The posterior medial meniscal root (PMMR) experiences variable and multiaxial forces during loading. Current methods to measure these forces are limited and fail to adequately characterize the loads ...in all three dimensions at the root. Our novel technique resolved these limitations with the installation of a 3-axis sensing construct that we hypothesized would not affect contact mechanics, would not impart extraneous loads onto the PMMR, would accurately measure forces, and would not deflect under joint loads. Six cadaveric specimens were dissected to the joint capsule and a sagittal-plane, femoral condyle osteotomy was performed to gain access to the root. The load sensor was placed below the PMMR and was validated across four tests. The contact mechanics test demonstrated a contact area precision of 44 mm2 and a contact pressure precision of 5.0 MPa between the pre-installation and post-installation states. The tibial displacement test indicated an average bone plug displacement of < 1 mm in all directions. The load validation test exhibited average precision values of 0.7 N in compression, 0.5 N in tension, 0.3 N in anterior-posterior shear, and 0.3 N in medial–lateral shear load. The bone plug deflection test confirmed < 2 mm of displacement in any direction when placed under a load. This is the first study to successfully validate a technique for measuring both magnitude and direction of forces experienced at the PMMR. This validated method has applications for improving surgical repair techniques and developing safer rehabilitation and postoperative protocols that decrease root loads.
Evolution has shaped the development of proteins with an incredible diversity of properties. Incorporating proteins into materials is desirable for applications including biosensing; however, ...high-throughput selection techniques for screening protein libraries in materials contexts is lacking. In this work, a high-throughput platform to assess the binding affinity for ordered sensing proteins was established. A library of fusion proteins, consisting of an elastin-like polypeptide block, one of 22 variants of rcSso7d, and a coiled-coil order-directing sequence, was generated. All selected variants had high binding in films, likely due to the similarity of the assay to magnetic bead sorting used for initial selection, while solution binding was more variable. From these results, both the assembly of the fusion proteins in their operating state and the functionality of the binding protein are key factors in the biosensing performance. Thus, the integration of directed evolution with assembled systems is necessary to the design of better materials.
Although a variety of pathological changes have been described in small airways of patients with COPD, the critical anatomic features determining airflow limitation remain incompletely characterised.
...We examined lung tissue specimens from 18 non-smokers without chronic lung disease and 55 former smokers with COPD for pathological features of small airways that could contribute to airflow limitation. Morphometric evaluation was performed for epithelial and subepithelial tissue thickness, collagen and elastin content, luminal mucus and radial alveolar attachments. Immune/inflammatory cells were enumerated in airway walls. Quantitative emphysema scoring was performed on chest CT scans.
Small airways from patients with COPD showed thickening of epithelial and subepithelial tissue, mucus plugging and reduced collagen density in the airway wall (in severe COPD). In patients with COPD, we also observed a striking loss of alveolar attachments, which are connective tissue septa that insert radially into the small airway adventitia. While each of these parameters correlated with reduced airflow (FEV
), multivariable regression analysis indicated that loss of alveolar attachments was the major determinant of airflow limitation related to small airways. Neutrophilic infiltration of airway walls and collagen degradation in airway adventitia correlated with loss of alveolar attachments. In addition, quantitative analysis of CT scans identified an association between the extent of emphysema and loss of alveolar attachments.
In COPD, loss of radial alveolar attachments in small airways is the pathological feature most closely related to airflow limitation. Destruction of alveolar attachments may be mediated by neutrophilic inflammation.
In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of ...myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).
Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).
ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34
cell phenotype at baseline, including decreased
and
expression, compared with nonresponders that exhibited a more proliferative CD34
phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.
These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
Significant progress has been made in recent years toward understanding the processes by which an iron mineral is deposited within members of the ferritin family of 24mer iron storage proteins, ...enabled by high-resolution structures together with spectroscopic and kinetic studies. These suggest common characteristics that are shared between ferritins, namely, a highly symmetric arrangement of subunits that provides a protein coat around a central cavity in which the mineral is formed, channels through the coat that facilitate ingress and egress of ions, and catalytic sites, called ferroxidase centers, that drive Fe
2+
oxidation. They also reveal significant variations in both structure and mechanism amongst ferritins. Here, we describe three general types of structurally distinct ferroxidase center and the mechanisms of mineralization that they are associated with. The highlighted variation leads us to conclude that there is no universal mechanism by which ferritins function, but instead there exists several distinct mechanisms of ferritin iron mineralization.
