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.
Abstract Cometary tails display dynamic behavior attributed to interactions with solar wind structures. Consequently, comet-tail observations can serve as in situ solar wind monitors. During 2021 ...December, Comet Leonard (C/2021 A1) was observed by the STEREO-A heliospheric imager. The comet tail exhibited various signatures of interactions with the solar wind including bending, kink formation, and finally complete disconnection. In this study, we compare the timing of these events with solar wind structures predicted by the Heliospheric Upwind eXtrapolation model with a time-dependency (or HUXt) solar wind model using new solar wind data assimilation (DA) techniques. This serves both to provide the most accurate solar wind context to interpret the cometary processes, but also as a test of the DA and an example of how comet observations can be used in model validation studies. Coronal mass ejections, stream interaction regions (SIRs), and heliospheric current sheet (HCS) crossings were all considered as potential causes of the tail disconnection. The results suggest the tail disconnection at Comet Leonard was the result of it crossing the HCS and into an SIR. The timing of these features agree better with the DA model results than the non-DA model, showing the value of this approach. Case studies such as this expand our understanding of comet–solar wind interactions, and in demonstrating the utility of DA for solar wind modeling. We note that this could lead to comets acting as additional in situ measures for solar wind conditions for regions where no in situ spacecraft are available, potentially improving solar wind DA in the future.
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.
Soft tissue sarcomas are malignant tumors of mesenchymal origin, encompassing a large spectrum of entities that were historically classified according to their histological characteristics. Over the ...last decades, molecular biology has allowed a better characterization of these tumors, leading to the incorporation of multiple molecular features in the latest classification of sarcomas as well as to molecularly-guided therapeutic strategies. This review discusses the main uses of molecular biology in current practice for the diagnosis and treatment of soft tissue sarcomas, in addition to perspectives for this rapidly evolving field of research.
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.
GPR120 is a long-chain fatty acid receptor that stimulates incretin hormone release from colonic endocrine cells and is implicated in macrophage and adipocyte function. The functional consequences of ...long (L) and short (S) human GPR120 splice variants, which differ by insertion of 16 amino acids in the third intracellular loop, are currently unknown. Here we compare signaling and intracellular trafficking of GPR120S and GPR120L receptors, using calcium mobilization and dynamic mass redistribution (DMR) assays, together with quantitative imaging measurements of β-arrestin2 association and receptor internalization. FLAG- or SNAP-tagged GPR120S receptors elicited both intracellular calcium mobilization and DMR responses in human embryonic kidney 293 cells, when stimulated with oleic acid, myristic acid, or the agonist 4-(3-phenoxyphenyl)methylaminobenzenepropanoic acid (GW9508). Responses were insensitive to pertussis toxin, but increases in intracellular calcium were attenuated by 2-aminoethoxydiphenyl borate, an inhibitor of store inositol trisphosphate receptors. Despite equivalent cell surface expression of SNAP-tagged GPR120L receptors, no specific calcium or DMR responses were observed in cells transfected with this isoform. However, agonist-stimulated GPR120S and GPR120L receptors both recruited β-arrestin2 and underwent robust internalization, with similar agonist potencies in each case. After oleic acid-induced internalization, neither GPR120 isoform recycled rapidly to the cell surface. In both cases, confocal microscopy indicated receptor targeting to lysosomal compartments. Thus, the third intracellular loop insertion in GPR120L prevents G protein-dependent intracellular calcium and DMR responses, but this receptor isoform remains functionally coupled to the β-arrestin pathway, providing one of the first examples of a native β-arrestin-biased receptor.
Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Reports on differences in reporting patterns between women and men exist nationally. The goal of the present study was ...to assess the global evidence on spontaneous post-marketing ADR reporting differences between reports for women and men.
We analysed data collected within VigiBase, the WHO global database of individual case safety reports, between 1967-2 January 2018. VigiBase contains more than 18 million reports from the 131 member countries of the WHO Programme for International Drug Monitoring.
Of the reports with information on sex, 9,056,566 (60.1%) concerned female and 6,012,804 (39.9%) male children and adults. More female ADR reports were submitted in all regions of the world and by all types of reporters. A higher proportion of female reports was seen in all age groups from the age group 12-17 years and older. The largest difference was observed in the age group of 18–44 years and could not be explained by hormonal contraceptive use. The proportion of serious and fatal reports was higher for male reports.
Global post marketing surveillance data on spontaneous reports indicate that women, from puberty and onwards and especially in their reproductive years, report more ADRs than men. However, there is a higher proportion of serious and fatal ADRs among male reports. Our results suggest important underlying sex-related differences in ADRs. These findings highlight the importance of considering sex throughout the entire life-cycle of drug development and surveillance and understanding the underlying reasons for reporting ADRs.
Caesarean section (CS) is one of the most performed operations worldwide. In many parts of the world, there has been a reduction in anaesthetic associated obstetric mortality, and this has been ...attributed to the increased use of neuraxial anaesthesia and improved safety of general anaesthesia, alongside improved training and organisational changes. In resource-limited countries, anaesthesia contributes disproportionately to maternal mortality, with one in seven deaths being due to anaesthesia. A major contributory factor to this is the severe shortage of trained anaesthetic providers. Goals for anaesthesia for CS include the woman's comfort and foetal well-being, focusing on strategies to minimise morbidity and mortality for both. Anaesthetic options for CS include neuraxial techniques (spinal or combined-spinal epidural or epidural extension of labour analgesia) and general anaesthesia. There is increasing evidence of the benefit of neuraxial techniques over general anaesthesia in terms of maternal and foetal outcomes. For elective CS, spinal and combined-spinal anaesthesia predominate. General anaesthesia is mainly reserved for Category 1 CS where there is an immediate threat to the life of the mother or the baby. This review discusses the practical aspects of neuraxial and general anaesthesia for CS.
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.
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