Inhibitor of growth protein 3 epigenetically silences endogenous retroviral elements and prevents innate immune activation

Endogenous retroviruses (ERVs) are subject to transcriptional repression in adult tissues, in part to prevent autoimmune responses. However, little is known about the epigenetic silencing of ERV expression. Here, we describe a new role for inhibitor of growth family member 3 (ING3), to add to an emerging group of ERV transcriptional regulators. Our results show that ING3 binds to several ERV promoters (for instance MER21C) and establishes an EZH2-mediated H3K27 trimethylation modification. Loss of ING3 leads to decreases of H3K27 trimethylation enrichment at ERVs, induction of MDA5-MAVS-interferon signaling, and functional inhibition of several virus infections. These data demonstrate an important new function of ING3 in ERV silencing and contributing to innate immune regulation in somatic cells

Autoreactivity and Exceptional CDR Plasticity (but Not Unusual Polyspecificity) Hinder Elicitation of the Anti-HIV Antibody 4E10

The broadly-neutralizing anti-HIV antibody 4E10 recognizes an epitope in the membrane-proximal external region of the HIV envelope protein gp41. Previous attempts to elicit 4E10 by vaccination with envelope-derived or reverse-engineered immunogens have failed. It was presumed that the ontogeny of 4E10-equivalent responses was blocked by inherent autoreactivity and exceptional polyreactivity. We generated 4E10 heavy-chain knock-in mice, which displayed significant B cell dysregulation, consistent with recognition of autoantigen/s by 4E10 and the presumption that tolerance mechanisms may hinder the elicitation of 4E10 or 4E10-equivalent responses. Previously proposed candidate 4E10 autoantigens include the mitochondrial lipid cardiolipin and a nuclear splicing factor, 3B3. However, using carefully-controlled assays, 4E10 bound only weakly to cardiolipin-containing liposomes, but also bound negatively-charged, non-cardiolipin-containing liposomes comparably poorly. 4E10/liposome binding was predominantly mediated by electrostatic interactions rather than presumed hydrophobic interactions. The crystal structure of 4E10 free of bound ligands showed a dramatic restructuring of the combining site, occluding the HIV epitope binding site and revealing profound flexibility, but creating an electropositive pocket consistent with non-specific binding of phospholipid headgroups. These results strongly suggested that antigens other than cardiolipin mediate 4E10 autoreactivity. Using a synthetic peptide library spanning the human proteome, we determined that 4E10 displays limited and focused, but unexceptional, polyspecificity. We also identified a novel autoepitope shared by three ER-resident inositol trisphosphate receptors, validated through binding studies and immunohistochemistry. Tissue staining with 4E10 demonstrated reactivity consistent with the type 1 inositol trisphosphate receptor as the most likely candidate autoantigen, but is inconsistent with splicing factor 3B3. These results demonstrate that 4E10 recognition of liposomes competes with MPER recognition and that HIV antigen and autoepitope recognition may be distinct enough to permit eliciting 4E10-like antibodies, evading autoimmunity through directed engineering. However, 4E10 combining site flexibility, exceptional for a highly-matured antibody, may preclude eliciting 4E10 by conventional immunization strategies

Chronic digital infection presenting with gross enlargement of the toes: two case reports and review of the literature

There are many conditions ranging from the benign to the malignant, which can present with enlargement of one or more digits. An understanding of the differential diagnosis is important such that the potentially serious aetiologies are not missed and patients can therefore be treated appropriately

All-charm tetraquarks

We investigate four-body states with only charm quarks. Working in a large but finite oscillator basis, we present a net binding analysis to determine if the resulting states are stable against breakup into a pair of c-cbar mesons. We find several close-lying bound states in the two models we examine.Comment: 24 pgs, 10 table

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up

Tacrolimus for the treatment of fistulas in patients with crohn’s disease: a randomized, placebo-controlled trial

