Optimizing oral immune tolerance to Type II collagen in patients with rheumatoid arthritis: The importance of dose, Interfering medication and Genetics.

OBJECTIVES: Oral immune tolerance (OT) is a complex process with unknown genetic regulation. Our aim is to explore possible genetic control of OT in patients with rheumatoid arthritis (RA). METHODS: RA patients with increased interferon γ production invitro when their isolated peripheral blood mononuclear cells (PBMC) were cultured with type II bovine collagen α1 chain [α1 (II)] were enrolled in this study and were randomly assigned to the "Low dose" type II collagen (CII) group (30 µg/day for 10 weeks, followed by 50 µg/day for 10 weeks, followed by 70 µg/day for 10 weeks) or "High dose" CII group (90 µg/day for 10 weeks, followed by 110 µg/day for 10 weeks, followed by 130 µg/day for 10 weeks). Heparinized blood was obtained at baseline and after each of the 10 weeks treatment for analysis of the invitro production of IFNγ by their PBMC stimulated by α1(II) . Single nucleotide polymorphism (SNP) analysis of the responders and non-responders to oral CII was conducted using GeneChip Mapping 10 K 2.0 Array. RESULTS: The SNP A-15,737 was found to associate with the ability of CII to suppress IFNγ production by α1(CII)-stimulated RA PBMC. The potential for SNP A-15,737 to associate with the OT response for patients with another autoimmune disease [OT induced by oral type I bovine collagen (CI) in patients with diffuse cutaneous systemic sclersodid (dsSSc)] was also explored. CONCLUSIONS: The ROT1 region plays a role in the control of IFNγ production after oral dosing of auto-antigens, thereby determining if oral tolerance to that antigen will develop.

Body mass index stratification enables cytokine-based prediction of ACPA status and Power-Doppler disease activity in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis can be classified according to ACPA and RF status. ACPA status may be associated with other pathophysiological differences, e.g., the cytokines driving inflammation. Obesity influences the course of RA, likely involving leptin; the exact mechanisms are not completely understood. This study investigates BMI influence on RA cytokine profiles and the possibility of predicting ACPA status and disease activity measured by Power-Doppler sonography (PDS). METHODS: Patients were examined using a multi-biomarker disease assay and PDS examination of wrists and MCP and PIP joints and stratified according to ACPA status and BMI, using prediction precision to determine BMI cutoff. Analysis was performed using elastic net regularization of logistic and multiple regression. We then attempted to predict ACPA status/PDS activity based on a bootstrap approach. RESULTS: A total of 120 measurements from 95 patients were performed. ACPA status prediction peaked at BMI 26 kg/m2, with AUC 0.82. PDS activity prediction had a mean average error of < 1.6 PDS points for all groups. In obese patients, cytokine profiles appear to align in ACPA-positive and -negative patients, with leptin playing a greater role in predicting PDS activity, but with some remaining differences. CONCLUSION: When stratified according to BMI, cytokine patterns can predict ACPA status and PDS activity in RA with a high degree of precision. This indicates that studies into the pathophysiology of RA should take BMI into account, to differentiate between disease- and obesity-associated phenomena. The underlying pathological processes of ACPA-negative and -positive RA appear different. Multi-cytokine evaluations may provide a deeper understanding of disease processes. Key Points • A multi-cytokine approach combined with ultrasonography and modern mathematical methods can contribute to a deeper understanding of the relationship between systemic and joint inflammation. • BMI influences cytokine profiles in rheumatoid arthritis and appears to "override" disease-specific processes. • Using cytokines only, and adjusting for BMI, it is possible to predict the ACPA status and joint inflammation with considerable precision.

Diaminocyclopentane - l-Lysine Adducts: Potent and selective inhibitors of human O-GlcNAcase.

