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BACKGROUND: The outcomes of single ventricle palliation in unbalanced atrioventricular canal defect with coarctation of aorta (uAVC+CoA) have not been well studied. These patients have a propensity to develop systemic ventricle outflow tract obstruction following aortic arch repair with pulmonary artery banding (arch-PAB); which may adversely affect survival and Fontan candidacy. METHODS: A retrospective review was performed of patients who underwent single ventricle palliation for uAVC+CoA from 2000 to 2022. Patients were divided into two groups based on initial palliation - (1) arch-PAB and (2) Norwood procedure. Demographic and clinical characteristics were analyzed and compared, along with survival data. RESULTS: 41 patients underwent stage 1 palliation for uAVC+CoA. Arch-PAB was performed in 14 infants and Norwood in 27 infants. Arch-PAB patients had more chromosomal abnormalities (28.6 vs 7.4%, p<0.009) and less severe systemic ventricle outflow tract obstruction on baseline echocardiogram (0.0 vs. 70.4%, p<0.001). Survival to stage 3 palliation was lower for the arch-PAB group (28.6 vs. 66.6%, p=0.02). Arch-PAB remained a significant risk factor for mortality (HR 2.93 [CI 1.05-8.53], p=0.04) after adjusting for chromosomal abnormalities and atrioventricular valve regurgitation. Following arch-PAB, systemic ventricle outflow tract obstruction was diagnosed in 13/14 patients. Echocardiography underestimated the degree of outflow tract obstruction in 10/13 arch-PAB patients. CONCLUSIONS: Arch-PAB has worse outcomes than Norwood for uAVC+CoA. Almost all patients develop systemic ventricle outflow tract obstruction following arch-PAB. Outflow tract obstruction is underestimated by echocardiogram, and requires a high index of suspicion along with advanced imaging to ensure timely diagnosis and management.
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Significance: Genetically encoded voltage indicators (GEVIs) are a valuable tool for studying neural circuits in vivo, but the relative merits and limitations of one-photon (1P) versus two-photon (2P) voltage imaging are not well characterized. Aim: We consider the optical and biophysical constraints particular to 1P and 2P voltage imaging and compare the imaging properties of commonly used GEVIs under 1P and 2P excitation. Approach: We measure the brightness and voltage sensitivity of voltage indicators from commonly used classes under 1P and 2P illumination. We also measure the decrease in fluorescence as a function of depth in the mouse brain. We develop a simple model of the number of measurable cells as a function of reporter properties, imaging parameters, and desired signal-to-noise ratio (SNR). We then discuss how the performance of voltage imaging would be affected by sensor improvements and by recently introduced advanced imaging modalities. Results: Compared with 1P excitation, 2P excitation requires â¼ 10 4 -fold more illumination power per cell to produce similar photon count rates. For voltage imaging with JEDI-2P in the mouse cortex with a target SNR of 10 (spike height to baseline shot noise), a measurement bandwidth of 1 kHz, a thermally limited laser power of 200 mW, and an imaging depth of > 300 µ m , 2P voltage imaging using an 80-MHz source can record from no more than â¼ 12 neurons simultaneously. Conclusions: Due to the stringent photon-count requirements of voltage imaging and the modest voltage sensitivity of existing reporters, 2P voltage imaging in vivo faces a stringent tradeoff between shot noise and tissue photodamage. 2P imaging of hundreds of neurons with high SNR at a depth of > 300 µ m will require either major improvements in 2P GEVIs or qualitatively new approaches to imaging.
