Identification of Transcriptional and Receptor Networks That Control Root Responses to Ethylene.

Transcriptomic analyses with high temporal resolution provide substantial new insight into hormonal response networks. This study identified the kinetics of genome-wide transcript abundance changes in response to elevated levels of the plant hormone ethylene in roots from light-grown Arabidopsis (Arabidopsis thaliana) seedlings, which were overlaid on time-matched developmental changes. Functional annotation of clusters of transcripts with similar temporal patterns revealed rapidly induced clusters with known ethylene function and more slowly regulated clusters with novel predicted functions linked to root development. In contrast to studies with dark-grown seedlings, where the canonical ethylene response transcription factor, EIN3, is central to ethylene-mediated development, the roots of ein3 and eil1 single and double mutants still respond to ethylene in light-grown seedlings. Additionally, a subset of these clusters of ethylene-responsive transcripts were enriched in targets of EIN3 and ERFs. These results are consistent with EIN3-independent developmental and transcriptional changes in light-grown roots. Examination of single and multiple gain-of-function and loss-of-function receptor mutants revealed that, of the five ethylene receptors, ETR1 controls lateral root and root hair initiation and elongation and the synthesis of other receptors. These results provide new insight into the transcriptional and developmental responses to ethylene in light-grown seedlings.

Transcriptional and Hormonal Regulation of Gravitropism of Woody Stems in Populus.

Angiosperm trees reorient their woody stems by asymmetrically producing a specialized xylem tissue, tension wood, which exerts a strong contractile force resulting in negative gravitropism of the stem. Here, we show, in Populus trees, that initial gravity perception and response occurs in specialized cells through sedimentation of starch-filled amyloplasts and relocalization of the auxin transport protein, PIN3. Gibberellic acid treatment stimulates the rate of tension wood formation and gravibending and enhances tissue-specific expression of an auxin-responsive reporter. Gravibending, maturation of contractile fibers, and gibberellic acid (GA) stimulation of tension wood formation are all sensitive to transcript levels of the Class I KNOX homeodomain transcription factor-encoding gene ARBORKNOX2 (ARK2). We generated genome-wide transcriptomes for trees in which gene expression was perturbed by gravistimulation, GA treatment, and modulation of ARK2 expression. These data were employed in computational analyses to model the transcriptional networks underlying wood formation, including identification and dissection of gene coexpression modules associated with wood phenotypes, GA response, and ARK2 binding to genes within modules. We propose a model for gravitropism in the woody stem in which the peripheral location of PIN3-expressing cells relative to the cambium results in auxin transport toward the cambium in the top of the stem, triggering tension wood formation, while transport away from the cambium in the bottom of the stem triggers opposite wood formation.

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo.

Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remains elusive, macrophages are a natural target for new interventions because they are recruited to lipid-rich lesions, actively internalize modified lipids, and convert to foam cells with diseased phenotypes. In this work, we present a nanomedicine platform to counteract plaque development based on two building blocks: first, at the single macrophage level, sugar-based amphiphilic macromolecules (AMs) were designed to competitively block oxidized lipid uptake via scavenger receptors on macrophages; second, for sustained lesion-level intervention, AMs were fabricated into serum-stable core/shell nanoparticles (NPs) to rapidly associate with plaques and inhibit disease progression in vivo. An AM library was designed and fabricated into NP compositions that showed high binding and down-regulation of both MSR1 and CD36 scavenger receptors, yielding minimal accumulation of oxidized lipids. When intravenously administered to a mouse model of cardiovascular disease, these AM NPs showed a pronounced increase in lesion association compared with the control nanoparticles, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. Thus, synthetic macromolecules configured as NPs are not only effectively mobilized to lipid-rich lesions but can also be deployed to counteract atheroinflammatory vascular diseases, highlighting the promise of nanomedicines for hyperlipidemic and metabolic syndromes.

Physiology and pathophysiology of excitation-contraction coupling: the functional role of ryanodine receptor.