A new class of compounds, namely highly substituted diaminocyclopentane-l-lysine adducts, have been discovered as potent inhibitors of O-GlcNAcase, an enzyme crucial for protein de-O-glycosylation. These inhibitors exhibit exceptional selectivity and reversibility and are the first example of human O-GlcNAcase inhibitors that are structurally related to the transition state of the rate-limiting step with the "aglycon" still in bond-length proximity. The ease of their preparation, remarkable biological activities, stability, and non-toxicity make them promising candidates for the development of anti-tau-phosphorylation agents holding significant potential for the treatment of Alzheimer's disease.

Application of inverse weighting analysis to assess the association of youth perceptions with the age of initiation of tobacco products.

Introduction: To examine if perceptions of harmfulness and addictiveness of hookah and cigarettes impact the age of initiation of hookah and cigarettes, respectively, among US youth. Youth (12-17 years old) users and never users of hookah and cigarettes during their first wave of PATH participation were analyzed by each tobacco product (TP) independently. The effect of perceptions of (i) harmfulness and (ii) addictiveness at the first wave of PATH participation on the age of initiation of ever use of hookah was estimated using interval-censoring Cox proportional hazards models. Methods: Users and never users of hookah at their first wave of PATH participation were balanced by multiplying the sampling weight and the 100 balance repeated replicate weights with the inverse probability weight (IPW). The IPW was based on the probability of being a user in their first wave of PATH participation. A Fay's factor of 0.3 was included for variance estimation. Crude hazard ratios (HR) and 95% confidence intervals (CIs) are reported. A similar process was repeated for cigarettes. Results: Compared to youth who perceived each TP as "a lot of harm", youth who reported perceived "some harm" had younger ages of initiation of these tobacco products, HR: 2.53 (95% CI: 2.87-4.34) for hookah and HR: 2.35 (95% CI: 2.10-2.62) for cigarettes. Similarly, youth who perceived each TP as "no/little harm" had an earlier age of initiation of these TPs compared to those who perceived them as "a lot of harm", with an HR: 2.23 (95% CI: 1.82, 2.71) for hookah and an HR: 1.85 (95% CI: 1.72, 1.98) for cigarettes. Compared to youth who reported each TP as "somewhat/very likely" as their perception of addictiveness, youth who reported "neither likely nor unlikely" and "very/somewhat unlikely" as their perception of addictiveness of hookah had an older age of initiation, with an HR: 0.75 (95% CI: 0.67-0.83) and an HR: 0.55 (95% CI: 0.47, 0.63) respectively. Discussion: Perceptions of the harmfulness and addictiveness of these tobacco products (TPs) should be addressed in education campaigns for youth to prevent early ages of initiation of cigarettes and hookah.

FOXO1 regulates expression of Neurod4 in the pituitary gland.

Pituitary gland function is regulated by the activity of various transcription factors that control cell fate decisions leading to cellular differentiation and hormone production. FOXO1 is necessary for normal somatotrope differentiation and function. Recent in vivo data implicate FOXO1 in the regulation of genes important for somatotrope differentiation including Gh1, Neurod4, and Pou1f1. In the current study, the somatotrope-like cell line GH3 was treated with a FOXO1 inhibitor, resulting in significant reduction in Neurod4 and Gh1 expression. Consistent with these findings, CRISPR/Cas9-mediated deletion of Foxo1 in GH3 cells significantly reduced expression of Gh1 and Neurod4. Chromatin immunoprecipitation sequencing identifies novel FOXO1 binding sites associated with the Neurod4, Gh1, and Pou1f1 genes. The FOXO1 binding site in the Neurod4 gene exhibits enhancer activity in somatotrope-like cells but not in gonadotrope-like cells. These data strongly suggest FOXO1 directly contributes to the transcriptional control of genes important for somatotrope differentiation.

Highly functionalized diaminocyclopentanes: A new route to potent and selective inhibitors of human O-GlcNAcase.

