Muscarinic acetylcholine receptors (mAChR) play important roles in regulating complex behaviors such as cognition, movement, and reward, making them ideally situated as potential drug targets for the ...treatment of several brain disorders. Recent advances in the discovery of subtype-selective allosteric modulators for mAChRs has provided an unprecedented opportunity for highly specific modulation of signaling by individual mAChR subtypes in the brain. Recently, mAChR allosteric modulators have entered clinical development for Alzheimer’s disease (AD) and schizophrenia, and have potential utility for other brain disorders. However, mAChR allosteric modulators can display a diverse array of pharmacological properties, and a more nuanced understanding of the mAChR will be necessary to best translate preclinical findings into successful clinical treatments.
mAChR allosteric modulators demonstrate unparalleled subtype selectivity, can possess a wide array of distinct pharmacological properties, and are rapidly advancing into the clinic for the treatment of multiple central nervous system disorders.M1 mAChR positive allosteric modulators (PAMs) may enhance cognition and reverse memory deficits in AD and schizophrenia, and may display a larger therapeutic window than acetylcholinesterase inhibitors.M4 PAMs can reduce dopamine release and demonstrate antipsychotic-like effects in preclinical animal models.Recent preclinical literature suggests that M5 negative allosteric modulators may effectively treat an array of substance use disorders without reducing the effects of natural rewards.
Endospores formed by Bacillus, Clostridia, and related genera are encased in a protein shell called the coat. In many species, including B. subtilis, the coat is the outermost spore structure, and in ...other species, such as the pathogenic organisms B. anthracis and B. cereus, the spore is encased in an additional layer called the exosporium. Both the coat and the exosporium have roles in protection of the spore and in its environmental interactions. Assembly of both structures is a function of the mother cell, one of two cellular compartments of the developing sporangium. Studies in B. subtilis have revealed that the timing of coat protein production, the guiding role of a small group of morphogenetic proteins, and several types of posttranslational modifications are essential for the fidelity of the assembly process. Assembly of the exosporium requires a set of novel proteins as well as homologues of proteins found in the outermost layers of the coat and of some of the coat morphogenetic factors, suggesting that the exosporium is a more specialized structure of a multifunctional coat. These and other insights into the molecular details of spore surface morphogenesis provide avenues for exploitation of the spore surface layers in applications for biotechnology and medicine.
Glycosylation is a key modification of proteins and lipids and is involved in most intermolecular and intercellular interactions. The gastrointestinal mucus gel is continuous and can be divided into ...two layers: a secreted loosely associated layer and a layer firmly attached to the mucosa. In addition, the membrane-bound glycosylated proteins and lipids create a glycocalyx, which remains adherent on each cell and is dynamic and responsive to the physiological state and environment of the cell. The secreted glycans form a mucus gel layer that serves as a physicochemical sensor and barrier network and is primarily composed of mucins and associated peptides. These glycans protect gut epithelial cells from chemical, biological and physical insults and are continuously renewed. Pathogens colonise and invade the host epithelial cells using protein-protein and glycan-lectin interactions. During the process of colonisation and infection, the glycosylation state of both host and pathogen change in response to the presence of the other. This complex modulation of glycan expression critically determines pathogenesis and the host response in terms of structural changes and immune response. In addition, by influencing host immunity and gut glycosylation, the microbiota can further effect protection against pathogens. In this review, the roles of host glycosylation in interactions with two prevalent bacterial pathogens, Campylobater jejuni and Helicobacter pylori, are discussed to illustrate important concepts in pathogenesis.
Proteins SpoIIQ and SpoIIIAH interact through two membranes to connect the forespore and the mother cell during endospore development in the bacterium Bacillus subtilis. SpoIIIAH consists of a ...transmembrane segment and an extracellular domain with similarity to YscJ proteins. YscJ proteins form large multimeric rings that are the structural scaffolds for the assembly of type III secretion systems in Gram-negative bacteria. The predicted ring-forming motif of SpoIIIAH and other evidence led to the model that SpoIIQ and SpoIIIAH form the core components of a channel or transporter through which the mother cell nurtures forespore development. Therefore, to understand the roles of SpoIIIAH and SpoIIQ in channel formation, it is critical to determine whether SpoIIIAH adopts a ring-forming structural motif, and whether interaction of SpoIIIAH with SpoIIQ would preclude ring formation. We report a 2.8-Å resolution structure of a complex of SpoIIQ and SpoIIIAH. SpoIIIAH folds into the ring-building structural motif, and modeling shows that the structure of the SpoIIQ–SpoIIIAH complex is compatible with forming a symmetrical oligomer that is similar to those in type III systems. The inner diameters of the two most likely ring models are large enough to accommodate several copies of other integral membrane proteins. SpoIIQ contains a LytM domain, which is found in metalloendopeptidases, but lacks residues important for metalloprotease activity. Other LytM domains appear to be involved in protein–protein interactions. We found that the LytM domain of SpoIIQ contains an accessory region that interacts with SpoIIIAH.
