β-Arrestins (βarrs) critically regulate G-protein-coupled receptor (GPCR) signaling and trafficking. βarrs have two isoforms, βarr1 and βarr2. Receptor phosphorylation is a key determinant for the ...binding of βarrs, and understanding the intricate details of receptor-βarr interaction is the next frontier in GPCR structural biology. The high-resolution structure of active βarr1 in complex with a phosphopeptide derived from GPCR has been revealed, but that of βarr2 remains elusive. Here, we present a 2.3-Å crystal structure of βarr2 in complex with a phosphopeptide (C7pp) derived from the carboxyl terminus of CXCR7. The structural analysis of C7pp-bound βarr2 reveals key differences from the previously determined active conformation of βarr1. One of the key differences is that C7pp-bound βarr2 shows a relatively small inter-domain rotation. Antibody-fragment-based conformational sensor and hydrogen/deuterium exchange experiments further corroborated the structural features of βarr2 and suggested that βarr2 adopts a range of inter-domain rotations.
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•The structure of β-arrestin 2 bound to CXCR7 phosphopeptide (C7pp) was solved•The C7pp-bound β-arrestin 2 shows small inter-domain rotation•The three C7pp phosphates bind with the positively charged residues on β-arrestin 2•The phosphate-binding pocket around Arg148 recognizes the first phosphate of C7pp
β-arrestins (βarrs) critically regulate GPCR signaling and trafficking. Min et al. present a 2.3-Å crystal structure of βarr2 in complex with a phosphopeptide (C7pp) derived from the carboxyl terminus of CXCR7, revealing that C7pp-bound βarr2 shows a relatively small inter-domain rotation compared with V2Rpp-bound βarr1.
Assembly of the peptidoglycan is crucial in maintaining viability of bacteria and in defining bacterial cell shapes, both of which are important for existence in the ecological niche that the ...organism occupies. Here, eight crystal structures for a member of the cell-shape-determining class of Campylobacter jejuni, the peptidoglycan peptidase 3 (Pgp3), are reported. Characterization of the turnover chemistry of Pgp3 reveals cell wall D,D-endopeptidase and D,D-carboxypeptidase activities. Catalysis is accompanied by large conformational changes upon peptidoglycan binding, whereby a loop regulates access to the active site. Furthermore, prior hydrolysis of the crosslinked peptide stem from the saccharide backbone of the peptidoglycan on one side is a pre-requisite for its recognition and turnover by Pgp3. These analyses reveal the noncanonical nature of the transformations at the core of the events that define the morphological shape for C. jejuni as an intestinal pathogen.
MicroRNAs (miRNA) are single-stranded short RNA molecules that regulate gene expression by either degradation or translational repression of mRNA. Although miRNAs control a number of conditions and ...diseases, few neuroprotective miRNAs have been described. In this study, we investigated neuroprotective miRNAs induced early in ischemic preconditioning.
Ischemic preconditioning or focal cerebral ischemia was induced in mice by transient occlusion of the middle cerebral artery for 15 or 120 minutes. We prepared RNA samples from the ischemic cortex at 3 or 24 hours after the onset of ischemia. Selective miRNAs then were synthesized and transfected into Neuro-2a cells before oxygen-glucose deprivation.
We detected a total of 360 miRNAs. Two miRNA families, miR-200 and miR-182, were selectively upregulated at 3 hours after ischemic preconditioning. Transfections of some of these were neuroprotective in in vitro ischemia. Among them, miR-200b, miR-200c, and miR-429 targeted prolyl hydroxylase 2 and had the best neuroprotective effect.
Two miRNA families, miR-200 and miR-182, were upregulated early after ischemic preconditioning and the miR-200 family was neuroprotective mainly by downregulating prolyl hydroxylase 2 levels. These miRNAs may be useful in future research and therapeutic applications.
Abstract
We tested the feasibility of pulmonary vein (PV) and left atrial (LA) posterior wall isolation using non-invasive stereotactic ablative body radiotherapy (SABR) and investigated pathological ...changes in irradiated lesions in a canine model. Seven male Mongrel dogs received single-fraction 33 Gy SABR. We designed the en-bloc circular target of total PVs and LA posterior wall to avoid the esophagus. The circular box lesion included the LA roof and ridge, low posterior wall, and posterior interatrial septum. At 6 weeks or 4 months post-SABR, electrical isolation of the SABR lesion was confirmed using LA posterior wall pacing, and histopathological review was performed. Electrical isolation of all PVs and the LA posterior wall was achieved in three of five dogs in the 4-month group. There was one target failure and one sudden death at 15 weeks. Although two dogs in the 6-week group failed to achieve electrical lesion isolation, the irradiated atrial myocardium showed diffuse hemorrhage with inflammatory cell infiltration. In successfully isolated 4-month model dogs, we observed transmural fibrotic scarring with extensive fibrosis on irradiated atrial tissue. The findings suggest that this novel circular box-design radiotherapy technique using SABR could be applied to humans after further studies are conducted to confirm safety.
