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In 2013, Congress reaffirmed tribes' inherent authority to prosecute all persons who commit dating violence, domestic violence, or violate a protective order against Indian women on tribal land in the Violence Against Women Reauthorization Act (VAWA). Congress required tribes to comply with strict procedural safeguards to implement VAWA. Although VAWA was not designed to stimulate tribal economies, its due process provisions may be considered judicial improvements. Stronger judiciaries have been consistently linked to greater economic performance. Accordingly, we test whether implementing VAWA improved tribal economies. This analysis compares the income growth of VAWA-implementing tribes in Arizona to neighboring non-implementing tribes. Our findings show that incomes grew faster for VAWA-implementing tribes than for non-implementing tribes in Arizona. [ABSTRACT FROM AUTHOR]

Localities have often been quicker than states to respond to public health concerns related to tobacco use by implementing restrictive policies.[1] However, some states preempt localities from passing laws that are more stringent than states' tobacco control policies.[1] The tobacco industry has historically supported state preemption to reverse existing local tobacco control laws and prevent future enactment of such laws.[2] A US federal government prevention plan called to eliminate state laws that preempt stronger local tobacco control laws.[3] Despite a consensus among public health advocates that state preemption has an adverse impact on local tobacco control efforts, limited published research to date has quantified its effects.[2] We studied the effects of state preemption of local smoke-free restrictions in worksites, restaurants, and bars on county-level adult cigarette smoking prevalence between 1997 and 2017. We used difference-in-differences regressions to compare smoking prevalence in our exposed counties (with smoke-free restrictions previously and then subject to state preemption) with that in our control counties (with smoke-free restrictions and never subject to state preemption) before and after state preemption. [Extracted from the article]

Technological advancements and the increasingly large amounts spent for elections have made it easier for get-out-the-vote (GOTV) campaigns to contact potential voters many times prior to elections. However, the effects of repeated exposure to GOTV treatment have received little attention in the academic literature. Multiple treatments can increase the intensive margin of treatment—by increasing the number of times that treated individuals are exposed to the treatment—or the extensive margin of treatment—by increasing the number of people who are exposed to at least one treatment attempt. We analyze the differences between a treatment with one automated GOTV call and a treatment with three GOTV calls to isolate the effect of changes in the extensive and intensive margins of treatment on voting rates. On the intensive margin, we find that answering one additional call is associated with an approximately 0.6% point increased probability to vote. On the extensive margin, we find that answering one additional call is associated with an approximately one percentage point increased probability to vote. This evidence is consistent with the academic literature on commercial advertising, which finds that repeated exposures to commercial advertisements have diminishing marginal effects. [ABSTRACT FROM AUTHOR]

Abstract Committee membership in mixed-member systems presents an informative setting for studying legislators' behavior under majoritarian vs. proportional electoral incentives. Committee membership allows for a determination as to whether legislators sort themselves into committees that are more consistent with an objective to win the next election in their electoral district, or more consistent with gaining a more prestigious position in their party. Using data from three large German states, we find that legislators elected in the electoral system's majoritarian tier more often become members of "district committees," i.e., committees that might give politicians greater opportunity than others to obtain government funds for the benefit of their home districts. This effect is strongest for legislators who won district elections by narrow margins. Moreover, we find that districts that are better represented on "district committees" receive more government funds. [ABSTRACT FROM AUTHOR]

Adverse selection theory predicts people with a high risk of death are more likely to own life insurance. Using a unique data set merging administrative and survey records, we test this theory and find the opposite: people with high death risk are less likely to own life insurance. We postulate advantageous selection and price discrimination swamp adverse selection in individual life insurance markets. To determine which effect is more powerful, we analyze group life insurance markets, where insurance companies cannot price discriminate as well as in individual markets. Our data suggest that price discrimination has a stronger effect than advantageous selection. ( JEL D8, G1, I1) [ABSTRACT FROM AUTHOR]

The effectiveness of cancer screening is a salient health policy issue that remains unresolved. This article sheds new light on the benefits of population-wide cancer screening. We investigate changes in mortality after the introduction of screening guidelines for breast and prostate cancers in the USA and UK. We use differences in the timing of guideline adoption, differences in ages recommended for screening, and differences in which cancers are detectable by screening to identify the effect of cancer screening guidelines. Our quadruple-differencing strategy finds a moderately sized mortality benefit from mammography and prostate-specific antigen (PSA) screening guidelines among recommended age groups and little change in mortality rates among age groups not recommended to receive screening. As a falsification test, we verify that prostate cancer rates among men did not fall after the introduction of mammography screening and breast cancer rates among women did not fall after the introduction of the PSA test. [ABSTRACT FROM AUTHOR]

