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The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.
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Linfócitos B , Proteínas de Ligação a DNA , Proteínas de Homeodomínio , Proteínas Nucleares , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Humanos , Tolerância Imunológica , Contagem de Linfócitos , Proteínas Nucleares/deficiênciaRESUMO
The three-dimensional structure of RNA molecules plays a critical role in a wide range of cellular processes encompassing functions from riboswitches to epigenetic regulation. These RNA structures are incredibly dynamic and can indeed be described aptly as an ensemble of structures that shifts in distribution depending on different cellular conditions. Thus, the computational prediction of RNA structure poses a unique challenge, even as computational protein folding has seen great advances. In this review, we focus on a variety of machine learning-based methods that have been developed to predict RNA molecules' secondary structure, as well as more complex tertiary structures. We survey commonly used modeling strategies, and how many are inspired by or incorporate thermodynamic principles. We discuss the shortcomings that various design decisions entail and propose future directions that could build off these methods to yield more robust, accurate RNA structure predictions.
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Epigênese Genética , RNA , RNA/metabolismo , Aprendizado de Máquina , Estrutura Secundária de Proteína , Biologia Computacional/métodosRESUMO
The flavoenzyme nicotine oxidoreductase (NicA2) is a promising injectable treatment to aid in the cessation of smoking, a behavior responsible for one in ten deaths worldwide. NicA2 acts by degrading nicotine in the bloodstream before it reaches the brain. Clinical use of NicA2 is limited by its poor catalytic activity in the absence of its natural electron acceptor CycN. Without CycN, NicA2 is instead oxidized slowly by dioxygen (O2), necessitating unfeasibly large doses in a therapeutic setting. Here, we report a genetic selection strategy that directly links CycN-independent activity of NicA2 to growth of Pseudomonas putida S16. This selection enabled us to evolve NicA2 variants with substantial improvement in their rate of oxidation by O2. The encoded mutations cluster around a putative O2 tunnel, increasing flexibility and accessibility to O2 in this region. These mutations further confer desirable clinical properties. A variant form of NicA2 is tenfold more effective than the wild type at degrading nicotine in the bloodstream of rats.
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Nicotina , Pseudomonas putida , Ratos , Animais , Oxigênio , Oxirredutases/metabolismo , OxirreduçãoRESUMO
Bile salts are secreted into the gastrointestinal tract to aid in the absorption of lipids. In addition, bile salts show potent antimicrobial activity in part by mediating bacterial protein unfolding and aggregation. Here, using a protein folding sensor, we made the surprising discovery that the Escherichia coli periplasmic glycerol-3-phosphate (G3P)-binding protein UgpB can serve, in the absence of its substrate, as a potent molecular chaperone that exhibits anti-aggregation activity against bile salt-induced protein aggregation. The substrate G3P, which is known to accumulate in the later compartments of the digestive system, triggers a functional switch between UgpB's activity as a molecular chaperone and its activity as a G3P transporter. A UgpB mutant unable to bind G3P is constitutively active as a chaperone, and its crystal structure shows that it contains a deep surface groove absent in the G3P-bound wild-type UgpB. Our work illustrates how evolution may be able to convert threats into signals that first activate and then inactivate a chaperone at the protein level in a manner that bypasses the need for ATP.