A new class of compounds inhibiting de-O-glycosylation of proteins has been identified. Highly substituted diaminocyclopentanes are impressively selective reversible non-transition state O-ß-N-acetyl-d-glucosaminidase (O-GlcNAcase) inhibitors. The ease of preparative access and remarkable biological activities provide highly viable leads for the development of anti-tau-phosphorylation agents with a view to eventually ameliorating Alzheimer's disease.

Ligand-Directed Chemistry on Glycoside Hydrolases - A Proof of Concept Study.

Selective covalent labelling of enzymes using small molecule probes has advanced the scopes of protein profiling. The covalent bond formation to a specific target is the key step of activity-based protein profiling (ABPP), a method which has become an indispensable tool for measuring enzyme activity in complex matrices. With respect to carbohydrate processing enzymes, strategies for ABPP so far involve labelling the active site of the enzyme, which results in permanent loss of activity. Here, we report in a proof of concept study the use of ligand-directed chemistry (LDC) for labelling glycoside hydrolases near - but not in - the active site. During the labelling process, the competitive inhibitor is cleaved from the probe, departs the active site and the enzyme maintains its catalytic activity. To this end, we designed a building block synthetic concept for small molecule probes containing iminosugar-based reversible inhibitors for labelling of two model ß-glucosidases. The results indicate that the LDC approach can be adaptable for covalent proximity labelling of glycoside hydrolases.

The Associations of Auto-Brewery Syndrome and Diabetes Mellitus: A Literature Review and Clinical Perspective.

Endogenous production of alcohol without the external intake of alcohol is called auto-brewery syndrome (ABS), and to get its levels to rise to a level that it has physical symptoms of alcohol intake is rare. The most common cause of ABS is the metabolism of ingested carbohydrates by intestinal microflora. This occurrence does not happen in all normal individuals but only in some high-risk individuals. Patients with diabetes mellitus (DM) have been hypothesized to be at high risk for ABS. We searched databases, such as PubMed, Medline, and PubMed Central, to search for existing literature with relevant keywords. In the finalized review, we have included 30 relevant articles. Alcohol formed in the gut gets absorbed in the bloodstream and immediately gets metabolized, so usually it does not achieve a level in blood high enough to cause symptoms. In high-risk patients, there is an increase in the level of bloodstream alcohol above a certain level, so it shows symptoms. Because there is higher blood glucose in DM, the patients have been shown to be at increased risk for developing ABS. Similarly, obesity is also a risk factor for DM, making it a high-risk condition for ABS. The most involved pathogens are Candida and Saccharomyces.

Cerebral Salt Wasting Syndrome Following Right Occipital Craniotomy in a Patient With Metastatic Lung Adenocarcinoma.

Cerebral salt wasting syndrome (CSW) is characterized by excessive natriuresis leading to hyponatremia and hypovolemia. It is commonly encountered among patients who have undergone brain trauma or subarachnoid hemorrhage. The occurrence of CSW after neurosurgical procedures has been frequently reported in the pediatric age group; however, it is a rare phenomenon in adults. We describe the case of a 59-year-old female who developed symptoms of polyuria and polydipsia after a right occipital craniotomy.

Sparse interleaved sampling for high resolution focal construct geometry X-ray tomography.

We demonstrate interleaved sampling by multiplexing conical subshells within the tomosynthesis and raster scanning a phantom through a 150 kV shell X-ray beam. Each view comprises pixels sampled on a regular 1 mm grid, which is then upscaled by padding with null pixels before tomosynthesis. We show that upscaled views comprising 1% sample pixels and 99% null pixels increase the contrast transfer function (CTF) computed from constructed optical sections from approximately 0.6 line pairs/mm to 3 line pairs/mm. The driver of our method is to complement work concerning the application of conical shell beams to the measurement of diffracted photons for materials identification. Our approach is relevant to time-critical, and dose-sensitive analytical scanning applications in security screening, process control and medical imaging.

The importance of ligand gated ion channels in sleep and sleep disorders.