Did the nuclear catastrophe at Fukushima in March 2011 cause individuals to reappraise the risks they attach to nuclear power plants? We investigate the change in home prices in the U.S. after the Fukushima event to test the hypothesis that home prices in the proximity of power plants fell due to an updated nuclear risk perception. Using a difference-in-differences approach, we do not find evidence in support of the hypothesis that individuals reappraised the risks associated with nuclear power plants. According to our results home prices close to nuclear reactor sites did not fall relative to home prices at other locations in the U.S. [ABSTRACT FROM AUTHOR]

Abstract: Many models predict that incumbent legislators use government spending – “pork barrel” spending – to increase their vote shares in elections. To date, however, evidence for this hypothesis is scarce. Using recently available data on the sponsorship of earmarks in U.S. appropriations legislation, this paper tests the effects of earmarks on the likelihood of legislators' reelection. The results show that secured earmarks lead to higher vote shares. The analysis demonstrates that a $10million increase in earmarks leads to as much as a one percentage point increase in vote share on election day. Furthermore, the paper tests for voter responses to earmarks when earmarks have few or many sponsors. [Copyright &y& Elsevier]

The field of corporate governance has long considered the costs of the separation of ownership from control in publicly traded corporations and the regulatory and market structures designed to limit those costs. The debate over the efficiency of regulations designed to limit agency costs has recently focused on the SEC's new rule requiring companies to include shareholder nominees on the company-financed proxy statement to facilitate insurgent challengers to incumbent board members in board elections. A recent vein of empirical literature has examined the stock price effects of events surrounding the new proxy access rule. We present a study that focuses on small companies that expected an exemption from the rule under the Dodd-Frank legislation that preceded the adoption of the SEC rule. We consider the effect of the August 25, 2010 announcement of the proxy access rule, comparing its effect on the value of medium and large firms, which expected to be subject to the full rule, against its effect on the value of small firms, which were unexpectedly given only a temporary exemption from part of the rule (Rule 14a-11) and no exemption from another part of the rule (Rule 14a-8). Supporters of proxy access have long argued that it will enhance shareholder value. Critics of proxy access have argued that it will empower investors with conflicted agendas that will destroy shareholder wealth. The unexpected application of the rule to small-cap companies on August 25 provides a natural experiment for this question and allows us to examine the differential effect of the rule on firms above and below the arbitrary SEC cutoff of $75 million dollars in market capitalization. We find that the unanticipated application of the proxy access rule to small firms, particularly when combined with the presence of investors with at least a 3% interest (who are able to use the rule), resulted in negative abnormal returns. We present multiple methods to measure that effect and demonstrate losses for our sample of roughly 1000 small companies of as much as $347 million. [ABSTRACT FROM AUTHOR]

Summary The LysR-type transcription factor LeuO is involved in regulation of pathogenicity determinants and stress responses in Enterobacteriaceae, and acts as antagonist of the global repressor H-NS. Expression of the leuO gene is repressed by H-NS, and it is upregulated in stationary phase and under amino acid starvation conditions. Here, we show that the heterodimer of the FixJ/NarL-type transcription regulators RcsB and BglJ strongly activates expression of leuO and that RcsB-BglJ regulates additional loci. Activation of leuO by RcsB-BglJ is independent of the Rcs phosphorelay system. RcsB-BglJ binds to the leuO promoter region and activates one of two leuO promoters mapped in vivo. Moreover, LeuO antagonizes activation of leuO by RcsB-BglJ and acts as negative autoregulator in vivo and in vitro. Further, the H-NS paralogue StpA causes repression of leuO in addition to H-NS. Together, our data suggest a complex arrangement of regulatory elements and they indicate a feedback control mechanism of leuO expression. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we estimate long-run effects of fetal exposure to the 1918/19 influenza pandemic for a European country. Using data from the 1970 Swiss census, we find that the male 1919 cohort that had a strongly increased likelihood of fetal exposure to the pandemic performs significantly worse in terms of educational attainment and has a lower chance of marriage than the surrounding cohorts. Further, we find similar results when we in addition use regional differences in influenza severity to test for the impact of influenza on later-life outcomes. A set of robustness tests confirm our findings. [Copyright &y& Elsevier]

