Four Weeks of Hericium erinaceus Supplementation Does Not Impact Markers of Metabolic Flexibility or Cognition

International Journal of Exercise Science 15(2): 1366-1380, 2022. Hericium erinaceus (HE), also known as Lion’s Mane mushroom, has been found to enhance cognition and metabolic flexibility in various animal models. To date however, only four studies exist in humans and none have evaluated the effects of HE on markers of metabolic flexibility or cognitive performance. A single-blind, placebo controlled, parallel-longitudinal study was used to determine the effects of HE on markers of metabolic flexibility and cognition. Twenty-four participants completed a graded exercise test on a cycle ergometer to analyze substrate oxidation rates and markers of cardiorespiratory fitness. Additionally, two dual-task challenges consisting of a Stroop Word Challenge interspersed with a Mental Arithmetic Challenge were performed, pre-post the graded exercise test, to evaluate markers of cognition in a pre-post fatigued state. Participants were stratified into two groups, receiving either 10 g of HE per day or placebo for 4-weeks in the form of two muffins identical in taste and appearance. Repeated-measures analysis of variance were conducted to evaluate potential interactions or main effects. Although group differences were noted at baseline, there were no significant interactions or main effects observed from HE ingestion for any dependent variable (all p \u3e 0.05). Our data suggest that ingesting 10 g of HE per day for 4-weeks had no impact on metabolic flexibility and cognition in a college-age cohort. Due to the limited research on HE supplementation, future research is needed to establish an effective supplement dose and duration for potential physiological changes to be observed in humans

One Year Follow-up of a Randomized, Double-Blind, Placebo-Controlled Trial of Percutaneous Peripheral Nerve Stimulation for Chronic Neuropathic Pain Following Amputation

Abstract INTRODUCTION Over 85% of patients experience residual limb (RLP) and/or phantom limb (PLP) pain following amputation. Peripheral nerve stimulation (PNS) is a non-opioid approach to relieve postamputation neuropathic pain. A recent multicenter, randomized, double-blind, placebo-controlled study using a novel percutaneous PNS system demonstrated clinically and statistically significant improvements in pain and pain interference with PNS compared to placebo (Gilmore et al, 2019). This work presents prospective 1-yr follow-up to assess durability of pain relief and functional improvements. METHODS Over 85% of patients experience residual limb (RLP) and/or phantom limb (PLP) pain following amputation. Peripheral nerve stimulation (PNS) is a non-opioid approach to relieve post-amputation neuropathic pain. A recent multicenter, randomized, double-blind, placebo-controlled study using a novel percutaneous PNS system demonstrated clinically and statistically significant improvements in pain and pain interference with PNS compared to placebo (Gilmore et al, 2019). This work presents prospective one-year follow-up to assess durability of pain relief and functional improvements. RESULTS A significantly greater proportion of subjects who completed the 12-mo visit reported = 50% pain relief on the BPI-SF (5/8, 63%; average pain relief = 73% among responders) compared to the placebo group at the time of crossover (0/14, 0%, P = .003; average pain relief = 23%). A majority of subjects also reported = 50% reductions in pain interference at 12 mo (5/8, 63%). Two of 13 (15%) subjects in the placebo group reported sustained improvements in pain interference (P = .06). Average reduction in pain interference among responders in the PNS group was 87%. CONCLUSION This work suggests that PNS delivered over 60 d may provide clinically significant and enduring pain relief, enabling improved function and potentially reducing the need for a permanently implanted system

Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo

Introduction: Bone metastasis remains incurable with treatment restricted to palliative care. Cabozantinib (CBZ) is targeted against multiple receptor tyrosine kinases involved in tumour pathobiology, including hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR-2). CBZ has demonstrated clinical activity in advanced prostate cancer with resolution of lesions visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of CBZ effects. We characterised the effects of short-term administration of CBZ on bone in a range of in vivo models to determine how CBZ affects bone in the absence of tumour. Methods: Studies were performed in a variety of in vivo models including male and female BALB/c nude mice (age 6– 17-weeks). Animals received CBZ (30 mg/kg, 5× weekly) or sterile H2O control for 5 or 10 days. Effects on bone integrity (μCT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and bone marrow composition were assessed. Effects of longer-term treatment (15-day & 6-week administration) were assessed in male NOD/SCID and beige SCID mice. Results: CBZ treatment had significant effects on the bone microenvironment, including reduced osteoclast and increased osteoblast numbers compared to control. Trabecular bone structure was altered after 8 administrations. A significant elongation of the epiphyseal growth plate, in particular the hypertrophic chondrocyte zone, was observed in all CBZ treated animals irrespective of administration schedule. Both male and female BALB/c nude mice had increased megakaryocyte numbers/mm2 tissue after 10-day CBZ treatment, in addition to vascular ectasia, reduced bone marrow cellularity and extravasation of red blood cells into the extra-vascular bone marrow. All CBZinduced effects were transient and rapidly lost following cessation of treatment. Conclusion: Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironmentin vivo highlighting a potential role in mediating treatment responses

