Targeting TLR4 during vaccination boosts MAdCAM-1+ lymphoid stromal cell activation and promotes the aged germinal center response

The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, the primary cellular defect underlying impaired GCs in aging has not been identified. Here, we used heterochronic parabiosis to demonstrate that GC formation was dictated by the age of the lymph node (LN) microenvironment rather than the age of the immune cells. Lymphoid stromal cells are a key determinant of the LN microenvironment and are also an essential component underpinning GC structure and function. Using mouse models, we demonstrated that mucosal adressin cell adhesion molecule-1 (MAdCAM-1)-expressing lymphoid stromal cells were among the first cells to respond to NP-KLH + Alum immunization, proliferating and up-regulating cell surface proteins such as podoplanin and cell adhesion molecules. This response was essentially abrogated in aged mice. By targeting TLR4 using adjuvants, we improved the MAdCAM-1+ stromal cell response to immunization. This correlated with improved GC responses in both younger adult and aged mice, suggesting a link between stromal cell responses to immunization and GC initiation. Using bone marrow chimeras, we also found that MAdCAM-1+ stromal cells could respond directly to TLR4 ligands. Thus, the age-associated defect in GC and stromal cell responses to immunization can be targeted to improve vaccines in older people

SUPPORT for ME Needs Assessment Summary.

Maine Department of Health and Human Services contracted with the Catherine Cutler Institute at the University of Southern Maine to conduct a baseline needs assessment. The overall goal was to better understand the current capacity to address substance use in Maine; find barriers to receiving and utilizing SUD treatment and recovery services; and identify any gaps in SUD-related services in the state. The Cutler team conducted interviews, surveys, community listening sessions and focus groups with healthcare key informants (leadership from health systems, residential care, recovery housing, behavioral health agencies), providers (medical, behavioral health, first responders, residential treatment, law enforcement, opioid treatment), youth ages 12-21, and community members across Maine. The team also analyzed health claims data to identify how common substance misuse is among MaineCare (Medicaid) members and what types of substance use disorder (SUD) treatment and support services MaineCare members use. For more information, please contact the principal investigator, M. Lindsey Smith, PhD, at [email protected]

The timing of death in patients with tuberculosis who die during anti-tuberculosis treatment in Andhra Pradesh, South India

Background: India has 2.0 million estimated tuberculosis (TB) cases per annum with an estimated 280,000 TBrelated deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India:- i) treatment outcomes including the number who died while on treatment, ii) the month of death and iii) characteristics associated with “early” death, occurring in the initial 8 weeks of treatment. Methods: This was a retrospective study in 16 selected Designated Microscopy Centres (DMCs) in Hyderabad, Krishna and Adilabad districts of Andhra Pradesh, South India. A review was performed of treatment cards and medical records of all TB patients (adults and children) registered and placed on standardized anti-tuberculosis treatment from January 2005 to September 2009. Results: There were 8,240 TB patients (5183 males) of whom 492 (6%) were known to have died during treatment. Case-fatality was higher in those previously treated (12%) and lower in those with extra-pulmonary TB (2%). There was an even distribution of deaths during anti-tuberculosis treatment, with 28% of all patients dying in the first 8 weeks of treatment. Increasing age and new as compared to recurrent TB disease were significantly associated with “early death”. Conclusion: In this large cohort of TB patients, deaths occurred with an even frequency throughout anti-TB treatment. Reasons may relate to i) the treatment of the disease itself, raising concerns about drug adherence, quality of anti-tuberculosis drugs or the presence of undetected drug resistance and ii) co-morbidities, such as HIV/ AIDS and diabetes mellitus, which are known to influence mortality. More research in this area from prospective and retrospective studies is needed

LC3-Associated Phagocytosis Is Required for Dendritic Cell Inflammatory Cytokine Response to Gut Commensal Yeast Saccharomyces cerevisiae