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Small, diffusible redox proteins play an essential role in electron transfer (ET) in respiration and photosynthesis, sustaining life on Earth by shuttling electrons between membrane-bound complexes via finely tuned and reversible interactions. Ensemble kinetic studies show transient ET complexes form in two distinct stages: an "encounter" complex largely mediated by electrostatic interactions, which subsequently, through subtle reorganization of the binding interface, forms a "productive" ET complex stabilized by additional hydrophobic interactions around the redox-active cofactors. Here, using single-molecule force spectroscopy (SMFS) we dissected the transient ET complexes formed between the photosynthetic reaction center-light harvesting complex 1 (RC-LH1) of Rhodobacter sphaeroides and its native electron donor cytochrome c2 (cyt c2). Importantly, SMFS resolves the distribution of interaction forces into low (â¼150 pN) and high (â¼330 pN) components, with the former more susceptible to salt concentration and to alteration of key charged residues on the RC. Thus, the low force component is suggested to reflect the contribution of electrostatic interactions in forming the initial encounter complex, whereas the high force component reflects the additional stabilization provided by hydrophobic interactions to the productive ET complex. Employing molecular dynamics simulations, we resolve five intermediate states that comprise the encounter, productive ET and leaving complexes, predicting a weak interaction between cyt c2 and the LH1 ring near the RC-L subunit that could lie along the exit path for oxidized cyt c2. The multimodal nature of the interactions of ET complexes captured here may have wider implications for ET in all domains of life.
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Rhodobacter sphaeroides , Rhodobacter sphaeroides/metabolismo , Transporte de Electrón , Proteínas del Complejo del Centro de Reacción Fotosintética/química , Proteínas del Complejo del Centro de Reacción Fotosintética/metabolismo , Citocromos c2/química , Citocromos c2/metabolismo , Complejos de Proteína Captadores de Luz/química , Complejos de Proteína Captadores de Luz/metabolismoRESUMEN
Candidacy for transcatheter pulmonary valve replacement utilizing newer valve platforms is aided by industry-driven fit analyses. We report augmentation of this decision-making process by visualization of 4-dimensional cine imaging of patient-specific right ventricular outflow tract anatomy and a virtual valve model within a virtual reality platform.
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Associations between Appropriate Use Criteria (AUC) ratings and medical decision-making in congenital heart disease are not well-established. We applied the 2020 AUC for multimodality imaging in follow-up care of pediatric and young adult patients with conotruncal defects to evaluate appropriateness of cardiac magnetic resonance (CMR) and computed tomography (CCT) use in this population and impact on clinical decision-making. Records were reviewed and assigned AUC indications and corresponding ratings for CMR and CCT. We examined the relationship between AUC indications, their ratings, and change in management. Of the 200 studies (133 CMR, 67 CCT) performed on 187 patients, no studies were rated Rarely Appropriate (R), and most studies were obtained for routine follow-up (151/200 [75.5%]) and were not prompted by clinical concerns. There were 70/200 (35.0%) studies which led to management changes; these included transcatheter intervention (29/70 [41.4%]), surgical intervention (25/70 [35.7%]), other interventions (10/70 [14.3%]), and medical intervention (6/70 [8.6%]). Among all studies, studies prompted by clinical concerns and studies rated M more frequently resulted in change in management (46.9 vs 31.1%, p = 0.04 and 54.1 vs 30.7%, p = 0.003, respectively). In conclusion, we found that all studies were ordered for indications rated Appropriate (A) or May be Appropriate (M), indicating compliance in ordering practices as outlined by published AUC. Studies ordered for clinical change or rated M more frequently led to management change in patient care. Findings may help inform provider expectations of testing yield in this population and serve as a platform for development of future iterations of AUC.
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Natural photosystems couple light harvesting to charge separation using a 'special pair' of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C2-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry. Spectroscopy revealed that the chlorophylls are excitonically coupled, and fluorescence lifetime imaging demonstrated energy transfer. The cryo-electron microscopy structure of a designed 24-chlorophyll octahedral nanocage with a special pair on each edge closely matched the design model. The results suggest that the de novo design of artificial photosynthetic systems is within reach of current computational methods.
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Clorofila , Clorofila/química , Clorofila/metabolismo , Cristalografía por Rayos X , Modelos Moleculares , Fotosíntesis , Transferencia de Energía , Microscopía por Crioelectrón , Conformación Proteica , Complejos de Proteína Captadores de Luz/química , Complejos de Proteína Captadores de Luz/metabolismoRESUMEN
Success of atrioventricular septal defect repair is defined by post-operative atrioventricular valve function and presence of residual intracardiac shunting. We evaluated differences in interpretation of atrioventricular valve function and residual defects between transesophageal and transthoracic echocardiography in a contemporary cohort of infants undergoing atrioventricular septal defect repair. Among 106 patients, we identified an increase in left and right atrioventricular valve regurgitation, right atrioventricular valve inflow gradient, and increased detection rate of residual intracardiac shunting on transthoracic compared to transesophageal echocardiograms, although residual shunts identified only on transthoracic echocardiogram were not haemodynamically significant. Findings may help inform expectation of post-operative transthoracic echocardiogram findings based on intraoperative assessment.
