SINGLE CELL DISSECTION OF DEVELOPMENTAL ORIGINS AND TRANSCRIPTIONAL HETEROGENEITY IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA.

Sequencing of bulk tumor populations has improved genetic classification and risk assessment of B-ALL, but does not directly examine intratumor heterogeneity or infer leukemia cellular origins. We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) and compared them to a reference map of normal human B-cell development established using both functional and molecular assays. Intra-sample heterogeneity was driven by cell cycle, metabolism, differentiation, and inflammation transcriptional programs. By inference of B lineage developmental state composition, nearly all samples possessed a high abundance of pro-B cells, with variation between samples mainly driven by sub-populations. However, ZNF384- r and DUX4- r B-ALL showed composition enrichment of hematopoietic stem cells, BCR::ABL1 and KMT2A -r ALL of Early Lymphoid progenitors, MEF2D -r and TCF3::PBX1 of Pre-B cells. Enrichment of Early Lymphoid progenitors correlated with high-risk clinical features. Understanding variation in transcriptional programs and developmental states of B-ALL by scRNA-seq refines existing clinical and genomic classifications and improves prediction of treatment outcome.

The role of spatial structure in at-risk metapopulation recoveries.

Metapopulations are often managed as a single contiguous population despite the spatial structure underlying their local and regional dynamics. Disturbances from human activities can also be spatially structured with mortality impacts concentrated to just a few local populations among the aggregate. Scale transitions between local and regional processes can generate emergent properties whereby the whole system can fail to recover as quickly as expected for an equivalent single population. Here, we draw on theory and empirical case studies to ask: what is the consequence of spatially structured ecological and disturbance processes on metapopulation recoveries? We suggest that exploring this question could help address knowledge gaps for managing metapopulations including: Why do some metapopulations recover quickly while others remain collapsed? And, what risks are unaccounted for when metapopulations are managed at aggregate scales? First, we used model simulations to examine how scale transitions among ecological and disturbance conditions interact to generate emergent metapopulation recovery outcomes. In general, we found that the spatial structure of disturbance was a strong determinant of recovery outcomes. Specifically, disturbances that unevenly impacted local populations consistently generated the slowest recoveries and highest conservation risks. Ecological conditions that dampened metapopulation recoveries included low dispersal, variable local demography, sparsely connected habitat networks, and spatially and temporally correlated stochastic processes. Second, we illustrate the unexpected challenges of managing metapopulations by examining the recoveries of three USA federally listed endangered species: Florida Everglade snail kites, California and Alaska sea otters, and Snake River Chinook salmon. Overall, our results show the pivotal role of spatial structure in metapopulation recoveries whereby the interplay between local and regional processes shapes the resilience of the whole system. With this understanding, we provide guidelines for resource managers tasked with conserving and managing metapopulations and identify opportunities for research to support the application of metapopulation theory to real-world challenges.

An Automated Continuous Synthesis and Isolation for the Scalable Production of Aryl Sulfonyl Chlorides.

In this work, a continuous system to produce multi-hundred-gram quantities of aryl sulfonyl chlorides is described. The scheme employs multiple continuous stirred-tank reactors (CSTRs) and a continuous filtration system and incorporates an automated process control scheme. The experimental process outlined is intended to safely produce the desired sulfonyl chloride at laboratory scale. Suitable reaction conditions were first determined using a batch-chemistry design of experiments (DOE) and several isolation methods. The hazards and incompatibilities of the heated chlorosulfonic acid reaction mixture were addressed by careful equipment selection, process monitoring, and automation. The approximations of the CSTR fill levels and pumping performance were measured by real-time data from gravimetric balances, ultimately leading to the incorporation of feedback controllers. The introduction of process automation demonstrated in this work resulted in significant improvements in process setpoint consistency, reliability, and spacetime yield, as demonstrated in medium- and large-scale continuous manufacturing runs.

Marine and freshwater regime changes impact a community of migratory Pacific salmonids in decline.

Marine and freshwater ecosystems are increasingly at risk of large and cascading changes from multiple human activities (termed "regime shifts"), which can impact population productivity, resilience, and ecosystem structure. Pacific salmon exhibit persistent and large fluctuations in their population dynamics driven by combinations of intrinsic (e.g., density dependence) and extrinsic factors (e.g., ecosystem changes, species interactions). In recent years, many Pacific salmon have declined due to regime shifts but clear understanding of the processes driving these changes remains elusive. Here, we unpacked the role of density dependence, ecosystem trends, and stochasticity on productivity regimes for a community of five anadromous Pacific salmonids (Steelhead, Coho Salmon, Pink Salmon, Dolly Varden, and Coastal Cutthroat Trout) across a rich 40-year time-series. We used a Bayesian multivariate state-space model to examine whether productivity shifts had similarly occurred across the community and explored marine or freshwater changes associated with those shifts. Overall, we identified three productivity regimes: an early regime (1976-1990), a compensatory regime (1991-2009), and a declining regime (since 2010) where large declines were observed for Steelhead, Dolly Varden, and Cutthroat Trout, intermediate declines in Coho and no change in Pink Salmon. These regime changes were associated with multiple cumulative effects across the salmon life cycle. For example, increased seal densities and ocean competition were associated with lower adult marine survival in Steelhead. Watershed logging also intensified over the past 40 years and was associated with (all else equal) ≥97% declines in freshwater productivity for Steelhead, Cutthroat, and Coho. For Steelhead, marine and freshwater dynamics played approximately equal roles in explaining trends in total productivity. Collectively, these changing environments limited juvenile production and lowered future adult returns. These results reveal how changes in freshwater and marine environments can jointly shape population dynamics among ecological communities, like Pacific salmon, with cascading consequences to their resilience.

