Late Challenge Research Articles

Exploring HD-tDCS Effect on μ-opioid Receptor and Pain Sensitivity in Temporomandibular Disorder: A Pilot Randomized Clinical Trial Study

This study explored the association between experimentally-induced pain sensitivity and µ-opioid receptor (μOR) availability in patients with temporomandibular disorder (TMD) and further investigated any changes in the pain and μOR availability following high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) with pilot randomized clinical trials. Seven patients with TMD completed either active (n = 3) or sham treatment (n = 4) for 10 daily sessions and underwent positron emission tomography (PET) scans with [11C]carfentanil, a selective μOR agonist, a week before and after treatment. PET imaging consisted of an early resting and late phase with the sustained masseteric pain challenge by computer-controlled injection of 5% hypertonic saline. We also included 12 patients with TMD, obtained from our previous study, for baseline PET analysis. We observed that patients with more sensitivity to pain, indicated by lower infusion rate, had less μOR availability in the right amygdala during the late phase. Moreover, active M1 HD-tDCS, compared to sham, increased μOR availability post-treatment in the thalamus during the early resting phase and the amygdala, hippocampus, and parahippocampal gyrus during the late pain challenge phase. Importantly, increased μOR availability post-treatment in limbic structures including the amygdala and hippocampus was associated with decreased pain sensitivity. The findings underscore the role of the μOR system in pain regulation and the therapeutic potential of HD-tDCS for TMD. Nonetheless, large-scale studies are necessary to establish the clinical significance of these results. Trial registrationClinicalTrial.gov (NCT03724032) PerspectiveThis study links pain sensitivity and µ-opioid receptors in patients with TMD. HD-tDCS over M1 improved µOR availability, which was associated with reduced pain sensitivity. Implications for TMD pain management are promising, but larger clinical trials are essential for validation.

The messy coloniality of gender and development in Indigenous Wixárika communities

ABSTRACT Understanding the coloniality of gendered lives, family dynamics, social arrangements, and political structures in Indigenous communities begins with confronting and interrogating a history written largely by and for men in positions of power. The archives are limited in terms of what can be gleaned about gender equality and what existed before the proliferation of European patriarchy. Indigenous Wixárika people tread a delicate balance between a lifeworld that is organised around a ritual–agricultural cycle, and the accelerating incorporation of the imperial mode of living and the coloniality of being, into their communities and culture. The ‘coloniality of gender’ explains how Indigenous women and men have been drawn into and shaped through contact zones, these sites of imperial intervention that have brought social, cultural, and structural changes to gender. Problematically, this concept assumes a one-way process of domination, whereby modern European power structures were imposed on Indigenous people. A critical exploration reveals how gender dynamics and equality were influenced by a much messier process, entangled with Wixárika’s cultural and religious systems as well as the leveraging of political collateral. This paper will draw on findings from a historical and ethnographic study of the coloniality of gender in Indigenous Wixárika communities. We will critically examine archival evidence alongside oral histories to suggest how social, development, and political interventions from the late 20th century challenge the idea of the ‘coloniality of gender’, and discuss how past and present actants collide and dialogue to bring about social change and greater gender equality.

Capsid-modified adeno-associated virus vectors as novel vaccine platform for cancer immunotherapy

Immunotherapy has significantly improved treatment outcomes in various cancer entities. To enhance immunogenicity and efficacy, and to further broaden its applicability, co-administration of anti-tumor vaccines is considered as a promising strategy. Here, we introduce adeno-associated virus (AAV) vectors, widely used for invivo gene therapy, as a potent cancer vaccine platform. Our AAV vector-based vaccine combines antigen display on the capsid surface with a vector-mediated antigen overexpression targeting different components of the immune system in a unique chronological order by a single intramuscular application. Thereby, both profound and long-lasting antigen-specific T and B cell immune responses were induced. Moreover, mice receiving the vaccine were protected against tumor growth, demonstrating its efficacy in two tumor models, including the low immunogenic and aggressive B16/F10-Ova melanoma model. Remarkably, this approach was even effective in conditions of a late tumor challenge, i.e., 80days post-vaccination, between 88% (B16/F10-Ova melanoma) and 100% (EG7 thymoma) of mice remained tumor free. Thus, decorating AAV vector particles with antigens by capsid engineering represents a potent vaccine concept for applications in cancer immunotherapy. Its modular and versatile "plug-and-play" framework enables the use of tumor antigens of choice and the easy implementation of additional modifications to enhance immunogenicity further.