Calcium (Ca2+) release from intracellular stores plays a key role in the regulation of skeletal muscle contraction. The type 1 ryanodine receptors (RyR1) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) of myocytes in skeletal muscle and is required for excitation-contraction (E-C) coupling. This article explores the role of RyR1 in skeletal muscle physiology and pathophysiology.

A kinetic analysis of the auxin transcriptome reveals cell wall remodeling proteins that modulate lateral root development in Arabidopsis.

To identify gene products that participate in auxin-dependent lateral root formation, a high temporal resolution, genome-wide transcript abundance analysis was performed with auxin-treated Arabidopsis thaliana roots. Data analysis identified 1246 transcripts that were consistently regulated by indole-3-acetic acid (IAA), partitioning into 60 clusters with distinct response kinetics. We identified rapidly induced clusters containing auxin-response functional annotations and clusters exhibiting delayed induction linked to cell division temporally correlated with lateral root induction. Several clusters were enriched with genes encoding proteins involved in cell wall modification, opening the possibility for understanding mechanistic details of cell structural changes that result in root formation following auxin treatment. Mutants with insertions in 72 genes annotated with a cell wall remodeling function were examined for alterations in IAA-regulated root growth and development. This reverse-genetic screen yielded eight mutants with root phenotypes. Detailed characterization of seedlings with mutations in cellulase3/glycosylhydrolase9b3 and leucine rich extensin2, genes not normally linked to auxin response, revealed defects in the early and late stages of lateral root development, respectively. The genes identified here using kinetic insight into expression changes lay the foundation for mechanistic understanding of auxin-mediated cell wall remodeling as an essential feature of lateral root development.

Complications With the Use of BMP-2 in Scaphoid Nonunion Surgery.

PURPOSE: In an effort to improve fracture healing and decrease the need for autologous bone graft, products such as recombinant human bone morphogenetic protein (rhBMP-2) have been developed and used in both spine and nonspine surgery. There is a paucity of literature regarding the use of rhBMP-2 in scaphoid nonunion surgery with very little reporting on the complications associated with its use. The objective of this study was to retrospectively review the complications documented for a case series of patients treated with revision fixation, bone graft, and rhBMP-2 in revision scaphoid nonunion surgery. METHODS: We retrospectively reviewed 6 cases of scaphoid nonunion revision surgery comprising open reduction and internal fixation (ORIF). All cases were performed for persistent nonunion after a previous scaphoid ORIF. All patients were treated with revision screw fixation, bone graft, and rhBMP-2. Union was determined by computed tomography in all cases. Complications of nonunion, heterotopic bone formation, delayed wound healing, functional loss of motion, and need for revision surgery are reported. RESULTS: Between 2011 and 2014, 6 cases in which rhBMP-2 was used in revision scaphoid nonunion surgery were identified. All patients had failed an initial attempt at ORIF after delayed union or nonunion. The time from injury to index ORIF ranged from 3 months to 4 years (mean, 24 months). Revision surgery with rhBMP-2 was performed at an average of 6 months from the index ORIF. Of the 6 cases, 2 had resultant persistent nonunion. Both underwent scaphoid excision and midcarpal arthrodesis. Four cases developed notable heterotopic ossification (one of which required revision surgery). One patient had a loss of functional motion after the revision surgery. There were no cases of delayed wound healing. Only one of the 6 patients healed without complications. CONCLUSIONS: In this case series, the use of rhBMP-2 in scaphoid nonunions was associated with a higher complication rate than reported in previous studies. Surgeons performing off-label use of rhBMP-2 should be aware of the potential for complications including heterotopic ossification. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Block of ATP-binding cassette B19 ion channel activity by 5-nitro-2-(3-phenylpropylamino)-benzoic acid impairs polar auxin transport and root gravitropism.

