The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-ß1-induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.

Milton assembles large mitochondrial clusters, mitoballs, to sustain spermatogenesis.

Mitochondria are dynamic organelles that undergo frequent remodeling to accommodate developmental needs. Here, we describe a striking organization of mitochondria into a large ball-like structure adjacent to the nucleus in premeiotic Drosophila melanogaster spermatocytes, which we term "mitoball". Mitoballs are transient structures that colocalize with the endoplasmic reticulum, Golgi bodies, and the fusome. We observed similar premeiotic mitochondrial clusters in a wide range of insect species, including mosquitos and cockroaches. Through a genetic screen, we identified that Milton, an adaptor protein that links mitochondria to microtubule-based motors, mediates mitoball formation. Flies lacking a 54 amino acid region in the C terminus of Milton completely lacked mitoballs, had swollen mitochondria in their spermatocytes, and showed reduced male fertility. We suggest that the premeiotic mitochondrial clustering is a conserved feature of insect spermatogenesis that supports sperm development.

Effects of varying blood flow rate during peripheral veno-arterial extracorporeal membrane oxygen (V-A ECMO) on left ventricular function measured by two-dimensional strain.

Background: We evaluated the effects of varying blood flow rate during peripheral veno-arterial extracorporeal membrane oxygen (V-A ECMO) on left ventricular function measured by two-dimensional strain. Methods: Adult patients who were supported by peripheral V-A ECMO were recruited. Serial hemodynamic and cardiac performance parameters were measured by transthoracic echocardiogram within the first 48 h after implementation of V-A ECMO. Measurements at 100%, 120%, and 50% of target blood flow (TBF) were compared. Results: A total of 54 patients were included and the main indications for V-A ECMO were myocardial infarction [32 (59.3%)] and myocarditis [6 (11.1%)]. With extracorporeal blood flow at 50% compared with 100% TBF, the mean arterial pressure was lower [66 ± 19 vs. 75 ± 18 mmHg, p < 0.001], stroke volume was greater [23 (12-34) vs. 15 (8-26) ml, p < 0.001], and cardiac index was higher [1.2 (0.7-1.7) vs. 0.8 (0.5-1.3) L/min/m2, p < 0.001]. Left ventricular contractile function measured by global longitudinal strain improved at 50% compared with 100% TBF [-2.8 (-7.6- -0.1) vs. -1.2 (-5.2-0) %, p < 0.001]. Similarly, left ventricular ejection fraction increased [24.4 (15.8-35.5) vs. 16.7 (10.0-28.5) %, p < 0.001] and left ventricular outflow tract velocity time integral increased [7.7 (3.8-11.4) vs. 4.8 (2.5-8.5) cm, p < 0.001]. Adding echocardiographic parameters of left ventricular systolic function to the Survival After Veno-arterial ECMO (SAVE) score had better discriminatory value in predicting eventual hospital mortality (AUROC 0.69, 95% CI 0.55-0.84, p = 0.008) and successful weaning from V-A ECMO (AUROC 0.68, 95% CI 0.53-0.83, p = 0.017). Conclusion: In the initial period of V-A ECMO support, measures of left ventricular function including left ventricular ejection fraction and global longitudinal strain were inversely related to ECMO blood flow rate. Understanding the heart-ECMO interaction is vital to interpretation of echocardiographic measures of the left ventricle while on ECMO.

Mitochondrial micropeptide MOXI promotes fibrotic gene transcription by translocation to the nucleus and bridging N-acetyltransferase 14 with transcription factor c-Jun.

Progressive fibrosis is a hallmark of chronic kidney disease, but we lack effective treatments to halt this destructive process. Micropeptides (peptides of no more than 100 amino acids) encoded by small open reading frames represent a new class of eukaryotic regulators. Here, we describe that the micropeptide regulator of ß-oxidation (MOXI) regulates kidney fibrosis. MOXI expression was found to be up-regulated in human fibrotic kidney disease, and this correlated with the degree of fibrosis and loss of kidney function. MOXI was expressed in the cytoplasm and mitochondria of cultured tubular epithelial cells and translocated to the nucleus upon Transforming Growth Factor-ß1 stimulation. Deletion of Moxi protected mice against fibrosis and inflammation in the folic acid and unilateral ureteral obstruction models. As a potential molecular therapy, treatment with an antisense MOXI oligonucleotide effectively knocked-down MOXI expression and protected against kidney fibrosis in both models. Bimolecular fluorescence complementation identified the enzyme N-acetyltransferase 14 (Nat14) and transcription factor c-Jun as MOXI binding partners. The MOXI/Nat14/c-Jun complex enhances basal and Transforming Growth Factor-ß1 induced collagen I gene promoter activity. Phosphorylation at T49 is required for MOXI nuclear localization and for complex formation with Nat14 and c-Jun. Furthermore, mice with a MoxiT49A point mutation were protected in the models of kidney fibrosis. Thus, our studies demonstrate a key role for the micropeptide MOXI in kidney fibrosis and identify a new function of MOXI in forming a transcriptional complex with Nat14 and c-Jun.

Advancing workforce diversity by leveraging the Clinical and Translational Science Awards (CTSA) program.

Clinical trials continue to disproportionately underrepresent people of color. Increasing representation of diverse backgrounds among clinical research personnel has the potential to yield greater representation in clinical trials and more efficacious medical interventions by addressing medical mistrust. In 2019, North Carolina Central University (NCCU), a Historically Black College and University with a more than 80% underrepresented student population, established the Clinical Research Sciences Program with support from the Clinical and Translational Science Awards (CTSA) program at neighboring Duke University. This program was designed to increase exposure of students from diverse educational, racial, and ethnic backgrounds to the field of clinical research, with a special focus on health equity education. In the first year, the program graduated 11 students from the two-semester certificate program, eight of whom now hold positions as clinical research professionals. This article describes how leveraging the CTSA program helped NCCU build a framework for producing a highly trained, competent, and diverse workforce in clinical research responsive to the call for increased diversity in clinical trial participation.

Predictors of Favorable Neurologic Outcomes in a Territory-First Extracorporeal Cardiopulmonary Resuscitation Program.

Extracorporeal cardiopulmonary resuscitation (ECPR) is an advanced resuscitation method that has been associated with better outcomes after cardiac arrest compared with conventional cardiopulmonary resuscitation. This is a retrospective analysis of all patients who received ECPR for cardiac arrest in Hong Kong's first ECPR program from 2012 to 2020. The primary outcome was favorable neurologic outcome at 3 months. A new risk prediction model was developed and its performance was compared with published risk scores. One-hundred two patients received ECPR and 19 (18.6%) patients survived with favorable neurologic outcome. Having a shockable rhythm was the strongest predictor of favorable neurologic outcome in multivariate analysis (odds ratio, 9.64; 95% confidence interval [CI], 1.49 to 62.30; P = 0.017). We developed a simple model with three parameters for the prediction of favorable neurologic outcomes - presence of shockable rhythm, mean arterial pressure after extracorporeal membrane oxygenation, and the Acute Physiology And Chronic Health Evaluation IV score, with an area under receiver operating characteristic curve of 0.85 (95% CI, 0.77 to 0.94). In Hong Kong's first ECPR program, 18.6% patients survived with favorable neurologic outcomes, and having a shockable rhythm at presentation was the strongest predictor. Risk scores are useful in predicting important patient outcomes and should be included in clinical decision-making for patients who received ECPR.

Mitochondrial heteroplasmy beyond the oocyte bottleneck.

Inheritance of the mitochondrial genome does not follow the rules of conventional Mendelian genetics. The mitochondrial DNA (mtDNA) is present in many copies per cell and is inherited through the maternal germline. In addition, mutations in the mtDNA will give rise to heteroplasmy, the coexistence of different mtDNA variants within a single cell, whose levels can vary considerably between cells, organs or organisms. The inheritance and subsequent accumulation of deleterious variants are the cause of severe progressive mitochondrial disorders and play a role in many other conditions, including aging, cancer and neurodegenerative disorders. Here, we discuss the processes that give rise to cell-to-cell variability in mtDNA composition, focussing on somatic mtDNA segregation and on less conventional sources of heteroplasmy: non-maternal inheritance and mtDNA recombination. Understanding how mtDNA variants and mutations emerge and evolve within an organism is of crucial importance to prevent and cure mitochondrial disease and can potentially impact more common aging-associated conditions.

A Comparative Study of the Diagnostic Potential of Plasma and Erythrocytic α-Synuclein in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by intracellular α-synuclein (α-Syn) deposition. Alternation of the α-Syn expression level in plasma or erythrocytes may be used as a potential PD biomarker. However, no studies have compared their prognostic value directly with the same cohort. METHODS: The levels of α-Syn in plasma and erythrocytes, obtained from 45 PD patients and 45 control subjects, were measured with enzyme-linked immunosorbent assay. Then, correlation and receiver operating characteristic curve (ROC) analysis were performed to characterize the predictive power of erythrocytic and plasma α-Syn. RESULTS: Our results showed that α-Syn expression levels in both plasma and erythrocytes were significantly higher in PD patients than in control subjects (823.14 ± 257.79 vs. 297.10 ± 192.82 pg/mL, p < 0.0001 in plasma; 3,104.14 ± 143.03 vs. 2,944.82 ± 200.41 pg/mL, p < 0.001 in erythrocytes, respectively). The results of the ROC analysis suggested that plasma α-Syn exhibited better predictive power than erythrocytic α-Syn with a sensitivity of 80.0%, specificity of 97.7%, and a positive predictive value of 77.8%. The expression level of plasma α-Syn correlated well with the age of patients, H-Y stage, MoCA scale, and UPDRS motor scale. On the contrary, there was no correlation between erythrocytic α-Syn level and clinical parameters in this study. CONCLUSION: Our results suggest that plasma α-Syn could be a specific and sensitive potential diagnostic biomarker for PD.

Bi2Se3/C Nanocomposite as a New Sodium-Ion Battery Anode Material.

Bi2Se3 was studied as a novel sodium-ion battery anode material because of its high theoretical capacity and high intrinsic conductivity. Integrated with carbon, Bi2Se3/C composite shows excellent cyclic performance and rate capability. For instance, the Bi2Se3/C anode delivers an initial capacity of 527 mAh g-1 at 0.1 A g-1 and maintains 89% of this capacity over 100 cycles. The phase change and sodium storage mechanism are also carefully investigated.

Development and validation of a training module on the use of acetic acid for the detection of Barrett's neoplasia.

Background and study aims Acetic acid chromoendoscopy (AAC) enhances the ability to correctly identify Barrett's neoplasia, and is increasingly used by both expert and nonexpert endoscopists. Despite its increasing use, there is no validated training strategy to achieve competence. The aims of our study were to develop a validated training tool in AAC-assisted lesion recognition, to assess endoscopists' baseline knowledge of AAC-assisted lesion recognition, and to evaluate the efficacy and impact of this training tool. Methods A validated assessment of 40 images and 20 videos was developed. A total of 13 endoscopists with experience of Barrett's endoscopy but no formal training in AAC were recruited to the study. Participants underwent: baseline assessment 1, online training, assessment 2, interactive seminar, assessment 3. Results Baseline assessment demonstrated a sensitivity of 83 % and a negative predictive value (NPV) of 83 %. The online training intervention significantly improved sensitivity to 95 % and NPV to 94 % (P < 0.01). Further improvement was seen after a 1-day interactive seminar including live cases, with sensitivity increasing to 98 % and NPV to 97 %. Conclusions The data demonstrate the need for training in AAC-assisted lesion recognition as baseline performance, even by Barrett's experts, was poor. The online training and testing tool for AAC for Barrett's neoplasia was successfully developed and validated. The training intervention improved performance of endoscopists to meet ASGE PIVI standards. The training tool increases the endoscopist's degree of confidence in the use of AAC. The training tool also leads to shift in attitudes of endoscopists from Seattle protocol towards AAC-guided biopsy protocol for Barrett's surveillance.

Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials.

This article highlights the role of prucalopride in the management of chronic constipation based upon the principles of meta-analysis using data reported in the published randomized, controlled trials. Sixteen randomized, controlled trials on 3943 patients reported the effectiveness of prucalopride in patients with chronic constipation. Prucalopride successfully increased the frequency of spontaneous bowel movements per week in all variable doses of 1 mg (standardized mean difference [SMD], 0.42 [95% CI, 0.18-0.66; P = 0.006]), 2 mg (SMD, 0.34 [95% CI, 0.11-0.56; P = 0.003]), and 4 mg (SMD, 0.33 [95% CI, 0.22-0.44; P = 0.00001]). The risks of adverse events or side effects such as headache, abdominal cramps, excessive flatulence, dizziness, diarrhea, and rash were higher (odds ratio, 1.70 [95% CI, 1.27 to -2.27; P = 0.0004]) in prucalopride group. Prucalopride is clinically a beneficial pharmacotherapy for chronic constipation and its routine use may be considered in patients with chronic simple laxative-resistant constipation.

Cerebrovascular events in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents.

BACKGROUND AND AIMS: Cerebrovascular accidents [CVA] have rarely been reported in inflammatory bowel disease [IBD] patients treated with anti-tumour necrosis alpha [anti-TNF alpha] agents. Our aim here was to describe the clinical course of CVA in these patients. METHODS: This was a European Crohn's and Colitis Organisation [ECCO] retrospective observational study, performed as part of the CONFER [COllaborative Network For Exceptionally Rare case reports] project. A call to all ECCO members was made to report on IBD patients afflicted with CVA during treatment with anti-TNF alpha agents. Clinical data were recorded in a standardised case report form and analysed for event association with anti-TNF alpha treatment. RESULTS: A total of 19 patients were identified from 16 centres: 14 had Crohn's disease, four ulcerative colitis and one IBD colitis unclassified [median age at diagnosis: 38.0 years, range: 18.6-62.5]. Patients received anti-TNF alpha for a median duration of 11.8 months [range: 0-62] at CVA onset; seven had previously been treated with at least one other anti-TNF alpha agent. Complete neurological recovery was observed in 16 patients. Anti-TNF alpha was discontinued in 16/19 patients. However, recurrent CVA or neurological deterioration was not observed in any of the 11 patients who received anti-TNF alpha after CVA [eight resumed after temporary cessation, three continued without interruption] for a median follow-up of 39.8 months [range: 5.6-98.2]. CONCLUSION: These preliminary findings do not unequivocally indicate a causal role of anti-TNF alpha in CVA complicating IBD. Resuming or continuing anti-TNF alpha in IBD patients with CVA may be feasible and safe in selected cases, but careful weighing of IBD activity versus neurological status is prudent.

Perturbative approach to Markovian open quantum systems.

The exact treatment of Markovian open quantum systems, when based on numerical diagonalization of the Liouville super-operator or averaging over quantum trajectories, is severely limited by Hilbert space size. Perturbation theory, standard in the investigation of closed quantum systems, has remained much less developed for open quantum systems where a direct application to the Lindblad master equation is desirable. We present such a perturbative treatment which will be useful for an analytical understanding of open quantum systems and for numerical calculation of system observables which would otherwise be impractical.

Light yield measurement method for milled nanosize inorganic crystals.

Composite scintillators consisting of nanosize inorganic crystals embedded in an organic matrix have been actively pursued in recent years. One method of producing nanosize crystals is through wet milling; however, since milling is known to introduce defects, the light yield of the milled crystals must be characterized. In this work, a new method of characterizing the light yield of milled inorganic crystals will be explored and discussed; this method will take into account explicitly the concentration of the inorganic crystals and the difference in stopping power between the crystals and the solvent.

3D morphology of the human hepatic ferritin mineral core: new evidence for a subunit structure revealed by single particle analysis of HAADF-STEM images.

Ferritin, the major iron storage protein, has dual functions; it sequesters redox activity of intracellular iron and facilitates iron turn-over. Here we present high angle annular dark field (HAADF) images from individual hepatic ferritin cores within tissue sections, these images were obtained using spherical aberration corrected scanning transmission electron microscopy (STEM) under controlled electron fluence. HAADF images of the cores suggest a cubic morphology and a polycrystalline (ferrihydrite) subunit structure that is not evident in equivalent bright field images. By calibrating contrast levels in the HAADF images using quantitative electron energy loss spectroscopy, we have estimated the absolute iron content in any one core, and produced a three dimensional reconstruction of the average core morphology. The core is composed of up to eight subunits, consistent with the eight channels in the protein shell that deliver iron to the central cavity. We find no evidence of a crystallographic orientation relationship between core subunits. Our results confirm that the ferritin protein shell acts as a template for core morphology and within the core, small (approximately 2 nm), surface-disordered ferrihydrite subunits connect to leave a low density centre and a high surface area that would allow rapid turn-over of iron in biological systems.

The superior mesenteric artery syndrome; an unusual cause of vomiting.

A 29-year-old female presented with anorexia, vomiting and weight loss. A diagnosis of superior mesenteric artery syndrome was made based upon contrast duodenography and then at laparotomy when the patient was successfully treated with a duodenojejunostomy. Superior mesenteric artery syndrome is a rare cause of vomiting not detectable by endoscopy, but is eminently amenable to treatment.

Duodenal ascorbate and ferric reductase in human iron deficiency.

BACKGROUND: The first step in iron absorption requires the reduction of ferric iron to ferrous iron, a change that is catalyzed by duodenal ferric reductase. Iron deficiency is associated with high iron absorption, high ferric reductase activity, and high duodenal ascorbate concentrations in experimental animals, but it is not known whether a relation between reductase and ascorbate is evident in humans. OBJECTIVE: The objective of the study was to assess the relation between ferric reductase activity in human duodenal biopsy specimens and ascorbate concentrations in iron-replete and iron-deficient subjects. DESIGN: Patients and control subjects were overnight-fasted adults presenting sequentially for upper gastrointestinal endoscopic investigation. Ferric reductase activity in duodenal biopsy specimens was assayed by using nitroblue tetrazolium. Ascorbate was assayed in duodenal biopsy specimens and plasma. RESULTS: Iron-deficient patients had significantly higher reductase activity (n = 6-9; P < 0.05) and duodenal (n = 20; P < 0.001) and plasma (n = 6; P < 0.001) ascorbate concentrations than did control subjects. Incubation of biopsy specimens with dehydroascorbate (to boost cellular ascorbate) increased reductase activity in the tissues that initially had normal activity (n = 9; P < 0.01) but inhibited reductase activity in the tissues that already had high reductase activity (n = 13; P < 0.001). CONCLUSIONS: Iron deficiency in humans is associated with increased duodenal ascorbate concentrations. This finding suggests that increased reductase activity is partly due to an increase in this substrate for duodenal cytochrome b reductase 1.

Neoplasia of the tongue in a patient with Crohn's disease treated with azathioprine: case report.

Azathioprine is now widely used for the maintenance treatment of Crohn's disease, but there are concerns whether azathioprine could predispose to malignancy in patients with inflammatory bowel disease. We report here a case of a 39-year-old non-smoking male with Crohn's disease who had been treated for 3 years with azathioprine and developed a lingual ulcer. Biopsy revealed squamous cell carcinoma, a tumour not previously associated with Crohn's disease.