl methylcellulose-based sustained release matrix to form a novel biphasic release system.

The study aims to (a) enhance the solubility of a poorly soluble drug by optimization of nanocrystal formulation using the top-down approach and (b) modify the release profile of this drug, which exhibits a short elimination half-life, by the integration of a fast-release phase containing the optimized nanocrystals and a sustained-release phase in a compression-coated tablet. Nanocrystals of the model drug (lornoxicam; LNX) was prepared by simultaneous application of jet-milling and ball-milling techniques. Investigation of the precipitation inhibition capacity, thermal property, and interaction of different polymers with the drug revealed polyvinyl pyrrolidone K30 (PVP) as the most effective stabilizer for nanocrystals. The immediate-release layer containing the optimized nanocrystals (size of 279.5 ± 11.25 nm and polydispersity index of 0.204 ± 0.01) was then compressed on a zero-order sustained-release matrix core using different derivatives of hydroxypropyl methylcellulose (HPMC). Application of the Design of Experiment approach (DoE) was applied to optimize the formulation of tablet. Analysis of drug concentration in dog plasma by liquid chromatography-tandem mass spectrometry demonstrated an improvement in the release behavior of LNX from the optimal compression-coated tablet integrating a HPMC-based sustained release matrix core and a PVP-stabilized lornoxicam nanocrystals coating layer compared to the reference product.

Transgenic mice with enhanced neuronal major histocompatibility complex class I expression recover locomotor function better after spinal cord injury.

Mice that are deficient in classical major histocompatibility complex class I (MHCI) have abnormalities in synaptic plasticity and neurodevelopment and have more extensive loss of synapses and reduced axon regeneration after sciatic nerve transection, suggesting that MHCI participates in maintaining synapses and axon regeneration. Little is known about the biological consequences of up-regulating MHCI's expression on neurons. To understand MHCI's neurobiological activity better, and in particular its role in neurorepair after injury, we have studied neurorepair in a transgenic mouse model in which classical MHCI expression is up-regulated only on neurons. Using a well-established spinal cord injury (SCI) model, we observed that transgenic mice with elevated neuronal MHCI expression had significantly better recovery of locomotor abilities after SCI than wild-type mice. Although previous studies have implicated inflammation as both deleterious and beneficial for recovery after SCI, our results point directly to enhanced neuronal MHCI expression as a beneficial factor for promoting recovery of locomotor function after SCI.

A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human ß-Cell Replication and Survival as well as GABA's Ability to Inhibit Inflammatory T Cells.

A major goal of T1D research is to develop new approaches to increase ß-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote ß-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat ß-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote ß-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased ß-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from ß-cells to increase ß-cell survival and replication. Treatment with both the PAM and GABA further enhanced human ß-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.

Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice.

Immune cells express γ-aminobutyric acid receptors (GABA-R), and GABA administration can inhibit effector T cell responses in models of autoimmune disease. The pharmacokinetic properties of GABA, however, may be suboptimal for clinical applications. The amino acid homotaurine is a type A GABA-R (GABAA-R) agonist with good pharmacokinetics and appears safe for human consumption. In this study, we show that homotaurine inhibits in vitro T cell proliferation to a similar degree as GABA but at lower concentrations. In vivo, oral homotaurine treatment had a modest ability to reverse hyperglycemia in newly hyperglycemic NOD mice but was ineffective after the onset of severe hyperglycemia. In severely diabetic NOD mice, the combination of homotaurine and low-dose anti-CD3 treatment significantly increased 1) disease remission, 2) the percentages of splenic CD4+and CD8+ regulatory T cells compared with anti-CD3 alone, and 3) the frequencies of CD4+ and CD8+ regulatory T cells in the pancreatic lymph nodes compared with homotaurine monotherapy. Histological examination of their pancreata provided no evidence of the large-scale GABAA-R agonist-mediated replenishment of islet ß-cells that has been reported by others. However, we did observe a few functional islets in mice that received combined therapy. Thus, GABAA-R activation enhanced CD4+and CD8+ regulatory T cell responses following the depletion of effector T cells, which was associated with the preservation of some functional islets. Finally, we observed that homotaurine treatment enhanced ß-cell replication and survival in a human islet xenograft model. Hence, GABAA-R agonists, such as homotaurine, are attractive candidates for testing in combination with other therapeutic agents in type 1 diabetes clinical trials.

Increased risk for T cell autoreactivity to ß-cell antigens in the mice expressing the Avy obesity-associated gene.