The relationship among chronic fatigue, depressive symptoms, and post-traumatic stress symptoms (PTSSs) among Middle East respiratory syndrome (MERS) survivors is poorly understood.
Of 148 survivors ...who consented to be registered and underwent assessments at 12 months (T1) and 18 months (T2) after the MERS outbreak, 72 (48.65%) were evaluated for chronic fatigue, depressive symptoms, and PTSSs based on the Impact of Event ScaleRevised (IES-R), the Patient Health Questionnaire-9 (PHQ-9), and the Fatigue Severity Scale (FSS). Data from 52 subjects, who completed both assessments, were analyzed using a regression-based serial multiple mediation model (PROCESS Model 6).
Bootstrap analyses indicated no direct effects of T1 FSS on T2 IES-R but significant positive indirect effects of T1 FSS on T2 IESR through T1 PHQ-9 and T2 PHQ-9 (B=2.1601, SE=1.3268, 95% confidence interval=0.4250-6.1307). In other words, both T1 PHQ-9 and T2 PHQ-9 fully mediated the relationship between T1 FSS and T2 IES.
Chronic fatigue 12 months after MERS had indirect effects on prolonged PTSSs 18 months after MERS via persisting depression in MERS survivors. This finding supports the need to promote interventional programs for emerging infectious disease survivors with chronic fatigue to reduce depression and prevent prolonged PTSSs.
Physicians and nurses working in acute care settings, such as tertiary hospitals, are involved in various stages of critical and terminal care, ranging from diagnosis of life-threatening diseases to ...care for the dying. It is well known that critical and terminal care causes moral distress to healthcare professionals. This study aimed to explore moral distress in critical and terminal care in acute hospital settings by analyzing the experiences of physicians and nurses from various departments. Semi-structured in-depth interviews were conducted in two tertiary hospitals in South Korea. The collected data were analyzed using grounded theory. A total of 22 physicians and nurses who had experienced moral difficulties regarding critical and terminal care were recruited via purposive maximum variation sampling, and 21 reported moral distress. The following points were what participants believed to be right for the patients: minimizing meaningless interventions during the terminal stage, letting patients know of their poor prognosis, saving lives, offering palliative care, and providing care with compassion. However, family dominance, hierarchy, the clinical culture of avoiding the discussion of death, lack of support for the surviving patients, and intensive workload challenged what the participants were pursuing and frustrated them. As a result, the participants experienced stress, lack of enthusiasm, guilt, depression, and skepticism. This study revealed that healthcare professionals working in tertiary hospitals in South Korea experienced moral distress when taking care of critically and terminally ill patients, in similar ways to the medical staff working in other settings. On the other hand, the present study uniquely identified that the aspects of saving lives and the necessity of palliative care were reported as those valued by healthcare professionals. This study contributes to the literature by adding data collected from two tertiary hospitals in South Korea.
Alopecia induced by aging or side effects of medications affects millions of people worldwide and impairs the quality of life; however, there is a limit to the current medications. Here, we identify ...a small transdermally deliverable 5‐mer peptide (GLYYF; P5) that activates adiponectin receptor 1 (AdipoR1) and promotes hair growth. P5 sufficiently reproduces the biological effect of adiponectin protein via AMPK signaling pathway, increasing the expression of hair growth factors in the dermal papilla cells of human hair follicle. P5 accelerates hair growth ex vivo and induces anagen hair cycle in mice in vivo. Furthermore, we elucidate a key spot for the binding between AdipoR1 and adiponectin protein using docking simulation and mutagenesis studies. This study suggests that P5 could be used as a topical peptide drug for alleviating pathological conditions, which can be improved by adiponectin protein, such as alopecia.
SYNOPSIS
This study presents an adiponectin‐derived, transdermally deliverable pentapeptide (GLYYF) that promotes hair growth by activating AdipoR1.
We discovered a small transdermally deliverable 5‐mer peptide (GLYYF: P5) that activates AdipoR1.
P5 promotes hair growth by activating AdipoR1 and could be potentially used as a topically applicable molecule for treatment of alopecia patients.
Furthermore, we identified a position and essential amino acid residues on AdipoR1 involved in binding of adiponectin protein.
This study presents an adiponectin‐derived, transdermally deliverable pentapeptide (GLYYF) that promotes hair growth by activating AdipoR1.