SUMMARY States have soft budget constraints when they can expect a bailout by the federal government in the event of a financial crisis. This gives rise to incentives for unsound state fiscal policy. We test whether states with softer budget constraints have higher debts and deficits, receive more bailout funds, spend funds less efficiently, and are more likely to allocate funds to programs benefiting special interests. Exogenous variation in soft budget constraints across states and over time allows the identification of the effect of budget constraint softness on state fiscal policy. We take advantage of the fact that in Germany the states' political influence per state citizen is exogenous and varies because voting weights differ in the upper chamber of the German parliament. The stronger the political influence per state citizen, the softer the budget constraint. We show that states with softer budget constraint have higher deficits and debts, and receive more bailout funds. Further, overrepresented states are less efficient in spending public funds and are more prone to respond to rent seeking by interest groups. [ABSTRACT FROM AUTHOR]

Abstract: This paper examines the long run education and labor market effects from early-life exposure to the Greek 1941–1942 famine. Given the short duration of the famine, we can separately identify the famine effects for cohorts exposed in utero, during infancy and at 1 year of age. We find that adverse outcomes due to the famine are largest for infants. Further, in our regression analysis we exploit the fact that the famine was more severe in urban than in rural areas. Consistent with our prediction, we find that urban-born cohorts show larger negative impacts on educational outcomes than rural-born cohorts. [Copyright &y& Elsevier]

Abstract: Plants, as many other organisms, synchronize the timing of their physiology and development by using an endogenous mechanism called circadian clock. Perception of environmental changes during the day–night cycle is crucial for circadian function, which relies on transcriptional feedback loops at the core of a central oscillator. Recent studies in Arabidopsis have shown that the transcriptional regulation of clock gene expression is governed by rhythmic changes in chromatin structure. The chromatin remodelling activities relevant for clock function are modulated by day-length or photoperiod, suggesting a mechanism by which the plant clock synchronizes development with the external time. Evidence that a central component of the mammalian clock has histone acetyltransferase activity suggests that chromatin remodelling has evolved as an important mechanism for circadian function. [Copyright &y& Elsevier]

In states with Certificate of Need (CON) laws, medical services providers must file an application and demonstrate community need before being permitted to start or expand a service. We examine CON laws for magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) scanners to test the hypothesis that the approval process favors established incumbent hospitals over new hospital entrants and nonhospital providers. Using Medicare claims data in 2013, we find that states with CON laws have 20 to 33% fewer providers, depending on the type of scanners to which the laws apply. As a result, residents of CON law states are 3.4–5.3 percentage points more likely to travel outside their home county to obtain imaging services than residents of non-CON states. In addition, there is a notable shift in the type of provider: CON laws are associated with 27–53% fewer scans by nonhospital providers per beneficiary, 23 to 70% fewer by new hospitals, but 6 to 21% more scans in older hospitals. • States requiring imaging services certificate-of-need (CON) laws have affected the provider type composition of the market. • CON laws are correlated with reductions in services provided by new hospitals and non-hospitals but not by pre-existing hospitals. • CON state residency is related to a higher likelihood of traveling outside one's home county to obtaining imaging services. [ABSTRACT FROM AUTHOR]

The recent academic literature suggests that pressure from special interest groups has little or no influence on whether initiatives and referendums are passed or defeated. Further, there is a consensus that, to the degree that groups' campaigning is important for explaining outcomes, groups opposing the initiative and favoring the status quo have an advantage over groups that support change. These studies have not considered that interest groups campaign strategically and therefore that campaigning is endogenous in ballot measure elections. This study examines the effect of campaigning on ballot proposition elections and develops a research design that accounts for strategic and endogenous campaign advertising. The research design uses a two-way fixed-effects model to estimate the effect of interest group pressure on ballot measure outcomes. The data are based on television advertising for or against California ballot measures from 2000 to 2004. The results show that supporting and opposing interest groups' campaigning has a quantitatively important and statistically significant influence on ballot measure outcomes. The campaigning of supporting interest groups is at least as productive as that of opposing interest groups. [ABSTRACT FROM AUTHOR]