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Bile/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Glicerofosfatos/metabolismo , Chaperonas Moleculares/metabolismo , Ampicilina/farmacologia , Proteínas de Transporte/genética , Dicroísmo Circular , Cristalografia por Raios X , Elementos de DNA Transponíveis/genética , Proteínas de Escherichia coli/genética , Deleção de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Concentração de Íons de Hidrogênio , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Conformação Molecular , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Proteoma/metabolismoRESUMO
The lack of intrinsic active sites for photocatalytic CO2 reduction reaction (CO2RR) and fast recombination rate of charge carriers are the main obstacles to achieving high photocatalytic activity. In this work, a novel phosphorus and boron binary-doped graphitic carbon nitride, highly porous material that exhibits powerful photocatalytic CO2 reduction activity, specifically toward selective CO generation, is disclosed. The coexistence of Lewis-acidic and Lewis-basic sites plays a key role in tuning the electronic structure, promoting charge distribution, extending light-harvesting ability, and promoting dissociation of excitons into active carriers. Porosity and dual dopants create local chemical environments that activate the pyridinic nitrogen atom between the phosphorus and boron atoms on the exposed surface, enabling it to function as an active site for CO2RR. The P-N-B triad is found to lower the activation barrier for reduction of CO2 by stabilizing the COOH reaction intermediate and altering the rate-determining step. As a result, CO yield increased to 22.45 µmol g-1 h-1 under visible light irradiation, which is ≈12 times larger than that of pristine graphitic carbon nitride. This study provides insights into the mechanism of charge carrier dynamics and active site determination, contributing to the understanding of the photocatalytic CO2RR mechanism.
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Carbon dots (CDs) are novel carbon-based luminescent materials with wide-ranging applications in biosensing, bioimaging, drug transportation, optical devices, and beyond. Their advantageous attributes, including biocompatibility, biodegradability, antioxidant activity, photostability, small particle size (< 10 nm), and strong light absorption and excitation across a broad range of wavelengths, making them promising candidates in the field of photodynamic therapy (PDT) as photosensitizers (PSs). Further enhancements in functionality are imperative to enhance the effectiveness of CDs in PDT applications, notwithstanding their inherent benefits. Recently, doping agents and solvents have been demonstrated to improve CDs' optical properties, solubility, cytotoxicity, and organelle targeting efficiency. These improvements result from modifications to the CDs' carbon skeleton matrices, functional groups on the surface state, and chemical structures. This review discusses the modification of CDs with heteroatom dopants, dye dopants, and solvents to improve their physicochemical and optical properties for PDT applications. The correlations between the surface chemistry, functional groups, structure of the CDs and their optical characteristics toward quantum yield, redshift feature and reactive oxygen species generation, have also been discussed. Finally, the progressive trends for the use of CDs in PDT applications are also addressed in this review.
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Herein, a low-cost and readily available sodium aluminate (NaAlO2) was used as a solid base catalyst for the depolymerization of polycarbonate (PC) via methanolysis in the presence of tetrahydrofuran (THF) as a solvent. NaAlO2 was highly active for the reaction, and the performance was comparable to that of soluble strong base SrO and much higher than those of MgO and CaO. By the reaction over the catalyst, a highly pure and crystalline bisphenol A (BPA) was obtained. Among tested organic solvents, THF was the best in aiding PC methanolysis over NaAlO2 due to the polarity similar to PC according to Hansen solubility parameters (HSPs). At 60 °C, 98.1% PC conversion and 96.8% BPA yield were achieved within just 2 h. NaAlO2 was reusable without any severe catalyst deactivation in at least four runs. The mechanistic study revealed that the reaction proceeded via the methoxide pathway, with THF aiding the dissolution of PC. The reaction over NaAlO2 possessed a low apparent activation energy (Ea) of 75.1 kJ mol-1, which is the lowest ever reported so far for the reaction over solid catalysts.
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Quantum mechanics/molecular mechanics (QM/MM) simulations offer an efficient way to model reactions occurring in complex environments. This study introduces a specialized set of charge and Lennard-Jones parameters tailored for electrostatically embedded QM/MM calculations, aiming to accurately model both adsorption processes and catalytic reactions in zirconium-based metal-organic frameworks (Zr-MOFs). To validate our approach, we compare adsorption energies derived from QM/MM simulations against experimental results and Monte Carlo simulation outcomes. The developed parameters showcase the ability of QM/MM simulations to represent long-range electrostatic and van der Waals interactions faithfully. This capability is evidenced by the prediction of adsorption energies with a low root mean square error of 1.1 kcal mol-1 across a wide range of adsorbates. The practical applicability of our QM/MM model is further illustrated through the study of glucose isomerization and epimerization reactions catalyzed by two structurally distinct Zr-MOF catalysts, UiO-66 and MOF-808. Our QM/MM calculations closely align with experimental activation energies. Importantly, the parameter set introduced here is compatible with the widely used universal force field (UFF). Moreover, we thoroughly explore how the size of the cluster model and the choice of density functional theory (DFT) methodologies influence the simulation outcomes. This work provides an accurate and computationally efficient framework for modeling complex catalytic reactions within Zr-MOFs, contributing valuable insights into their mechanistic behaviors and facilitating further advancements in this dynamic area of research.
