Toward a more accurate 3D atlas of C. elegans neurons.

BACKGROUND: Determining cell identity in volumetric images of tagged neuronal nuclei is an ongoing challenge in contemporary neuroscience. Frequently, cell identity is determined by aligning and matching tags to an "atlas" of labeled neuronal positions and other identifying characteristics. Previous analyses of such C. elegans datasets have been hampered by the limited accuracy of such atlases, especially for neurons present in the ventral nerve cord, and also by time-consuming manual elements of the alignment process. RESULTS: We present a novel automated alignment method for sparse and incomplete point clouds of the sort resulting from typical C. elegans fluorescence microscopy datasets. This method involves a tunable learning parameter and a kernel that enforces biologically realistic deformation. We also present a pipeline for creating alignment atlases from datasets of the recently developed NeuroPAL transgene. In combination, these advances allow us to label neurons in volumetric images with confidence much higher than previous methods. CONCLUSIONS: We release, to the best of our knowledge, the most complete full-body C. elegans 3D positional neuron atlas, incorporating positional variability derived from at least 7 animals per neuron, for the purposes of cell-type identity prediction for myriad applications (e.g., imaging neuronal activity, gene expression, and cell-fate).

Preoperative prediction of sagittal imbalance in kyphosis secondary to ankylosing spondylitis after one-level three-column osteotomy.

BACKGROUND: This study aimed to determine preoperative predictors for sagittal imbalance in kyphosis secondary to ankylosing spondylitis (AS) after one-level three-column osteotomy. METHODS: A total of 55 patients with AS who underwent one-level three-column osteotomy were enrolled. The patients were divided into two groups according to sagittal vertical axis (SVA) value at the final follow-up (group A: SVA > 5 cm; group B: SVA ≤ 5 cm). The radiographic measures included global kyphosis, lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), sacral slope, T1 pelvic angle (TPA), SVA, osteotomized vertebral angle and PI and LL mismatch (PI - LL). Postoperative clinical outcomes were evaluated using Scoliosis Research Society-22 questionnaire (SRS-22) and Oswestry Disability Index (ODI). RESULTS: Fifty-five AS patients had an average follow-up of 30.6 ± 10.2 months (range 24-84 months). Group A had larger preoperative and postoperative LL, PT, PI - LL, TPA and SVA values compared with group B (P < 0.05), and no significant differences were found in ODI and SRS-22 scores between the two groups (P > 0.05). Preoperative LL, PT, PI - LL, TPA, and SVA values were positively correlated with the follow-up SVA value (P < 0.05). Among them, TPA > 40.9°, PI - LL > 32.5° and SVA > 13.7 cm were the top three predictors with the best accuracy to predict sagittal imbalance. Immediate postoperative SVA value of ≤ 7.4 cm was a key factor in reducing the risk of sagittal imbalance during follow-up. CONCLUSIONS: Preoperative TPA > 40.9°, PI - LL > 32.5° and SVA > 13.7 cm could predict sagittal imbalance in AS kyphosis after one-level three-column osteotomy, and additional osteotomies were recommended for this condition. Immediate postoperative SVA ≤ 7.4 cm was an optimal indicator for preventing sagittal imbalance. LEVEL OF EVIDENCE: IV.

Pareto-Optimal Data Compression for Binary Classification Tasks.

The goal of lossy data compression is to reduce the storage cost of a data set X while retaining as much information as possible about something (Y) that you care about. For example, what aspects of an image X contain the most information about whether it depicts a cat? Mathematically, this corresponds to finding a mapping X → Z ≡ f ( X ) that maximizes the mutual information I ( Z , Y ) while the entropy H ( Z ) is kept below some fixed threshold. We present a new method for mapping out the Pareto frontier for classification tasks, reflecting the tradeoff between retained entropy and class information. We first show how a random variable X (an image, say) drawn from a class Y ∈ { 1 , … , n } can be distilled into a vector W = f ( X ) ∈ R n - 1 losslessly, so that I ( W , Y ) = I ( X , Y ) ; for example, for a binary classification task of cats and dogs, each image X is mapped into a single real number W retaining all information that helps distinguish cats from dogs. For the n = 2 case of binary classification, we then show how W can be further compressed into a discrete variable Z = g ß ( W ) ∈ { 1 , … , m ß } by binning W into m ß bins, in such a way that varying the parameter ß sweeps out the full Pareto frontier, solving a generalization of the discrete information bottleneck (DIB) problem. We argue that the most interesting points on this frontier are "corners" maximizing I ( Z , Y ) for a fixed number of bins m = 2 , 3 , … which can conveniently be found without multiobjective optimization. We apply this method to the CIFAR-10, MNIST and Fashion-MNIST datasets, illustrating how it can be interpreted as an information-theoretically optimal image clustering algorithm. We find that these Pareto frontiers are not concave, and that recently reported DIB phase transitions correspond to transitions between these corners, changing the number of clusters.

A new vaccine targeting RANKL, prepared by incorporation of an unnatural Amino acid into RANKL, prevents OVX-induced bone loss in mice.

Bone homeostasis is maintained by a dynamic balance between osteoblastic bone formation and osteoclastic bone resorption. The receptor activator of nuclear-κB ligand (RANKL) is essential for the function of the bone-resorbing osteoclasts, and targeting RANKL has been proved highly successful in osteoporosis patients. This study aimed to design a novel vaccine targeting RANKL and evaluate its therapeutic effects in OVX-induced bone loss model. Anti-RANKL vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (pNO2Phe) into selected sites in the murine RANKL (mRANKL) molecule. Specifically, mutation of a single tyrosine residue Tyr234 (Y234) or Tyr240 (Y240) of mRANKL to pNO2Phe (thereafter named as Y234pNO2Phe or Y240pNO2Phe) induced a high titer antibody response in mice, whereas no significant antibody response was observed for the wild type mRANKL (WT mRANKL). The antiserum induced by Y234pNO2Phe or Y240pNO2Phe could efficiently prevent osteoclastogenesis in vitro. Moreover, immunization with Y234pNO2Phe or Y240pNO2Phe could also prevent OVX-induced bone loss in mice, suggesting that selected pNO2Phe-substituted mRANKL may pave the way for creating a novel vaccine to treat osteoporosis.

Neurological complications of thoracic posterior vertebral column resection for severe congenital spinal deformities.

PURPOSE: The risk of neurological injury during vertebral column resection is high. In this study, we investigated the incidence and risk factors for neurological complications when treating spinal deformities by thoracic posterior vertebral column resection (PVCR). METHODS: Between 2008 and 2013, there were 62 consecutive patients (34 female patients and 28 male; the mean age: 16.3 years, range 6-46 years) treated with thoracic PVCR. We retrospectively reviewed the clinical records to obtain demographic and radiographic data, operative time, estimated blood loss (EBL, the ratio between circulating and lost blood), bleeding volume (the lost blood), number of vertebrae fused, number of vertebrae resected, usage of titanium mesh cage, and intraoperative neuromonitoring data. Multi-factor logistic regression was used to find the major risk factors for neurological complications. RESULTS: The average follow-up period was 46 months (range 24-88 months); no patients were lost to follow up. The average operative time was 524.8 ± 156.8 min (range 165.0-880.0 min), the average bleeding volume was 2585 ± 2210 ml (100-9600 ml), and the average estimated blood loss was 75.8% (9-278%). Ten patients (16.1%) developed post-operative neurological complications (nine transient and one permanent). Multi-factor logistic regression revealed that the risk factors for neurological complications were age ≥18 years, pulmonary dysfunction, and EBL >50%. CONCLUSIONS: Thoracic PVCR can lead to satisfactory outcomes in the treatment of severe spinal deformities. Risk factors for neurological complications include the age over 18 years, presence of pulmonary dysfunction, and EBL greater than 50%. The pulmonary dysfunction can be regarded as the most valuable indicator to measure the severity of the spine deformity.

Preventing and reversing vacuum-induced optical losses in high-finesse tantalum (V) oxide mirror coatings.

High-finesse optical cavities placed under vacuum are foundational platforms in quantum information science with photons and atoms. We study the vacuum-induced degradation of high-finesse optical cavities with mirror coatings composed of SiO2-Ta2O5 dielectric stacks, and present methods to protect these coatings and to recover their initial low loss levels. For separate coatings with reflectivities centered at 370 nm and 422 nm, a vacuum-induced continuous increase in optical loss occurs if the surface-layer coating is made of Ta2O5, while it does not occur if it is made of SiO2. The incurred optical loss can be reversed by filling the vacuum chamber with oxygen at atmospheric pressure, and the recovery rate can be strongly accelerated by continuous laser illumination at 422 nm. Both the degradation and the recovery processes depend strongly on temperature. We find that a 1 nm-thick layer of SiO2 passivating the Ta2O5 surface layer is sufficient to reduce the degradation rate by more than a factor of 10, strongly supporting surface oxygen depletion as the primary degradation mechanism.

Mucoid Degeneration of the Anterior Cruciate Ligament: Characteristics and Conservative Management.

Clinical and radiographic characteristics of mucoid degeneration of the anterior cruciate ligament (MD-ACL) were poorly documented in previous literature. And the optimal management strategy for MD-ACL remains unclear. Here, we summarized the characteristics associated with MD-ACL, and evaluated the clinical outcome of conservative management to MD-ACL.A total of 18 knees in 18 patients diagnosed with MD-ACL were collected and reviewed retrospectively. Sixteen patients underwent conservative management and two patients underwent arthroscopic surgery. Baseline demographic, clinical data, and pathologic changes of knee in magnetic resonance imaging (MRI) were recorded. Clinical outcome was evaluated with Visual Analogue Scale (VAS) and Oxford Knee Score (OKS).The most common clinical characteristic in patients with MD-ACL was knee pain (18/18), and seconded by mobility limitation (38.9%, 7/18). All patients presented a typical celery stalk sign with increased signal and diffuse thickening volume in the ACL in MRI. Thirteen patients companied with meniscus tear (72.2%, 13/18), and nine complicated with cartilage injury (50.0%, 9/18). Sixteen patients who underwent conservative treatment were followed up for 21.8 months, and a positive clinical outcome was observed with VAS decreasing from 5.3 ± 2.3 to 1.5 ± 1.9 and OKS decreasing from 27.5 ± 12.7 to 17.9 ± 11.8 (p < 0.001). The post-OKS score was highly correlated with age, duration of disease, and meniscus tear (r = 0.844, 0.707, and 0.474, p < 0.05, respectively). And the post-VAS highly correlated with age (r = 0.693, p < 0.05). Two patients who underwent arthroscopic surgery were followed up for 24.5 months, and the pain and function of knee was improved.Knee pain and meniscus tear was the main characteristic of MD-ACL in clinical and radiographic exam. Conservative treatment could be an alternative management for treatment of MD-ACL with positive clinical outcome. Old age, long duration of disease and complications from meniscus tears were associated with inferior outcome of conservative treatment for MD-ACL. LEVEL OF EVIDENCE: IV.

Electrochemical Detection of Different Foodborne Bacteria for Point-of-Care Applications.

Bacterial infections resulting from foodborne pathogenic bacteria cause millions of infections that greatly threaten human health and are one of the leading causes of mortality around the world. To counter this, the early, rapid, and accurate detection of bacterial infections is very important to address serious health issue concerns. We, therefore, present an electrochemical biosensor based on aptamers that selectively bind with the DNA of specific bacteria for the accurate and rapid detection of various foodborne bacteria for the selective determination of bacterial infection types. Different aptamers were synthesized and immobilized on Au electrodes for selective bindings of different types of bacterial DNA (Escherichia coli, Salmonella enterica, and Staphylococcus aureus) for the accurate detection and quantification of bacterial concentrations from 101 to 107 CFU/mL without using any labeling methods. Under optimized conditions, the sensor showed a good response to the various concentrations of bacteria, and a robust calibration curve was obtained. The sensor could detect the bacterial concentration at meager quantities and possessed an LOD of 4.2 × 101, 6.1 × 101, and 4.4 × 101 CFU/mL for S. Typhimurium, E. Coli, and S. aureus, respectively, with a linear range from 100 to 104 CFU/mL for the total bacteria probe and 100 to 103 CFU/mL for individual probes, respectively. The proposed biosensor is simple and rapid and has shown a good response to bacterial DNA detections and thus can be applied in clinical applications and food safety monitoring.

Prediction formulae of sagittal alignment in thoracolumbar kyphosis secondary to ankylosing spondylitis after osteotomy.

To construct and validate prediction formulae of sagittal alignment in thoracolumbar kyphosis secondary to ankylosing spondylitis (AS) after osteotomy. A total of 115 AS patients who suffered from thoracolumbar kyphosis and underwent osteotomy were enrolled, with 85 patients in derivation group and 30 patients in validation group. Radiographic parameters were measured on lateral radiographs, including thoracic kyphosis, lumbar lordosis (LL), T1 pelvic angel (TPA), sagittal vertical axis (SVA), osteotomized vertebral angle, pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), and PI and LL mismatch (PI-LL). Prediction formulae of SS, PT, TPA and SVA were established; and their effectiveness was evaluated. There was no significant difference in baseline characteristics between the two groups (p > 0.05). In derivation group, LL and PI-LL were correlated with SS, and were then used to establish the prediction formula of SS[SS = - 12.791-0.765 × (LL) + 0.357 × (PI-LL), R2 = 68.3%]; PI and PI-LL were correlated with PT, and the prediction formula of PT were thus established[PT = 12.108 + 0.402 × (PI-LL) + 0.252 × (PI), R2 = 56.8%]; PT, PI-LL and LL were correlated with TPA, and were used to establish the prediction formula of TPA[TPA = 0.225 + 0.597 × (PT) + 0.464 × (PI-LL)-0.161 × (LL), R2 = 87.4%]; PT, PI-LL and age were correlated with SVA, and were used to establish the prediction formula of SVA[SVA = 36.157 + 2.790 × (PI-LL) + 1.657 × (Age)-1.813 × (PT), R2 = 41.5%]. In validation group, the predictive SS, PT, TPA and SVA were basically consistent with corresponding real values; and the mean error between predictive values and real values was of 1.3° in SS, 1.2° in PT, 1.1° in TPA and 8.6 mm in SVA. Postoperative SS, PT, TPA and SVA could be predicted with PI and the planned LL and PI-LL using prediction formulae, providing a method for AS kyphosis to plan postoperative sagittal alignment. Change of pelvic posture after osteotomy was quantitatively evaluated using the formulae.

Pathway-based mean-field model for Escherichia coli chemotaxis.

We develop a mean-field theory for Escherichia coli chemotaxis based on the coupled spatiotemporal dynamics of the cell population and the mean receptor methylation level field. This multiscale model connects the cells' population level motility behavior with the molecular level pathway dynamics. It reveals a simple scaling dependence of the chemotaxis velocity on the adaptation rate in exponential gradients. It explains the molecular origin of a maximum chemotaxis velocity. Simulations of our model in various spatiotemporal stimuli profiles show quantitative agreements with experiments. Moreover, it predicts a surprising reversal of chemotaxis group velocity in traveling wave environments. Our approach may be used to bridge molecular level pathway dynamics with cellular behavior in other biological systems.

Frequency-dependent Escherichia coli chemotaxis behavior.

We study Escherichia coli chemotaxis behavior in environments with spatially and temporally varying attractant sources by developing a unique microfluidic system. Our measurements reveal a frequency-dependent chemotaxis behavior. At low frequency, the E. coli population oscillates in synchrony with the attractant. In contrast, in fast-changing environments, the population response becomes smaller and out of phase with the attractant waveform. These observations are inconsistent with the well-known Keller-Segel chemotaxis equation. A new continuum model is proposed to describe the population level behavior of E. coli chemotaxis based on the underlying pathway dynamics. With the inclusion of a finite adaptation time and an attractant consumption rate, our model successfully explains the microfluidic experiments at different stimulus frequencies.

Optimal immediate sagittal alignment for kyphosis in ankylosing spondylitis following corrective osteotomy.

Purpose: To investigate the optimal immediate sagittal alignment of kyphosis in ankylosing spondylitis (AS) following corrective osteotomy. Methods: Seventy-seven AS patients who underwent osteotomy were enrolled. Radiographic parameters, including global kyphosis (GK), lumbar lordosis (LL), T1 spinopelvic inclination (T1SPI), sagittal vertical axis (SVA), T1 pelvic angle (TPA), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), and PI and LL mismatch (PI-LL), were collected. The clinical outcome was evaluated using the Scoliosis Research Society-22 (SRS-22) questionnaire and Oswestry Disability Index (ODI). At the final follow-up, SVA > 5 cm was regarded as sagittal imbalance, and a total ODI ≤ 20 or total SRS-22 score ≥4 was considered to indicate a good clinical outcome. Results: Seventy-seven patients with an average age of 37.4 ± 8.6 years were followed up for 29.4 ± 4.2 months. At the final follow-up, GK, LL, PT, SS, TPA, and T1SPI showed some degree of correction loss (P < 0.05). The follow-up parameters could be predicted with the immediate postoperative parameters through their linear regression equation (P < 0.05). The postoperative immediate T1SPI, TPA, SVA, and PI were also highly correlated with the clinical outcome (ODI and/or SRS-22) at the final follow-up (P < 0.05). Based on the relationship, the optimal immediate sagittal alignment for obtaining good clinical outcome was determined: T1SPI ≤ 0.9°, TPA ≤ 31.5°, and SVA ≤ 9.3cm. AS patients with PI ≤ 49.2° were more likely to achieve the optimal alignment and obtained lower ODI and a lower incidence of sagittal imbalance than those with PI > 49.2° at the final follow-up (P < 0.05). Conclusion: Postoperative immediate parameters could be used to predict the final follow-up parameters and clinical outcome. The optimal postoperative immediate sagittal alignment of AS patients was T1SPI ≤ 0.9°, TPA ≤ 31.5°, and SVA ≤ 9.3 cm, providing a reference for kyphosis correction and a means for clinical outcome evaluation. Patients with a lower PI (≤49.2°) were more likely to achieve optimal alignment and obtain satisfactory clinical outcomes.

Toward an artificial intelligence physicist for unsupervised learning.

We investigate opportunities and challenges for improving unsupervised machine learning using four common strategies with a long history in physics: divide and conquer, Occam's razor, unification, and lifelong learning. Instead of using one model to learn everything, we propose a paradigm centered around the learning and manipulation of theories, which parsimoniously predict both aspects of the future (from past observations) and the domain in which these predictions are accurate. Specifically, we propose a generalized mean loss to encourage each theory to specialize in its comparatively advantageous domain, and a differentiable description length objective to downweight bad data and "snap" learned theories into simple symbolic formulas. Theories are stored in a "theory hub," which continuously unifies learned theories and can propose theories when encountering new environments. We test our implementation, the toy "artificial intelligence physicist" learning agent, on a suite of increasingly complex physics environments. From unsupervised observation of trajectories through worlds involving random combinations of gravity, electromagnetism, harmonic motion, and elastic bounces, our agent typically learns faster and produces mean-squared prediction errors about a billion times smaller than a standard feedforward neural net of comparable complexity, typically recovering integer and rational theory parameters exactly. Our agent successfully identifies domains with different laws of motion also for a nonlinear chaotic double pendulum in a piecewise constant force field.

A novel recombinant RANKL vaccine prepared by incorporation of an unnatural amino acid into RANKL and its preventive effect in a murine model of collagen-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis, bone atrophy, and subsequent progressive destruction of articular tissue. Targeted inhibition of receptor activator of NF-kB ligand (RANKL) has been highly successful in preventing RA-mediated bone erosion in animal models and patients, suggesting that development of a RANKL vaccine might be of therapeutic value. Our previous study has shown that the recombinant RANKL vaccine Y234pNO2Phe, generated by replacement of a single tyrosine residue (Tyr234) in murine RANKL (mRANKL) with p-nitrophenylalanine (pNO2Phe), induces a high titer antibody response and prevents ovariectomy (OVX)-induced bone loss in mice. This aim of this study was to further evaluate the vaccine's preventive effects in a murine model of collagen-induced arthritis. The results of this study showed that Y234pNO2Phe not only induced a high titer antibody response and inhibited osteoclastogenesis but also significantly prevented bone erosion and ameliorated the severity of a collagen-induced arthritis (CIA) model in mice. Moreover, use of the vaccine improved the clinical situations of the CIA mice. These results suggest a potential application of an anti-RANKL vaccine in the treatment of RA-induced bone erosion.

Safety and Efficacy of Single-Stage Surgical Treatment for Congenital Scoliosis Associated with Intraspinal Mass.

For congenital scoliosis associated with intraspinal anomaly, surgical treatment is often advocated. However, the safety and efficacy of single-stage intraspinal mass resection and scoliosis correction remain unclear. The purpose of this study was to retrospectively evaluate the feasibility and risk factors of single-stage surgical treatment for congenital scoliosis associated with intraspinal mass. Patients' clinical records were reviewed for demographic and radiographic data, operating time, intraoperative blood loss, perioperative complications, and postoperative pathologic results. Two female and 5 male patients with an average age of 19.14 ± 7.52 years (range, 11-31 years) were evaluated. Patients were followed for a minimum of 24 months after initial surgical treatment, with an average of 49.71 ± 32.90 months (range, 27-99 months). Spinal curvature was corrected from an average of 69.57 ± 20.44° to 29.14 ± 9.87°, demonstrating a mean correction rate of 55.05% ± 18.75%. No obvious loss of correction was observed at the final follow-up. Complications included transient neurologic deficit, cerebrospinal fluid leakage, and intraspinal mass recurrence in 1 patient each. There was no paralysis or permanent nerve damage. In conclusion, simultaneous intraspinal mass resection and scoliosis correction appears to be safe and effective.