Recent Advances in the Treatment of Opioid Use Disorder

PURPOSE OF REVIEW: Opioid use disorder (OUD) remains a national epidemic with an immense consequence to the United States\u27 healthcare system. Current therapeutic options are limited by adverse effects and limited efficacy. RECENT FINDINGS: Recent advances in therapeutic options for OUD have shown promise in the fight against this ongoing health crisis. Modifications to approved medication-assisted treatment (MAT) include office-based methadone maintenance, implantable and monthly injectable buprenorphine, and an extended-release injectable naltrexone. Therapies under investigation include various strategies such as heroin vaccines, gene-targeted therapy, and biased agonism at the G protein-coupled receptor (GPCR), but several pharmacologic, clinical, and practical barriers limit these treatments\u27 market viability. This manuscript provides a comprehensive review of the current literature regarding recent innovations in OUD treatment

Multiple signals mediate proliferation, differentiation, and survival from the granulocyte colony-stimulating factor receptor in myeloid 32D cells

Granulocyte colony-stimulating factor (G-CSF) regulates neutrophil production through activation of its cognate receptor, the G-CSF-R. Previous studies with deletion mutants have shown that the membrane-proximal cytoplasmic domain of the receptor is sufficient for mitogenic signaling, whereas the membrane-distal domain is required for differentiation signaling. However, the function of the four cytoplasmic tyrosines of the G-CSF-R in the control of proliferation, differentiation, and survival has remained unclear. Here we investigated the role of these tyrosines by expressing a tyrosine 'null' mutant and single tyrosine 'add back' mutants in maturation-competent myeloid 32D cells. Clones expressing the null mutant showed only minimal proliferation and differentiation, with survival also reduced at low G-CSF concentrations. Analysis of clones expressing the add-back mutants revealed that multiple tyrosines contribute to proliferation, differentiation, and survival signals from the G-CSF-R. Analysis of signaling pathways downstream of these tyrosines suggested a positive role for STAT3 activation in both differentiation and survival signaling, whereas SHP-2, Grb2 and Shc appear important for proliferation signaling. In addition, we show that a tyrosine- independent 'differentiation domain' in the membrane-distal region of the G- CSF-R appears necessary but not sufficient for mediating neutrophilic differentiation in these cells

Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals

AbstractBiomarkers for active tuberculosis (TB) are urgently needed to improve rapid TB diagnosis. The objective of this study was to identify serum protein expression changes associated with TB but not latent Mycobacterium tuberculosis infection (LTBI), uninfected states, or respiratory diseases other than TB (ORD). Serum samples from 209 HIV uninfected (HIV−) and co-infected (HIV+) individuals were studied. In the discovery phase samples were analyzed via liquid chromatography and mass spectrometry, and in the verification phase biologically independent samples were analyzed via a multiplex multiple reaction monitoring mass spectrometry (MRM-MS) assay. Compared to LTBI and ORD, host proteins were significantly differentially expressed in TB, and involved in the immune response, tissue repair, and lipid metabolism. Biomarker panels whose composition differed according to HIV status, and consisted of 8 host proteins in HIV− individuals (CD14, SEPP1, SELL, TNXB, LUM, PEPD, QSOX1, COMP, APOC1), or 10 host proteins in HIV+ individuals (CD14, SEPP1, PGLYRP2, PFN1, VASN, CPN2, TAGLN2, IGFBP6), respectively, distinguished TB from ORD with excellent accuracy (AUC=0.96 for HIV− TB, 0.95 for HIV+ TB). These results warrant validation in larger studies but provide promise that host protein biomarkers could be the basis for a rapid, blood-based test for TB

Dynamic action of the Sec machinery during initiation, protein translocation and termination

Protein translocation across cell membranes is a ubiquitous process required for protein secretion and membrane protein insertion. In bacteria, this is mostly mediated by the conserved SecYEG complex, driven through rounds of ATP hydrolysis by the cytoplasmic SecA, and the trans-membrane proton motive force. We have used single molecule techniques to explore SecY pore dynamics on multiple timescales in order to dissect the complex reaction pathway. The results show that SecA, both the signal sequence and mature components of the pre-protein, and ATP hydrolysis each have important and specific roles in channel unlocking, opening and priming for transport. After channel opening, translocation proceeds in two phases: a slow phase independent of substrate length, and a length-dependent transport phase with an intrinsic translocation rate of ~40 amino acids per second for the proOmpA substrate. Broad translocation rate distributions reflect the stochastic nature of polypeptide transport

Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene

In approximately 20% of cases of severe congenital neutropenia (SCN), mutations are found in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R). These mutations introduce premature stop codons, which result in truncation of 82-98 COOH-terminal amino acids of the receptor. SCN patients who develop secondary myelodysplastic syndrome and acute myeloid leukemia almost invariably acquired a GCSFR mutation, suggesting that this genetic alteration represents a key step in leukemogenesis. Here we show that an equivalent mutation targeted in mice (gcsfr-Delta715) results in the selective expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the bone marrow. In addition, in vivo treatment of gcsfr-Delta715 mice with G-CSF results in increased production of neutrophils leading to a sustained neutrophilia. This hyperproliferative response to G-CSF is accompanied by prolonged activation of signal transducer and activator of transcription (STAT) complexes and extended cell surface expression of mutant receptors due to defective internalization. In view of the continuous G-CSF treatment of SCN patients, these data provide insight into why progenitor cells expressing truncated receptors clonally expand in vivo, and why these cells may be targets for additional genetic events leading to leukemia