Biology subjects

Forsyth, C.

Publications and source records attributed to Forsyth, C..

5 recordsLinked to original sources

bioRxiv2024

Dysregulation of cholesterol and bile acid homeostasis across the gut-liver axis following Cryptosporidium intestinal infection

Cryptosporidium spp., an apicomplexan protozoan, is one of the most common pathogens causing moderate-to-severe diarrhea in children under 2 years of age and is also an important opportunistic pathogen for patients with AIDS. There are currently no effective vaccines or therapies available. Infection in children is associated with malnutrition, growth defects, and even impaired cognitive development, but underlying mechanisms remain unclear. We report here that C. parvum infection in neonatal mice impairs bile acid reabsorption in the ileum, disrupts lipid metabolism in the liver, and alters bile acid homeostasis in the enterohepatic circulation. The reduction of bile acid pool further impairs lipid absorption in the small intestine. Additionally, replenishing bile prevents the decline in lipid absorption in infected neonatal mice. Strikingly, bile gavage significantly reduces the infection burden and ameliorates the dysregulated homeostasis of cell proliferation and migration in intestinal epithelium following infection. These findings may guide novel therapeutic approaches for cryptosporidiosis.

microbiology↗

bioRxiv2022

A common mechanism of Sec61 translocon inhibition by small molecules

The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum (ER) membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit the Sec61 channel, generating cellular effects that are potentially useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of the human Sec61 channel inhibited by a comprehensive panel of structurally distinct small molecules-- cotransin, decatransin, apratoxin F, ipomoeassin F, mycolactone, cyclotriazadisulfonamide (CADA) and eeyarestatin I (ESI). Remarkably, all inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of the channel. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain of Sec61 in a closed state, thereby preventing the protein-translocation pore from opening. Our study reveals molecular interactions between Sec61 and its inhibitors in atomic detail and offers the structural framework for further pharmacological studies and drug design.

biochemistry↗

bioRxiv2021

Colon epithelial cell-specific Bmal1 deletion impairs bone formation in mice

The circadian clock system regulates multiple metabolic processes, including bone metabolism. Previous studies have demonstrated that both central and peripheral circadian signaling regulate skeletal growth and homeostasis. Disruption in central circadian rhythms has been associated with a decline in bone mineral density and the global and osteoblast-specific disruption of clock genes in bone tissue leads to lower bone mass. Gut physiology is highly sensitive to circadian disruption. Since the gut is also known to affect bone remodeling, we sought to test the hypothesis that circadian signaling disruption in colon epithelial cells affects bone. We therefore assessed structural, functional, and cellular properties of bone in 8 week old Ts4-Cre and Ts4-Cre;Bmal1fl/fl (cBmalKO) mice, where the clock gene Bmal1 is deleted in colon epithelial cells. Axial and appendicular trabecular bone volume was significantly lower in cBmalKO compared to Ts4-Cre 8-week old mice in a sex-dependent fashion, with male but not female mice showing the phenotype. Similarly, the whole bone mechanical properties were deteriorated in cBmalKO male mice. The tissue level mechanisms involved suppressed bone formation with normal resorption, as evidenced by serum markers and dynamic histomorphometry. Our studies demonstrate that colon epithelial cell-specific deletion of Bmal1 leads to trabecular and cortical bone loss in male mice.

physiology↗

bioRxiv2019

Regeneration of dorsal spinal cord neurons after injury via in situ NeuroD1-mediated astrocyte-to-neuron conversion

Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms. In vivo neuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors. We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimers disease by overexpressing a single neural transcription factor NeuroD1 via retroviruses. Here we demonstrate regeneration of dorsal spinal cord neurons from reactive astrocytes after SCI via adeno-associated virus (AAV), a more clinically relevant gene delivery system. We find that NeuroD1 converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency ([~]95%). Interestingly, NeuroD1-converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate of conversion. Electrophysiological recordings show that the NeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show that NeuroD1-mediated neuronal conversion can occur in the contusive SCI model, allowing future studies of evaluating this reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift for spinal cord repair using in vivo astrocyte-to-neuron conversion technology to generate functional neurons in the grey matter.

neuroscience↗

bioRxiv2019

Chagas disease awareness and socioeconomic characteristics of Bolivian immigrants living in Sao Paulo, Brazil.

In this study, part of a research project on Chagas disease among residents of Bolivia in Sao Paulo, we describe socioeconomic characteristics, knowledge about the disease and access to health services. A structured questionnaire was applied to a sample of 472 Bolivian adults (> 18 years) living in Sao Paulo enrolled in the Barra Funda School Health Center. The median age of participants was 28.5 years, 75.0% from the Bolivian department of La Paz, who were living in Sao Paulo for an average of 5.8 years. Regarding knowledge about the disease and exposure to certain risk factors, 47.7% indicated familiarity with the vector, 23.9% had seen vinchuca in their homes in Bolivia and 6.4% reported having been bitten by a triatomine. The conditions of living in rural areas in Bolivia or in other department than La Paz, have a relative with illness, high school graduation and have seen or been bitten by a vinchuca were significantly associated with the knowledge of the vector. This study provides a view on migration that has important implications for the distribution of Chagas disease and access to health care by providing subsidies for proposing public health policies.\n\nAuthor summaryThis article expresses part of the results of a research project called \"Chagas disease in a population of Bolivian immigrants in Sao Paulo: an analysis of the prevalence of Trypanosoma cruzi infection and morbidity of Chagas disease, knowledge of the population about the disease and access to different levels of health care\". The problem of chronic Chagas disease occurs in many countries, including those not considered endemic, as a result of population movements, mainly by immigration due to urbanization which has led to its globalization. It is now considered an emerging disease with significant potential for transmission via blood transfusions, organ transplants and congenital via, in the absence of appropriate strategies in terms of public health, as well as reactivation of chronic disease in urban centers. Its no different this phenomenon to the city of Sao Paulo. This study analyzed the sociodemographic inserts, labor, migration and knowledge about Chagas disease and its impact on personal, family and professional life of Bolivian immigrants living in Sao Paulo.

scientific communication and education↗