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The reaction centre-light harvesting 1 (RC-LH1) core complex is indispensable for anoxygenic photosynthesis. In the purple bacterium Rhodobacter (Rba.) sphaeroides RC-LH1 is produced both as a monomer, in which 14 LH1 subunits form a C-shaped antenna around 1 RC, and as a dimer, where 28 LH1 subunits form an S-shaped antenna surrounding 2 RCs. Alongside the five RC and LH1 subunits, an additional polypeptide known as PufX provides an interface for dimerisation and also prevents LH1 ring closure, introducing a channel for quinone exchange that is essential for photoheterotrophic growth. Structures of Rba. sphaeroides RC-LH1 complexes revealed several new components; protein-Y, which helps to form the quinone channel; protein-Z, of unknown function and seemingly unique to dimers; and a tightly bound sulfoquinovosyl diacylglycerol (SQDG) lipid that interacts with two PufX arginine residues. This lipid lies at the dimer interface alongside weak density for a second molecule, previously proposed to be an ornithine lipid. In this work we have generated strains of Rba. sphaeroides lacking protein-Y, protein-Z, SQDG or ornithine lipids to assess the roles of these previously unknown components in the assembly and activity of RC-LH1. We show that whilst the removal of either protein-Y, protein-Z or ornithine lipids has only subtle effects, SQDG is essential for the formation of RC-LH1 dimers but its absence has no functional effect on the monomeric complex.
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Proteínas Bacterianas , Complejos de Proteína Captadores de Luz , Multimerización de Proteína , Rhodobacter sphaeroides , Rhodobacter sphaeroides/metabolismo , Rhodobacter sphaeroides/genética , Complejos de Proteína Captadores de Luz/metabolismo , Complejos de Proteína Captadores de Luz/química , Complejos de Proteína Captadores de Luz/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Glucolípidos/metabolismo , Glucolípidos/química , Modelos Moleculares , Cristalografía por Rayos XRESUMEN
Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.
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Hidrazinas , Neoplasias Renales , Triazoles , Tumor de Wilms , Humanos , Proteína Exportina 1 , Transporte Activo de Núcleo Celular , Carioferinas/genética , Carioferinas/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Línea Celular Tumoral , Apoptosis , Recurrencia Local de Neoplasia , Doxorrubicina/farmacología , Tumor de Wilms/tratamiento farmacológico , Tumor de Wilms/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMEN
Microbial rhodopsin-derived genetically encoded voltage indicators (GEVIs) are powerful tools for mapping bioelectrical dynamics in cell culture and in live animals. Förster resonance energy transfer (FRET)-opsin GEVIs use voltage-dependent changes in opsin absorption to modulate the fluorescence of an attached fluorophore, achieving high brightness, speed, and voltage sensitivity. However, the voltage sensitivity of most FRET-opsin GEVIs has been reported to decrease or vanish under two-photon (2P) excitation. Here we investigated the photophysics of the FRET-opsin GEVIs Voltron1 and 2. We found that the voltage sensitivity came from a photocycle intermediate, not from the opsin ground state. The voltage sensitivities of both GEVIs were nonlinear functions of illumination intensity; for Voltron1, the sensitivity reversed sign under low-intensity illumination. Using photocycle-optimized 2P illumination protocols, we demonstrate 2P voltage imaging with Voltron2 in barrel cortex of a live mouse. These results open the door to high-speed 2P voltage imaging of FRET-opsin GEVIs in vivo.