In many states of the United States, candidates must meet certain requirements in order to be listed on the ballot. Such requirements include filing fees and minimum number of collected signatures. Incumbents have incentives to use these requirements to protect themselves from competition by reducing entry of potential challengers. To date, there is very little evidence regarding whether such requirements have negative consequences for candidate competition in elections and challenger entry into electoral races. This paper examines the impact of filing fees and signature requirements on the number of candidates in U.S. state races in state Lower House elections in 1998 and 2000. The findings show that higher filing fees reduce both the number of major-party and minor-party candidates. However, filing fees are more effective in deterring minor-party candidates from contesting political office than major-party candidates. More stringent signature requirements reduce the number of major-party candidates. [Copyright &y& Elsevier]

Background: A rapid phage display method for the elucidation of cognate peptide specific ligand for receptors is described. The approach may be readily integrated into the interface of genomic and proteomic studies to identify biologically relevant ligands. Methods: A gene fragment library from influenza coat protein haemagglutinin (HA) gene was constructed by treating HA cDNA with DNAse I to create 50 - 100 bp fragments. These fragments were cloned into plasmid pORFES IV and in-frame inserts were selected. These in-frame fragment inserts were subsequently cloned into a filamentous phage display vector JC-M13-88 for surface display as fusions to a synthetic copy of gene VIII. Two well characterized antibodies, mAb 12CA5 and pAb 07431, directed against distinct known regions of HA were used to pan the library. Results: Two linear epitopes, HA peptide 112 - 126 and 162-173, recognized by mAb 12CA5 and pAb 07431, respectively, were identified as the cognate epitopes. Conclusion: This approach is a useful alternative to conventional methods such as screening of overlapping synthetic peptide libraries or gene fragment expression libraries when searching for precise peptide protein interactions, and may be applied to functional proteomics. [ABSTRACT FROM AUTHOR]

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population oft cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2[supg7] MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome. [ABSTRACT FROM AUTHOR]

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome. [ABSTRACT FROM AUTHOR]

Presents a model predicting that voting behavior of legislators is more variable early in their career and that junior members are more likely to vote with their party than senior members. Decline in party line voting and variability of voting decisions with increase in seniority; View that changes in voting behavior are induced by redistricting.

Analyzes whether vote trading occurs in the US Congress. Trades between interests favoring subsidies for city interests, labor interests and farm interests; Congressional behavior; Role of parties in logrolling.

Swine influenza viruses (SIVs), the causal agents of swine influenza, are not only important to control due to the economic losses in the swine industry, but also can be pandemic pathogens. Vaccination is one of the most relevant strategies to control and prevent influenza infection. Current human vaccines against influenza induce strain-specific immunity and annual update is required due to the virus antigenic shift phenomena. Previously, our group has reported the use of conserved hemagglutinin peptides (HA-peptides) derived from H1-influenza virus as a potential multivalent vaccine candidate. Immunization of swine with these HA-peptides elicited antibodies that recognized and neutralized heterologous influenza viruses in vitro and demonstrated strong hemagglutination-inhibiting activity. In the present work, we cloned one HA-peptide (named NG34) into a plasmid fused with cytotoxic T lymphocyte-associated antigen (CTLA4) which is a molecule that modifies T cell activation and with an adjuvant activity interfering with the adaptive immune response. The resulting plasmid, named pCMV-CTLA4-Ig-NG34, was administered twice to animals employing a needle-free delivery approach. Two studies were carried out to test the efficacy of pCMV-CTLA4-Ig-NG34 as a potential swine influenza vaccine, one in seronegative and another in seropositive pigs against SIV. The second one was aimed to evaluate whether pCMV-CTLA4-Ig-NG34 vaccination would overcome maternally derived antibodies (MDA). After immunization, all animals were intranasally challenged with an H3N2 influenza strain. A complete elimination or significant reduction in the viral shedding was observed within the first week after the challenge in the vaccinated animals from both studies. In addition, no challenged heterologous virus load was detected in the airways of vaccinated pigs. Overall, it is suggested that the pCMV-CTLA4-Ig-NG34 vaccine formulation could potentially be used as a multivalent vaccine against influenza viruses. [ABSTRACT FROM AUTHOR]