The human fungal microbiota known as mycobiota is increasingly recognized as a critical factor in human gut health and disease. Non-pathogenic commensal yeasts such as Saccharomyces cerevisiae promote homeostasis in the gut, whereas dysbiosis of the gut mycobiota is associated with inflammation. Glycan-binding receptors (lectins) are key host factors in host–mycobiota interaction in the gut. They are expressed on immune cells such as dendritic cells (DCs) and recognize fungal polysaccharides. This interaction is imperative to mount appropriate immune responses for immune homeostasis in the gut as well as clearance of fungal pathogens. Recent studies demonstrate that microtubule-associated protein light-chain 3 (LC3)-associated phagocytosis (LAP) is involved in lectin–fungi interactions. Yet, the biological impact of LAP on the lectin function remains largely elusive. In this report, we demonstrate that in mouse LAP is linked to dendritic cell-associated lectin 2 (Dectin-2), a C-type lectin specific to fungal α-mannan polysaccharide. We found that mouse Dectin-2 recognizes commensal yeast S. cerevisiae and Kazachstania unispora. Mouse bone marrow-derived DCs (BMDCs) produced inflammatory cytokines TNFα and IL-1β in response to the yeasts in a Dectin-2 and spleen tyrosine kinase (Syk)-dependent manner. We found that S. cerevisiae and K. unispora induced LAP in mouse BMDCs upon internalization. Furthermore, LC3 was activated by stimulation of BMDCs with the yeasts in a Dectin-2 and Syk-dependent manner. To address the biological impact of LAP on Dectin-2 yeast interaction, we established a knock-in mouse strain (Atg16L1E230, thereafter called E230), which BMDCs exhibit autophagy-active and LAP-negative phenotypes. When stimulated with yeasts, E230 BMDCs produced significantly less amounts of TNFα and IL-1β. Taken together, we revealed a novel link between Dectin-2 and LAP that enables host immune cells to respond to mycobiota

Molecular cloning and expression analysis of a zebrafish novel zinc finger protein gene rnf141

ZNF230 is a novel zinc finger gene cloned by our laboratory. In order to understand the potential functions of this gene in vertebrate development, we cloned the zebrafish orthologue of human ZNF230, named rnf141. The cDNA fragment of rnf141 was obtained by rapid amplification of cDNA ends (RACE). The open reading frame (ORF) encodes a polypeptide of 222 amino acids which shares 75.65% identity with the human ZNF230. RT-PCR analysis in zebrafish embryo and adult tissues revealed that rnf141 transcripts are maternally derived and that rnf141 mRNA has a broad distribution. Zygotic rnf141 message is strongly localized in the central nervous system, as shown by whole-mount in situ hybridization. Knockdown and over expression of rnf141 can induce abnormal phenotypes, including abnormal development of brain, as well as yolk sac and axis extendsion. Marker gene analysis showed that rnf141 may play a role in normal dorsoventral patterning of zebrafish embryos, suggesting that rnf141 may have a broad function during early development of vertebrates

Understanding Dwarf Galaxies in order to Understand Dark Matter

Much progress has been made in recent years by the galaxy simulation community in making realistic galaxies, mostly by more accurately capturing the effects of baryons on the structural evolution of dark matter halos at high resolutions. This progress has altered theoretical expectations for galaxy evolution within a Cold Dark Matter (CDM) model, reconciling many earlier discrepancies between theory and observations. Despite this reconciliation, CDM may not be an accurate model for our Universe. Much more work must be done to understand the predictions for galaxy formation within alternative dark matter models.Comment: Refereed contribution to the Proceedings of the Simons Symposium on Illuminating Dark Matter, to be published by Springe

Asiatic Acid Inhibits Liver Fibrosis by Blocking TGF-beta/Smad Signaling In Vivo and In Vitro