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BACKGROUND: Mitral stenosis/aortic atresia (MS/AA) has been reported as a high-risk variant of hypoplastic left heart syndrome (HLHS), potentially related to ventriculocoronary connections (VCCs) or endocardial fibroelastosis (EFE) and myocardial hypoperfusion. We aimed to identify echocardiographic and clinical factors associated with early death or transplant in this group. METHODS: Patients with HLHS MS/AA treated at our center between 2000 and 2020 were included. Pre-stage I palliation echocardiograms were reviewed. Certain imaging factors, such as determination of VCC, EFE, and measurement of tricuspid annular plane systolic excursion were measured from retrospective review of preoperative images; others were derived from clinical reports. Groups were compared according to primary outcome of death or transplant prior to stage II palliation. RESULTS: Of 141 patients included, 39 (27.7%) experienced a primary outcome. Ventriculocoronary connections were identified in 103 (73.0%) patients and EFE in 95 (67.4%) patients. Among imaging variables, smaller ascending aorta size (median, 2.2 [interquartile range (IQR) 1.7-2.8] vs 2.6 [2.2-3.4] mm, P = .01) was associated with primary outcome. There was similar frequency of VCC (74.4% vs 72.5%, P = .83), EFE (59.0% vs 72.5%, P = .19), moderate or greater tricuspid regurgitation (5.1% vs 5.9%, P = 1.00), and similar right ventricular systolic function (indexed tricuspid annular plane systolic excursion 32.5 ± 7.3 vs 31.4 ± 7.2 mm/m2, P = .47) in the primary outcome group compared to other patients. Clinical factors associated with primary outcome included lower birth weight (mean, 2.8 ± SD 0.8 vs 3.3 ± 0.5 kg, P = .0003), gestational age <37 weeks (31.6% vs 4.9%, P < .0001), longer cardiopulmonary bypass time (median, 112 [IQR, 93-162] vs 82 [71-119] minutes, P = .001), longer intensive care unit length of stay (median, 19 [IQR, 10-30] vs 10 [7-15] days, P = .001), and extracorporeal membrane oxygenation following stage I palliation (43.6% vs 8.8%, P < .0001). Presence of VCCs and EFE was not associated with death or transplant after controlling for birth weight and era of stage I palliation. CONCLUSIONS: In one of the largest reported single-center cohorts of HLHS MS/AA, there were few pre-stage I palliation imaging characteristics associated with primary outcome. Imaging findings evaluated in this study, including the presence of VCC and/or EFE as determined using highly sensitive echocardiogram criteria, should not preclude intervention, although impact on long-term outcomes requires further evaluation.
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Ecocardiografía , Síndrome del Corazón Izquierdo Hipoplásico , Estenosis de la Válvula Mitral , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/complicaciones , Síndrome del Corazón Izquierdo Hipoplásico/diagnóstico por imagen , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Síndrome del Corazón Izquierdo Hipoplásico/fisiopatología , Femenino , Masculino , Estudios Retrospectivos , Estenosis de la Válvula Mitral/complicaciones , Estenosis de la Válvula Mitral/fisiopatología , Estenosis de la Válvula Mitral/diagnóstico por imagen , Estenosis de la Válvula Mitral/diagnóstico , Ecocardiografía/métodos , Recién Nacido , LactanteRESUMEN
Deep-learning methods have revolutionized protein structure prediction and design but are presently limited to protein-only systems. We describe RoseTTAFold All-Atom (RFAA), which combines a residue-based representation of amino acids and DNA bases with an atomic representation of all other groups to model assemblies that contain proteins, nucleic acids, small molecules, metals, and covalent modifications, given their sequences and chemical structures. By fine-tuning on denoising tasks, we developed RFdiffusion All-Atom (RFdiffusionAA), which builds protein structures around small molecules. Starting from random distributions of amino acid residues surrounding target small molecules, we designed and experimentally validated, through crystallography and binding measurements, proteins that bind the cardiac disease therapeutic digoxigenin, the enzymatic cofactor heme, and the light-harvesting molecule bilin.