Children transition from simple associations to explicitly reasoned social learning strategies between age four and eight

To differentiate the use of simple associations from use of explicitly reasoned selective social learning, we can look for age-related changes in children’s behaviour that might signify a switch from one social learning strategy to the other. We presented 4- to 8-year-old children visiting a zoo in Scotland (N = 109) with a task in which the perceptual access of two informants was determined by the differing opacity of two screens of similar visual appearance during a hiding event. Initially success could be achieved by forming an association or inferring a rule based on salient visual (but causally irrelevant) cues. However, following a switch in the scenario, success required explicit reasoning about informants’ potential to provide valuable information based on their perceptual access. Following the switch, older children were more likely to select a knowledgeable informant. This suggests that some younger children who succeeded in the pre-switch trials had inferred rules or formed associations based on superficial, yet salient, visual cues, whereas older children made the link between perceptual access and the potential to inform. This late development and apparent cognitive challenge are consistent with proposals that such capacities are linked to the distinctiveness of human cumulative culture.

Porcine reproductive and respiratory virus 2 infection of the fetus results in multi-organ cell cycle suppression

Porcine reproductive and respiratory syndrome virus (PRRSV) infection during late gestation negatively affects fetal development. The objective of this study was to identify the fetal organs most severely impacted following infection, and evaluate the relationship between this response and fetal phenotypes. RNA was extracted from fetal heart, liver, lung, thymus, kidney, spleen, and loin muscle, collected following late gestation viral challenge of pregnant gilts. Initially, gene expression for three cell cycle promoters (CDK1, CDK2, CDK4) and one inhibitor (CDKN1A) were evaluated in biologically extreme phenotypic subsets including gestational age-matched controls (CON), uninfected (UNIF), high-viral load viable (HV-VIA), and high-viral load meconium-stained (HV-MEC) fetuses. There were no differences between CON and UNIF groups for any gene, indicating no impact of maternal infection alone. Relative to CON, high-viral load (HV-VIA, HV-MEC) fetuses showed significant downregulation of at least one CDK gene in all tissues except liver, while CDKN1A was upregulated in all tissues except muscle, with the heart and kidney most severely impacted. Subsequent evaluation of additional genes known to be upregulated following activation of P53 or TGFb/SMAD signaling cascades indicated neither pathway was responsible for the observed increase in CDKN1A. Finally, analysis of heart and kidney from a larger unselected population of infected fetuses from the same animal study showed that serum thyroxin and viral load were highly correlated with the expression of CDKN1A in both tissues. Collectively these results demonstrate the widespread suppression in cell division across all tissues in PRRSV infected fetuses and indicate a non-canonical regulatory mechanism.

Earlier onset of the Early Cretaceous Equatorial humidity belt

The long-standing view on the Cretaceous climate zones suggests the inception of an Equatorial Humid Belt (EHB) in the Albian. This inception contrasts with recent sedimentological and palynological evidence of sustained low-latitude, wetter paleoenvironment in the South American and African landmasses during the Aptian. The trigger for this early-stage EHB stands on two hypotheses: [1] the first major marine incursions to the equatorial Gondwana; [2] the southward displacement of a proto-Intertropical Convergence Zone (ITCZ). We provide new palynological, ichnological, and sedimentological data from the Codó Formation obtained from borehole 2-ANP-5-MA, drilled in the São Luís Basin, Brazilian equatorial margin. This integrated analysis allowed recovering well-preserved palynomorph assemblages of the upper Aptian Codó Formation. Based on three palynomorph-based climate indicators (sporomorph genera richness, the relative abundance of reworked palynomorphs, and climate-indicative palynofloras), and independent climate-indicative sedimentological indicators, our results show an interval of increasingly humid climate, which precedes the first major marine incursion. It also confirms that sporomorph genera richness scales directly with precipitation levels. Based on that, we reconstructed coeval late Aptian humidity patterns from thirteen South American and African sedimentary basins. Our findings support the establishment of the EHB in the late Aptian and challenge the view of a dominantly arid Equatorial Gondwana before the Albian. We argue that decreasing Proto-North Atlantic/South Atlantic sea-surface temperature (SST) gradient may have triggered a southward EHB displacement, leading to wetter, low-latitude biomes with broad and complex ecosystems. For the first time, a plausible mechanism is raised to explain the linkage between changing interhemispheric SST gradient and the dynamics of a proto-ITCZ in the Early Cretaceous.