Altruistic punishment is a fundamental driver for cooperation in human interactions. In this paper, we expand our understanding of this form of pro-social behavior to help explain a puzzle of voting: why do individuals who are indifferent between two potential policy outcomes of an election participate when voting is costly? Using a simple voting experiment, we provide robust evidence that many voters are willing to engage in voting as a form of punishment, even when voting is costly and the voter has no monetary stake in the election outcome. In our sample, and in a robustness check through Monte Carlo simulation, we show that at least fourteen percent of individuals are willing to incur a cost to vote against candidates who broke their electoral promises, even when they have no pecuniary interest in the election outcome. [ABSTRACT FROM AUTHOR]

The yjjQ and bglJ genes encode LuxR-type transcription factors conserved in several enterobacterial species. YjjQ is a potential virulence factor in avian pathogenic Escherichia coli. BglJ counteracts the silencing of the bgl (β-glucoside) operon by H-NS in E. coli K-12. Here we show that yjjQ and bglJ form an operon carried by E. coli K-12, whose expression is repressed by the histone-like nucleoid structuring (H-NS) protein. The LysR-type transcription factor LeuO counteracts this repression. Furthermore, the yjjP gene, encoding a membrane protein of unknown function and located upstream in divergent orientation to the yjjQ-bglJ operon, is likewise repressed by H-NS. Mapping of the promoters as well as the H-NS and LeuO binding sites within the 555-bp intergenic region revealed that H-NS binds to the center of the AT-rich regulatory region and distal to the divergent promoters. LeuO sites map to the center and to positions distal to the yjjQ promoters, while one LeuO binding site overlaps with the divergent yjjP promoter. This latter LeuO site is required for full derepression of the yjjQ promoters. The arrangement of regulatory sites suggests that LeuO restructures the nucleoprotein complex formed by H-NS. Furthermore, the data support the conclusion that LeuO, whose expression is likewise repressed by H-NS and which is a virulence factor in Salmonella enterica, is a master regulator that among other loci, also controls the yjjQ-bglJ operon and thus indirectly the presumptive targets of YjjQ and BglJ. [ABSTRACT FROM AUTHOR]

We model two-candidate elections in which (1) voters are uncertain about candidates' attributes; and (2) candidates can inform voters of their attributes by sending advertisements. We compare between political campaigns with truthful advertising and campaigns in which there is a small chance of deceptive advertising. Our model predicts that voters should vote in-line with an advertisement's information. We test our model's predictions using laboratory elections. We find, in the presence of even a small probability that an advertisement is deceptive, voters become substantially more likely to elect a 'low-quality' candidate. We discuss implications of this for existing models of voting decisions. ( JEL C92, D72, D82) [ABSTRACT FROM AUTHOR]

Abstract: We present results from laboratory experimental elections in which voter information is endogenously provided by candidates and voting is voluntary. We also compare advertisements that are costless to voters with those that reduce voter payoffs. We find that informative advertisements increase voter participation and thus informative campaign advertising turns out voters. However, the effect of information is less than that found in previous experimental studies where information is exogenously provided by the experimenter. Furthermore, we find that when advertising by winning candidates reduces voter payoffs, informed voters are less likely to participate, thus are turned off rather than turned out. Finally, we discover that candidates tend to overadvertise, and contrary to theoretical predictions, advertise significantly more when voting is voluntary than when it is compulsory. [Copyright &y& Elsevier]

While the autoimmune destruction of pancreatic ß-cells underlying type 1 diabetes (1D) development is ultimately mediated by T-cells in NOD mice and also likely humans, B-lymphocytes play an additional key pathogenic role. It appears expression of plasma membrane bound immunoglobulin (Ig) molecules that efficiently capture ß-cell antigens allows autoreactive B-lymphocytes bypassing normal tolerance induction processes to be the subset of antigen presenting cells most efficiently activating diabetogenic T-cells. NOD mice transgenically expressing Ig molecules recognizing antigens that are (insulin) or not (hen egg lysozyme; HEL) expressed by ß-cells have proven useful in dissecting the developmental basis of diabetogenic B-lymphocytes. However, these transgenic Ig specificities were originally selected for their ability to recognize insulin or HEL as foreign, rather than autoantigens. Thus, we generated and characterized NOD mice transgenically expressing an Ig molecule representative of a large proportion of naturally occurring islet-infiltrating B-lymphocytes in NOD mice recognizing the neuronal antigen peripherin. Transgenic peripherin autoreactive B-lymphocytes infiltrate NOD pancreatic islets, acquire an activated proliferative phenotype, and potently support accelerated T1D development. These results support the concept of neuronal autoimmunity as a pathogenic feature of T1D, and targeting such responses could ultimately provide an effective disease intervention approach. [ABSTRACT FROM AUTHOR]