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The present study explores visible light-assisted photodegradation of ciprofloxacin hydrochloride (CIP) antibiotic as a promising solution to water pollution. The focus is on transforming the optical and electronic properties of BiOCl through the generation of oxygen vacancies (OVs) and the exposure of (110) facets, forming a robust S-scheme heterojunction with WS2. The resultant OVs mediated composite with an optimal ratio of WS2 and BiOCl-OV (4-WS2/BiOCl-OV) demonstrated remarkable efficiency (94.3%) in the visible light-assisted photodegradation of CIP antibiotic within 1.5 h. The CIP degradation using 4-WS2/BiOCl-OV followed pseudo-first-order kinetics with the rate constant of 0.023 min-1, outperforming bare WS2, BiOCl, and BiOCl-OV by 8, 6, and 4 times, respectively. Density functional theory (DFT) analysis aligned well with experimental results, providing insights into the structural arrangement and bandgap analysis of the photocatalysts. Liquid chromatography-mass spectrometry (LC-MS) analysis utilized for identifying potentially degraded products while scavenging experiments and electron paramagnetic resonance (EPR) spin trapping analysis elucidated the S-scheme charge transfer mechanism. This research contributes to advancing the design of oxygen vacancy-mediated S-scheme systems in the realm of photocatalysis, with potential implications for addressing water pollution concerns.
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Ciprofloxacina , Oxigênio , Fotólise , Águas Residuárias , Poluentes Químicos da Água , Ciprofloxacina/química , Poluentes Químicos da Água/química , Águas Residuárias/química , Oxigênio/química , Bismuto/química , Antibacterianos/química , Tungstênio/química , Catálise , Luz , Teoria da Densidade FuncionalRESUMO
Simultaneous profiling of multiomic modalities within a single cell is a grand challenge for single-cell biology. While there have been impressive technical innovations demonstrating feasibility-for example, generating paired measurements of single-cell transcriptome (single-cell RNA sequencing [scRNA-seq]) and chromatin accessibility (single-cell assay for transposase-accessible chromatin using sequencing [scATAC-seq])-widespread application of joint profiling is challenging due to its experimental complexity, noise, and cost. Here, we introduce BABEL, a deep learning method that translates between the transcriptome and chromatin profiles of a single cell. Leveraging an interoperable neural network model, BABEL can predict single-cell expression directly from a cell's scATAC-seq and vice versa after training on relevant data. This makes it possible to computationally synthesize paired multiomic measurements when only one modality is experimentally available. Across several paired single-cell ATAC and gene expression datasets in human and mouse, we validate that BABEL accurately translates between these modalities for individual cells. BABEL also generalizes well to cell types within new biological contexts not seen during training. Starting from scATAC-seq of patient-derived basal cell carcinoma (BCC), BABEL generated single-cell expression that enabled fine-grained classification of complex cell states, despite having never seen BCC data. These predictions are comparable to analyses of experimental BCC scRNA-seq data for diverse cell types related to BABEL's training data. We further show that BABEL can incorporate additional single-cell data modalities, such as protein epitope profiling, thus enabling translation across chromatin, RNA, and protein. BABEL offers a powerful approach for data exploration and hypothesis generation.
