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"Watson, Sarah"
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Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis
Environmental factors, mucosal permeability and defective immunoregulation drive overactive immunity to a subset of resident intestinal bacteria that mediate multiple inflammatory conditions. GUT-103 and GUT-108, live biotherapeutic products rationally designed to complement missing or underrepresented functions in the dysbiotic microbiome of IBD patients, address upstream targets, rather than targeting a single cytokine to block downstream inflammation responses. GUT-103, composed of 17 strains that synergistically provide protective and sustained engraftment in the IBD inflammatory environment, prevented and treated chronic immune-mediated colitis. Therapeutic application of GUT-108 reversed established colitis in a humanized chronic T cell-mediated mouse model. It decreased pathobionts while expanding resident protective bacteria; produced metabolites promoting mucosal healing and immunoregulatory responses; decreased inflammatory cytokines and Th-1 and Th-17 cells; and induced interleukin-10-producing colonic regulatory cells, and IL-10-independent homeostatic pathways. We propose GUT-108 for treating and preventing relapse for IBD and other inflammatory conditions characterized by unbalanced microbiota and mucosal permeability.
Fecal microbiota transplantation and probiotics have been tested/used as potential therapeutics against inflammatory bowel diseases (IBD). Here the authors use a bottom-up rational consortium design approach that combines well-characterized strains isolated from healthy human stool samples to produce two consortia of metabolically interdependent strains for the treatment of IBD.
Journal Article
Children's Arithmetic Development: It Is Number Knowledge, Not the Approximate Number Sense, That Counts
In this article, we present the results of an 11-month longitudinal study (beginning when children were 6 years old) focusing on measures of the approximate number sense (ANS) and knowledge of the Arabic numeral system as possible influences on the development of arithmetic skills. Multiple measures of symbolic and nonsymbolic magnitude judgment were shown to define a unitary factor that appears to index the efficiency of an ANS system, which is a strong longitudinal correlate of arithmetic skills. However, path models revealed that knowledge of Arabic numerals at 6 years was a powerful longitudinal predictor of the growth in arithmetic skills, whereas variations in magnitude-comparison ability played no additional role in predicting variations in arithmetic skills. These results suggest that verbal processes concerned with learning the labels for Arabic numerals, and the ability to translate between Arabic numerals and verbal codes, place critical constraints on arithmetic development.
Journal Article
ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions
Subsets of primitive round-cell sarcomas remain difficult to diagnose and classify. Among these is a rare round-cell sarcoma that harbors a
CIC
gene rearrangement known as
CIC-
rearranged undifferentiated round-cell sarcoma, which is most commonly fused to the
DUX4
gene. Owing to its aggressive clinical behavior and potential therapeutic implications, accurate identification of this novel soft tissue sarcoma is necessary. Definitive diagnosis requires molecular confirmation, but only a few centers are as yet able to perform this test. Several studies have shown that
PEA3
subfamily genes, notably
ETV4
(belonging to the family of
ETS
transcription factors), are upregulated in
CIC-
rearranged undifferentiated round-cell sarcomas. We performed a detailed immunohistochemical analysis to investigate ETV4 expression in
CIC-
rearranged undifferentiated round-cell sarcomas and their potential mimics (especially Ewing sarcomas). The study cohort included 17 cases of
CIC-
rearranged undifferentiated round-cell sarcomas, and 110 tumors that morphologically mimic
CIC-
rearranged undifferentiated round-cell sarcomas: 43 Ewing sarcomas, 25 alveolar rhabdomyosarcomas, 20 poorly differentiated round-cell synovial sarcomas, 10 desmoplastic round-cell tumors, 5
BCOR-CCNB3
sarcomas, 5 lymphoblastic lymphomas, and 2 rhabdoid tumors. All
CIC-
rearranged undifferentiated round-cell sarcomas (on core needle biopsies and open biopsies) were ETV4-positive with a strong diffuse nuclear pattern. Among the other 110 tumors, only six cases (four Ewing sarcomas, one alveolar rhabdomyosarcoma, and one desmoplastic round-cell tumor) showed focal (<5% of tumor cells) and very weak nuclear expression of ETV4; all other tumors were completely negative for ETV4. We conclude that systematic immunohistochemical analysis of ETV4 makes it possible to diagnose undifferentiated round-cell sarcomas (with no molecular markers for sarcoma-associated translocation) such as
CIC-
rearranged undifferentiated round-cell sarcoma.
Journal Article
Black enough : stories of being young & black in America
A collection of short stories explore what it is like to be young and black, centering on the experiences of black teenagers and emphasizing that one person's experiences, reality, and personal identity are different than someone else.
Book
Age, sex and Alzheimer’s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer’s patients
Background
Aging and sex are major risk factors for developing late-onset Alzheimer’s disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer’s disease, no longer consistently exhibit standard Alzheimer’s neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer’s disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.
Methods
We aged male and female, 3xTg-AD and B6129 control mice across their respective lifespans (
n
= 3–8 mice per sex, strain, and age group) and longitudinally assessed neuropathological hallmarks of Alzheimer’s disease, markers of hepatic inflammation, splenic mass and morphology, as well as plasma cytokine levels. We conducted RNA sequencing analysis on bulk brain tissue and examined differentially expressed genes (DEGs) between 3xTg-AD and B6129 samples and across ages in each sex. We also examined DEGs between clinical Alzheimer’s and control parahippocampal gyrus brain tissue samples from the Mount Sinai Brain Bank study in each sex.
Results
3xTg-AD females significantly outlived 3xTg-AD males and exhibited progressive Alzheimer’s neuropathology, while 3xTg-AD males demonstrated progressive hepatic inflammation, splenomegaly, circulating inflammatory proteins, and minimal Alzheimer’s neuropathological hallmarks. Instead, 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females. Our clinical investigations revealed that individuals with Alzheimer’s disease develop similar sex-specific alterations in neuronal and immune function. In diseased males of both species, we observed greater upregulation of complement-related gene expression, and lipopolysaccharide was predicted as the top upstream regulator of DEGs.
Conclusions
Our data demonstrate that chronic inflammation and complement activation are associated with increased mortality, indicating that age-related changes in immune response contribute to sex differences in Alzheimer’s disease trajectories. We provide evidence that aging and transgene-driven disease progression trigger a widespread inflammatory response in 3xTg-AD males, which mimics the impact of lipopolysaccharide stimulation despite the absence of infection.
Journal Article
Novel strains of Campylobacter cause diarrheal outbreak in Rhesus macaques (Macaca mulatta) of Kathmandu Valley
Campylobacter spp . is often underreported and underrated bacteria that present real health risks to both humans and animals, including non-human primates. It is a commensal microorganism of gastrointestinal tract known to cause gastroenteritis in humans. Commonly found in many wild animals including non-human primates (monkeys- Rhesus macaques) these pathogens are known to be a common cause of diarrhea in humans in many parts of developing and under developed countries. Rhesus macaques from the two holy sites in Kathmandu (Pashupati and Swoyambhu) were included in this cross-sectional study. Diarrheal samples of monkeys were analyzed to detect and characterize the pathogen using 16S rRNA-based PCR screening, followed by DNA sequencing and phylogenetic analysis. Out of a total 67 collected diarrheal samples, Campylobacter spp . were detected in the majority of the samples (n = 64; 96%). DNA sequences of the amplified PCR products were successfully obtained from 13 samples. Phylogenetic analysis identified Candidatus Campylobacter infans (n = 10, Kimura-2 parameter (K2P) pairwise distance values of 0.002287). Remaining three sequences might potentially belong to a novel Campylobacter species/sub-species- closely relating to known species of C . helviticus (K2P pairwise distance of 0.0267). Both Candidatus Campylobacter infans and C . helvitucus are known to infect humans and animals. Additionally, we also detected the bacteria in water and soil samples from the sites. Campylobacter spp . caused the 2018 diarrhea outbreak in Rhesus macaques in the Kathmandu valley. Campylobacter might be one of the important contributing pathogens in diarrheal outbreaks-both in humans and animals (monkeys) in Nepal. Due to close interactions of these animals with humans and other animals, One Health approach might be the most effective way to prevent and mitigate the threat posed by this pathogen.
Journal Article
Improved Statistical Signal Detection in Pharmacovigilance by Combining Multiple Strength-of-Evidence Aspects in vigiRank
Background
Detection of unknown risks with marketed medicines is key to securing the optimal care of individual patients and to reducing the societal burden from adverse drug reactions. Large collections of individual case reports remain the primary source of information and require effective analytics to guide clinical assessors towards likely drug safety signals. Disproportionality analysis is based solely on aggregate numbers of reports and naively disregards report quality and content. However, these latter features are the very fundament of the ensuing clinical assessment.
Objective
Our objective was to develop and evaluate a data-driven screening algorithm for emerging drug safety signals that accounts for report quality and content.
Methods
vigiRank is a predictive model for emerging safety signals, here implemented with shrinkage logistic regression to identify predictive variables and estimate their respective contributions. The variables considered for inclusion capture different aspects of strength of evidence, including quality and clinical content of individual reports, as well as trends in time and geographic spread. A reference set of 264 positive controls (historical safety signals from 2003 to 2007) and 5,280 negative controls (pairs of drugs and adverse events not listed in the Summary of Product Characteristics of that drug in 2012) was used for model fitting and evaluation; the latter used fivefold cross-validation to protect against over-fitting. All analyses were performed on a reconstructed version of VigiBase ® as of 31 December 2004, at around which time most safety signals in our reference set were emerging.
Results
The following aspects of strength of evidence were selected for inclusion into vigiRank: the numbers of informative and recent reports, respectively; disproportional reporting; the number of reports with free-text descriptions of the case; and the geographic spread of reporting. vigiRank offered a statistically significant improvement in area under the receiver operating characteristics curve (AUC) over screening based on the Information Component (IC) and raw numbers of reports, respectively (0.775 vs. 0.736 and 0.707, cross-validated).
Conclusions
Accounting for multiple aspects of strength of evidence has clear conceptual and empirical advantages over disproportionality analysis. vigiRank is a first-of-its-kind predictive model to factor in report quality and content in first-pass screening to better meet tomorrow’s post-marketing drug safety surveillance needs.
Journal Article