Polar transport of the hormone auxin through tissues and organs depends on membrane proteins, including some B-subgroup members of the ATP-binding cassette (ABC) transporter family. The messenger RNA level of at least one B-subgroup ABCB gene in Arabidopsis (Arabidopsis thaliana), ABCB19, increases upon treatment with the anion channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), possibly to compensate for an inhibitory effect of the drug on ABCB19 activity. Consistent with this hypothesis, NPPB blocked ion channel activity associated with ABCB19 expressed in human embryonic kidney cells as measured by patch-clamp electrophysiology. NPPB inhibited polar auxin transport through Arabidopsis seedling roots similarly to abcb19 mutations. NPPB also inhibited shootward auxin transport, which depends on the related ABCB4 protein. NPPB substantially decreased ABCB4 and ABCB19 protein levels when cycloheximide concomitantly inhibited new protein synthesis, indicating that blockage by NPPB enhances the degradation of ABCB transporters. Impairing the principal auxin transport streams in roots with NPPB caused aberrant patterns of auxin signaling reporters in root apices. Formation of the auxin-signaling gradient across the tips of gravity-stimulated roots, and its developmental consequence (gravitropism), were inhibited by micromolar concentrations of NPPB that did not affect growth rate. These results identify ion channel activity of ABCB19 that is blocked by NPPB, a compound that can now be considered an inhibitor of polar auxin transport with a defined molecular target.

Nitric oxide plays a role in stem cell niche homeostasis through its interaction with auxin.

Nitric oxide (NO) is a unique reactive nitrogen molecule with an array of signaling functions that modulates plant developmental processes and stress responses. To explore the mechanisms by which NO modulates root development, we used a pharmacological approach and NO-deficient mutants to unravel the role of NO in establishing auxin distribution patterns necessary for stem cell niche homeostasis. Using the NO synthase inhibitor and Arabidopsis (Arabidopsis thaliana) NO biosynthesis mutants (nitric oxide-associated1 [noa1], nitrate reductase1 [nia1] and nia2, and nia1 nia2 noa1), we show that depletion of NO in noa1 reduces primary root elongation and increases flavonol accumulation consistent with elevated reactive oxygen species levels. The elevated flavonols are required for the growth effect, because the transparent testa4 mutation reverses the noa1 mutant root elongation phenotype. In addition, noa1 and nia1 nia2 noa1 NO-deficient mutant roots display small root meristems with abnormal divisions. Concomitantly, auxin biosynthesis, transport, and signaling are perturbed. We further show that NO accumulates in cortex/endodermis stem cells and their precursor cells. In endodermal and cortical cells, the noa1 mutant acts synergistically to the effect of the wuschel-related homeobox5 mutation on the proximal meristem, suggesting that NO could play an important role in regulating stem cell decisions, which has been reported in animals.

Transcription factor WRKY23 assists auxin distribution patterns during Arabidopsis root development through local control on flavonol biosynthesis.

Gradients of the plant hormone auxin, which depend on its active intercellular transport, are crucial for the maintenance of root meristematic activity. This directional transport is largely orchestrated by a complex interaction of specific influx and efflux carriers that mediate the auxin flow into and out of cells, respectively. Besides these transport proteins, plant-specific polyphenolic compounds known as flavonols have been shown to act as endogenous regulators of auxin transport. However, only limited information is available on how flavonol synthesis is developmentally regulated. Using reduction-of-function and overexpression approaches in parallel, we demonstrate that the WRKY23 transcription factor is needed for proper root growth and development by stimulating the local biosynthesis of flavonols. The expression of WRKY23 itself is controlled by auxin through the Auxin Response Factor 7 (ARF7) and ARF19 transcriptional response pathway. Our results suggest a model in which WRKY23 is part of a transcriptional feedback loop of auxin on its own transport through local regulation of flavonol biosynthesis.

Ethylene inhibits lateral root development, increases IAA transport and expression of PIN3 and PIN7 auxin efflux carriers.