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Carcinoma/genética , Genômica/métodos , Análise de Célula Única/métodos , Software , Animais , Carcinoma/metabolismo , Aprendizado Profundo , Humanos , Camundongos , Proteoma/genética , Proteoma/metabolismo , TranscriptomaRESUMO
PURPOSE: As osteoarthritis (OA) of the trapeziometacarpal (TMC) joint leads to a high degree of disease burden with compromises in rudimentary and fine movements of the hand, intra-articular injections may be a desirable treatment option. However, because there are no evidence-based guidelines, the choice of intra-articular injection type is left to the discretion of the individual surgeon in collaboration with the patient. The purpose of our study was to perform a systematic review and meta-analysis using level I studies to compare outcomes following corticosteroid and alternative methods of intra-articular injections for the management of TMC OA. Our hypothesis was that intra-articular corticosteroid injections were no more effective than other methods of intra-articular injections for the management of TMC OA. METHODS: A systematic literature search was performed. Eligible for inclusion were randomized control trials reporting on intra-articular corticosteroid injection for the management of TMC OA. Clinical outcomes were recorded. RESULTS: The 10 included studies comprised 673 patients. The mean age was 57.8 ± 8.3 years, with a mean follow-up of 6.4 ± 2.7 months. There was no significant difference in visual analog scale scores, grip strength and tip pinch strength between corticosteroids and hyaluronic acid at short- and medium-term follow-up. Further, there was no difference in visual analog scale pain scores at rest at medium-term follow-up between corticosteroids and platelet-rich plasma. CONCLUSIONS: Despite short-term improvement with intra-articular corticosteroid injections, there was no significant difference in pain and functional outcomes following intra-articular corticosteroid injections compared to hyaluronic acid or platelet-rich plasma administration. Given the affordability, ease of administration, and efficacy associated with corticosteroids, they are a favorable option when considering the choice of intra-articular injection for the management of TMC OA. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.
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Corticosteroides , Articulações Carpometacarpais , Osteoartrite , Ensaios Clínicos Controlados Aleatórios como Assunto , Trapézio , Humanos , Injeções Intra-Articulares , Osteoartrite/tratamento farmacológico , Corticosteroides/administração & dosagem , Ácido Hialurônico/administração & dosagem , Força da Mão , Resultado do TratamentoRESUMO
BACKGROUND: Recent mandates from the Center for Medicare and Medicaid Services (CMS) require United States hospitals to disclose healthcare service pricing. Yet, there's a gap in understanding how state-level factors affect hospital service pricing, like total shoulder arthroplasty (TSA). Comprehending these influences can help policymakers and healthcare providers manage costs and improve care access for vulnerable populations. The purpose of this study was to examine the effect of state characteristics such as partisan lean, Certificate of Need (CON) status, and Medicaid expansion, on TSA price. METHODS: TSA price data was extracted from the Turquoise Health Database using CPT code 23472. State partisan lean was determined by evaluating each state during the 2020 election year for its legislature (both senate and house), governor, presidential vote, and Insurance Commissioner affiliation, categorizing states as either "Republican-leaning" or "Democratic-leaning." CON status, Medicaid expansion, area deprivation index (ADI), and population density information was obtained from publicly available sources. Multivariable regression models were used to assess the relationship between these factors and TSA price. RESULTS: The study included 2,068 hospitals nationwide. The median (IQR) price of TSA across these hospitals was $12,607 ($9,185). In the multivariable analysis, hospitals in Republican-leaning states were associated with a significantly greater price of +$210 (p = 0.0151), while Medicaid expansion was also associated with greater price +$1,878 (p < 0.0001). CON status was associated with a significant reduction in TSA prices of -$2,880 (p < 0.0001). In North Carolina an ADI >85 was associated with a reduction in price (p = 0.0045), while urbanization designation did not significantly impact TSA price (p = 0.8457). CONCLUSION: This cross-sectional observational study found that Republican-leaning states and Medicaid expansion were associated with increased TSA prices, while an ADI >85 and CON laws were associated with reduced TSA prices.