There has been considerable debate as to whether obesity can act as an accelerator of type 1 diabetes (T1D). We assessed this possibility using transgenic mice (MIP-TF mice) whose ß-cells express enhanced green fluorescent protein (EGFP). Infecting these mice with EGFP-expressing murine herpes virus-68 (MHV68-EGFP) caused occasional transient elevation in their blood glucose, peri-insulitis, and Th1 responses to EGFP which did not spread to other ß-cell antigens. We hypothesized that obesity-related systemic inflammation and ß-cell stress could exacerbate the MHV68-EGFP-induced ß-cell autoreactivity. We crossed MIP-TF mice with Avy mice which develop obesity and provide models of metabolic disease alongside early stage T2D. Unlike their MIP-TF littermates, MHV68-EGFP-infected Avy/MIP-TF mice developed moderate intra-insulitis and transient hyperglycemia. MHV68-EGFP infection induced a more pronounced intra-insulitis in older, more obese, Avy/MIP-TF mice. Moreover, in MHV68-EGFP-infected Avy/MIP-TF mice, Th1 reactivity spread from EGFP to other ß-cell antigens. Thus, the spreading of autoreactivity among ß-cell antigens corresponded with the transition from peri-insulitis to intra-insulitis and occurred in obese Avy/MIP-TF mice but not lean MIP-TF mice. These observations are consistent with the notion that obesity-associated systemic inflammation and ß-cell stress lowers the threshold necessary for T cell autoreactivity to spread from EGFP to other ß-cell autoantigens.

Drug-Induced Anaphylaxis in a Vietnamese Pharmacovigilance Database: Trends and Specific Signals from a Disproportionality Analysis.

INTRODUCTION: Despite the numerous studies investigating drug-induced anaphylaxis (DIA), understanding and quantitative data analysis in developing countries remain limited. The aim of our study is to describe and quantify DIA using the National Pharmacovigilance Database of Vietnam (NPDV). METHODS: Spontaneous reporting of adverse drug reactions (ADRs) recorded between 2010 and 2016 were retrospectively analysed to identify DIA reports. The trend and characteristics of DIA cases were described. Multivariate disproportionality analysis was used for signal generation. RESULTS: Overall, 4873 DIA cases (13.2% of total ADRs) were recorded in the NPDV, 111 of which resulted in death (82% of total ADR-induced deaths) over a 7-year period. There was a remarkable increase in DIA reporting over time (p < 0.001). The incidence rates of DIA reporting per total ADRs and per 100,000 inhabitants remained high (mean rates [95% CI] of 12.06 [9.88-14.24] and 0.77 [0.33-1.20], respectively). Concerning suspected drugs, systemic antibiotics (n = 3318, 68%) were mostly reported with a reporting odds ratio (ROR) and 95% CI of 2.35 [2.20-2.51]. In the case of antibiotic-induced anaphylaxis, the third-generation cephalosporins were predominant (n = 1961, 40.2%, ROR 2.39 [2.24-2.55]). We also noted drugs generally associated with DIA such as contrast agents (ROR 2.43 [2.04-2.88]) and anaesthetics (ROR 4.02 [3.30-4.89]). Furthermore, unexpected signals were observed for alpha-chymotrypsin (ROR 1.75 [1.23-2.44]) and amoxicillin/sulbactam (ROR 1.59 [1.18-2.10]), uncommonly reported in western countries. CONCLUSION: In recent years, cases of drug-induced DIA have increased in Vietnam, mostly due to antibiotics and third-generation cephalosporins. The inappropriate use of these drugs should be taken into account. Our findings also highlighted typical Vietnamese signals for alpha-chymotrypsin- and amoxicillin/sulbactam-induced anaphylaxis, which may relate to a specific sociological context in resource-limited countries.

Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis.

There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer's disease clinical trials. Homotaurine also acts as GABAA-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8+CD122+PD-1+ and CD4+Foxp3+ Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABAA-R agonists as a new class of treatment to enhance CD8+ and CD4+ Treg responses and limit Th17 and Th1-medaited inflammation in the CNS.

Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication.

A key goal of diabetes research is to develop treatments to safely promote human ß-cell replication. It has recently become appreciated that activation of γ-aminobutyric acid receptors (GABA-Rs) on ß-cells can promote their survival and replication. A number of positive allosteric modulators (PAMs) that enhance GABA's actions on neuronal GABAA-Rs are in clinical use. Repurposing these GABAA-R PAMs to help treat diabetes is theoretically appealing because of their safety and potential to enhance the ability of GABA, secreted from ß-cells, or exogenously administered, to promote ß-cell replication and survival. Here, we show that clinically applicable GABAA-R PAMs can increase significantly INS-1 ß-cell replication, which is enhanced by exogenous GABA application. Furthermore, a GABAA-R PAM promoted human islet cell replication in vitro. This effect was abrogated by a GABAA-R antagonist. The combination of a PAM and low levels of exogenous GABA further increased human islet cell replication. These findings suggest that PAMs may potentiate the actions of GABA secreted by islet ß-cells on GABAA-Rs and provide a new class of drugs for diabetes treatment. Finally, our findings may explain a past clinical observation of a GABAA-R PAM reducing HbA1c levels in diabetic patients.