We used genetic and molecular approaches to identify mechanisms by which the gaseous plant hormone ethylene reduces lateral root formation and enhances polar transport of the hormone auxin. Arabidopsis thaliana mutants, aux1, lax3, pin3 and pin7, which are defective in auxin influx and efflux proteins, were less sensitive to the inhibition of lateral root formation and stimulation of auxin transport following treatment with the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC). By contrast, pin2 and abcb19 mutants exhibited wild-type ACC responses. ACC and indole-3-acetic acid (IAA) increased the abundance of transcripts encoding auxin transport proteins in an ETR1 and EIN2 (ethylene signaling)-dependent and TIR1 (auxin receptor)-dependent fashion, respectively. The effects of ACC on these transcripts and on lateral root development were still present in the tir1 mutant, suggesting independent signaling networks. ACC increased auxin-induced gene expression in the root apex, but decreased expression in regions where lateral roots form and reduced free IAA in whole roots. The ethylene synthesis inhibitor aminoethoxyvinylglycine (AVG) had opposite effects on auxin-dependent gene expression. These results suggest that ACC affects root development by altering auxin distribution. PIN3- and PIN7-GFP fluorescence was increased or decreased after ACC or AVG treatment, respectively, consistent with the role of PIN3 and PIN7 in ACC-elevated transport. ACC treatment abolished a localized depletion of fluorescence of PIN3- and PIN7-GFP, normally found below the site of primordia formation. These results suggest that ACC treatment increased PIN3 and PIN7 expression, resulting in elevated auxin transport, which prevented the localized accumulation of auxin needed to drive lateral root formation.

Amphiphilic nanoparticles repress macrophage atherogenesis: novel core/shell designs for scavenger receptor targeting and down-regulation.

Atherosclerosis, an inflammatory lipid-rich plaque disease is perpetuated by the unregulated scavenger-receptor-mediated uptake of oxidized lipoproteins (oxLDL) in macrophages. Current treatments lack the ability to directly inhibit oxLDL accumulation and foam cell conversion within diseased arteries. In this work, we harness nanotechnology to design and fabricate a new class of nanoparticles (NPs) based on hydrophobic mucic acid cores and amphiphilic shells with the ability to inhibit the uncontrolled uptake of modified lipids in human macrophages. Our results indicate that tailored NP core and shell formulations repress oxLDL internalization via dual complementary mechanisms. Specifically, the most atheroprotective molecules in the NP cores competitively reduced NP-mediated uptake to scavenger receptor A (SRA) and also down-regulated the surface expression of SRA and CD36. Thus, nanoparticles can be designed to switch activated, lipid-scavenging macrophages to antiatherogenic phenotypes, which could be the basis for future antiatherosclerotic therapeutics.

Nitric oxide causes root apical meristem defects and growth inhibition while reducing PIN-FORMED 1 (PIN1)-dependent acropetal auxin transport.

Nitric oxide (NO) is considered a key regulator of plant developmental processes and defense, although the mechanism and direct targets of NO action remain largely unknown. We used phenotypic, cellular, and genetic analyses in Arabidopsis thaliana to explore the role of NO in regulating primary root growth and auxin transport. Treatment with the NO donors S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and S-nitrosoglutathione reduces cell division, affecting the distribution of mitotic cells and meristem size by reducing cell size and number compared with NO depletion by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO). Interestingly, genetic backgrounds in which the endogenous NO levels are enhanced [chlorophyll a/b binding protein underexpressed 1/NO overproducer 1 (cue1/nox1) mirror this response, together with an increased cell differentiation phenotype. Because of the importance of auxin distribution in regulating primary root growth, we analyzed auxin-dependent response after altering NO levels. Both elevated NO supply and the NO-overproducing Arabidopsis mutant cue1/nox1 exhibit reduced expression of the auxin reporter markers DR5pro:GUS/GFP. These effects were accompanied by a reduction in auxin transport in primary roots. NO application and the cue1/nox1 mutation caused decreased PIN-FORMED 1 (PIN1)-GFP fluorescence in a proteasome-independent manner. Remarkably, the cue1/nox1-mutant root phenotypes resemble those of pin1 mutants. The use of both chemical treatments and mutants with altered NO levels demonstrates that high levels of NO reduce auxin transport and response by a PIN1-dependent mechanism, and root meristem activity is reduced concomitantly.

Retrospective Comparison of Capitolunate Arthrodesis Using Headless Compression Screws Versus Nitinol Memory Staples for SLAC and SNAC Wrist: Radiographic, Functional, and Patient-Reported Outcomes.

BACKGROUND: Nitinol memory compression staples have been proposed as an effective alternative to compression screws for capitolunate arthrodesis (CLA) for scaphoid nonunion advanced collapse (SNAC) and scapholunate advanced collapse (SLAC) wrist. The purpose of this study was to compare the clinical outcomes of CLA for SNAC or SLAC wrist treatment using either compression screws or nitinol staples. METHODS: In all, 47 patients with CLA for SLAC or SNAC wrist with screws or nitinol staples were retrospectively identified. Primary outcome was fusion on radiographs and/or computed tomography. Secondary outcomes were hardware-related complications (HWCs) and other complications, range of motion, grip strength, and patient-reported outcome measures (PROMs), including Visual Analogue Pain scale; Disabilities of the Arm, Shoulder, and Hand score; and patient-rated wrist evaluation. RESULTS: Of the 47 eligible patients, 40 (85%) were included: 31 patients in the staple group and 9 patients in the screw group. The average age was 49 (17-80) years. There was an 89% union rate for the screw group and a 97% union rate for the staple group. Two patients had screw backout: one who went onto union after screw removal and the other who went onto nonunion after hardware removal. There were 2 (6.5%) HWCs in the staple group. One patient had staple loosening requiring revision and the other dorsal impingement requiring staple removal after radiographic union. In all subsequent cases, the staples were countersunk with no impingement. No significant differences existed between any additional outcomes. CONCLUSIONS: We found no differences between nitinol staples and screws for CLA regarding HWCs or PROMs. Nitinol staples may offer additional benefits as a safe and effective alternative to compression screws for wrist fusions.

AUXIN UP-REGULATED F-BOX PROTEIN1 regulates the cross talk between auxin transport and cytokinin signaling during plant root growth.

Plant root development is mediated by the concerted action of the auxin and cytokinin phytohormones, with cytokinin serving as an antagonist of auxin transport. Here, we identify the AUXIN UP-REGULATED F-BOX PROTEIN1 (AUF1) and its potential paralog AUF2 as important positive modifiers of root elongation that tether auxin movements to cytokinin signaling in Arabidopsis (Arabidopsis thaliana). The AUF1 mRNA level in roots is strongly up-regulated by auxin but not by other phytohormones. Whereas the auf1 single and auf1 auf2 double mutant roots grow normally without exogenous auxin and respond similarly to the wild type upon auxin application, their growth is hypersensitive to auxin transport inhibitors, with the mutant roots also having reduced basipetal and acropetal auxin transport. The effects of auf1 on auxin movements may be mediated in part by the misexpression of several PIN-FORMED (PIN) auxin efflux proteins, which for PIN2 reduces its abundance on the plasma membrane of root cells. auf1 roots are also hypersensitive to cytokinin and have increased expression of several components of cytokinin signaling. Kinematic analyses of root growth and localization of the cyclin B mitotic marker showed that AUF1 does not affect root cell division but promotes cytokinin-mediated cell expansion in the elongation/differentiation zone. Epistasis analyses implicate the cytokinin regulator ARR1 or its effector(s) as the target of the SKP1-Cullin1-F Box (SCF) ubiquitin ligases assembled with AUF1/2. Given the wide distribution of AUF1/2-type proteins among land plants, we propose that SCF(AUF1/2) provides additional cross talk between auxin and cytokinin, which modifies auxin distribution and ultimately root elongation.

Auxin and ethylene induce flavonol accumulation through distinct transcriptional networks.