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Nonspecific orbital inflammation (NSOI), colloquially known as orbital pseudotumor, sometimes presents a diagnostic and therapeutic challenge in ophthalmology. This review aims to dissect NSOI through a molecular lens, offering a comprehensive overview of its pathogenesis, clinical presentation, diagnostic methods, and management strategies. The article delves into the underpinnings of NSOI, examining immunological and environmental factors alongside intricate molecular mechanisms involving signaling pathways, cytokines, and mediators. Special emphasis is placed on emerging molecular discoveries and approaches, highlighting the significance of understanding molecular mechanisms in NSOI for the development of novel diagnostic and therapeutic tools. Various diagnostic modalities are scrutinized for their utility and limitations. Therapeutic interventions encompass medical treatments with corticosteroids and immunomodulatory agents, all discussed in light of current molecular understanding. More importantly, this review offers a novel molecular perspective on NSOI, dissecting its pathogenesis and management with an emphasis on the latest molecular discoveries. It introduces an integrated approach combining advanced molecular diagnostics with current clinical assessments and explores emerging targeted therapies. By synthesizing these facets, the review aims to inform clinicians and researchers alike, paving the way for molecularly informed, precision-based strategies for managing NSOI.
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Cristalino , Oftalmologia , Pseudotumor Orbitário , Humanos , Inflamação/diagnóstico , Inflamação/terapia , Pseudotumor Orbitário/diagnóstico , Pseudotumor Orbitário/patologia , Cristalino/patologia , CitocinasRESUMO
The eye's complex anatomical structures present formidable barriers to effective drug delivery across a range of ocular diseases, from anterior to posterior segment pathologies. Emerging as a promising solution to these challenges, nanotechnology-based platforms-including but not limited to liposomes, dendrimers, and micelles-have shown the potential to revolutionize ophthalmic therapeutics. These nanocarriers enhance drug bioavailability, increase residence time in targeted ocular tissues, and offer precise, localized delivery, minimizing systemic side effects. Focusing on pediatric ophthalmology, particularly on retinoblastoma, this review delves into the recent advancements in functionalized nanosystems for drug delivery. Covering the literature from 2017 to 2023, it comprehensively examines these nanocarriers' potential impact on transforming the treatment landscape for retinoblastoma. The review highlights the critical role of these platforms in overcoming the unique pediatric eye barriers, thus enhancing treatment efficacy. It underscores the necessity for ongoing research to realize the full clinical potential of these innovative drug delivery systems in pediatric ophthalmology.
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Sistemas de Liberação de Medicamentos , Retinoblastoma , Retinoblastoma/tratamento farmacológico , Humanos , Portadores de Fármacos/química , Criança , Nanopartículas/química , Micelas , Lipossomos/química , Dendrímeros/química , Neoplasias da Retina/tratamento farmacológico , Administração Oftálmica , Nanotecnologia/métodosRESUMO
BACKGROUND: The ability to degrade hyaluronic acid (HA)-based fillers with hyaluronidase allows for better management of adverse effects and reversal of suboptimal treatment outcomes. OBJECTIVES: The aim of this study was to compare the enzymatic degradation kinetics of 16 commercially available HA-based fillers, representing 6 manufacturing technologies. METHODS: In this nonclinical study, a recently developed in vitro multidose hyaluronidase administration protocol was used to induce degradation of HA-based fillers, enabling real-time evaluation of viscoelastic properties under near-static conditions. Each filler was exposed to repeated doses of hyaluronidase at intervals of 5â minutes to reach the degradation threshold of G' ≤ 30â Pa. RESULTS: Noticeable differences in degradation characteristics were observed based on the design and technology of different filler classes. Vycross fillers were the most difficult to degrade and the Cohesive Polydensified Matrix filler was the least difficult to degrade. Preserved Network Technology products demonstrated proportional increases in gel degradation time and enzyme volume required for degradation across the individual resilient hyaluronic acid (RHA) products and indication categories. No obvious relationship was observed between gel degradation characteristics and the individual parameters of HA concentration, HA chain length, or the degree of modification of each filler when analyzed separately; however, a general correlation was identified with certain physicochemical properties. CONCLUSIONS: Manufacturing technology was the most important factor influencing the reversibility of an HA product. An understanding of the differential degradation profiles of commercially available fillers will allow clinicians to select products that offer a higher margin of safety due to their preferential reversibility.