Abstract Objectives The purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal ...function, and clinical outcomes. Background High-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation. Methods This study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity PRA and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes. Results Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, and higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median: +1.66 vs. +0.66 ng/ml/h with continuous vs. bolus infusion, respectively, p = 0.021; +4.05 vs. +0.56 ng/ml/h with UF vs. stepped care, respectively, p = 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio HR for a doubling of 1.05; 95% confidence interval CI: 0.98 to 1.13; p = 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; p = 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5). Conclusions High-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure DOSE-AHF; NCT00577135 ; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome CARRESS; NCT00608491 )
Blood flow restriction (BFR) training has been reported to have significant benefits on local skeletal muscle including increasing local muscle mass, strength, and endurance while exercising with ...lower resistance. As a result, patients unable to perform traditional resistance training may benefit from this technique. However, it is unclear what effects BFR may have on other body systems, such as the cardiovascular and pulmonary systems. It is important to explore the systemic effects of BFR training to ensure it is safe for use in physical therapy.
The purpose of this study was to systematically review the systemic effects of blood flow restriction training when combined with exercise intervention.
Systematic review.
Three literature searches were performed: June 2019, September 2019, and January 2020; using MedLine, ScienceDirect, PubMed, Cochrane Reviews and CINAHL Complete. Inclusion criteria included: at least one outcome measure addressing a cardiovascular, endocrinological, systemic or proximal musculoskeletal, or psychosocial outcome, use of clinically available blood flow restriction equipment, use of either resistance or aerobic training in combination with BFR, and use of quantitative measures. Exclusion criteria for articles included only measuring local or distal musculoskeletal changes due to BFR training, examining only passive BFR or ischemic preconditioning, articles not originating from a scholarly peer-reviewed journal, CEBM level of evidence less than two, or PEDro score less than four. Articles included in this review were analyzed with the CEBM levels of evidence hierarchy and PEDro scale.
Thirty-five articles were included in the review. PEDro scores ranged between 4 and 8, and had CEBM levels of evidence of 1 and 2. Common systems studied included cardiovascular, musculoskeletal, endocrine, and psychosocial. This review found positive or neutral effects of blood flow restriction training on cardiovascular, endocrinological, musculoskeletal, and psychosocial outcomes.
Although BFR prescription parameters and exercise interventions varied, the majority of included articles reported BFR training to produce favorable or non-detrimental effects to the cardiovascular, endocrine, and musculoskeletal systems. This review also found mixed effects on psychosocial outcomes when using BFR. Additionally, this review found no detrimental outcomes directly attributed to blood flow restriction training on the test subjects or outcomes tested. Thus, BFR training may be an effective intervention for patient populations that are unable to perform traditional exercise training with positive effects other than traditional distal muscle hypertrophy and strength and without significant drawbacks to the individual.
1b.
Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum(IV) prodrugs of cisplatin and perfluoroaryl peptide ...macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem-like cells. We investigate the pharmacokinetics of this conjugate in mice and show that the amount of platinum in the brain after treatment with the conjugate is 15-fold greater than with cisplatin after 5 h.
The iron redox cycle in ferritins is not completely understood. Bacterioferritins are distinct from other ferritins in that they contain haem groups. It is acknowledged that the two iron motifs in ...bacterioferritins, the di‐nuclear ferroxidase centre and the haem B group, play key roles in two opposing processes, iron sequestration and iron mobilisation, respectively, and the two redox processes are independent. Herein, we show that in Escherichia coli bacterioferritin, there is an electron transfer pathway from the haem to the ferroxidase centre suggesting a new role(s) haem might play in bacterioferritins.
The haem in bacterioferritins has been shown before to provide an electron to the ferritin's mineral core—to reduce Fe3+ to water soluble Fe2+. This work shows that the haem can also provide an electron, over a distance of approximately 13 Å, to the di‐iron ferroxidase centre of the protein, in a redox process not yet known.
Protein–polymer bioconjugate self-assembly has attracted a great deal of attention as a method to fabricate protein nanomaterials in solution and the solid state. To identify protein properties that ...affect phase behavior in protein–polymer block copolymers, a library of 15 unique protein-b-poly(N-isopropylacrylamide) (PNIPAM) copolymers comprising 11 different proteins was compiled and analyzed. Many attributes of phase behavior are found to be similar among all studied bioconjugates regardless of protein properties, such as formation of micellar phases at high temperature and low concentration, lamellar ordering with increasing temperature, and disordering at high concentration, but several key protein-dependent trends are also observed. In particular, hexagonal phases are only observed for proteins within the molar mass range 20–36 kDa, where ordering quality is also significantly enhanced. While ordering is generally found to improve with increasing molecular weight outside of this range, most large bioconjugates exhibited weaker than predicted assembly, which is attributed to chain entanglement with increasing polymer molecular weight. Additionally, order–disorder transition boundaries are found to be largely uncorrelated to protein size and quality of ordering. However, the primary finding is that bioconjugate ordering can be accurately predicted using only protein molecular weight and percentage of residues contained within β sheets. This model provides a basis for designing protein–PNIPAM bioconjugates that exhibit well-defined self-assembly and a modeling framework that can generalize to other bioconjugate chemistries.
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