Auxin and ethylene are key regulators of plant growth and development, and thus the transcriptional networks that mediate responses to these hormones have been the subject of intense research. This study dissected the hormonal cross talk regulating the synthesis of flavonols and examined their impact on root growth and development. We analyzed the effects of auxin and an ethylene precursor on roots of wild-type and hormone-insensitive Arabidopsis (Arabidopsis thaliana) mutants at the transcript, protein, and metabolite levels at high spatial and temporal resolution. Indole-3-acetic acid (IAA) and 1-aminocyclopropane-1-carboxylic acid (ACC) differentially increased flavonol pathway transcripts and flavonol accumulation, altering the relative abundance of quercetin and kaempferol. The IAA, but not ACC, response is lost in the transport inhibitor response1 (tir1) auxin receptor mutant, while ACC responses, but not IAA responses, are lost in ethylene insensitive2 (ein2) and ethylene resistant1 (etr1) ethylene signaling mutants. A kinetic analysis identified increases in transcripts encoding the transcriptional regulators MYB12, Transparent Testa Glabra1, and Production of Anthocyanin Pigment after hormone treatments, which preceded increases in transcripts encoding flavonoid biosynthetic enzymes. In addition, myb12 mutants were insensitive to the effects of auxin and ethylene on flavonol metabolism. The equivalent phenotypes for transparent testa4 (tt4), which makes no flavonols, and tt7, which makes kaempferol but not quercetin, showed that quercetin derivatives are the inhibitors of basipetal root auxin transport, gravitropism, and elongation growth. Collectively, these experiments demonstrate that auxin and ethylene regulate flavonol biosynthesis through distinct signaling networks involving TIR1 and EIN2/ETR1, respectively, both of which converge on MYB12. This study also provides new evidence that quercetin is the flavonol that modulates basipetal auxin transport.

Auxin transport into cotyledons and cotyledon growth depend similarly on the ABCB19 Multidrug Resistance-like transporter.

ABCB19 of Arabidopsis thaliana (formerly known as MDR1 and PGP19) belongs to the Multidrug Resistance-like (MDR) or B group of the ATP-binding cassette (ABC) transporter superfamily, and mediates polar auxin transport in stems and roots. Here we have investigated the role of ABCB19 and auxin distribution in cotyledon development. During embryogenesis, confocal microscopy showed ABCB19 protein to be present in cotyledons during their main growth phase, but not later. Analysis of ProDR5:GFP expression patterns showed a significantly diminished and restricted auxin distribution pattern in abcb19 cotyledons. Nonetheless, development of abcb19 embryonic cotyledons was very similar to that of wild-type. Post-germination, ABCB19 was present in the plasma membrane of cotyledon epidermal, mesophyll and petiole cells during blade expansion. Post-germination cotyledon blade expansion in abcb19 was 65% slower than in wild-type, although the epidermal cell area was reduced by only 17%. The growth rate reduction quantitatively correlated with reduced auxin levels rather than auxin sensitivity as indicated by quantitative ProDR5:GUS assays and direct auxin measurements, and may be explained by the 50% reduction in the import of auxin through the petioles of abcb19 cotyledons during the period of maximum expansion. Taken together, these data indicate that cotyledon expansion during the establishment of photoautotrophic growth depends on ABCB19-mediated auxin import.

A Conditional Mutation in SCD1 Reveals Linkage Between PIN Protein Trafficking, Auxin Transport, Gravitropism, and Lateral Root Initiation.