On average, humans spend about 26 years of their life sleeping. Increased sleep duration and quality has been linked to reduced disease risk; however, the cellular and molecular underpinnings of sleep remain open questions. It has been known for some time that pharmacological modulation of neurotransmission in the brain can promote either sleep or wakefulness thereby providing some clues about the molecular mechanisms at play. However, the field of sleep research has developed an increasingly detailed understanding of the requisite neuronal circuitry and key neurotransmitter receptor subtypes, suggesting that it may be possible to identify next generation pharmacological interventions to treat sleep disorders within this same space. The aim of this work is to examine the latest physiological and pharmacological findings highlighting the contribution of ligand gated ion channels including the inhibitory GABAA and glycine receptors and excitatory nicotinic acetylcholine receptors and glutamate receptors in the sleep-wake cycle regulation. Overall, a better understanding of ligand gated ion channels in sleep will help determine if these highly druggable targets could facilitate a better night's sleep.

Longitudinal Transition Patterns of Tobacco Use Among Youth and Young Adults Never Tobacco Product Users: Findings From the Population Assessment of Tobacco and Health Study, 2014-2019.

Aims: To identify, visualize, and describe the prevalence of within-product patterns of tobacco use behaviors for e-cigarettes, cigarettes, and hookah (TP) by 3 age groups (ie, 12-14-year-old, 15-17-year-old, and 18-20-year-old) with U.S. nationally representative data. Methods: In 2014-2015, never users of each (TP) and age group were followed-up longitudinally between 2015-2019 using five transition states: non-susceptible to (TP) use, susceptible to (TP) use, ever (TP) use, past 30-day (TP) use, and discontinued past 30-day (TP) use. Sankey diagrams were used to graphically visualize patterns in tobacco use behaviors across time. Results: Among 12-14-year-old who were never users and susceptible to each TP from 2014-2017, 7% initiated ever e-cigarette use and 9.4% first reported past 30-day use by 2018-2019; 5.8% initiated ever cigarette use and 3% first reported past 30-day cigarette use by 2018-2019; and, 4.5% initiated ever hookah use and 1.0% first reported past 30-day hookah use by 2018-2019. Among 15-17-year-old who were never users and susceptible to each TP from 2014-2017, 4.2% initiated ever e-cigarette use and 9.0% first reported past 30-day use by 2018-2019; 4.5% initiated ever cigarette use and 3% first reported past 30-day cigarette use by 2018-2019; and, 4.5% initiated ever hookah use and 2.4% first reported past 30-day hookah use by 2018-2019. Among 18-20-year-old who were never users and susceptible to each TP from 2014-2017, 3.2% initiated ever e-cigarette use and 3.6% first reported past 30-day e-cigarette use by 2018-2019; 3.0% initiated ever cigarette use and 2.3% first reported past 30-day cigarette use; and, 2.8% initiated ever hookah use and 1.0% first reported past 30-day hookah use by 2018-2019. Conclusions: From 2014 to 2019, onset and progression of e-cigarette, cigarette, and hookah use occurred more frequently in 12-14 and 15-17-year-old than in young adults 18-20-year-old.

Sphingoid Bases Regulate the Sigma-1 Receptor-Sphingosine and N,N'-Dimethylsphingosine Are Endogenous Agonists.

Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones occur ubiquitously in mammalian cell membranes. Endogenous compounds that regulate the S1R are important for controlling S1R responses to cellular stress. Herein, we interrogated the S1R in intact Retinal Pigment Epithelial cells (ARPE-19) with the bioactive sphingoid base, sphingosine (SPH), or the pain-provoking dimethylated SPH derivative, N,N'-dimethylsphingosine (DMS). As informed by a modified native gel approach, the basal and antagonist (BD-1047)-stabilized S1R oligomers dissociated to protomeric forms in the presence of SPH or DMS (PRE-084 as control). We, thus, posited that SPH and DMS are endogenous S1R agonists. Consistently, in silico docking of SPH and DMS to the S1R protomer showed strong associations with Asp126 and Glu172 in the cupin beta barrel and extensive van der Waals interactions of the C18 alkyl chains with the binding site including residues in helices 4 and 5. Mean docking free energies were 8.73-8.93 kcal/mol for SPH and 8.56-8.15 kcal/mol for DMS, and calculated binding constants were ~40 nM for SPH and ~120 nM for DMS. We hypothesize that SPH, DMS, and similar sphingoid bases access the S1R beta barrel via a membrane bilayer pathway. We further propose that the enzymatic control of ceramide concentrations in intracellular membranes as the primary sources of SPH dictates availability of endogenous SPH and DMS to the S1R and the subsequent control of S1R activity within the same cell and/or in cellular environments.

