Discovery of noncanonical translation initiation sites through mass spectrometric analysis of protein N termini

Translation initiation generally occurs at AUG codons in eukaryotes, although it has been shown that non-AUG or non-canonical translation initiation can also occur. However, the evidence for noncanonical translation initiation sites (TISs) is largely indirect and based on ribosome profiling (Ribo-seq) studies. Here, using a strategy specifically designed to enrich N termini of proteins, we demonstrate that many human proteins are translated at noncanonical TISs. The large majority of TISs that mapped to 5' untranslated regions were noncanonical and led to N-terminal extension of annotated proteins or translation of upstream small open reading frames (uORF). It has been controversial whether the amino acid corresponding to the start codon is incorporated at the TIS or methionine is still incorporated. We found that methionine was incorporated at almost all noncanonical TISs identified in this study. Comparison of the TISs determined through mass spectrometry with ribosome profiling data revealed that about two-thirds of the novel annotations were indeed supported by the available ribosome profiling data. Sequence conservation across species and a higher abundance of noncanonical TISs than canonical ones in some cases suggests that the noncanonical TISs can have biological functions. Overall, this study provides evidence of protein translation initiation at noncanonical TISs and argues that further studies are required for elucidation of functional implications of such noncanonical translation initiation

Analysis of the Relationship between Cerebellar Volume and Psychological Parameters in 20s Male Adults

AbstractThis study measured the cerebellar volume of normal male adults in 20s with magnetic resonance imaging (MRI) and analysed the relationship between cerebellar volume and various psychological parameters. The cerebellar volume of 58 males (mean age, 24.0-2.8 years) was measured using MRI. The Symptom Checklist-90-R (SCL-90-R) and the Component of Type A Behavior tests were performed. Using linear regression analysis, the relationship between cerebellar volume and psychological parameters was analysed. As phobic anxiety and ambition increased, cerebellar volume of normal male subjects in 20s decreased. This study showed that for even normal male adults, there exists a possible relationship between various psychological parameters and cerebellar volume

Plasmodium sporozoite phospholipid scramblase interacts with mammalian carbamoyl-phosphate synthetase 1 to infect hepatocytes

After inoculation by the bite of an infected mosquito, Plasmodium sporozoites enter the blood stream and infect the liver, where each infected cell produces thousands of merozoites. These in turn, infect red blood cells and cause malaria symptoms. To initiate a productive infection, sporozoites must exit the circulation by traversing the blood lining of the liver vessels after which they infect hepatocytes with unique specificity. We screened a phage display library for peptides that structurally mimic (mimotope) a sporozoite ligand for hepatocyte recognition. We identified HP1 (hepatocyte-binding peptide 1) that mimics a ~50 kDa sporozoite ligand (identified as phospholipid scramblase). Further, we show that HP1 interacts with a ~160 kDa hepatocyte membrane putative receptor (identified as carbamoyl-phosphate synthetase 1). Importantly, immunization of mice with the HP1 peptide partially protects them from infection by the rodent parasite P. berghei. Moreover, an antibody to the HP1 mimotope inhibits human parasite P. falciparum infection of human hepatocytes in culture. The sporozoite ligand for hepatocyte invasion is a potential novel pre-erythrocytic vaccine candidate. © 2021, The Author(s).1

Erratum: Nation-Wide Korean Breast Cancer Data from 2008 Using the Breast Cancer Registration Program

nation-wide breast cancer data and analyzed the data using their online registration program biannually. The purpose of this study was to evaluate the characteristics of Korean breast cancer from 2008 and examine chronological based patterns. Methods: Data were collected from 38 medical schools (67 hospitals), 20 general hospitals, and 10 private clinics. The data on the total number, gender, and age distribution were collected through a questionnaire as well as other detailed data analyzed via the online registration program. Results: In 2008, there were 13,908 patients who were newly diagnosed with breast cancer. The crude incidence rate of female breast cancer was 57.3 among 100,000 and the median age was 49 years. The age distribution had not changed since the initial survey; however the proportion of postmenopausal patients had increased and median age was older than the past. In staging distribution, the proportion of early breast cancer (stage 0, I) was 47.2 % with, breast-conserving surgery performed in 58 % and mastectomy in 39.5%. Conclusion: Compared to past data, the incidence of breast cancer in Korea continues to rise. Furthermore, the proportion of those detected by screening and breast conservation surgery has increased remarkably. To understand the patterns of Korean breast cancer, the nation-wide data should continuously investigated

Analgesic effect of highly reversible ω-conotoxin FVIA on N type Ca2+ channels

<p>Abstract</p> <p>Background</p> <p>N-type Ca²⁺channels (Ca_v2.2) play an important role in the transmission of pain signals to the central nervous system. ω-Conotoxin (CTx)-MVIIA, also called ziconotide (Prialt^®), effectively alleviates pain, without causing addiction, by blocking the pores of these channels. Unfortunately, CTx-MVIIA has a narrow therapeutic window and produces serious side effects due to the poor reversibility of its binding to the channel. It would thus be desirable to identify new analgesic blockers with binding characteristics that lead to fewer adverse side effects.</p> <p>Results</p> <p>Here we identify a new CTx, FVIA, from the Korean <it>Conus Fulmen </it>and describe its effects on pain responses and blood pressure. The inhibitory effect of CTx-FVIA on N-type Ca²⁺channel currents was dose-dependent and similar to that of CTx-MVIIA. However, the two conopeptides exhibited markedly different degrees of reversibility after block. CTx-FVIA effectively and dose-dependently reduced nociceptive behavior in the formalin test and in neuropathic pain models, and reduced mechanical and thermal allodynia in the tail nerve injury rat model. CTx-FVIA (10 ng) also showed significant analgesic effects on writhing in mouse neurotransmitter- and cytokine-induced pain models, though it had no effect on acute thermal pain and interferon-γ induced pain. Interestingly, although both CTx-FVIA and CTx-MVIIA depressed arterial blood pressure immediately after administration, pressure recovered faster and to a greater degree after CTx-FVIA administration.</p> <p>Conclusions</p> <p>The analgesic potency of CTx-FVIA and its greater reversibility could represent advantages over CTx-MVIIA for the treatment of refractory pain and contribute to the design of an analgesic with high potency and low side effects.</p

