IRE1α recognizes a structural motif in cholera toxin to activate an unfolded protein response.

IRE1α is an endoplasmic reticulum (ER) sensor that recognizes misfolded proteins to induce the unfolded protein response (UPR). We studied cholera toxin (CTx), which invades the ER and activates IRE1α in host cells, to understand how unfolded proteins are recognized. Proximity labeling colocalized the enzymatic and metastable A1 segment of CTx (CTxA1) with IRE1α in live cells, where we also found that CTx-induced IRE1α activation enhanced toxicity.

Consensus and Controversial Aspects of Vitamin D and COVID-19.

Objective: This work aims to review and discuss controversial topics in the field of vitamin D, SARS-CoV-2 infection, and COVID-19.

Methods: The International Conferences "Controversies in Vitamin D" are a series of workshops that started in 2017 featuring international experts and leaders in vitamin D research and clinical practice. The fifth annual conference was held in Stresa, Italy, September 15 to 18, 2021.

The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development.

Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1β, a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1α. How ERN2 functions at the host-environment interface and why a second paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that ERN2 was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon.

Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis.

Background: P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical link in communication between intestinal mucosal barrier function and the innate immune system. Yet, despite knowledge for over 10 years that P-gp plays a central role in gastrointestinal homeostasis, the precise molecular mechanism that controls its functional expression and regulation remains unclear.

IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress.

IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1β have an attenuated unfolded protein response to ER stress. When modeled in HEK293 cells and with purified protein, IRE1β diminishes expression and inhibits signaling by the closely related stress sensor IRE1α.

Microtubule motors power plasma membrane tubulation in clathrin-independent endocytosis.

How the plasma membrane is bent to accommodate clathrin-independent endocytosis remains uncertain. Recent studies suggest Shiga and cholera toxin induce membrane curvature required for their uptake into clathrin-independent carriers by binding and cross-linking multiple copies of their glycosphingolipid receptors on the plasma membrane. But it remains unclear if toxin-induced sphingolipid crosslinking provides sufficient mechanical force for deforming the plasma membrane, or if host cell factors also contribute to this process.

The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling.

The plasma membrane and all membrane-bound organelles except for the Golgi and endoplasmic reticulum (ER) are equipped with pattern-recognition molecules to sense microbes or their products and induce innate immunity for host defense. Here, we report that inositol-requiring-1α (IRE1α), an ER protein that signals in the unfolded protein response (UPR), is activated to induce inflammation by binding a portion of cholera toxin as it co-opts the ER to cause disease. Other known UPR transducers, including the IRE1α-dependent transcription factor XBP1, are dispensable for this signaling.

Intoxication of zebrafish and mammalian cells by cholera toxin depends on the flotillin/reggie proteins but not Derlin-1 or -2.

Cholera toxin (CT) causes the massive secretory diarrhea associated with epidemic cholera. To induce disease, CT enters the cytosol of host cells by co-opting a lipid-based sorting pathway from the plasma membrane, through the trans-Golgi network (TGN), and into the endoplasmic reticulum (ER). In the ER, a portion of the toxin is unfolded and retro- translocated to the cytosol.

N-terminal extension of the cholera toxin A1-chain causes rapid degradation after retrotranslocation from endoplasmic reticulum to cytosol.

Cholera toxin travels from the plasma membrane to the endoplasmic reticulum of host cells, where a portion of the toxin, the A1-chain, is unfolded and targeted to a protein-conducting channel for retrotranslocation to the cytosol. Unlike most retrotranslocation substrates, the A1-chain escapes degradation by the proteasome and refolds in the cytosol to induce disease. How this occurs remains poorly understood.

A biochemical method for tracking cholera toxin transport from plasma membrane to Golgi and endoplasmic reticulum.

Asiatic cholera is a rapidly progressing disease resulting in extreme diarrhea and even death. The causative agent, cholera toxin, is an AB5-subunit enterotoxin produced by the bacterium Vibrio cholera. The toxin must enter the intestinal cell to cause disease.

Role of p97 AAA-ATPase in the retrotranslocation of the cholera toxin A1 chain, a non-ubiquitinated substrate.