Oral lichen planus (OLP) is a chronic T cell-mediated mucocutaneous disease of unknown etiopathogenesis. Although various antigens have been considered, what actually triggers the inflammatory ...response of T cells is unknown. In the present study, we propose that intracellular bacteria present within tissues trigger T cell infiltration and provide target antigens. Sections of OLP (n = 36) and normal (n = 10) oral mucosal tissues were subjected to in situ hybridization using a universal probe targeting the bacterial 16S rRNA gene and immunohistochemistry with anti-CD3, anti-CD4, anti-CD8, and anti-macrophage-specific antibodies. Bacteria were abundant throughout the epithelium and the lamina propria of OLP tissues, which exhibited positive correlations with the levels of infiltrated CD3(+), CD4(+), and CD8(+) cells. Furthermore, bacteria were detected within the infiltrated T cells. Pyrosequencing analysis of the mucosal microbiota from OLP patients (n = 13) and control subjects (n = 11) revealed a decrease in Streptococcus and increases in gingivitis/periodontitis-associated bacteria in OLP lesions. Using the selected bacterial species, we demonstrated that certain oral bacteria damage the epithelial physical barrier, are internalized into epithelial cells or T cells, and induce production of T cell chemokines CXCL10 and CCL5. Our findings provide insights into the pathogenesis of OLP.
Introduction
Neuroendocrine tumors have malignant potential, and lymph node metastasis can occur. This study aimed to identify predictive factors of lymph node metastasis and prognostic factors for ...survival in rectal neuroendocrine tumors.
Methods
Sixty-four patients underwent endoscopic or surgical treatment for rectal NET. The data on these patients were collected in our database prospectively and reviewed retrospectively.
Results
Transanal excision was performed in 28 (43.8%) patients, endoscopic mucosal resection or submucosal dissection was performed in 15 (23.4%) patients, and radical resection was performed in 21 (31.8%) patients. Lymph node and distant metastasis was present in 16 (25.0%) and fir (7.8%) patients. The significant risk factors for lymph node metastasis identified in the multivariable analyses were tumor size (≥ 2 cm,
p
= 0.003) and tumor grade (G2,
p
< 0.001; G3,
p
= 0.008). In patients with a tumor smaller than 2 cm, the risk factors for lymph node metastasis included the tumor grade, mitosis count, and Ki-67 index. The median follow-up period was 30.0 months, and recurrence developed in four (6.8%) patients. The significant prognostic factors for survival included tumor size, T stage, lymph node metastasis, and tumor grade.
Conclusion
Tumor grade combined with tumor size is an important predictive factor for lymph node metastasis and could serve as a prognostic factor for survival outcomes.
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•Patients with NAFLD had alterations in cardiac remodeling.•Hepatic steatosis and fibrosis are associated with diastolic heart dysfunction.•Those without NAFLD were more likely to ...have higher myocardial glucose uptake.•Hepatic fibrosis was correlated with decreased myocardial glucose uptake.
Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk. Among categories of NAFLD, hepatic fibrosis is most likely to affect mortality. Myocardial function and its energy metabolism are tightly linked, which might be altered by an insulin resistant condition such as NAFLD. We investigated whether hepatic steatosis and fibrosis were associated with myocardial dysfunction relative to myocardial glucose uptake.
A total of 308 patients (190 without NAFLD, 118 with NAFLD) were studied in a tertiary care hospital. Myocardial glucose uptake was evaluated at fasted state using 18F-fluorodeoxyglucose-positron emission tomography (18FDG-PET). Hepatic steatosis and fibrosis were assessed by transient liver elastography (Fibroscan®) with controlled attenuation parameter, which quantifies hepatic fat and by surrogate indices (fatty liver index and NAFLD fibrosis score). Cardiac structure and function were examined by echocardiogram.
Compared to those without NAFLD, patients with NAFLD had alterations in cardiac remodeling, manifested by increased left ventricular mass index, left ventricular end-diastolic diameter, and left atrial volume index (all p <0.05). Hepatic steatosis was significantly associated with left ventricular filling pressure (E/e’ ratio), which reflects diastolic dysfunction (p for trend <0.05). Those without NAFLD were more likely to have higher myocardial glucose uptake compared to those with NAFLD. Significant hepatic fibrosis was also correlated with diastolic dysfunction and impaired myocardial glucose uptake. Using multivariable linear regression, E/e’ ratio was independently associated with hepatic fibrosis (standardized β = 0.12 to 0.27; all p <0.05). Association between hepatic steatosis and E/e’ ratio was also significant (standardized β = 0.10 to 0.15; all p <0.05 excluding the model adjusted for adiposity).
Hepatic steatosis and fibrosis are significantly associated with diastolic heart dysfunction. This association is linked with myocardial glucose uptake evaluated by 18FDG-PET.
Non-alcoholic fatty liver disease is associated with an increased risk of cardiovascular disease. More severe forms of non-alcoholic fatty liver disease, where hepatic fibrosis occurs, are linked to increased mortality. In this study, we have shown that hepatic steatosis and fibrosis are associated with subclinical myocardial dysfunction. This association is linked to altered myocardial glucose uptake.
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