Prebiotics, Probiotics, and Bacterial Infections

Bacterial pathogens have developed exquisite virulence mechanisms to survive in the host cells. These virulence mechanisms help them bind and internalize into host cells, replicate, and evade the host immune response. The mammalian host itself has developed its own repertoire of weapons to prevent this from happening. One important component of host response in preventing infections in the gut lumen is the diverse commensal microbiota present. Dysbiosis of the gut microbiota has been implicated in the development of many gastrointestinal diseases. A potential therapeutic pathway to solve these diseases would be by providing probiotics and/or prebiotics to help stimulate growth of the beneficial commensal bacteria. Here, we will present evidence of commensal microbiota imbalance in the development of disease as well as potential therapies to restore gut harmony

Technologies for Detecting Botulinum Neurotoxins in Biological and Environmental Matrices

Biomonitoring of food and environmental matrices is critical for the rapid and sensitive diagnosis, treatment, and prevention of diseases caused by toxins. The U.S. Centers for Disease Control and Prevention (CDC) has noted that toxins from bacteria, fungi, algae, and plants present an ongoing public health threat, especially since some of these toxins could compromise security of the food supply. Botulinum neurotoxins (BoNTs), produced by Clostridium spp., are among those bacterial toxins that pose life-threatening danger to humans. BoNTs inhibit the release of acetylcholine at peripheral cholinergic nerve terminals and cause flaccid paralysis. BoNTs are grouped in seven serotypes and many subtypes within these groups. Rapid and accurate identification of these toxins in contaminated food as well as in environmental matrices can help direct treatment. Herein, we discuss current methods to detect BoNTs with a focus on how these technologies have been used to identify toxins in various food and environmental matrices. We also discuss the emergence of new serotypes and subtypes of BoNTs and the increasing number of cases of botulism in wildlife. Finally, we consider how environmental changes impact food safety for humans and present new challenges for detection technology

Highly Potent 1H-1,2,3-Triazole-Tethered Isatin-Metronidazole Conjugates Against Anaerobic Foodborne, Waterborne, and Sexually-Transmitted Protozoal Parasites

Parasitic infections like amebiasis, trichomoniasis, and giardiasis are major health threats in tropical and subtropical regions of the world. Metronidazole (MTZ) is the current drug of choice for amebiasis, giardiasis, and trichomoniasis but it has several adverse effects and potential resistance is a concern. In order to develop alternative antimicrobials, a library of 1H-1,2,3-triazole-tethered metronidazole-isatin conjugates was synthesized using Huisgen\u27s azide-alkyne cycloaddition reaction and evaluated for their amebicidal, anti-trichomonal, and anti-giardial potential. Most of the synthesized conjugates exhibited activities against Trichomonas vaginalis, Tritrichomonas foetus, Entamoeba histolytica, and Giardia lamblia. While activities against T. vaginalis and T. foetus were comparable to that of the standard drug MTZ, better activities were observed against E. histolytica and G. lamblia. Conjugates 9d and 10a were found to be 2–3-folds more potent than MTZ against E. histolytica and 8–16-folds more potent than MTZ against G. lamblia. Further analysis of these compounds on fungi and bacteria did not show inhibitory activity, demonstrating their specific anti-protozoal properties

Health literacy development is central to the prevention and control of non-communicable diseases

Funding Information: This study was funded in part by National Health and Medical Research Council (Principal Research Fellowship APP1155125). Publisher Copyright: © 2022 Author(s). Published by BMJ.The WHO's report Health literacy development for the prevention and control of non-communicable diseases (NCDs) delivers practical what-to-do how-to-do guidance for health literacy development to build, at scale, contextually-relevant public health actions to reduce inequity and the burden of NCDs on individuals, health systems and economies. The key premise for health literacy development is that people's health awareness and behaviours are linked to lifelong experiences and social practices, which may be multilayered, hidden and beyond their control. Meaningful community engagement, local ownership and locally driven actions are needed to identify health literacy strengths, challenges and preferences to build locally fit-for-purpose and implementable actions. Health literacy development needs to underpin local and national policy, laws and regulations to create enabling environments that reduce community exposures to NCD risk factors. Deficit approaches and siloed health system and policy responses need to be avoided, focusing instead on integrating community-based solutions through co-design, cognisant of people's daily experiences and social practices.publishersversionpublishe

First Measurement of Monoenergetic Muon Neutrino Charged Current Interactions

We report the first measurement of monoenergetic muon neutrino charged current interactions. MiniBooNE has isolated 236 MeV muon neutrino events originating from charged kaon decay at rest ($K^+ \rightarrow \mu^+ \nu_\mu$) at the NuMI beamline absorber. These signal $\nu_\mu$-carbon events are distinguished from primarily pion decay in flight $\nu_\mu$ and $\overline{\nu}_\mu$ backgrounds produced at the target station and decay pipe using their arrival time and reconstructed muon energy. The significance of the signal observation is at the 3.9$\sigma$ level. The muon kinetic energy, neutrino-nucleus energy transfer ($\omega=E_\nu-E_\mu$), and total cross section for these events is extracted. This result is the first known-energy, weak-interaction-only probe of the nucleus to yield a measurement of $\omega$ using neutrinos, a quantity thus far only accessible through electron scattering.Comment: 6 pages, 4 figure