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Técnicas Cosméticas , Preenchedores Dérmicos , Ácido Hialurônico , Hialuronoglucosaminidase , Hialuronoglucosaminidase/metabolismo , Hialuronoglucosaminidase/química , Ácido Hialurônico/química , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/metabolismo , Preenchedores Dérmicos/química , Preenchedores Dérmicos/administração & dosagem , Cinética , Humanos , Teste de Materiais , Viscosidade , ElasticidadeRESUMO
This systematic review and meta-analysis delved into the impact of race and ethnicity on outcomes following foot and ankle surgery, an area garnering increasing attention within the medical community. Despite significant literature on postsurgical clinical and functional outcomes, limited research has explored the influence of racial and ethnic factors on postoperative outcomes. In this study, data from 33 relevant studies, involving a total of 557,734 patients, were analyzed to assess outcomes across different racial and ethnic groups. Notably, only 6 studies met the criteria for inclusion in the final meta-analysis due to variations in outcome reporting. Findings revealed disparities in functional scores, pain levels, and resource utilization among different racial and ethnic cohorts. Specifically, non-White and minority patients exhibited higher rates of foot and ankle fractures and lower extremity surgeries, worse functional outcomes, increased pain, longer hospital stays, and a greater incidence of complications compared to their White counterparts. However, some studies presented contradictory results, emphasizing the necessity for further investigation to elucidate these discrepancies fully. This research underscores the importance of considering racial and ethnic factors in foot and ankle surgery outcomes and highlights the need for targeted interventions to address existing disparities.
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BACKGROUND: As total ankle arthroplasty (TAA) increases in popularity nationwide for the management of end-stage arthritis, it is essential to understand ways to mitigate the risk of infection. Diabetes increases the risk of infection due to compromised immunity and impaired wound-healing mechanisms. However, there is limited research on how diabetic management, inclusive of medications and glucose control, may impact infection risks post-TAA. This study aims to demonstrate the impact of diabetic management on the occurrence of periprosthetic joint infection (PJI) following TAA. METHODS: This was a retrospective study of patients who underwent a TAA at a single academic institution from March 2002 to May 2022. Patients with diabetes who developed an intraarticular infection following TAA were propensity score matched (1:3) to diabetic patients who did not. Data collection included demographics, implant types, diabetic medications, and preoperative hemoglobin A1c. PJI was diagnosed based on Musculoskeletal Infection Society (MSIS) criteria. Statistical analyses assessed differences in medication use, glucose control, and infection rates between groups. RESULTS: Of the 1863 patients who underwent TAA, 177 patients had a diagnosis of diabetes. The infection rate in patients with diabetes (2.8%) was higher than the total cohort rate (0.8%). Five patients with diabetes developed a PJI at an average of 2.2 months postoperatively. This cohort (n = 5) was compared to propensity score-matched controls (n = 15). There was no significant difference in diabetic medication use. Patients who developed PJI had higher rates of uncontrolled diabetes (60.0% vs. 6.7%) and average A1c levels (7.02% vs. 6.29%) compared to controls. CONCLUSION: Our findings suggest that the elevated risk of PJI observed in individuals with diabetes subsequent to TAA may be attributed not solely to the presence of diabetes, but to inadequate glycemic control. Effectively managing blood glucose levels is imperative for achieving favorable outcomes following TAA. LEVEL OF EVIDENCE: III.