Age-specific fecundity under pathogenic threat in an insect: Terminal investment versus reproductive restraint.

The terminal investment hypothesis predicts that as an organism's prospects for survival decrease, through age or when exposed to a pathogenic infection, it will invest more in reproduction, which should trade-off against somatic maintenance (including immunity) and therefore future survival. Attempts to test this hypothesis have produced mixed results, which, in addition, mainly rely on the assessment of changes in reproductive effort and often overlooking its impact on somatic defences and survival. Alternatively, animals may restrain current reproduction to sustain somatic protection, increasing the chance of surviving for additional reproductive opportunities. We tested both of these hypotheses in females of the yellow mealworm beetle, Tenebrio molitor, an iteroparous insect with reproductive tactics similar to that of long-lived organisms. To achieve this, we mimicked pathogenic bacterial infections early or late in the life of breeding females by injecting them with a suspension of inactivated Bacillus cereus, a known natural pathogen of T. molitor, and measured female age-specific fecundity, survival, body mass and immunity. Inconsistent with a terminal investment, females given either an early or late-life immune challenge did not exhibit reduced survival or enhance their reproductive output. Female fecundity declined with age and was reduced by the early but not the late immune challenge. Both early and late-life fecundity correlated positively with life expectancy. Finally, young and old females exhibited similar antibacterial immune responses, suggesting that they both restrained reproduction to sustain immunity. Our results clearly demonstrate that age-specific reproduction of T. molitor females under pathogenic threat is inconsistent with a terminal investment. In contrast, our results instead suggest that females used a reproductive restraint strategy to sustain immunity and therefore subsequent reproductive opportunities. However, as infections were mimicked only, the fitness benefit of this reproductive restraint could not be shown.

Rethinking Criminal Propensity and Character: Cohort Inequalities and the Power of Social Change

The social transformations of crime and punishment in the late twentieth and early twenty-first centuries challenge traditional conceptions of criminal propensity and character. A life-course framework on cohort differences in growing up during these times of social change highlights large-scale inequalities in life experiences. Entire cohorts of children have come of age in such different historical contexts that typical markers of a crime-prone character, such as being a chronic offender or having an arrest record, are as much a function of societal change as of an individual’s early life propensities or background characteristics, including classic risk factors emphasized in criminology. When we are thus matters as much as, and perhaps more than, who we are—despite law, practice, and theory privileging the latter. Because crime over the life course is shaped by changing sociohistorical conditions, it must be studied as such. Multicohort studies provide a key strategy for doing so, inspiring a reconsideration of criminal propensity and policies premised on unchanging predictors of future criminality. Developmental and life-course criminology should elevate the study of cohort differences in social change and, ultimately, societal character.

Intranasal immunization with chitosan microparticles enhances LACK-DNA vaccine protection and induces specific long-lasting immunity against visceral leishmaniasis

Development of a protective vaccine against Leishmania depends on antigen formulation and adjuvants that induce specific immunity and long-lasting immune responses. We previously demonstrated that BALB/c mice intranasally vaccinated with a plasmid DNA encoding the p36/LACK leishmanial antigen (LACK-DNA) develop a protective immunity for up to 3 months after vaccination, which was linked with the systemic expression of vaccine mRNA in peripheral organs. In this study, LACK-DNA vaccine was associated with biocompatible chitosan microparticles cross-linked with glyceraldehyde (CMC) to boost the long-lasting immunity against the late Leishmania infantum challenge. Infection at 7 days, 3 or 6 months after vaccination resulted in significantly lower parasite loads when compared with non-vaccinated controls. Besides, LACK-DNA-chitosan vaccinated mice showed long-time protection observed after the late time point challenge. The achieved protection was correlated with an enhanced spleen cell responsiveness to parasite antigens, marked by increased proliferation and IFN-γ as well as decreased IL-10 production. Moreover, we found diminished systemic levels of TNF-α that was compatible with the better health condition observed in LACK-DNA/CMC vaccinated-infected mice. Together, our data indicate the feasibility of chitosan microparticles as a delivery system tool to extend the protective immunity conferred by LACK-DNA vaccine, which may be explored in vaccine formulations against Leishmania parasite infections.

