Routine entomological monitoring data are used to quantify the abundance of Ae. aegypti. The public health utility of these indicators is based on the assumption that greater mosquito abundance ...increases the risk of human DENV transmission, and therefore reducing exposure to the vector decreases incidence of infection. Entomological survey data from two longitudinal cohort studies in Iquitos, Peru, linked with 8,153 paired serological samples taken approximately six months apart were analyzed. Indicators of Ae. aegypti density were calculated from cross-sectional and longitudinal entomological data collected over a 12-month period for larval, pupal and adult Ae. aegypti. Log binomial models were used to estimate risk ratios (RR) to measure the association between Ae. aegypti abundance and the six-month risk of DENV seroconversion. RRs estimated using cross-sectional entomological data were compared to RRs estimated using longitudinal data. Higher cross-sectional Ae. aegypti densities were not associated with an increased risk of DENV seroconversion. Use of longitudinal entomological data resulted in RRs ranging from 1.01 (95% CI: 1.01, 1.02) to 1.30 (95% CI: 1.17, 1.46) for adult stage density estimates and RRs ranging from 1.21 (95% CI: 1.07, 1.37) to 1.75 (95% CI: 1.23, 2.5) for categorical immature indices. Ae. aegypti densities calculated from longitudinal entomological data were associated with DENV seroconversion, whereas those measured cross-sectionally were not. Ae. aegypti indicators calculated from cross-sectional surveillance, as is common practice, have limited public health utility in detecting areas or populations at high risk of DENV infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The storage of long-term memories is a dynamic process. Reminder cues can destabilize previously consolidated memories, rendering them labile and modifiable. However, memories that are strongly ...encoded or relatively remote at the time of reactivation can resist destabilization only being rendered labile under conditions that favour memory updating. Using the object location recognition task, here we show in male C57BL/6 mice that novelty-induced destabilization of strongly-encoded memories requires muscarinic acetylcholine receptor (mAChR) activation. Furthermore, we use the objects-in-updated locations task to show that updating of object location memories is mAChR-dependent. Thus, mAChR stimulation appears to be critical for spatial memory destabilization and related memory updating. Enhancing our understanding of the role of ACh in memory updating should inform future research into the underlying causes of behavioural disorders that are characterized by persistent maladaptive memories, such as age-related cognitive inflexibility and post-traumatic stress disorder.
Flaviviridae: A growing family of human pathogens Among the major contributors to the positive-strand RNA virus global disease burden are the flaviviruses, a genus of enveloped viruses that includes ...Yellow fever virus (YFV), Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV) and is closely related to Hepatitis C virus (HCV) 2. Cer, ceramide; Chol, cholesterol; DAG, diacylglycerol; ER, endoplasmic reticulum; FFA, free fatty acids; GalCer, galactosylceramide; GlcCer, glucosylceramide; GSPL, complex glycosphingolipids; mTOR, mammalian target of rapamycin; NS, nonstructural; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PIP2, phosphatidylinositol-(4,5)-bisphosphate; PI, phosphatidylinositol; PIP3, phosphatidylinositol-(3,4,5)-trisphosphate; PM, plasma membrane; PS, phosphatidylserine; S1P, sphingosine-1-phosphate; SM, sphingomyelin; TAG, triacylglycerol; Ve, invaginated vesicles. https://doi.org/10.1371/journal.ppat.1006952.g001 Replication complex assembly remakes the host lipid landscape Inducing the negative membrane curvature required for vesicle formation is a thermodynamically unfavorable process 16. ...LD lipids may be required for multiple aspects of flavivirus infection and pathogenesis, from providing the raw materials and energy for replication to supporting efficient encapsidation and assembly of viral particles. Fatty acid synthesis is regulated by sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors also responsible for controlling cholesterol biosynthesis 30.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long-term memory storage is a dynamic process requiring flexibility to ensure adaptive behavioural responding in changing environments. Indeed, it is well established that memory reactivation can ..."destabilize" consolidated traces, leading to various forms of updating. However, the neurobiological mechanisms rendering long-term memories labile and modifiable remain poorly described. Moreover, boundary conditions, such as the age or strength of the memory, can reduce the likelihood of this destabilization; yet, intuitively, these most behaviourally influential of memories should also be modifiable under appropriate conditions. Here, we provide evidence that salient novelty at the time of memory reactivation promotes integrative updating of resistant object memories in rats. Furthermore, blockade of muscarinic acetylcholine receptors (mAChRs; with pirenzepine) or disruption of calcium/calmodulin (Ca
/CaM) with KN-93, a Ca
/CaM-binding molecule that inhibits calcium/calmodulin-dependent protein kinase II (CaMKII) activation, in perirhinal cortex (PRh) prevented novelty-induced destabilization and updating of resistant object memories. Finally, PRh M
mAChR activation (with CDD-0102A) was sufficient to destabilize resistant object memories for updating, and this effect was blocked by KN-93, possibly via inhibition of CaMKII activity. Thus, mAChRs and activation of CaMKII appear to interact as part of a mechanism to override boundary conditions on resistant object memories to ensure integrative modification with novel information. These findings therefore have important implications for understanding the dynamic nature of long-term memory storage and potential treatments for conditions characterized by maladaptive and inflexible memories.
Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV ...infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi) that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Humans who experience a primary dengue virus (DENV) infection develop antibodies that preferentially neutralize the homologous serotype responsible for infection. Affected individuals also generate ...cross-reactive antibodies against heterologous DENV serotypes, which are non-neutralizing. Dengue cross-reactive, non-neutralizing antibodies can enhance infection of Fc receptor bearing cells and, potentially, exacerbate disease. The actual binding sites of human antibody on the DENV particle are not well defined. We characterized the specificity and neutralization potency of polyclonal serum antibodies and memory B-cell derived monoclonal antibodies (hMAbs) from 2 individuals exposed to primary DENV infections. Most DENV-specific hMAbs were serotype cross-reactive and weakly neutralizing. Moreover, many hMAbs bound to the viral pre-membrane protein and other sites on the virus that were not preserved when the viral envelope protein was produced as a soluble, recombinant antigen (rE protein). Nonetheless, by modifying the screening procedure to detect rare antibodies that bound to rE, we were able to isolate and map human antibodies that strongly neutralized the homologous serotype of DENV. Our MAbs results indicate that, in these two individuals exposed to primary DENV infections, a small fraction of the total antibody response was responsible for virus neutralization.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
SARS-CoV-2 and its variants continue to infect hundreds of thousands every day despite the rollout of effective vaccines. Therefore, it is essential to understand the levels of protection ...that these vaccines provide in the face of emerging variants. Here, we report two demographically balanced cohorts of BNT162b2 vaccine recipients and COVID-19 patients, from which we evaluate neutralizing antibody titers against SARS-CoV-2 as well as the B.1.1.7 (alpha) and B.1.351 (beta) variants. We show that both B.1.1.7 and B.1.351 are less well neutralized by serum from vaccinated individuals, and that B.1.351, but not B.1.1.7, is less well neutralized by convalescent serum. We also find that the levels of variant-specific anti-spike antibodies are proportional to neutralizing activities. Together, our results demonstrate the escape of the emerging SARS-CoV-2 variants from neutralization by serum antibodies, which may lead to reduced protection from re-infection or increased risk of vaccine breakthrough.
Abstract Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological ...disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs (e.g., amiodarone) selectively enhance G protein coupling efficacy. The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M 1 receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a , c which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish ( Danio rerio ) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a , c , reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.
This study examines the relationship between age and neutralizing antibody titers against the SARS-CoV-2 USA-WA1/2020 strain and the P.1 variant after 2 doses of the BNT162b2 vaccine.
Current coronavirus disease 2019 (COVID-19) vaccines effectively reduce overall morbidity and mortality and are vitally important to controlling the pandemic. Individuals who previously recovered ...from COVID-19 have enhanced immune responses after vaccination (hybrid immunity) compared with their naïve-vaccinated peers; however, the effects of post-vaccination breakthrough infections on humoral immune response remain to be determined. Here, we measure neutralizing antibody responses from 104 vaccinated individuals, including those with breakthrough infections, hybrid immunity, and no infection history. We find that human immune sera after breakthrough infection and vaccination after natural infection broadly neutralize SARS-CoV-2 (severe acute respiratory coronavirus 2) variants to a similar degree. Although age negatively correlates with antibody response after vaccination alone, no correlation with age was found in breakthrough or hybrid immune groups. Together, our data suggest that the additional antigen exposure from natural infection substantially boosts the quantity, quality, and breadth of humoral immune response regardless of whether it occurs before or after vaccination.
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