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BACKGROUND: Collapse of the talus and peri-talar arthritis pose treatment challenges due to the anatomy and location of the talus as a keystone of the foot and ankle. Custom 3D-printed total talus replacement (TTR) and combined total ankle total talus replacement (TATTR) have emerged as treatment options for these pathologies. However, the safety and efficacy of these implants is unknown due to the limited number of cases and short follow-up durations. METHODS: This was a retrospective study to assess surgical outcomes of patients who underwent a TTR and TATTR with or without subtalar fusion. Patient demographics, intraoperative parameters, device related surgical and non-surgical events, imaging and clinical evaluations, and patient reported outcome (PRO) measures were compiled. RESULTS: A total of 38 patients received a custom 3D-printed implant with mean follow-up time of 22.1 (range: 12-45) months. In this cohort, 7 (18.4 %) required secondary surgery and 3 (7.9 %) required implant removal. Multivariate logistic regression revealed that patient diagnosis of depression was a significant predictor of secondary surgery with an OR 17.50 (p = 0.037). Significant postoperative improvements were observed in the talocalcaneal height (p = 0.005) and talar declination angle (p = 0.013) for the TATTR group. VAS and PROMIS pain interference (PI) scores demonstrated an initial significant improvement in pain, but this improvement did not maintain significance at most recent follow-up. However, there was a significant increase in the PROMIS physical function (PF) scores (p = 0.037) at most recent follow-up. CONCLUSION: These results demonstrate that TTR and TATTR provide significant improvement in post-operative radiographic foot and ankle alignment and physical function at the two-year timepoint. PRO findings suggest that patients are more active after surgery. Surgeons considering proceeding with either of these procedures should counsel patients about pain and functional outcomes as well as realistic expectations in patients with depression. LEVEL OF EVIDENCE: Level 3.
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Designing a nanofluidic membrane with high selectivity and fast ion transport property is the key towards high-performance osmotic energy conversion. However, most of reported membranes can produce power density less than commercial benchmark (5â W/m2), due to the imbalance between ion selectivity and permeability. Here, we report a novel nanoarchitectured design of a heterogeneous membrane with an ultrathin and dense zirconium-based UiO-66-NH2 metal-organic framework (MOF) layer and a highly aligned and interconnected branched alumina nanochannel membrane. The design leads to a continuous trilayered pore structure of large geometry gradient in the sequence from angstrom-scale to nano-scale to sub-microscale, which enables the enhanced directional ion transport, and the angstrom-sized (~6.6-7â Å) UiO-66-NH2 windows render the membrane with high ion selectivity. Consequently, the novel heterogeneous membrane can achieve a high-performance power of ~8â W/m2 by mixing synthetic seawater and river water. The power density can be largely upgraded to an ultrahigh ~17.1â W/m2 along with ~48.5 % conversion efficiency at a 50-fold KCl gradient. This work not only presents a new membrane design approach but also showcases the great potential of employing the zirconium-based MOF channels as ion-channel-mimetic membranes for highly efficient blue energy harvesting.
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In 2001, our curiosity to understand the stereochemistry of C-H metalation with Pd prompted our first studies in Pd(II)-catalyzed asymmetric C-H activation (RSC Research appointment: 020 7451 2545, Grant: RG 36873, Dec. 2002). We identified four central challenges: 1.â poor reactivity of simple Pd salts with native substrates; 2.â few strategies to control site selectivity for remote C-H bonds; 3.â the lack of chiral catalysts to achieve enantioselectivity via asymmetric C-H metalation, and 4.â low practicality due to limited coupling partner scope and the use of specialized oxidants. These challenges necessitated new strategies in catalyst and reaction development. For reactivity, we developed approaches to enhance substrate-catalyst affinity together with novel bifunctional ligands which participate in and accelerate the C-H cleavage step. For site-selectivity, we introduced the concept of systematically modulating the distance and geometry between a directing template, catalyst, and substrate to selectively access remote C-H bonds. For enantioselectivity, we devised predictable stereomodels for catalyst-controlled enantioselective C-H activation based on the participation of bifunctional ligands. Finally, for practicality, we have developed varied catalytic manifolds for Pd(II) to accommodate diverse coupling partners while employing practical oxidants such as simple peroxides. These advances have culminated in numerous C-H activation reactions, setting the stage for broad industrial applications.