Timing of Gastrografin administration in the management of adhesive small bowel obstruction (ASBO): Does it matter?

BackgroundGastrografin challenge is increasingly used as a diagnostic tool to predict patients who may benefit from nonoperative management in adhesive small bowel obstruction. This study explores the optimal timing of Gastrografin in the management of adhesive small bowel obstruction by comparing early versus late Gastrografin challenge. MethodsA retrospective chart review from January 2016 to January 2018 identified patients with adhesive small bowel obstruction who underwent Gastrografin challenge. A receiver operating characteristic curve, to predict a duration of stay less than 5 days, calculated a 12-hour limit which separated early and late groups. Nonoperative and operative patients were compared separately. Our primary outcome was duration of stay. Secondary outcomes included operative requirement, time to the operating room, complication rate, and 1-year mortality. In a separate analysis, multivariable logistic regression identified independent risk factors for 1-year mortality. ResultsOne hundred thirty-four patients were identified (58 early, 76 late). In nonoperative patients, the early group had a shorter duration of stay (3.2 days vs 5.4 days), fewer complications, and a lower complication and 1-year mortality rate (P < .05). In operative patients, the early group had a shorter preoperative duration of stay (1.8 days vs 3.9 days) (P < .05). On multivariable regression, congestive heart failure, any postoperative complication, and operative requirement were the best predictors of 1-year mortality (R2 = 0.321; P < .05). ConclusionGastrografin administration within 12 hours of adhesive small bowel obstruction diagnosis had favorable outcomes in terms of duration of stay, complications, and mortality in nonoperative patients. Moreover, in operative patients, preoperative duration of stay was shortened. Our findings suggest protocolizing early Gastrografin challenge may be an important principle in adhesive small bowel obstruction management.

Controlling the Colonization of Clostridium perfringens in Broiler Chickens by an Electron-Beam-Killed Vaccine.

Simple SummaryClostridium perfringens (Cp) is a bacterium that causes necrotic enteritis in chickens and is responsible for an economic loss of about 6 billion U.S. dollars in the poultry industry worldwide. Consumption of Cp contaminated chicken meat causes foodborne illnesses in humans. Although Cp can be controlled in chickens by administering antibiotics through feed and water, the ban on the antibiotics owing to concerns on antibiotic resistance has created the need to identify alternative control approaches. As vaccination could be used as an alternative, we used electron beam irradiation (eBeam) to kill the bacterium and use the killed cells as vaccine to control the colonization of Cp in broiler chickens. In this study, we exposed three different strains of Cp to eBeam irradiation and used them as a vaccine to day-18 embryos. After the embryos hatched, the birds in each treatment were segregated into two groups for live Cp challenge at two time points. The results indicate that the vaccine effectively controlled the colonization of all three strains of Cp when challenged with live Cp, indicating that the vaccinated birds had acquired immunity. The current approach can reduce Cp colonization in chickens, thereby reducing economic loss.Clostridium perfringens (Cp) is a Gram-positive anaerobe that is one of the causative agents of necrotic enteritis (NE) in chickens, which leads to high mortality. Owing to the ban of administering antibiotics in feed to chickens, there has been an increase in the number of NE outbreaks all over the world, and the estimated loss is approximately 6 billion U.S. dollars. The best alternative method to control NE without antibiotics could be vaccination. In this study, we exposed three different strains of Cp to electron beam (eBeam) irradiation to inactivate them and then used them as a killed vaccine to control the colonization of Cp in broiler chickens. The vaccine was delivered to 18-day old embryos in ovo and the chickens were challenged with the respective vaccine strain at two different time points (early and late) to test the protective efficacy of the vaccine. The results indicate that an effective eBeam dose of 10 kGy inactivated all three strains of Cp, did not affect the cell membrane or epitopes, induced significant levels of IgY in the vaccinated birds, and further reduced the colonization of Cp strains significantly (p < 0.0001) in late challenge (JGS4064: 4 out of 10; JGS1473: 0 out of 10; JGS4104: 3 out of 10). Further studies are necessary to enhance the efficacy of the vaccine and to understand the mechanism of vaccine protection.

