Multiple studies suggest a key role for gut microbiota in IgE-mediated food allergy (FA) development, but to date, none has studied it in the persistent state.
To characterize the gut microbiota ...composition and short-chain fatty acid (SCFAs) profiles associated with major food allergy groups, we recruited 233 patients with FA including milk (N = 66), sesame (N = 38), peanut (N = 71), and tree nuts (N = 58), and non-allergic controls (N = 58). DNA was isolated from fecal samples, and 16S rRNA gene sequences were analyzed. SCFAs in stool were analyzed from patients with a single allergy (N = 84) and controls (N = 31).
The gut microbiota composition of allergic patients was significantly different compared to age-matched controls both in α-diversity and β-diversity. Distinct microbial signatures were noted for FA to different foods. Prevotella copri (P. copri) was the most overrepresented species in non-allergic controls. SCFAs levels were significantly higher in the non-allergic compared to the FA groups, whereas P. copri significantly correlated with all three SCFAs. We used these microbial differences to distinguish between FA patients and non-allergic healthy controls with an area under the curve of 0.90, and for the classification of FA patients according to their FA types using a supervised learning algorithm. Bacteroides and P. copri were identified as taxa potentially contributing to KEGG acetate-related pathways enriched in non-allergic compared to FA. In addition, overall pathway dissimilarities were found among different FAs.
Our results demonstrate a link between IgE-mediated FA and the composition and metabolic activity of the gut microbiota.
Rumination is a form of thought characterized by repetitive focus on discomforting emotions or stimuli. In chronic pain disorders, rumination can impede treatment efficacy. The brain mechanisms ...underlying rumination about chronic pain are not understood. Interestingly, a link between rumination and functional connectivity (FC) of the brain's default mode network (DMN) has been identified within the context of mood disorders. We, and others, have also found DMN dysfunction in chronic pain populations. The medial prefrontal cortex (mPFC) is a key node of the DMN that is anatomically connected with the descending pain modulatory system. Therefore, we tested the hypothesis that in patients with chronic pain, the mPFC exhibits abnormal FC related to the patient's degree of rumination about their pain. Seventeen patients with idiopathic temporomandibular disorder (TMD) and 17 age- and sex-matched healthy controls underwent resting state functional MRI, and rumination about pain was assessed through the rumination subscale of the Pain Catastrophizing Scale. Compared with healthy controls, we found that TMD patients exhibited enhanced mPFC FC with other DMN regions, including the posterior cingulate cortex (PCC)/precuneus (PCu) and retrosplenial cortex. We also found that individual differences in pain rumination in the chronic pain patients (but not in healthy controls) were positively correlated to mPFC FC with the PCC/PCu, retrosplenial cortex, medial thalamus, and periaqueductal/periventricular gray. These data implicate communication within the DMN and of the DMN with the descending modulatory system as a mechanism underlying the degree to which patients ruminate about their chronic pain.
Although the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomic and clinical studies show that it also has a role in reward-processing. However, ...the way in which the movement-related and the reward-related neural activity interact at the level of the cerebellar cortex and contribute toward learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when 2 male monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol-hand association and a novel symbol-hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys' reaction times, or the novelty of the visual symbols. The simple spike activity changed throughout the learning process, but the concurrent complex spikes did not instruct that change. Although these neurons also have reward-related activity, the reward-related and movement-related signals were independent. We suggest that this mixed selectivity may facilitate the flexible learning of difficult reinforcement learning problems.
The cerebellum receives both motor-related and reward-related information. However, it is unclear how these two signals interact at the level of cerebellar cortex and contribute to learning nonmotor skills. Here we show that in the mid-lateral cerebellum, the reward information is encoded independently from the motor information such that during reward-based learning, only the reward information carried by the Purkinje cells inform learning while the motor information remains unchanged with learning.
We present bacterial biogeography as sampled from the human gastrointestinal tract of four healthy subjects. This study generated >32 million paired-end sequences of bacterial 16S rRNA genes (V3 ...region) representing >95,000 unique operational taxonomic units (OTUs; 97% similarity clusters), with >99% Good's coverage for all samples. The highest OTU richness and phylogenetic diversity was found in the mouth samples. The microbial communities of multiple biopsy sites within the colon were highly similar within individuals and largely distinct from those in stool. Within an individual, OTU overlap among broad site definitions (mouth, stomach/duodenum, colon and stool) ranged from 32-110 OTUs, 25 of which were common to all individuals and included OTUs affiliated with Faecalibacterium prasnitzii and the TM7 phylum. This first comprehensive characterization of the abundant and rare microflora found along the healthy human digestive tract represents essential groundwork to investigate further how the human microbiome relates to health and disease.