AbstractBackground & Aims:This study determined the effectiveness of tacrolimus for the treatment of Crohn's disease fistulas.Methods:The study was a randomized, double-blind, placebo-controlled, multicenter clinical trial. Forty-eight patients with Crohn's disease and draining perianal or enterocutaneous fistulas were randomized to treatment with oral tacrolimus 0.2 mg · kg−1 · day−1 or placebo for 10 weeks. The primary outcome measure was fistula improvement as defined by closure of ≥50% of particular fistulas that were draining at baseline and maintenance of that closure for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks.Results:Forty-three percent of tacrolimus-treated patients had fistula improvement compared with 8% of placebo-treated patients (P = 0.004). Ten percent of tacrolimus-treated patients had fistula remission compared with 8% of placebo-treated patients (P = 0.86). Adverse events significantly associated with tacrolimus, including headache, increased serum creatinine level, insomnia, leg cramps, paresthesias, and tremor, were managed with dose reduction.Conclusions:Oral tacrolimus 0.2 mg · kg−1 · day−1 is effective for fistula improvement, but not fistula remission, in patients with perianal Crohn's disease. Adverse events associated with tacrolimus can be managed by dose reduction. Lower doses of tacrolimus should be evaluated

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Nuggets, Pearls, and Vignettes of Master Heart Failure Clinicians

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73696/1/j.1527-5299.2001.00307.x.pd

Distribution and correlates of plantar hyperkeratotic lesions in older people

<p>Abstract</p> <p>Background</p> <p>Plantar hyperkeratotic lesions are common in older people and are associated with pain, mobility impairment and functional limitations. However, little has been documented in relation to the frequency or distribution of these lesions. The aim of this study was to document the occurrence of plantar hyperkeratotic lesions and the patterns in which they occur in a random sample of older people.</p> <p>Methods</p> <p>A medical history questionnaire was administered to a random sample of 301 people living independently in the community (117 men, 184 women) aged between 70 and 95 years (mean 77.2, SD 4.9), who also underwent a clinical assessment of foot problems, including the documentation of plantar lesion locations, toe deformities and the presence and severity of hallux valgus.</p> <p>Results</p> <p>Of the 301 participants, 180 (60%) had at least one plantar hyperkeratotic lesion. Those with plantar lesions were more likely to be female (χ²= 18.75, <it>p </it>< 0.01; OR = 2.86), have moderate to severe hallux valgus (χ²= 6.15, <it>p </it>< 0.02; OR = 2.95), a larger dorsiflexion range of motion at the ankle (39.4 ± 9.3 <it>vs </it>36.3 ± 8.4°; <it>t </it>= 2.68, <it>df </it>= 286, <it>p </it>< 0.01), and spent more time on their feet at home (5.1 ± 1.0 <it>vs </it>4.8 ± 1.3 hours, <it>t </it>= -2.46, <it>df </it>= 299, <it>p </it>= 0.01). No associations were found between the presence of plantar lesions and body mass index, obesity, foot posture, dominant foot or forefoot pain. A total of 53 different lesions patterns were observed, with the most common lesion pattern being "roll-off" hyperkeratosis on the medial aspect of the 1^stmetatarsophalangeal joint (MPJ), accounting for 12% of all lesion patterns. "Roll-off" lesions under the 1^stMPJ and interphalangeal joint were significantly associated with moderate to severe hallux valgus (<it>p </it>< 0.05), whereas lesions under the central MPJs were significantly associated with deformity of the corresponding lesser toe (<it>p </it>< 0.05). Factor analysis indicated that 62% of lesion patterns could be grouped under three broad categories, relating to medial, central and lateral locations.</p> <p>Conclusion</p> <p>Plantar hyperkeratotic lesions affect 60% of older people and are associated with female gender, hallux valgus, toe deformity, increased ankle flexibility and time spent on feet, but are not associated with obesity, limb dominance, forefoot pain or foot posture. Although there are a wide range of lesion distribution patterns, most can be classified into medial, central or lateral groups. Further research is required to determine whether these patterns are related to the dynamic function of the foot or other factors such as foot pathology or morphology.</p