Associations Between Perceptions of e-Cigarette Harmfulness and Addictiveness and the Age of E-Cigarette Initiation Among the Population Assessment of Tobacco and Health (PATH) Youth.

Introduction: Youth perceptions of harmfulness and addictiveness of e-cigarettes may impact the age that they initiate e-cigarette use, but this has not been investigated previously. Methods: Youth (12-17 years old) never e-cigarette users at their first wave of PATH participation (waves 1-3, 2013-2016) were included. PATH questions on absolute perceptions of e-cigarette harmfulness and addictiveness were used as exposures. Interval-censored Cox proportional hazards models were used to estimate the impact of perceptions of harmfulness, and perceptions of addictiveness on (i) the age of initiation of e-cigarette use and (ii) age of first reporting past 30-day e-cigarette use, while controlling for covariates. Results: Youth who perceive e-cigarettes as having no/little harm had increased risk of initiating both ever e-cigarette use (AHR = 2.04; 95%CI = 1.74-2.40) and past 30-day e-cigarette use (AHR = 2.64; 95%CI = 2.07-3.37) at earlier ages compared to youth who perceive e-cigarettes as having a lot of harm. Youth who perceive the likelihood of becoming addicted to e-cigarettes to be very/somewhat unlikely had increased risk of an earlier age of both ever (AHR = 1.28; 95%CI = 1.07-1.52) and past 30-day (AHR = 1.36; 95%CI = 1.04-1.79) e-cigarette initiation compared to youth who perceived the likelihood of becoming addicted to e-cigarettes to be somewhat/very likely. Conclusion: These results highlight the importance of communicating to youth the potential for health harms and addiction from e-cigarette use in prevention and intervention campaigns, as those with the lowest perceptions of harmfulness and addictiveness had the earliest ages of e-cigarette initiation.

The association of perceptions of harmfulness and addictiveness on the age of initiation of cigar product use among youth: Findings from the Population Assessment of Tobacco and Health (PATH) study, 2013-2017.

Background: Perceptions of cigar products' harmfulness and addictiveness in youth are associated with subsequent cigar product initiation, but their association on the age of initiation of cigar product use is unknown. Methods: The association of perceptions of harmfulness and addictiveness at youth's first wave of PATH participation (waves 1 or 2 in years 2013-2015) on the age of initiation of (i) ever. (ii) past 30-day, and (iii) fairly regular use of any cigar products (cigarillos, filtered cigars, or traditional cigars) during the followed-up in PATH waves 2-4 (2014-2017) was estimated using weighted interval-censored Cox proportional hazards models. Also, the association of the interaction between perceptions of harmfulness and addictiveness and the age of initiation of any cigar use are reported. Hazard ratios (HR) and 95% confidence intervals (CI) are reported. Results: Among youth who had ever heard of cigar products, youth who perceived cigars to be "low-medium harmfulness and low-medium addictiveness" had 60% (HR: 1.60, 95%CI: 1.36-1.89) higher hazard risk to initiate ever cigar product use at an earlier age, and had 46% (HR:1.46, 95%CI: 1.14-1.86) higher hazard risk to initiate past 30-day cigar product use at younger ages than those who perceived cigars to be "high harmfulness and high addictiveness." Moreover, youth who perceived cigars to be "low-medium harmfulness and high addictiveness" had 33% (HR: 1.33, 95%CI: 1.15-1.53) higher hazard risk to initiate ever cigar product use at younger ages than those who perceived cigars to be "high harmfulness and high addictiveness." Youth who reported "high harmfulness and low-medium addictiveness" (HR: 0.24, 95% CI: 0.07-0.83) had 76% lower hazard risk to initiate fairly regular use of cigar products at younger ages compared to youth who reported "high harmfulness and high addictiveness." Conclusions: Prevention and awareness campaigns should reinforce the unique potential for harm and addiction of cigar products to curb cigar product initiation among US youth.