Immune responses and clinical effects of experimental challenge of elk with Brucella abortus strain 2308

To assess the effects of challenge dose and stage of gestation on infection and abortion, 35 elk were conjunctivally challenged with virulent Brucella abortus strain 2308 (S2308) during pregnancy. Seventeen elk were experimentally challenged early in the second trimester of gestation (December) with high (approximately 108 CFU) or low challenge (approximately 107 CFU) treatments having 8 and 9 pregnant elk, respectively. Other pregnant elk were experimentally challenged at a later challenge time (approximately early third trimester, February), with high and low challenge treatments having 8 and 10 elk, respectively. Conjunctival swabs from all animals were culture positive for the S2308 strain at 7 days after experimental challenge. All animals seroconverted on a B. abortus ELISA but optical density readings were not influenced (P > 0.05) by time of challenge or by challenge dosage. In the early challenge group, abortions occurred in 2 of 9 (22%) in the low challenge treatment and 3 of 8 (37%) in the high challenge treatment, whereas in the later challenge group, 1 of 8 (12.5%) in the low challenge treatment and 2 of 10 (20%) in the high challenge treatment aborted. The ability to recover B. abortus from samples obtained at necropsy did not differ (P > 0.05) between early and late challenges or between high and low challenge treatments. Despite the lack of abortions observed after experimental challenge, recovery from maternal tissues ranged from 50% (low dose, late challenge) to 77% (low dose, early challenge). Our data suggests that naïve elk do not abort as frequently after experimental infection with B. abortus strain 2308 as compared to similar data in cattle and bison.

A single lentivector DNA based immunization contains a late heterologous SIVmac251 mucosal challenge infection

Variety of conventional vaccine strategies tested against HIV-1 have failed to induce protection against HIV acquisition or durable control of viremia. Therefore, innovative strategies that can induce long lasting protective immunity against HIV chronic infection are needed. Recently, we developed an integration-defective HIV lentiDNA vaccine that undergoes a single cycle of replication in target cells in which most viral antigens are produced. A single immunization with such lentiDNA induced long-lasting T-cell and modest antibody responses in cynomolgus macaques. Here eighteen months after this single immunization, all animals were subjected to repeated low dose intra-rectal challenges with a heterologous pathogenic SIVmac251 isolate. Although the viral set point in SIVmac-infected cynomolgus is commonly lower than that seen in Indian rhesus macaques, the vaccinated group of macaques displayed a two log reduction of peak of viremia followed by a progressive and sustained control of virus replication relative to control animals. This antiviral control correlated with antigen-specific CD4+ and CD8+ T cells with high capacity of recall responses comprising effector and central memory T cells but also memory T cell precursors. This is the first description of SIV control in NHP model infected at 18 months following a single immunization with a non-integrative single cycle lentiDNA HIV vaccine. While not delivering sterilizing immunity, our single immunization strategy with a single-cycle lentivector DNA vaccine appears to provide an interesting and safe vaccine platform that warrants further exploration.

Maternal and fetal thyroid dysfunction following porcine reproductive and respiratory syndrome virus2 infection

To better understand the host response to porcine reproductive and respiratory virus-2 (PRRSV2) we evaluated circulating thyroid hormone and associated gene expression in a late gestation challenge model. Pregnant gilts were inoculated at gestation day 85 and fetal samples collected at either 12 or 21 days post-infection (dpi). A subset of fetuses was selected for analysis based on viability and viral load categorized as either uninfected-viable (UNIF), high viral load viable (HV-VIA) or high viral load meconium stained (HV-MEC) and were compared with gestational age matched controls (CON). In dams, circulating levels of total T3 and T4 decreased in the acute period following infection and rebounded by 21 dpi. A similar effect was observed in fetuses, but was largely restricted to HV-VIA and HV-MEC, with minimal decrease noted in UNIF relative to CON at 21 dpi. Gene expression in fetal heart at 12 dpi showed significant decompensatory transcription of thyroid hormone transporters (SLC16A2) and deiodinases (DIO2, DIO3), which was not observed in brain. Correspondingly, genes associated with cell cycle progression (CDK1,2,4) were downregulated in only the heart of highly infected fetuses, while expression of their inhibitor (CDKN1A) was upregulated in both tissues. Finally, expression of genes associated with cardiac stress including CAMKD and AGT were upregulated in the hearts of highly infected fetuses, and a shift in expression of MYH6 to MYH7 was observed in HV-MEC fetuses specifically. Collectively, the results suggest PRRSV2 infection causes a hypothyroid state that disproportionally impacts the fetal heart over the brain.