Introduction: The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes. Objective: To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes. Methods: A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides. Results: We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion. Conclusions: We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases. [ABSTRACT FROM AUTHOR]

Autoreactive B cells are essential for the pathogenesis of type 1 diabetes. The genesis and dynamics of autoreactive B cells remain unknown. In this study, we analyzed the immune response in the NOD mouse model to the neuronal protein peripherin (PRPH), a target Ag of islet-infiltrating B cells. PRPH autoreactive B cells recognized a single linear epitope of this protein, in contrast to the multiple epitope recognition commonly observed during autoreactive B cell responses. Autoantibodies to this epitope were also detected in the disease-resistant NOR and C57BL/6 strains. To specifically detect the accumulation of these B cells, we developed a novel approach, octameric peptide display, to follow the dynamics and localization of anti-PRPH B cells during disease progression. Before extended insulitis was established, anti-PRPH B cells preferentially accumulated in the peritoneum. Anti-PRPH B cells were likewise detected in C57BL/6 mice, albeit at lower frequencies. As disease unfolded in NOD mice, anti-PRPH B cells invaded the islets and increased in number at the peritoneum of diabetic but not prediabetic mice. Isotype-switched B cells were only detected in the peritoneum. Anti-PRPH B cells represent a heterogeneous population composed of both B1 and B2 subsets. In the spleen, anti-PRPH B cell were predominantly in the follicular subset. Therefore, anti-PRPH B cells represent a heterogeneous population that is generated early in life but proliferates as diabetes is established. These findings on the temporal and spatial progression of autoreactive B cells should be relevant for our understanding of B cell function in diabetes pathogenesis. [ABSTRACT FROM AUTHOR]

CD4 T cells are crucial effectors in the pathology of type 1 diabetes (T1D). Successful therapeutic interventions for prevention and cure of T1D in humans are still elusive. Recent research efforts have focused on the manipulation of T cells by treatment with DNA. In this paper, we studied the effects of a DNA treatment strategy designed to target antigenic peptides to the lysosomal compartment on a monospecific T cell population termed 2.5mi+ T cells that shares reactivity with the diabetogenic T cell clone BDC-2.5 in the NOD mouse. MHC class II tetramer analysis showed that repeated administrations were necessary to expand 2.5mi+ T cells in vivo. This expansion was independent of Ag presentation by B cells. A single peptide epitope was sufficient to induce protection against T1D, which was not due to Ag-specific T cell anergy. Typical Th2 cytokines such as IL-10 or IL-4 were undetectable in 2.5mi+ T cells, arguing against a mechanism of immune deviation. Instead, the expanded 2.5mi+ T cell population produced IFN-γ similar to 2.5mi+ T cells from naive mice. Protection against T1D by DNA treatment was completely lost in NOD.CD28-/- mice which are largely deficient of natural regulatory T cells (Treg). Although Ag-specific Foxp3+ Treg did not expand in response to DNA treatment, diabetes onset was delayed in Treg-reconstituted and DNA-treated NOD.SCID mice. These observations provide evidence for a Treg-mediated protective mechanism that is independent of the expansion or de novo generation of Ag-specific Treg. [ABSTRACT FROM AUTHOR]

Aminoacyl-tRNA synthetases (ARS) are modular enzymes that aminoacylate transfer RNAs (tRNA) for their use by the ribosome during protein synthesis. ARS are essential and universal components of the genetic code that were almost com- pletely established before the appearance of the last common ancestor of all living species. This long evolutionary history explains the growing number of functions being discovered for ARS, and for ARS homologues, beyond their canonical role in gene translation. Here we present a previously uncharacterized paralogue of seryl-tRNA synthetase named SLIM P (seryl- tRNA synthetase-like insect mitochondrial protein). SLIMP is the result of a duplication of a mitochondrial seryl-tRNA synthetase (SRS) gene that took place in early metazoans and was fixed in Insecta, Here we show that SLIMP is localized in the mitochondria, where it carries out an essential function that is unrelated to the aminoacylation of tRNA. The knockdown of SLIMP by RNA interference (RNAi) causes a decrease in respiration capacity and an increase in mitochondrial mass in the form of aberrant mitochondria. [ABSTRACT FROM AUTHOR]