Diaminocyclopentane-derived O-GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer's disease.

We developed potent and selective aminocyclopentane-derived inhibitors of human O-N-acetyl-ß-D-glucosaminidase (OGA) implicated in Alzheimer's disease. For example compound 13 was a nanomolar OGA inhibitor with 92 000-fold selectivity over human HexB. It was non-toxic and increased protein O-GlcNAcylation in the culture of murine neural cells, showing new alternatives in the treatment of tauopathies.

Internalizing and externalizing problems on the age of e-cigarette initiation in youth: Findings from the Population Assessment of Tobacco and Health (PATH), 2013-2017.

Previous research has established an association between internalizing and externalizing problems with e-cigarette use in youth. Secondary analysis of Population Assessment of Tobacco and Health youth waves 1-4(2013-2017). Age of initiation of ever e-cigarette use and age of first report of past 30-day e-cigarette use were prospectively estimated among never e-cigarette users(waves 1-3). Weighted interval-censoring multivariable Cox proportional hazard models were fit to assess differences in each e-cigarette outcome among youth with internalizing and externalizing problems, as well as the interaction between internalizing and externalizing problems, while adjusting for covariates. Weighted interval-censoring survival analyses estimated the age of initiation of ever and age of first report of past 30-day e-cigarette use stratified by internalizing and externalizing problems. Among youth never e-cigarette users, those with high internalizing problems and high externalizing problems had increased risk of initiating ever e-cigarette use at earlier ages compared to youth with none/low internalizing and externalizing problems, respectively. Youth with high internalizing problems and high externalizing problems had increased risk of first reporting past 30-day e-cigarette use at earlier ages compared to youth with none/low internalizing problems, respectively. By age 17, 36.3% of youth with high internalizing problems and 38.5% of youth with high externalizing problems initiated ever e-cigarette use. By age 17, 16.8% of youth with high internalizing and 18.7% of youth with high externalizing problems first reported past 30-day e-cigarette use. Youth with internalizing and externalizing problems should be screened for e-cigarette use and provided with proper resources to prevent onset of e-cigarette use.

The Effect of Perceptions of Hookah Harmfulness and Addictiveness on the Age of Initiation of Hookah Use among Population Assessment of Tobacco and Health (PATH) Youth.

Despite the negative health consequence of hookah, hookah risk perceptions are misguided among youth. Secondary data analysis of 12-17-year-old never hookah users at their first wave of PATH participation (2013-2019) was performed. The effect of perceptions of hookah harmfulness and addictiveness on the age of initiation ever, past 30-day, and fairly regular hookah use were estimated using interval-censored Cox proportional hazards models. The distribution of the age of initiation of hookah outcomes by perception levels of harmfulness and addictiveness are reported as cumulative incidence and 95% CI. Youth who perceived hookah to be neither harmful nor addictive were 173% more likely to initiate ever, 166% more likely to first report past 30-day use, and 142% more likely to first report fairly regular hookah use at earlier ages compared to youth who considered hookah to be both harmful and addictive. By age 18, 25.5% of youth who perceived hookah as neither harmful nor addictive were estimated to initiate ever hookah use while 9.3% of youth who perceived hookah as harmful and addictive were estimated to initiate ever hookah use. These findings indicate the need to provide prevention and education campaigns to change perceptions of the harmfulness and addictiveness of hookah to delay the age of initiation of hookah use.