RELIGION, SCIENCE, AND DISENCHANTMENT IN LATE MODERNITY

AbstractLate modernity has witnessed a growing semantic shift from “religion” to “spirituality.” In this article, I argue what underlies this shift is a cultural structure I call the religion of the heart. I begin with an explication of what I mean by the “religion of the heart,” and draw on the work of Ernst Troeltsch and Colin Campbell to identify what I take to be its historical antecedents. Second, I analyze the ambiguous relationships fostered between the religion of the heart and the discourses of science and religion, respectively, in late modernity. I illuminate how the social conditions of late modernity undermine or challenge what we conventionally think of as scientific and religious authorities, while at the same time creating existential needs that the religion of the heart is well adapted to meet. I conclude with a brief discussion of the implications of this process, especially as it relates to the sustainability of science and religion, as independent enterprises, in the twenty‐first century.

Popular Healing in Printed Medical Books

In 1759, Zhao Xuemin 趙學敏, a scholar and physician from Qiantang County (present-day Hangzhou), compiled his Chuanya 串雅. Based on certain editions of this work, modern scholars have assumed that this text is composed of recipes collected from itinerant healers, and that it was its author’s intention to transmit folk healing practices through the printed word. The original manuscript that Zhao Xuemin compiled probably never appeared in print, however, whereas the extant editions of this text found numerous new editions and re-printings. Focusing on several manuscripts and printed editions of the Chuanya which emerged between the late Qing and Republican period, this article traces the processes through which various different agents created and recreated the Chuanya. In contrast to past studies where the connection between the Chuanya and popular healing is taken for granted, I argue that any conclusion should primarily take into account the various editions of this work. By the case study of this text, I hope to clarify a broader dimension around the authorship of printed medical books in late imperial China and challenge the assumption that we can understand them outside the context of their edition and publication.

Telomere erosion varies with sex and age at immune challenge but not with maternal antibodies in pigeons.

Conditions experienced early in life have profound impact on adult fitness, and telomere erosion could be a key mechanism in this process. In particular, early exposure to parasites is a frequent phenomenon in young vertebrates, which is associated with several short- and long-term costs such as telomere erosion. However, the timing of exposure to parasites during ontogeny and maternal antibodies can strongly modulate the costs of immunity, and could differentially affect telomere erosion. Here, we compared the effects of an early or late immune challenge on telomere erosion rate in male and female young feral pigeons (Columba livia) having received or not maternal antibodies. More specifically, we tested whether (i) early or late injections of antigens had different effects on nestling telomere erosion rate, (ii) whether this effect was different between male and female nestlings, and (iii) whether maternal antibodies could modulate telomere erosion rate. Our results show an interaction between sex and age at injection. Late-injected nestlings (injected at 14 days of age) had an accelerated erosion rate compared with the early-injected nestlings (injected at 3 days of age), and this effect was higher in females compared with the males. However, we did not find any effect of maternal antibodies on telomere erosion rate. These results suggest that the age at which an immune challenge occurs is important for telomere erosion and that sex-specific approaches are needed to better understand the short-term and long-term costs of parasite exposure in young vertebrates.

Chronic lurasidone treatment normalizes GABAergic marker alterations in the dorsal hippocampus of mice exposed to prenatal immune activation

Prenatal maternal infection represents a risk factor for the development of psychopathologic conditions later in life. Clinical evidence is also supported by animal models in which the vulnerability to develop a schizophrenic-like phenotype likely originates from inflammatory processes as early as in the womb. Prenatal immune challenge, for example, induces a variety of long-term behavioral alterations in mice, such as deficits in recognition and spatial working memory, perseverative behaviors and social impairments, which are relevant to different symptom clusters of schizophrenia.Here, we investigated the modulation of GABAergic markers in the dorsal and ventral hippocampus of adult mice exposed to late prenatal immune challenge with the viral mimetic Poly(I:C) (polyriboinosinic-polyribocytidilic-acid) at gestational day 17, and we evaluated the ability of chronic treatment with the multi-receptor antipsychotic lurasidone to modulate the alterations produced by maternal infection. Poly(I:C) mice show a significant reduction of key GABAergic markers, such as GAD67 and parvalbumin, specifically in the dorsal hippocampus, which were normalized by chronic lurasidone administration. Moreover, chronic drug administration increases the expression of the pool of brain derived neurotrophic factor (BDNF) transcripts with the long 3’-UTR as well as the levels of mature BDNF protein in the synaptosomal compartment, selectively in dorsal hippocampus.All in all, our findings demonstrate that lurasidone is effective in ameliorating molecular abnormalities observed in Poly(I:C) mice, providing further support to the neuroplastic properties of this multi-receptor antipsychotic drug.