Auxin is transported in plants with distinct polarity, defined by transport proteins of the PIN-formed (PIN) family. Components of the complex trafficking machinery responsible for polar PIN protein localization have been identified by genetic approaches, but severe developmental phenotypes of trafficking mutants complicate dissection of this pathway. We utilized a temperature sensitive allele of Arabidopsis thaliana SCD1 (stomatal cytokinesis defective1) that encodes a RAB-guanine nucleotide exchange factor. Auxin transport, lateral root initiation, asymmetric auxin-induced gene expression after gravitropic reorientation, and differential gravitropic growth were reduced in the roots of the scd1-1 mutant relative to wild type at the restrictive temperature of 25°C, but not at the permissive temperature of 18°C. In scd1-1 at 25°C, PIN1- and PIN2-GFP accumulated in endomembrane bodies. Transition of seedlings from 18 to 25°C for as little as 20 min resulted in the accumulation of PIN2-GFP in endomembranes, while gravitropism and root developmental defects were not detected until hours after transition to the non-permissive temperature. The endomembrane compartments that accumulated PIN2-GFP in scd1-1 exhibited FM4-64 signal colocalized with ARA7 and ARA6 fluorescent marker proteins, consistent with PIN2 accumulation in the late or multivesicular endosome. These experiments illustrate the power of using a temperature sensitive mutation in the gene encoding SCD1 to study the trafficking of PIN2 between the endosome and the plasma membrane. Using the conditional feature of this mutation, we show that altered trafficking of PIN2 precedes altered auxin transport and defects in gravitropism and lateral root development in this mutant upon transition to the restrictive temperature.

Steindler Flexorplasty: A Description of Current Technique and Case Series.

This year marks the 100th anniversary of Dr Steindler's original report of a proximal transfer of the flexor pronator mass to restore elbow flexion. The authors present their updated surgical technique to perform the Steindler flexorplasty. In this procedure, the flexor-pronator mass origin on the medial epicondyle is transferred proximally to the anterior humerus to restore elbow flexion. They also report a retrospective case series of patients from 2007 to 2017 who underwent a Steindler flexorplasty at their institution to restore elbow flexion. In the series, 8 of 9 patients achieved at least 90 degrees of active antigravity (M3) or greater elbow flexion. Outcomes following the Steindler flexorplasty have been reported in the literature over the course of the past 100 years. Although alternative techniques to improve elbow flexion have been developed and performed over the last century, this time tested procedure remains a powerful reconstructive option.

Restoration of Elbow Flexion.

Active elbow flexion is required to position the hand in space, and loss of this function is debilitating. Nerve transfers or nerve grafts to restore elbow flexion may be options when the target muscle is viable, but in delayed reconstruction when the biceps and brachialis are atrophied or damaged, muscle transfer options should be considered. Muscle transfer options are discussed with attention to the advantages and disadvantages of each transfer option.

Amphiphilic macromolecule nanoassemblies suppress smooth muscle cell proliferation and platelet adhesion.

While the development of second- and third-generation drug-eluting stents (DES) have significantly improved patient outcomes by reducing smooth muscle cell (SMC) proliferation, DES have also been associated with an increased risk of late-stent thrombosis due to delayed re-endothelialization and hypersensitivity reactions from the drug-polymer coating. Furthermore, DES anti-proliferative agents do not counteract the upstream oxidative stress that triggers the SMC proliferation cascade. In this study, we investigate biocompatible amphiphilic macromolecules (AMs) that address high oxidative lipoprotein microenvironments by competitively binding oxidized lipid receptors and suppressing SMC proliferation with minimal cytotoxicity. To determine the influence of nanoscale assembly on proliferation, micelles and nanoparticles were fabricated from AM unimers containing a phosphonate or carboxylate end-group, a sugar-based hydrophobic domain, and a hydrophilic poly(ethylene glycol) domain. The results indicate that when SMCs are exposed to high levels of oxidized lipid stimuli, nanotherapeutics inhibit lipid uptake, downregulate scavenger receptor expression, and attenuate scavenger receptor gene transcription in SMCs, and thus significantly suppress proliferation. Although both functional end-groups were similarly efficacious, nanoparticles suppressed oxidized lipid uptake and scavenger receptor expression more effectively compared to micelles, indicating the relative importance of formulation characteristics (e.g., higher localized AM concentrations and nanotherapeutic stability) in scavenger receptor binding as compared to AM end-group functionality. Furthermore, AM coatings significantly prevented platelet adhesion to metal, demonstrating its potential as an anti-platelet therapy to treat thrombosis. Thus, AM micelles and NPs can effectively repress early stage SMC proliferation and thrombosis through non-cytotoxic mechanisms, highlighting the promise of nanomedicine for next-generation cardiovascular therapeutics.