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Aprendizaje Profundo , Ingeniería de Proteínas , Proteínas , Aminoácidos/química , Cristalografía , ADN/química , Modelos Moleculares , Proteínas/química , Ingeniería de Proteínas/métodosRESUMEN
Older adults demonstrate impairments in navigation that cannot be explained by general cognitive and motor declines. Previous work has shown that older adults may combine sensory cues during navigation differently than younger adults, though this work has largely been done in dark environments where sensory integration may differ from full-cue environments. Here, we test whether aging adults optimally combine cues from two sensory systems critical for navigation: vision (landmarks) and body-based self-motion cues. Participants completed a homing (triangle completion) task using immersive virtual reality to offer the ability to navigate in a well-lit environment including visibility of the ground plane. An optimal model, based on principles of maximum-likelihood estimation, predicts that precision in homing should increase with multisensory information in a manner consistent with each individual sensory cue's perceived reliability (measured by variability). We found that well-aging adults (with normal or corrected-to-normal sensory acuity and active lifestyles) were more variable and less accurate than younger adults during navigation. Both older and younger adults relied more on their visual systems than a maximum likelihood estimation model would suggest. Overall, younger adults' visual weighting matched the model's predictions whereas older adults showed sub-optimal sensory weighting. In addition, high inter-individual differences were seen in both younger and older adults. These results suggest that older adults do not optimally weight each sensory system when combined during navigation, and that older adults may benefit from interventions that help them recalibrate the combination of visual and self-motion cues for navigation.
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Envejecimiento , Señales (Psicología) , Navegación Espacial , Humanos , Anciano , Masculino , Femenino , Envejecimiento/fisiología , Adulto Joven , Adulto , Navegación Espacial/fisiología , Persona de Mediana Edad , Percepción Visual/fisiología , Realidad Virtual , Percepción de Movimiento/fisiología , Anciano de 80 o más Años , AdolescenteRESUMEN
With the increasing demand for new materials for light-harvesting applications, spatiotemporal microscopy techniques are receiving increasing attention as they allow direct observation of the nanoscale diffusion of excitons. However, the use of pulsed and tightly focused laser beams generates light intensities far above those expected under sunlight illumination, leading to photodamage and nonlinear effects that seriously limit the accuracy and applicability of these techniques, especially in biological or atomically thin materials. In this work, we present a novel spatiotemporal microscopy technique that exploits structured excitation in order to dramatically decrease the excitation intensity, up to 10,000-fold when compared with previously reported spatiotemporal photoluminescence microscopy experiments. We tested our method in two different systems, reporting the first exciton diffusion measurement at illumination conditions below sunlight, both considering average power and peak exciton densities in an organic photovoltaic sample (Y6), where we tracked the excitons for up to five recombination lifetimes. Next, nanometer-scale energy transport was directly observed for the first time in both space and time in a printed monolayer of the light-harvesting complex 2 from purple bacteria.
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Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Through in vitro pharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.
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Endocycling cells grow and repeatedly duplicate their genome without dividing. Cells switch from mitotic cycles to endocycles in response to developmental signals during the growth of specific tissues in a wide range of organisms. The purpose of switching to endocycles, however, remains unclear in many tissues. Additionally, cells can switch to endocycles in response to conditional signals, which can have beneficial or pathological effects on tissues. However, the impact of these unscheduled endocycles on development is underexplored. Here, we use Drosophila ovarian somatic follicle cells as a model to examine the impact of unscheduled endocycles on tissue growth and function. Follicle cells normally switch to endocycles at mid-oogenesis. Inducing follicle cells to prematurely switch to endocycles resulted in the lethality of the resulting embryos. Analysis of ovaries with premature follicle cell endocycles revealed aberrant follicular epithelial structure and pleiotropic defects in oocyte growth, developmental gene amplification, and the migration of a special set of follicle cells known as border cells. Overall, these findings reveal how unscheduled endocycles can disrupt tissue growth and function to cause aberrant development.