Familial breast and ovarian cancer are often caused by inherited mutations of BRCA1. While current prognoses for such patients are rather poor, inhibition of poly-ADP ribose polymerase 1 (PARP1) ...induces synthetic lethality in cells that are defective in homologous recombination. BMN 673 is a potent PARP1 inhibitor that is being clinically evaluated for treatment of BRCA-mutant cancers. Using the Brca1-deficient murine epithelial ovarian cancer cell line BR5FVB1-Akt, we investigated whether the antitumor effects of BMN 673 extend beyond its known pro-apoptotic function. Administration of modest amounts of BMN 673 greatly improved the survival of mice bearing subcutaneous or intraperitoneal tumors. We thus hypothesized that BMN 673 may influence the composition and function of immune cells in the tumor microenvironment. Indeed, BMN 673 significantly increases the number of peritoneal CD8+ T cells and NK cells as well as their production of IFN-γ and TNF-α. These data suggest that the cell stress caused by BMN 673 induces not only cancer cell-intrinsic apoptosis but also cancer cell-extrinsic antitumor immune effects in a syngeneic murine model of ovarian cancer. BMN 673 may therefore serve as a promising adjuvant therapy to immunotherapy to achieve durable responses among patients whose tumors harbor defects in homologous recombination.
•First study of BMN 673 in immunocompetent mice reveals new mechanism of activity.•This PARP inhibitor enhances recruitment of leukocytes to ovarian tumors.•BMN 673 enhances production of antitumor cytokines by CD8+ T cells and NK cells.
Objective To describe the natural course of IgE-mediated cow's milk allergy (IgE-CMA) and to determine risk factors for its persistence in a population-based cohort. Study design In a prospective ...cohort study, 54 infants with IgE-CMA were identified from a population of 13 019 children followed from birth. Diagnosis of IgE-CMA was based on history, skin prick test (SPT), and an oral food challenge (OFC) when indicated. Allergic infants were followed for 48-60 months. Families were contacted by telephone every 6 months and asked about recent exposures to milk. OFC was repeated to evaluate for recovery. Clinical characteristics, SPT, and OFC outcomes were compared between infants with persistent IgE-CMA and infants who recovered. Results Thirty-one infants (57.4%) recovered from IgE-CMA during the study period. Most infants (70.9%) recovered within the first 2 years. Risk factors for persistence on multivariate analysis included a reaction to <10 mL of milk on OFC (or on first exposure as estimated by the guardian, if OFC was not performed) ( P = .01), a larger wheal size on SPT ( P = .014), and age of ≤30 days at time of first reaction ( P = .05). Conclusions Resolution occurs in most infants with IgE-CMA. Infants reacting to <10 mL of milk or in the first month of life, and those with a larger wheal size on SPT, are at increased risk for persistence.
Gain fields, the eye-position modulation of visual responses, are thought to provide a mechanism by which the motor system can accurately calculate target position in space despite a constantly ...moving eye. Current gain-field models assume that the modulation of visual responses by eye position is accurate at all times, even around the time of a saccade. Here, we show that for at least 150 ms after a saccade, gain fields in the lateral intraparietal area (LIP) are unreliable. The majority of LIP cells with steady-state gain fields reflect the presaccadic eye position. The remainder of the cells have responses that cannot be predicted by their steady-state gain fields. Nonetheless, a monkey’s oculomotor performance is accurate during this time. These results suggest that current models built upon a simple gain-field algorithm cannot be used to calculate the position of a target in space that flashes briefly after a saccade.
► 150 ms after a saccade, 2/3 of LIP responses reflect the presaccadic eye position ► The other 1/3 of LIP responses cannot be predicted by the steady-state gain fields ► The monkeys’ behavior to visual stimuli presented during this period is accurate ► Steady-state gain-field models cannot explain how the brain calculates target position
The brain is thought to use gain fields, eye-position modulation of visual responses, to calculate target position in space. Xu et al. show that after a saccade parietal gain fields are inaccurate, but the monkey’s oculomotor performance is accurate.
Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we provide behavioral, anatomical ...and computational evidence to demonstrate a causal role for the primate posterior lateral cerebellum in learning new visuomotor associations. Reversible inactivation of the posterior lateral cerebellum of male monkeys impeded the learning of new visuomotor associations, but had no effect on movement parameters, or on well-practiced performance of the same task. Using retrograde transneuronal transport of rabies virus, we identified a distinct cerebro-cerebellar network linking Purkinje cells in the posterior lateral cerebellum with a region of the prefrontal cortex that is critical in learning visuomotor associations. Together, these results demonstrate a causal role for the primate posterior lateral cerebellum in non-motor, reinforcement learning.
Short interfering RNAs (siRNAs) mediate the catalytic sequence-specific cleavage of target messenger RNA (mRNA) molecules, resulting in the silencing of gene products in an efficient and precise ...manner. One apparent application of this technology is the knockdown of genes responsible for cancer progression, including pro-proliferative oncogenes, inhibitors of apoptosis, and mediators of angiogenesis. Delivery of siRNAs into particular cells has remained the principal obstacle to the realization of the potential of RNA interference (RNAi) in the clinic. Several groups have worked to develop carriers that facilitate siRNA delivery into ovarian cancer cells in mouse models of ovarian cancer. The results have been promising, often leading to significant survival extension. Such benefit is critical for a disease that is characterized by very poor outcomes and demands novel treatment options. This review describes advancements in siRNA delivery for the treatment of ovarian cancer.
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