Cognitive deficits are now widely recognized to be an important component of anxiety. In particular, anxiety is thought to restrict the capacity of working memory by competing with task-relevant ...processes. The evidence for this claim, however, has been mixed. Although some studies have found restricted working memory in anxiety, others have not. Within studies that have found impairments, there is little agreement regarding the boundary conditions of the anxiety/WMC association. The aim of this review is to critically evaluate the evidence for anxiety-related deficits in working memory capacity. First, a meta-analysis of 177 samples (N = 22,061 individuals) demonstrated that self-reported measures of anxiety are reliably related to poorer performance on measures of working memory capacity (g = −.334, p < 10−29). This finding was consistent across complex span (e.g., OSPAN; g = −.342, k = 30, N = 3,196, p = .000001), simple span (e.g., digit span; g = −.318, k = 127, N = 17,547, p < 10−17), and dynamic span tasks (e.g., N-Back; g = −.437, k = 20, N = 1,318, p = .000003). Second, a narrative review of the literature revealed that anxiety, whether self-reported or experimentally induced, is related to poorer performance across a wide variety of tasks. Finally, the review identified a number of methodological limitations common in the literature as well as avenues for future research.
Support for the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signaling as an approach for treatment of ...this devastating disease. The ability of metabotropic glutamate (mGlu) receptors to modulate glutamatergic neurotransmission has thus attracted considerable attention for the development of novel antipsychotics. Consisting of eight subtypes classified into three groups based on sequence homology, signal transduction, and pharmacology, the mGlu receptors provide a wide range of targets to modulate NMDAR function as well as glutamate release. Recently, allosteric modulators of mGlu receptors have been developed that allow unprecedented selectivity among subtypes, not just groups, facilitating the investigation of the effects of subtype-specific modulation. In preclinical animal models, positive allosteric modulators (PAMs) of the group I mGlu receptor mGlu
have efficacy across all three symptom domains of schizophrenia (positive, negative, and cognitive). The discovery and development of mGlu
PAMs that display unique signal bias suggests that efficacy can be retained while avoiding the neurotoxic effects of earlier compounds. Interestingly, mGlu
negative allosteric modulators (NAMs) appear efficacious in positive symptom models of the disease but are still in early preclinical development. While selective group II mGlu receptor (mGlu
) agonists have reached clinical trials but were unsuccessful, specific mGlu
or mGlu
receptor targeting still hold great promise. Genetic studies implicated mGlu
in the antipsychotic effects of group II agonists and mGlu
PAMs have since entered into clinical trials. Additionally, mGlu
appears to play an important role in cognition, may confer neuroprotective effects, and thus is a promising target to alleviate cognitive deficits in schizophrenia. Although group III mGlu receptors (mGlu
) have attracted less attention, mGlu
agonists and PAMs appear to have efficacy across all three symptoms domains in preclinical models. The recent discovery of heterodimers comprising mGlu
and mGlu
may explain the efficacy of mGlu
selective compounds but this remains to be determined. Taken together, compounds targeting mGlu receptors, specifically subtype-selective allosteric modulators, provide a compelling alternative approach to fill the unmet clinical needs for patients with schizophrenia.