Intramammary immunization with ultraviolet-killed Escherichia coli shows partial protection against late gestation intramammary challenge with a homologous strain.

The objective of this study was to evaluate the efficacy of intramammary immunization with UV-killed Escherichia coli ECC-Z on prevention of intramammary colonization after a challenge with a dose of the homologous E. coli ECC-Z live bacteria. A total of 10 cows were included in a study to evaluate the efficacy of intramammary immunization. All 10 cows received an intramammary immunization of 100 cfu of UV-killed E. coli ECC-Z bacteria into one hind quarter at the time of dry off. Approximately 2wk before the anticipated calving date, both hind quarters of all cows were challenged with 100 cfu of live E. coli ECC-Z bacteria. Five of the cows were vaccinated parenterally with a commercial J5 bacterin, and 5 cows served as controls with no parenteral vaccination. The cows were then followed over time and infection risk, clinical scores, somatic cell count, and milk production were observed over time. The results of these 10 cows showed partial protection of intramammary immunization on the outcome of a subsequent homologous intramammary challenge. Immunization resulted in a lower probability of infection, a lower bacteria count, lower somatic cell counts and milk conductivity, a lower clinical mastitis score, and increased milk production compared with unimmunized control quarters. Once the analysis was corrected for immunization, parenteral J5 vaccination had no significant effect on any of the measured parameters. These results provide the first evidence that intramammary immunization may improve the outcome of an intramammary E. coli infection in late gestation and onset of mastitis immediately following parturition. Unlike systemic vaccination, which generally does not reduce the intramammary infection risk, the intramammary immunization did show a 5-times reduced odds of an established intramammary infection after challenge. Cytokine profiles indicated a local return of proinflammatory response after challenge as the data showed a more pronounced increase in in IFN-γ with a subsequent negative feedback due to a spike in the level of IL-10 in immunized quarters relative to nonimmunized quarters. Although these results are preliminary and obtained on only 10 cows, the results provide insight into the biological benefits of triggering mucosal immunity in the mammary gland.

Reverse genetics based rgH5N2 vaccine provides protection against high dose challenge of H5N1 avian influenza virus in chicken

An inactivated vaccine was developed using the rgH5N2 virus (6 + 2 reassortant) generated by plasmid based reverse genetics system (RGS) with WSN/33/H1N1 as backbone virus. Following mutation of the basic amino acid cleavage site RRRKKR*GLF to IETR*GLF, the H5-HA (haemagglutinin) gene of the selected donor H5N1 virus (A/chicken/West Bengal/80995/2008) of antigenic clade 2.2 was used along with the N2-NA gene from H9N2 field isolate (A/chicken/Uttar Pradesh/2543/2004) for generation of the rgH5N2 virus. A single dose (0.5 ml/bird) of the inactivated rgH5N2 vaccine protected 100% of the vaccinated chickens (n = 10) on 28th dpv (early challenge) and 90% of the vaccinated chickens (n = 10) on 200th dpv (late challenge) against high dose challenge with HPAI virus (109 EID50/bird). Challenge virus shedding via oropharynx and cloaca of the vaccinated chickens was detectable by realtime RT-PCR during 1–5 dpc and 1–9 days dpc in the early and the late challenge, respectively. The protective level of antibodies (mean HI titre > 128) was maintained without booster vaccination for 200 days. The present study provides the experimental evidence about the extent of protection provided by a reverse genetics based vaccine for clade 2.2 H5N1 viruses against challenge with high dose of field virus at two different time points (28 dpv and 200 dpv). The challenge study is uniquely different from the previous similar experiments on account of 1000 times higher dose of challenge and protection at 200 dpv. The protection and virus shedding data of the study may be useful for countries planning to use H5 vaccine in poultry especially against the clade 2.2 H5N1 viruses.