The recently discovered prokaryotic CRISPR/Cas defence system provides immunity against viral infections and plasmid conjugation. It has been demonstrated that in Escherichia coli transcription of the Cascade genes ( casABCDE) and to some extent the CRISPR array is repressed by heat-stable nucleoid-structuring (H-NS) protein, a global transcriptional repressor. Here we elaborate on the control of the E. coli CRISPR/Cas system, and study the effect on CRISPR-based anti-viral immunity. Transformation of wild-type E. coli K12 with CRISPR spacers that are complementary to phage Lambda does not lead to detectable protection against Lambda infection. However, when an H-NS mutant of E. coli K12 is transformed with the same anti-Lambda CRISPR, this does result in reduced sensitivity to phage infection. In addition, it is demonstrated that LeuO, a LysR-type transcription factor, binds to two sites flanking the casA promoter and the H-NS nucleation site, resulting in derepression of casABCDE12 transcription. Overexpression of LeuO in E. coli K12 containing an anti-Lambda CRISPR leads to an enhanced protection against phage infection. This study demonstrates that in E. coli H-NS and LeuO are antagonistic regulators of CRISPR-based immunity. [ABSTRACT FROM AUTHOR]

Abstract: Rearrangement analysis of immunoglobulin genes is an exceptional opportunity to look back at the B lymphocyte differentiation during ontogeny and the subsequent immune response, and thus to study the selective pressures involved in autoimmune disorders. In a recent study to characterize the antigenic specificity of B lymphocytes during T1D progression, we generated hybridomas of islet-infiltrating B lymphocytes from NOD mice and other related strains developing insulitis, but with different degrees of susceptibility to T1D. We found that a sizable proportion of hybridomas produced monoclonal antibodies reactive to peripherin, an intermediate filament protein mainly found in the peripheral nervous system. Moreover, we found that anti-peripherin antibody-producing hybridomas originated from B lymphocytes that had undergone immunoglobulin class switch recombination, a characteristic of secondary immune response. Therefore, in the present study we performed immunoglobulin VL and VH analysis of these hybridomas to ascertain whether they were derived from B lymphocytes that had undergone antigen-driven selection. The results indicated that whereas some anti-peripherin hybridomas showed signs of oligoclonality, somatic hypermutation and/or secondary rearrangements (receptor edition and receptor revision), others seemed to directly derive from the preimmune repertoire. In view of these results, we conclude that anti-peripherin B lymphocytes are positively selected and primed in the course of T1D development in NOD mice, and reinforce the idea that peripherin is a relevant autoantigen targeted during T1D development in this animal model. [Copyright &y& Elsevier]

RcsB is the response regulator of the complex Rcs two-component system, which senses perturbations in the outer membrane and peptidoglycan layer. BglJ is a transcriptional regulator whose constitutive expression causes activation of the H-NS- and StpA-repressed bgl (aryl-β,D-glucoside) operon in Escherichia coli. RcsB and BglJ both belong to the LuxR-type family of transcriptional regulators with a characteristic C-terminal DNA-binding domain. Here, we show that BglJ and RcsB interact and form heterodimers that presumably bind upstream of the bgl promoter, as suggested by mutation of a sequence motif related to the consensus sequence for RcsA-RcsB heterodimers. Heterodimerization of BglJ-RcsB and relief of H-NS-mediated repression of bgl by BglJ-RcsB are apparently independent of RcsB phosphorylation. In addition, we show that LeuO, a pleiotropic LysR-type transcriptional regulator, likewise binds to the bgl upstream regulatory region and relieves repression of bgl independently of BglJ-RcsB. Thus, LeuO can affect bgl directly, as shown here, and indirectly by activating the H-NS-repressed yjjQ-bglJ operon, as shown previously. Taken together, heterodimer formation of RcsB and BglJ expands the role of the Rcs two-component system and the network of regulators affecting the bgl promoter. [ABSTRACT FROM AUTHOR]