Oral leukoplakia presents as a white patch on the oral mucosa and is recognized as having significant malignant potential. Although colonization of these patches with
is common, little is known about ...the bacterial microbiota of these patches. In the current study we analyzed the microbiome of oral leukoplakia in 36 patients compared to healthy mucosal tissue from the same patients and healthy control subjects to determine if specific microbial enrichments could be identified early in the malignant process that could play a role in the progression of the disease. This was carried out by sequence analysis of the V1-V2 region of the bacterial 16S rRNA gene using the Illumina MiSeq. Oral leukoplakia exhibited increased abundance of Fusobacteria and reduced levels of Firmicutes (Metastats
< 0.01).
colonization was also more prevalent in leukoplakia patients relative to healthy controls (
= 0.025). Bacterial colonization patterns on oral leukoplakia were highly variable and five distinct bacterial clusters were discerned. These clusters exhibited co-occurrence of
, and
species (Pearson
< 0.01), which is strikingly similar to the microbial co-occurrence patterns observed on colorectal cancers (Warren et al., 2013). Increased abundance of the acetaldehydogenic microorganism
was also apparent on oral leukoplakias from lingual sites (
0.0012). Severe dysplasia was associated with elevated levels of
spp. and
(
< 0.05). Oral leukoplakia exhibits an altered microbiota that has similarities to the microbiome of colorectal cancer.
Food allergies have increased at an alarming rate over the past 2 decades, indicating that environmental factors are driving disease progression. It has been postulated that sensitization to foods, ...in particular, peanut, occurs through impaired skin. Peanut allergens have been quantified in household dust and may be the culprit source. Indeed, TH2 cell–skewing innate cytokines can be driven by application of food antigens on both intact and impaired skin of mice, resulting in antigen-specific IgE production and anaphylaxis following allergen exposure. However, allergy induction through the skin can be prevented by induction of oral tolerance before skin exposure. These observations led to the dual allergen exposure hypothesis, according to which oral exposure to food antigens leads to tolerance and antigen exposure on impaired skin leads to allergy. Here, we propose the airway as an alternative route of sensitization in the dual allergen exposure hypothesis that leads to food allergy. Specifically, we will provide evidence from mouse models and human cell–based studies that together implicate the airway as a plausible route of sensitization.
Research involving event-related brain potentials has revealed that anxiety is associated with enhanced error monitoring, as reflected in increased amplitude of the error-related negativity (ERN). ...The nature of the relationship between anxiety and error monitoring is unclear, however. Through meta-analysis and a critical review of the literature, we argue that anxious apprehension/worry is the dimension of anxiety most closely associated with error monitoring. Although, overall, anxiety demonstrated a robust, "small-to-medium" relationship with enhanced ERN (r = -0.25), studies employing measures of anxious apprehension show a threefold greater effect size estimate (r = -0.35) than those utilizing other measures of anxiety (r = -0.09). Our conceptual framework helps explain this more specific relationship between anxiety and enhanced ERN and delineates the unique roles of worry, conflict processing, and modes of cognitive control. Collectively, our analysis suggests that enhanced ERN in anxiety results from the interplay of a decrease in processes supporting active goal maintenance and a compensatory increase in processes dedicated to transient reactivation of task goals on an as-needed basis when salient events (i.e., errors) occur.
Background
One in 3 US adults has high blood pressure, or hypertension. As prior projections suggest hypertension is the costliest of all cardiovascular diseases, it is important to define the ...current state of healthcare expenditures related to hypertension.
Methods and Results
We used a nationally representative database, the Medical Expenditure Panel Survey, to calculate the estimated annual healthcare expenditure for patients with hypertension and to measure trends in expenditure longitudinally over a 12‐year period. A 2‐part model was used to estimate adjusted incremental expenditures for individuals with hypertension versus those without hypertension. Sex, race/ethnicity, education, insurance status, census region, income, marital status, Charlson Comorbidity Index, and year category were included as covariates. The 2003–2014 pooled data include a total sample of 224 920 adults, of whom 36.9% had hypertension. Unadjusted mean annual medical expenditure attributable to patients with hypertension was $9089. Relative to individuals without hypertension, individuals with hypertension had $1920 higher annual adjusted incremental expenditure, 2.5 times the inpatient cost, almost double the outpatient cost, and nearly triple the prescription medication expenditure. Based on the prevalence of hypertension in the United States, the estimated adjusted annual incremental cost is $131 billion per year higher for the hypertensive adult population compared with the nonhypertensive population.
Conclusions
Individuals with hypertension are estimated to face nearly $2000 higher annual healthcare expenditure compared with their nonhypertensive peers. This trend has been relatively stable over 12 years. Healthcare costs associated with hypertension account for about $131 billion. This warrants intense effort toward hypertension prevention and management.
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