Bacterial profile of suction drains and the relationship thereof to surgical-site infections in prosthetic breast reconstruction

Background Despite the increasing popularity of prosthetic breast reconstruction, scant data exist on the microbiological profile of drainage fluid from closed-suction drains and the relationship thereof to surgical-site infections (SSIs) in breast reconstruction surgery. This study aimed to determine whether bacteria isolated from drainage fluid were associated with the development of SSIs, and whether the bacterial profile of drainage fluid could be a clinically useful predictor of SSIs. Methods We performed a retrospective chart review of 61 women who underwent tissue expander/implant or direct-to-implant reconstructions. Patient demographics and culture studies of drainage fluid from suction drains collected on postoperative day 7 were evaluated. Results Sixteen patients (26.23%) were culture-positive, and 45 patients (73.77%) were culture-negative. The most frequently isolated bacteria were coagulase-negative staphylococci, followed by Staphylococcus aureus. SSIs were diagnosed in seven patients and were mostly resolved by systemic antibiotics; however, the tissue expander or implant was explanted in two patients. Positive culture of drainage fluid from closed-suction drains was significantly associated with the development of SSIs (P<0.05). The positive predictive value was 37.50%,and the negative predictive value was 97.78%. Conclusions To our knowledge, this study is the first to demonstrate a significant association between the microbiological profile of drainage fluid from closed-suction drains and the development of SSIs in patients with prosthetic breast reconstructions. The high negative predictive value suggests that microbial testing of drainage fluid from closed-suction drains may have clinical utility. Further prospective studies with larger sample sizes are required to confirm our findings

Allopurinol Protects against Ischemia/Reperfusion-Induced Injury in Rat Urinary Bladders

Bladder ischemia-reperfusion (I/R) injury results in the generation of reactive oxygen species (ROS) and markedly elevates the risk of lower urinary tract symptoms (LUTS). Allopurinol is an inhibitor of xanthine oxidase (XO) and thus can serve as an antioxidant that reduces oxidative stress. Here, a rat model was used to assess the ability of allopurinol treatment to ameliorate the deleterious effects of urinary bladder I/R injury. I/R injury reduced the in vitro contractile responses of longitudinal bladder strips, elevated XO activity in the plasma and bladder tissue, increased the bladder levels of tumor necrosis factor-α (TNF-α), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase, reduced the bladder levels of extracellular regulated kinase (ERK), and decreased and increased the bladder levels of Bcl-2 and Bax, respectively. I/R injury also elevated lipid peroxidation in the bladder. Allopurinol treatment in the I/R injury was generated significantly ameliorating all I/R-induced changes. Moreover, an in situ fluorohistological approach also showed that allopurinol reduces the generation of intracellular superoxides enlarged by I/R injury. Together, the beneficial effects of allopurinol reducing ROS production may be mediated by normalizing the activity of the ERK, JNK, and Bax/Bcl-2 pathways and by controlling TNF-α expression

Identification of gut dysbiosis in axial spondyloarthritis patients and improvement of experimental ankylosing spondyloarthritis by microbiome-derived butyrate with immune-modulating function

IntroductionDysbiosis is an environmental factor that affects the induction of axial spondyloarthritis (axSpA) pathogenesis. In the present study, we investigated differences in the gut microbiota of patients with axSpA and revealed an association between specific gut microbiota and their metabolites, and SpA pathogenesis.MethodUsing 16S rRNA sequencing data derived from feces samples of 33 axSpA patients and 20 healthy controls (HCs), we examined the compositions of their gut microbiomes.ResultsAs a result, axSpA patients were found to have decreased α-diversity compared to HCs, indicating that axSpA patients have less diverse microbiomes. In particular, at the species level, Bacteroides and Streptococcus were more abundant in axSpA patients than in HCs, whereas Faecalibacterium (F). prausnitzii, a butyrate-producing bacteria, was more abundant in HCs. Thus, we decided to investigate whether F. prausnitzii was associated with health conditions by inoculating F. prausnitzii (0.1, 1, and 10 μg/mL) or by administrating butyrate (0.5 mM) into CD4+ T cells derived from axSpA patients. The levels of IL-17A and IL-10 in the CD4+ T cell culture media were then measured. We also assessed osteoclast formation by administrating butyrate to the axSpA-derived peripheral blood mononuclear cells. The CD4+ IL-17A+ T cell differentiation, IL-17A levels were decreased, whereas IL-10 was increased by F. prausnitzii inoculation. Butyrate reduced CD4+ IL-17A+ T cell differentiation and osteoclastogenesis.DiscussionWe found that CD4+ IL-17A+ T cell polarization was reduced, when F. prausnitzii or butyrate were introduced into curdlan-induced SpA mice or CD4+ T cells of axSpA patient. Consistently, butyrate treatment was associated with the reduction of arthritis scores and inflammation levels in SpA mice. Taken together, we concluded that the reduced abundance of butyrate-producing microbes, particularly F. prausnitzii, may be associated with axSpA pathogenesis