Repurposing Lesogaberan to Promote Human Islet Cell Survival and ß-Cell Replication.

The activation of ß-cell's A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation of α-cell GABAA-Rs promotes their conversion into ß-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS). Lesogaberan (AZD3355) is a peripherally restricted high-affinity GABAB-R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD) that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival and ß-cell replication. Treatment with lesogaberan significantly enhanced replication of human islet cells in vitro, which was abrogated by a GABAB-R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted human ß-cell replication and islet cell survival in vivo as effectively as GABA (which activates both GABAA-Rs and GABAB-Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.

Mouse salivary glands and human beta-defensin-2 as a study model for antimicrobial gene therapy: technical considerations.

Transduction of salivary glands with antimicrobial peptide genes has great potential for oral infection control. Our ultimate goal is to introduce antimicrobial peptide genes into salivary glands that secrete these peptides into saliva to control bacterial/fungal infection in the oral cavity. However, an animal study model to test this potential has not been established. Therefore, we determined to test (i) whether the potent antimicrobial peptide human beta-defensin-2 (hBD-2) can be overexpressed in saliva after transduction of salivary glands and (ii) whether oral fungal infection can be developed in a NOD/SCID murine model. Lentiviral vector SIN18cPPTRhMLV bearing hBD-2 cDNA was introduced into SCID mouse submandibular glands via cannulation. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry or enzyme-linked immunosorbent assay (ELISA) were performed to detect hBD-2 expression in glands or in saliva. Candida albicans 613p was inoculated orally into SCID mice to establish oral candidiasis. Whilst expression of hBD-2 was detected in mouse salivary glands by RT-PCR and immunohistochemistry 1 day or 1 week following delivery of lentivirus, hBD-2 was not detected in saliva. There was recoverable C. albicans from the oral cavity and gastrointestinal tract 4 days to 4 weeks after infection, but there was no establishment of observable oral candidiasis in SCID mice under a stereomicroscope. Our data indicate that lentiviral vectors transduce mouse salivary glands, but not at a sufficient level to allow hBD-2 detection in saliva. Other vectors for gene transduction and additional treatment of SCID mice to establish oral candidiasis are needed in order to utilise mouse salivary glands to test antimicrobial gene therapy.

Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting ß-cell replication in newly diabetic NOD mice.

Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few ß-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast-acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. γ-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote ß-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other ß-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to ß-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted ß-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T-cell responses, induce Treg responses, promote ß-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention.

γ-Aminobutyric acid regulates both the survival and replication of human ß-cells.

γ-Aminobutyric acid (GABA) has been shown to inhibit apoptosis of rodent ß-cells in vitro. In this study, we show that activation of GABAA receptors (GABAA-Rs) or GABAB-Rs significantly inhibits oxidative stress-related ß-cell apoptosis and preserves pancreatic ß-cells in streptozotocin-rendered hyperglycemic mice. Moreover, treatment with GABA, or a GABAA-R- or GABAB-R-specific agonist, inhibited human ß-cell apoptosis following islet transplantation into NOD/scid mice. Accordingly, activation of GABAA-Rs and/or GABAB-Rs may be a useful adjunct therapy for human islet transplantation. GABA-R agonists also promoted ß-cell replication in hyperglycemic mice. While a number of agents can promote rodent ß-cell replication, most fail to provide similar activities with human ß-cells. In this study, we show that GABA administration promotes ß-cell replication and functional recovery in human islets following implantation into NOD/scid mice. Human ß-cell replication was induced by both GABAA-R and GABAB-R activation. Hence, GABA regulates both the survival and replication of human ß-cells. These actions, together with the anti-inflammatory properties of GABA, suggest that modulation of peripheral GABA-Rs may represent a promising new therapeutic strategy for improving ß-cell survival following human islet transplantation and increasing ß-cells in patients with diabetes.

Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization.

We studied cultured hippocampal neurons from embryonic wildtype, major histocompatibility complex class I (MHCI) heavy chain-deficient (K(b)D(b)-/-) and NSE-D(b) (which have elevated neuronal MHCI expression) C57BL/6 mice. K(b)D(b)-/- neurons displayed slower neuritogenesis and establishment of polarity, while NSE-D(b) neurons had faster neurite outgrowth, more primary neurites, and tended to have accelerated polarization. Additional studies with ß2M-/- neurons, exogenous ß2M, and a self-MHCI monomer suggest that free heavy chain cis interactions with other surface molecules can promote neuritogenesis while tripartite MHCI interactions with classical MHCI receptors can inhibit axon outgrowth. Together with the results of others, MHCI appears to differentially modulate neuritogenesis and synaptogenesis.