Liver fibrosis is a major cause of liver failure, but treatment remains ineffective. In the present study, we investigated the mechanisms and anti-hepatofibrotic activities of asiatic acid (AA) in a rat model of liver fibrosis induced by carbon tetrachloride (CCl4) and in vitro in TGF-beta1-stimulated rat hepatic stellate cell line (HSC-T6). Treatment with AA significantly attenuated CCl4-induced liver fibrosis and functional impairment in a dosage-dependent manner, including blockade of the activation of HSC as determined by inhibiting de novo alpha smooth muscle actin (a-SMA) and collagen matrix expression, and an increase in ALT and AST (all p<0.01). The hepatoprotective effects of AA on fibrosis were associated with upregulation of hepatic Smad7, an inhibitor of TGF-beta signaling, thereby blocking upregulation of TGF-beta1 and CTGF and the activation of TGF-beta/Smad signaling. The anti-fibrosis activity and mechanisms of AA were further detected in vitro in HSC-T6. Addition of AA significantly induced Smad7 expression by HSC-T6 cells, thereby inhibiting TGF-beta1-induced Smad2/3 activation, myofibroblast transformation, and collagen matrix expression in a dosage-dependent manner. In contrast, knockdown of Smad7 in HSC-T6 cells prevented AA-induced inhibition of HSC-T6 cell activation and fibrosis in response to TGF-beta1, revealing an essential role for Smad7 in AA-induced anti-fibrotic activities during liver fibrosis in vivo and in vitro. In conclusion, AA may be a novel therapeutic agent for liver fibrosis. Induction of Smad7-dependent inhibition of TGF-beta/Smad-mediated fibrogenesis may be a central mechanism by which AA protects liver from injury

Accrual of Atherosclerotic Vascular Events in a Multicenter Inception Systemic Lupus Erythematosus Cohort

Objective: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. / Methods: A large 33‐center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient‐years, and univariable and multivariable relative risk regression models. / Results: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow‐up visit after enrollment, for a total of 13,666 patient‐years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient‐years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32–0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55–10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04–7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17–9.27], P < 0.001). / Conclusion: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors

Cannabis in medicine: a national educational needs assessment among Canadian physicians

BACKGROUND: There is increasing global awareness and interest in the use of cannabis for therapeutic purposes (CTP). It is clear that health care professionals need to be involved in these decisions, but often lack the education needed to engage in informed discussions with patients. This study was conducted to determine the educational needs of Canadian physicians regarding CTP. METHODS: A national needs assessment survey was developed based on previous survey tools. The survey was approved by the Research Ethics Board of the McGill University Health Centre Research Institute and was provided online using LimeSurvey®. Several national physician organizations and medical education organizations informed their members of the survey. The target audience was Canadian physicians. We sought to identify and rank using 5-point Likert scales the most common factors involved in decision making about using CTP in the following categories: knowledge, experience, attitudes, and barriers. Preferred educational approaches and physician demographics were collected. Gap analysis was conducted to determine the magnitude and importance of differences between perceived and desired knowledge on all decision factors. RESULTS: Four hundred and twenty six responses were received, and physician responses were distributed across Canada consistent with national physician distribution. The most desired knowledge concerned “potential risks of using CTP” and “safety, warning signs and precautions for patients using CTP”. The largest gap between perceived current and desired knowledge levels was “dosing” and “the development of treatment plans”. CONCLUSIONS: We have identified several key educational needs among Canadian physicians regarding CTP. These data can be used to develop resources and educational programs to support clinicians in this area, as well as to guide further research to inform these gaps

Treatment of active lupus nephritis with the novel immunosuppressant 15-deoxyspergualin: an open-label dose escalation study

Introduction: As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN). Methods: Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of 9 times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects. Results: 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. 5 patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. 11/20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and one patient was not assessable. 12 patients completed all 9 cycles; in those patients, proteinuria decreased from 5.88g/day to 3.37g/day (P = 0.028), Selena-SLEDAI decreased from 17.6 to 11.7. In 13/20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1g/day. Conclusions: Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials