Single-Cell and Spatial Transcriptomic Analysis of Human Skin Delineates Intercellular Communication and Pathogenic Cells.

Epidermal homeostasis is governed by a balance between keratinocyte proliferation and differentiation with contributions from cell-cell interactions, but conserved or divergent mechanisms governing this equilibrium across species and how an imbalance contributes to skin disease are largely undefined. To address these questions, human skin single-cell RNA sequencing and spatial transcriptomics data were integrated and compared with mouse skin data. Human skin cell-type annotation was improved using matched spatial transcriptomics data, highlighting the importance of spatial context in cell-type identity, and spatial transcriptomics refined cellular communication inference. In cross-species analyses, we identified a human spinous keratinocyte subpopulation that exhibited proliferative capacity and a heavy metal processing signature, which was absent in mouse and may account for species differences in epidermal thickness. This human subpopulation was expanded in psoriasis and zinc-deficiency dermatitis, attesting to disease relevance and suggesting a paradigm of subpopulation dysfunction as a hallmark of the disease. To assess additional potential subpopulation drivers of skin diseases, we performed cell-of-origin enrichment analysis within genodermatoses, nominating pathogenic cell subpopulations and their communication pathways, which highlighted multiple potential therapeutic targets. This integrated dataset is encompassed in a publicly available web resource to aid mechanistic and translational studies of normal and diseased skin.

High-fidelity qutrit entangling gates for superconducting circuits.

Ternary quantum information processing in superconducting devices poses a promising alternative to its more popular binary counterpart through larger, more connected computational spaces and proposed advantages in quantum simulation and error correction. Although generally operated as qubits, transmons have readily addressable higher levels, making them natural candidates for operation as quantum three-level systems (qutrits). Recent works in transmon devices have realized high fidelity single qutrit operation. Nonetheless, effectively engineering a high-fidelity two-qutrit entanglement remains a central challenge for realizing qutrit processing in a transmon device. In this work, we apply the differential AC Stark shift to implement a flexible, microwave-activated, and dynamic cross-Kerr entanglement between two fixed-frequency transmon qutrits, expanding on work performed for the ZZ interaction with transmon qubits. We then use this interaction to engineer efficient, high-fidelity qutrit CZ† and CZ gates, with estimated process fidelities of 97.3(1)% and 95.2(3)% respectively, a significant step forward for operating qutrits on a multi-transmon device.

DNA Methylation, Aging, and Cancer Risk: A Mini-Review.

Accumulation of somatic mutations and genomic instability are hallmarks of both aging and cancer. Epigenetic alterations occur across cell types and tissues with advancing age. DNA methylation-based estimates of biologic age can predict important age-related outcomes, including risk of frailty and mortality, and most recently have been shown to be associated with risk of developing cancer. In this mini-review, we examine pathways known to exhibit altered methylation in aging tissues, pre-malignant lesions, and tumors and review methodologies of epigenetic clocks that reliably predict cancer risk, including those derived from methylation studies of peripheral blood, as well as those methylation levels from within the tissues at high risk of cancer.

Increased Rate of Epigenetic Aging in Men Living With HIV Prior to Treatment.

Background: Epigenetic aging is accelerated in tissues of persons living with HIV (PLWH) and may underlie the early onset of age-related illnesses. This study examines the rate-of-change in epigenetic age in PLWH following HIV infection but before HAART, using archived longitudinal samples from the Multicenter AIDS Cohort Study. Methods: DNA was isolated from cryopreserved peripheral blood mononuclear cells from 101 men living with HIV, with baseline visit <2.5 years after HIV seroconversion (Visit 1) and follow-up visit <1.5 years before the initiation of HAART (Visit 2), and 100 HIV-uninfected men matched on age and visits with comparable time intervals. DNA methylation (DNAm) age was estimated for five clocks (Pan-tissue, Extrinsic, Phenotypic, Grim, and Skin & Blood age), and a DNAm-based estimate of telomere length (DNAmTL). Multivariate linear regression models were used to examine baseline factors associated with rate-of-aging, defined as (DNAm age visit 2-DNAm age visit 1)/(age visit 2-age visit 1). Results: Epigenetic age increased approximately twice as fast in PLWH as uninfected controls (Pan-tissue, Extrinsic, and Phenotypic clocks). Shortening of DNAmTL was nearly 3-fold faster in PLWH than controls. Faster rate-of-aging was associated with HIV status (Pan-Tissue, Extrinsic, Phenotypic, and DNAmTL), white race (Extrinsic, DNAmTL), higher cumulative HIV viral load (Grim), and lower baseline DNAm age (Phenotypic, Skin & Blood). Conclusion: Epigenetic rates-of-aging were significantly faster for untreated PLWH. Our findings expand on the important impact of HIV infection on biologic aging, both in elevating epigenetic age and increasing the rate-of-aging in the years following infection.

Design and validation of a cadaveric knee joint loading device compatible with magnetic resonance imaging and computed tomography.

PURPOSE: Design and validation of a magnetic resonance and computed tomography compatible device capable of applying physiologically relevant muscle forces to cadaveric knee joints with high levels of repeatability and reproducibility. METHODS: Repeatability and reproducibility were assessed with two porcine stifle joints. Load was applied to joints at full extension, five and 15 degrees of flexion through two cables simulating the lines of action of the quadriceps and hamstrings muscles. Five repeatability and five reproducibility trials were performed at each flexion angle. Standard deviations (SDs) of joint angle and load were recorded. RESULTS: For repeatability, the maximum SDs for joint angle were 1.26° (flexion), 1.54° (ab/adduction) and 0.90° (in/external rotation). The maximum SDs for joint load were 4.60 N (anterior/posterior), 7.36 N (medial/lateral), and 42.6N (axial). For reproducibility, the maximum SDs for joint angle were 0.84° (flexion), 0.66° (ab/adduction) and 0.92° (in/external rotation). The maximum SDs for joint load were 6.40 N (anterior/posterior), 11.7 N (medial/lateral), and 39.7 N (axial). CONCLUSIONS: This level of repeatability and reproducibility is within intra-subject variability of measured gait kinematics. Therefore, this device is considered to be an effective tool for in vitro testing of knee soft tissue repair.

A novel mathematical model of the sagittal spine: application to pedicle subtraction osteotomy for correction of fixed sagittal deformity.

BACKGROUND CONTEXT: The C7 plumb line method oversimplifies the true complexity of the spine. In a previous study, we mathematically modeled the normal spine using the spline function, enabling quantification of previously undescribed measurements such as area under the curve (AUC) and average sagittal position. The spine in fixed sagittal imbalance and the results of surgical correction have not been studied in a similar manner. PURPOSE: To quantitatively evaluate changes in spinal conformation in patients who underwent pedicle subtraction osteotomy (PSO) using measures derived from the spline model and to correlate these changes with functional outcome. STUDY DESIGN: Application of a mathematical model to a cohort of patients who underwent deformity surgery. PATIENT SAMPLE: Thirty-four consecutive patients with fixed sagittal imbalance who underwent PSO from 2001 to 2003. OUTCOME MEASURES: Preoperative and postoperative 22-item Scoliosis Research Society (SRS-22) Outcomes Questionnaire scores were used for functional assessment. METHODS: Radiographs of the 34 patients who underwent thoracic or lumbar PSO with at least 2 years of follow-up were examined at three time points. The posterosuperior aspect of each vertebral body was chosen as a representative point for the spinal sagittal curve. A cubic spline function was derived from these points. From this function, the AUCs and average sagittal positions of the thoracic, lumbar, and thoracolumbar segments were calculated. RESULTS: The average sagittal position does not overlap the C7 plumb line in deformity patients, but is a much more stable measure. In the lumbar PSO cohort, the lumbar AUC and average sagittal position were not significantly different among normal, preoperative, and postoperative groups. The thoracic and thoracolumbar AUCs and average sagittal positions were dramatically more positive in the preoperative cohort compared with normals; these values significantly decreased toward neutrality after lumbar PSO, but remained abnormal. In the thoracic PSO cohort, the lumbar, thoracic, and thoracolumbar AUCs and average sagittal positions were not significantly different among normal, preoperative, and postoperative groups. The changes in thoracolumbar AUC and average sagittal position were better predictors of the SRS-22 total score than the change in C7 plumb line. CONCLUSIONS: The average sagittal position more comprehensively captures the nuances of a nonlinear spinal curve. Subcurve analysis enabled by the spline model is particularly helpful in assessing deformity and surgical correction on a segmental level. Increased sensitivity to the nuances of the spinal curve in this model results in superior correlation with clinical outcomes when compared with the C7 plumb line. We feel that a critical examination of the spinal curve will lead to improved understanding of deformity and planning for an optimal correction.

Clinical and radiographic outcomes of thoracic and lumbar pedicle subtraction osteotomy for fixed sagittal imbalance.

OBJECT: The authors conducted a study to evaluate the radiographically documented and functional outcomes obtained in patients who underwent pedicle subtraction osteotomy (PSO). They also compared outcomes after classification of cases into thoracic and lumbar PSO subgroups. METHODS: The authors analyzed data obtained in 35 consecutive PSO-treated patients with sagittal imbalance. One surgeon performed all surgeries. The minimal follow-up period was 2 years. Events during the perioperative course and complications were noted. Standing long-film radiographs of the spine were obtained and measurements were made preoperatively, immediately postoperatively, and at most recent follow-up examination. The modified Prolo Scale and the 22-item Scoliosis Research Society (SRS-22) Outcomes Questionnaire were administered. Early complications after PSO included neurological injury, wound-related problems, and nosocomial infections. Late complications were limited to pseudarthrosis and attendant instrumentation failure. Early and late complication rates ranged from 10 to 30% for both thoracic and lumbar PSO cohorts. Lumbar PSO was associated with improvements in local, segmental, and global measures of sagittal balance, whereas thoracic PSO was only associated with local improvement. Most patients rated their functional status as fair to good according to the modified Prolo Scale and reported, according to the SRS-22 Outcomes Questionnaire, that they were satisfied with the overall treatment of their back condition. CONCLUSIONS: The ability to perform a PSO at both lumbar and thoracic levels is a powerful asset for the spine surgeon treating spinal deformity. In the present study radiographic and clinical outcomes were superior when PSO was used to treat lumbar deformity rather than thoracic deformity because of several anatomical and technical obstacles that hindered the thoracic procedure. Nevertheless, the thoracic PSO proved a useful addition with which to produce regional improvement in sagittal balance for patients with a fixed thoracic kyphosis.