The enzymatic A1 chain of cholera toxin retrotranslocates across the endoplasmic reticulum membrane into the cytosol, where it induces toxicity. Almost all other retrotranslocation substrates are modified by the attachment of polyubiquitin chains and moved into the cytosol by the ubiquitin-interacting p97 ATPase complex. The cholera toxin A1 chain, however, can induce toxicity in the absence of ubiquitination, and the motive force that drives retrotranslocation is not known.

[Particular aspects of rhinitis and rhino-conjunctivitis].

The authors report their experience of 28 years of practice in the opthalmology service of the CHRU at Rennes. The describe certain particular aspects of rhinitis and rhino-conjuctivitis where the danger resides in an extensive risk to the uvula or the bronchi. They insist on the importance of understanding polyvalents in internal medicine (rôle of the seat of gingivodentary "ideas", value of research into indicative markers of protection A2 and B40 in the HLA system.

1,25-dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells.

The effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3) on nerve growth factor (NGF) synthesis was investigated in primary cultures of astrocytes prepared from brain of neonatal rats. 1,25-(OH)2 D3 elicited a dose-dependent increase of NGF mRNA with a maximal effect at 10(-7) M, which persisted for at least 48 h. Northern blot analysis revealed an expression of the vitamin D3 receptor (VDR) gene in primary glial cells.

Clinical trial of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 in uremic patients on hemodialysis: preliminary report.

A clinical trial was done by the Group, Japan to evaluate the efficacy of 26,27-F6-1,25(OH)2D3 on the calcium and bone metabolism of 43 uremic patients on hemodialysis, 24 men and 19 women with a mean age of 50.9 +/- 2.1 years.

Nonspecific immunoglobulin E in aqueous humor: evaluation in uveitis.

The levels of immunoglobulin E (IgE) in aqueous humor (AH) and serum were determined in 74 uveitis patients and 13 control patients with senile cataract. Uveitis patients' levels ranged from less than 0.06 to 460 IU/ml according to the paper radioimmunosorbent test (PRIST; limit of sensitivity, 0.

General toxicity of water-soluble iodinated contrast media. Pathogenic concepts.

Despite many studies, the mechanism of the general accidents induced by the intravascular injection of water-soluble iodinated contrast media remains unclear. Two theories are proposed; until now, they have not been related to each other. Lalli emphasizes the role of a cerebral impact related to stress, which induces a chain of accidents that are perhaps more aggressive when the molecules cross the blood-brain barrier.

[In the Argentinian Republic, health education activities for and with the entire community].

To be efficient, health education must be part of the economic social and cultural development of the target populations and must facilitate the interdisciplinary and multisectorial participation of the community. Argentina with its geographical immensity, heterogeneous cultural and socio-economic conditions, makes it necessary to establish health and educational structures adapted to each particular region. The Argentinian Committee for health education of the populations participates intensively in the training of health teams, volunteers and above all teachers.

[Decrease in transcortin binding activity in depression].

In a preliminary study, Cortico-Binding Globuline (CBG) has been determined in 10 depressed major inpatients (DSM3) and compared with healthy volunteers. A clear cut fall of binding activity of transcortin is reported in depressed patients associated with an increase of total and free plasmatic cortisol.

Metabolism and binding properties of 24,24-difluoro-25-hydroxyvitamin D3.

To evaluate possible functional roles for 24,25-dihydroxyvitamin D3, 24,24-difluoro-25-hydroxyvitamin D3 has been synthesized and shown to be equally as active as 25-hydroxyvitamin D3 in all known functions of vitamin D. The use of the difluoro compound for this purpose is based on the assumption that the C-F bonds are stable in vivo and that the fluorine atom does not act as hydroxyl in biological systems. No 24,25-dihydroxyvitamin D3 was detected in the serum obtained from vitamin D-deficient rats that had been given 24,24-difluoro-25-hydroxyvitamin D3, while large amounts were found when 25-hydroxyvitamin D3 was given.

Temperature-dependent inactivation of nucleic acid binding and aggregation of the 1,25-dihydroxyvitamin D3 receptor.

The interaction of the 1 alpha,25-dihydroxyvitamin D3 receptor with immobilized calf thymus DNA has been compared with its sedimentation properties on hypotonic sucrose gradients. Forty to sixty percent of total hormone:receptor complexes formed at 4 degrees C were retained by DNA-cellulose and could be eluted by 0.18 to 0.