Highly Potent 1H-1,2,3-Triazole-Tethered Isatin-Metronidazole Conjugates Against Anaerobic Foodborne, Waterborne, and Sexually-Transmitted Protozoal Parasites

Parasitic infections like amebiasis, trichomoniasis, and giardiasis are major health threats in tropical and subtropical regions of the world. Metronidazole (MTZ) is the current drug of choice for amebiasis, giardiasis, and trichomoniasis but it has several adverse effects and potential resistance is a concern. In order to develop alternative antimicrobials, a library of 1H-1,2,3-triazole-tethered metronidazole-isatin conjugates was synthesized using Huisgen's azide-alkyne cycloaddition reaction and evaluated for their amebicidal, anti-trichomonal, and anti-giardial potential. Most of the synthesized conjugates exhibited activities against Trichomonas vaginalis, Tritrichomonas foetus, Entamoeba histolytica, and Giardia lamblia. While activities against T. vaginalis and T. foetus were comparable to that of the standard drug MTZ, better activities were observed against E. histolytica and G. lamblia. Conjugates 9d and 10a were found to be 2–3-folds more potent than MTZ against E. histolytica and 8–16-folds more potent than MTZ against G. lamblia. Further analysis of these compounds on fungi and bacteria did not show inhibitory activity, demonstrating their specific anti-protozoal properties

A review of research on the intersection between breast cancer and cardiovascular research in the Women’s Health Initiative (WHI)

Both obesity and metabolic syndrome are linked to increased incidence of type 2 diabetes, cardiovascular disease (CVD), and cancers of the breast (post-menopausal), and other obesity-related cancers. Over the past 50 years, the worldwide prevalence of obesity and metabolic syndrome has increased, with a concomitant higher incidence of associated co-morbidities and mortality. The precise mechanism linking metabolic syndrome to increased cancer incidence is incompletely understood, however, individual components of metabolic syndrome have been linked to increased breast cancer incidence and worse survival. There is a bidirectional relationship between the risk of CVD and cancer due to a high burden of shared risk factors and higher rates of CVD among cancer survivors, which may be impacted by the pro-inflammatory microenvironment associated with metabolic syndrome and cancer-directed therapies. The Women’s Health Initiative (WHI) is an excellent resource to study a dual relationship between cancer and CVD (cardio-oncology) with extensive information on risk factors and long-term outcomes. The purpose of this review is to provide an overview of research on cardio-oncology conducted utilizing WHI data with focus on studies evaluating both breast cancer and CVD including shared risk factors and outcomes after cancer. The review also includes results on other obesity related cancers which were included in the analyses of breast cancer, articles looking at cancer after heart disease (reverse cardio-oncology) and the role of Clonal Hematopoiesis of Indeterminate Potential (CHIP) as a shared risk factor between CVD and cancer. A summary of pertinent WHI literature helps to delineate the direction of future research evaluating the relationship between CVD and other cancer sites, and provides information on the opportunity for other novel analyses within the WHI

Cinnamoyl-Oxaborole Amides: Synthesis and Their in Vitro Biological Activity.

Due to the increased interest in their application in the treatment of infectious diseases, boron-containing compounds have received a significant coverage in the literature. Herein, a small set of novel cinnamoly-oxaborole amides were synthesized and screened against nagana Trypanosoma brucei brucei for antitrypanosomal activity. Compound 5g emerged as a new hit with an in vitro IC50 value of 0.086 μM against T. b. brucei without obvious inhibitory activity against HeLa cell lines. The same series was also screened against other human pathogens, including Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), for which moderate to weak activity (10 to >125 μM) was observed. Similarly, these compounds exhibited moderate activity against the human protozoal pathogen Trichomonas vaginalis with no observed effect on common microbiome bacterial species. The cross-species inhibitory activity presents the possibility of these compounds serving as broad-spectrum antibiotics for these prevalent three human pathogens

Implications for an imidazol-2-yl carbene intermediate in the rhodanase-catalyzed C-S bond formation reaction of anaerobic ergothioneine biosynthesis

In the anaerobic ergothioneine biosynthetic pathway, a rhodanese domain containing enzyme (EanB) activates tne hercynine's sp2 ε-C-H Dona ana replaces it with a C-S bond to produce ergothioneine. The key intermediate for this trans-sulfuration reaction is the Cys412 persulfide. Substitution of the EanB-Cys412 persulfide with a Cys412 perselenide does not yield the selenium analog of ergothioneine, selenoneine. However, in deuterated buffer, the perselenide-modified EanB catalyzes the deuterium exchange between hercynine's sp2 ε-C-H bond and D2O. Results from QM/MM calculations suggest that the reaction involves a carbene intermediate and that Tyr353 plays a key role. We hypothesize that modulating the pKa of Tyr353 will affect the deuterium-exchange rate. Indeed, the 3,5-difluoro tyrosine containing EanB catalyzes the deuterium exchange reaction with k ex of ~10-fold greater than the wild-type EanB (EanBWT). With regards to potential mechanisms, these results support the involvement of a carbene intermediate in EanB-catalysis, rendering EanB as one of the few carbene-intermediate involving enzymatic systems.R01 GM106443 - NIGMS NIH HHSAccepted manuscrip

Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

SummarySomatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk