Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization ...of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of β-thalassemia Hbb(th3/+) mice and used these antibodies as tools to further characterize ERFE's mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti–ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE–BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.
•The N terminus of ERFE binds BMP6 with nanomolar affinity and is sufficient to inhibit BMP signaling and suppress hepcidin in vivo.•Anti–N-terminal ERFE antibodies prevent EPO-induced hepcidin suppression and decrease iron accumulation and anemia in thalassemic mice.
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Highlights • Opinions on vaccine product attributes and procurement decision-making processes were collected from 158 immunization stakeholders. • Personnel at national, subnational, and ...health-facility levels in Brazil, China, India, Peru, the Philippines, and Tanzania were interviewed. • Respondents preferred single-dose over low-dose liquid vaccine without preservative. • Decreasing the time required to prepare a dose was valued more highly by those closest to the actual work of administering vaccines.
This chapter makes the case for the urgency to address the racial transfer gap that pervades the vertical transfer function involving community colleges and universities. Lessons from research on ...high‐performing transfer partnerships lay a foundation for transfer policies and practices described in other chapters in this volume of New Directions for Community Colleges (NDCC).
Recent advances in plasmonic nanopore technologies have enabled the use of concurrently acquired bimodal optical-electrical data for improved quantification of molecular interactions. This work ...presents the use of a new plasmonic nanosensor employing self-induced back-action (SIBA) for optical trapping to enable SIBA-actuated nanopore electrophoresis (SANE) for quantifying antibody-ligand interactions. T-cell receptor-like antibodies (TCRmAbs) engineered to target peptide-presenting major histocompatibility complex (pMHC) ligands, representing a model of target ligands presented on the surface of cancer cells, were used to test the SANE sensor's ability to identify specific antibody-ligand binding. Cancer-irrelevant TCRmAbs targeting the same pMHCs were also tested as a control. It was found that the sensor could provide bimodal molecular signatures that could differentiate between antibody, ligand and the complexes that they formed, as well as distinguish between specific and non-specific interactions. Furthermore, the results suggested an interesting phenomenon of increased antibody-ligand complex bound fraction detected by the SANE sensor compared to that expected for corresponding bulk solution concentrations. A possible physical mechanism and potential advantages for the sensor's ability to augment complex formation near its active sensing volume at concentrations lower than the free solution equilibrium binding constant (KD) are discussed.
Firefighters are exposed to many different contaminants during structural fires. Moreover, if their protective gear is not successfully decontaminated, firefighters are at risk of being repeatedly ...exposed to contaminants from previous fires. Thus, the successful removal of contaminants from firefighter turnout gear is necessary to prevent or reduce repeated exposure risks. Laundering methods can reduce the probability of re-exposure to contaminants, such as heavy metals, thus reducing repeated exposure risks. In this study, the efficiencies of heavy metal removal from the firefighter turnout gear outer textile by Decon7 cleaning solution and a standard reference detergent were compared. Nitric acid digests were used to extract metals from textile samples, which were cut from small sections of firefighter jackets, before and after their laundering with either cleaning solution. Inductively coupled plasma mass spectrometry (ICP-MS) was utilized to determine metal contents, including arsenic (As), antimony (Sb), cadmium (Cd), chromium (Cr), and lead (Pb) concentrations. Results from multiplicate samples indicated that, on average, Decon7 was significantly more efficient than a standard detergent in decreasing the concentrations of the five metals studied herein.
Introduction
Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic pathway that negatively regulates thrombin production during coagulation. Under haemophilic conditions, ...where the intrinsic coagulation pathway is impaired, inhibition of TFPI may improve clotting.
Aim
We investigated the ex vivo effects of a human TFPI neutralizing antibody, marstacimab (previously PF‐06741086), in coagulation assays including rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay, performed in haemophilic whole blood and plasmas. We compared the effects of marstacimab to the effects of recombinant coagulation factors and investigated the reproducibility of marstacimab in restoring haemostasis by comparing its effect in whole blood collected from the same study participants on differing days.
Methods
Citrated whole blood and plasmas obtained from haemophilia participants were supplemented ex vivo with vehicle, marstacimab, recombinant FVIII (rFVIII) or recombinant factor IX (rFIX) and analysed in ROTEM, TGA and the dPT assay using low tissue factor concentrations to trigger coagulation.
Results
Marstacimab induced pro‐coagulant responses in ROTEM parameters including reduction in clotting times and increases in angle. Similarly, participant plasmas supplemented with marstacimab exhibited improvements in TGA parameters, including reduced lag times, increased peak thrombin concentrations and reductions in dPT clotting time. Concentrations of marstacimab tested showed activity comparable to addition of rFVIII or rFIX and were reproducible.
Conclusions
These studies show the ex vivo potency of marstacimab in restoring haemostasis in whole blood and plasmas from haemophilia participants and comparability to ex vivo reconstitution with recombination coagulation factors.
Everett Community College (EvCC) made numerous changes to retain and support students enrolled in science, technology, engineering, and mathematics (STEM) education during the coronavirus pandemic. ...Drawing on insights from EvCC faculty and staff affiliated with a National Science Foundation (NSF) S-STEM scholarship grant called the "EvCC STEM Scholar" program, as well as interview data gathered from 23 EvCC students, this article reports on curricular and co-curricular changes to better meet student needs during COVID-19. Results reveal efforts EvCC faculty and staff took to keep students on track to complete the STEM pathway and how students experienced college during the peak of the pandemic. The article concludes with lessons learned and plans made by EvCC faculty and staff to improve STEM education in the future.
Patients with CKD have a high prevalence of cardiovascular disease associated with or exacerbated by inactivity. This randomized, controlled study investigated whether a renal rehabilitation exercise ...program for patients with stages 3 or 4 CKD would improve their physical function and quality of life.
In total, 119 adults with CKD stages 3 and 4 were randomized, and 107 of these patients proceeded to usual care or the renal rehabilitation exercise intervention consisting of usual care plus guided exercise two times per week for 12 weeks (24 sessions). Physical function was determined by three well established performance-based tests: 6-minute walk test, sit-to-stand test, and gait-speed test. Health-related quality of life was assessed by the RAND 36-Item Short Form Health Survey.
At baseline, no differences in self-reported level of activity, 6-minute walk test, and sit-to-stand test scores were observed between the usual care (n=48) and renal rehabilitation exercise (n=59) groups, although baseline gait-speed test score was higher in the renal rehabilitation exercise group (P<0.001). At follow-up, the renal rehabilitation exercise group but not the usual care group showed significant improvements in the 6-minute walk test (+210.4±266.0 ft 19% improvement versus -10±219.9 ft; P<0.001), the sit-to-stand test (+26.9±27% of age prediction 29% improvement versus +0.7±12.1% of age prediction; P<0.001), and the RAND-36 physical measures of role functioning (P<0.01), physical functioning (P<0.01), energy/fatigue levels (P=0.01), and general health (P=0.03) and mental measure of pain scale (P=0.04). The renal rehabilitation exercise regimen was generally well tolerated.
A 12-week/24-session renal rehabilitation exercise program improved physical capacity and quality of life in patients with CKD stages 3 and 4. Longer follow-up is needed to determine if these findings will translate into decreased mortality rates.
Objective
This research sought to bring awareness to positive communication skills and social components that may be helpful with closing the persistent academic achievement gap between White and ...Black students in junior high school and high school. In underserved Black American populations it is often believed that parents have little communication concerning the need for educational attainment; however, there is some research to explain that Black American parents participate in much communication with their children pertaining to academic well-being.
Methods
Questionnaires were distributed to 167 adolescents, ages 11–19 years old, in sixth through twelfth grades. Once data were collected, we completed moderated-mediation analyses using the bootstrapping technique in Process.
Results
We found support for self-efficacy and social skills as mediators in the relationship between parent–adolescent communication (PAC) and academic performance. However, the findings were conditional for moderators, grade level and household make up. Results for self-efficacy and social skills were mixed for junior high school and high school in the relationship between PAC and academic performance. Furthermore, single parent homes revealed low amounts of self-efficacy and social skills as expected in the moderated-mediation.
Conclusion
Implications for the study suggest more direct PAC in the Black American community surrounding self-efficacy, social skills and academic performance in order to promote academic success.
Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts ...long-term functional recovery in rodent models, motivating the present multicenter study in patients.
Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods.
Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-104-117 mmHg associated with neurological recovery.
We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention.
NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).
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