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Proteínas de Drosophila , Drosophila , Animales , Femenino , Drosophila/genética , Proteínas de Drosophila/genética , Oogénesis/genética , Ciclo Celular/genética , Folículo Ovárico , Drosophila melanogaster/genéticaRESUMEN
Light-harvesting 2 (LH2) and reaction-centre light-harvesting 1 (RC-LH1) complexes purified from the photosynthetic bacterium Rhodobacter (Rba.) sphaeroides were reconstituted into proteoliposomes either separately, or together at three different LH2:RC-LH1 ratios, for excitation energy transfer studies. Atomic force microscopy (AFM) was used to investigate the distribution and association of the complexes within the proteoliposome membranes. Absorption and fluorescence emission spectra were similar for LH2 complexes in detergent and liposomes, indicating that reconstitution retains the structural and optical properties of the LH2 complexes. Analysis of fluorescence emission shows that when LH2 forms an extensive series of contacts with other such complexes, fluorescence is quenched by 52.6 ± 1.4%. In mixed proteoliposomes, specific excitation of carotenoids in LH2 donor complexes resulted in emission of fluorescence from acceptor RC-LH1 complexes engineered to assemble with no carotenoids. Extents of energy transfer were measured by fluorescence lifetime microscopy; the 0.72 ± 0.08 ns lifetime in LH2-only membranes decreases to 0.43 ± 0.04 ns with a ratio of 2:1 LH2 to RC-LH1, and to 0.35 ± 0.05 ns for a 1:1 ratio, corresponding to energy transfer efficiencies of 40 ± 14% and 51 ± 18%, respectively. No further improvement is seen with a 0.5:1 LH2 to RC-LH1 ratio. Thus, LH2 and RC-LH1 complexes perform their light harvesting and energy transfer roles when reconstituted into proteoliposomes, providing a way to integrate native, non-native, engineered and de novo designed light-harvesting complexes into functional photosynthetic systems.
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Proteolípidos , Rhodobacter sphaeroides , Rhodobacter sphaeroides/química , Rhodobacter sphaeroides/metabolismo , Citoplasma/metabolismo , Fotosíntesis , Transferencia de Energía , Proteínas Bacterianas/metabolismoRESUMEN
Stem cell therapies have become widely popular in orthopaedic surgery, with a recent interest in adipose-derived therapeutics. Adipose-derived mesenchymal signaling cells (ADSCs) and micronized adipose tissue (MAT) are unique therapies derived from different processing methods. Characterizing the most influential studies in lipoaspirate research can help clarify controversies in definitions, identify core literature, and further collective knowledge for educational purposes. The Science Citation Index Expanded subsection of the Web of Science Core Collection was systematically searched to identify the top 50 most cited publications (based on citation/year) on orthopaedic ADSCs or MAT research. Publication and study characteristics were extracted and reported using descriptive statistics. Level of evidence was assessed for applicable studies, and Spearman correlations were calculated to assess the relationship between citation data and level of evidence. The top 50 articles were published between the years 2003 and 2020, with 78% published in the year 2010 or later. The mean number of citations was 103.1 ± 81.1. The mean citation rate was 12.4 ± 6.0 citations per year. Of the 21 studies for which level of evidence was assessed, the majority were level III (10, 47.6%). The single study design most common among the top 50 cited articles was in vitro basic science studies (17 studies, 34%). Twenty-nine articles (58%) were classified as basic science or translational. Application to treat knee osteoarthritis was the most common focus of studies (14 studies, 28%), followed by in vitro analysis of growth factor and cell signaling markers (11 studies, 22%). No correlation was found between rank, citation rate, or year of publication and level of evidence. This study provides a current landscape on the most cited articles in lipoaspirates in orthopaedic surgery. With the expansion of ADSCs and MAT in the past two decades, this study provides the first historical landmark of the literature and a launching point for future research. Studies should explicitly state their processing methodology and whether their study investigates ADSCs or MAT to avoid misinformation.
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Procedimientos Ortopédicos , Ortopedia , Humanos , Bibliometría , Obesidad , Células MadreRESUMEN
Endocycling cells grow and repeatedly duplicate their genome without dividing. Cells switch from mitotic cycles to endocycles in response to developmental signals during the growth of specific tissues in a wide range of organisms. The purpose of switching to endocycles, however, remains unclear in many tissues. Additionally, cells can switch to endocycles in response to conditional signals, which can have beneficial or pathological effects on tissues. However, the impact of these unscheduled endocycles on development is underexplored. Here, we use Drosophila ovarian somatic follicle cells as a model to examine the impact of unscheduled endocycles on tissue growth and function. Follicle cells normally switch to endocycles at mid-oogenesis. Inducing follicle cells to prematurely switch to endocycles resulted in lethality of the resulting embryos. Analysis of ovaries with premature follicle cell endocycles revealed aberrant follicular epithelial structure and pleiotropic defects in oocyte growth, developmental gene amplification, and the migration of a special set of follicle cells known as border cells. Overall, these findings reveal how unscheduled endocycles can disrupt tissue growth and function to cause aberrant development.