Modeling and Simulation of Fabricated Graphene Nanoplates/Polystyrene Nanofibrous Membrane for DCMD.

Membrane distillation is an active technique that provides pure water with very good rejection and could be applied to water of extremely high salinity. The low productivity of membrane distillation needs intensive efforts to be competitive with other desalination techniques. In this current study, a composite (PS/GNP) membrane, which is composed of polystyrene (PS) based and 0.25% weight percent graphene nanoplates (GNP) has been fabricated via electrospinning and compared with the blank PS membrane. SEM, FTIR, contact angle and porosity characterization have been performed, and the results show that the validity of the predefined conditions, and the contact angle of the composite membrane, which is found to be 91.68°, proved the hydrophobic nature of the composite membrane. A numerical simulation using Ansys 2020 software has been introduced to study the performance of the fabricated composite membrane when used in direct contact membrane distillation (DCMD). The numerical model has been validated with experimental work from the literature and showed an excellent match. The blank PS and composite PS/GNP membranes have been investigated and compared at different operating conditions, i.e., hot water supply temperature and system flow rate. The results show that the composite PS/GNP membrane outperforms the blank PS membrane at all studied operating conditions.

Impact of femoroacetabular impingement and dysplasia of the hip on hip joint sphericity.

BACKGROUND: This paper presents a parametric investigation into the effect of femoroacetabular impingement (FAI) and developmental dysplasia of the hip (DDH) on the sphericity of the femoral supra-equatorial region and acetabulum. METHODS: Radiographic parameters from x-rays, sphericity calculations and visualisation and joint contact area and pressure from FE models of 10 DDH, FAI and normal hips were analysed and compared both within and between hip groups. RESULTS: The sphericity of the acetabulum and femoral head of both the DDH and FAI groups was found to be less than that for normal hips but the variation in sphericity was greater (range 2.4% for normal hips, compared to 3.3% and 3.1% for the FAI and DDH groups respectively). For the DDH group, femoral head sphericity was found to correlate strongly with 2 of the radiographic parameters used to diagnose the condition, CE angle and Sharp angle. For FAI and DDH hips peak contact pressure primarily occurred in Ilizaliturri Zone 2 (anterior-superior region) in the acetabulum and femoral head which corresponded with increased aspherity in this region compared to the normal hip group. These findings correlate with loading and damage patterns reported in the literature. Additionally, our analysis identified a protrusion of bone in Ilizaliturri Zones 1 and 6 (anterior-inferior region) of the acetabulum of a subgroup of FAI hips, whose existence was confirmed using a full-scale hip model fabricated using a 3D printer, which we believe could result in cartilage damage. CONCLUSION: We postulate that such protrusions could potentially explain residual symptoms and unaddressed structural deformity in patients who have undergone FAI surgery.

Performance evaluation of surgical techniques for treatment of scapholunate instability in a type II wrist.

We investigated the performance of three tenodesis techniques, modified Brunelli, Corella, and scapholunate axis (SLAM) methods in repairing scapholunate interosseous ligament (SLIL) disruption for a type II wrist using finite element-based virtual surgery and compared the results with those of a previous investigation for a type I wrist. In addition, a comparison of the carpal mechanics of type I and type II wrists was undertaken in order to elucidate the difference between the two types. For the type II wrist, following simulated SLIL disruption, the Corella reconstruction technique provided a superior outcome, restoring dorsal gap, volar gap, and SL angle to within 3.5%, 7.1%, and 8.4%, respectively, of the intact wrist. Moreover, application of the ligament reconstruction techniques did not significantly alter the motion pattern of the type II and type I wrists. For the type I wrist, SLIL disruption resulted in no contact between scaphoid-lunate cartilage articulation, whereas for the type II wrist, some contact was maintained. We conclude that the Corella ligamentous reconstruction technique is best able to restore SL gap, angle, and stability following SL ligament injury for both type II and type I wrists and is able to do so without altering wrist kinematics. Our findings also support the view that type I wrists exhibit row behaviour and type II wrists column behaviour. In addition, our analysis suggests that the extra articulation between the lunate and hamate in a type II wrist may help improve stability following SL ligament injury.

Effect of Femoral Head Size, Subject Weight, and Activity Level on Acetabular Cement Mantle Stress Following Total Hip Arthroplasty.

In cases where cemented components are used in total hip arthroplasty, damage, or disruption of the cement mantle can lead to aseptic loosening and joint failure. Currently, the relationship between subject activity level, obesity, and prosthetic femoral head size and the risk of aseptic loosening of the acetabular component in cemented total hip arthroplasty is not well understood. This study aims to provide an insight into this. Finite element models, validated with experimental data, were developed to investigate stresses in the acetabular cement mantle and pelvic bone resulting from the use of three prosthetic femoral head sizes, during a variety of daily activities and one high impact activity (stumbling) for a range of subject body weights. We found that stresses in the superior quadrants of the cortical bone-cement interface increased with prosthetic head size, patient weight, and activity level. In stumbling, average von Mises stresses (22.4 MPa) exceeded the bone cement yield strength for an obese subject (143 kg) indicating that the cement mantle would fail. Our results support the view that obesity and activity level are potential risk factors for aseptic loosening of the acetabular component and provide insight into the increased risk of joint failure associated with larger prosthetic femoral heads. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1771-1783, 2019.

Cement interface and bone stress in total hip arthroplasty: Relationship to head size.

The use of larger prosthetic femoral heads in total hip arthroplasty (THA) has increased considerably in recent years in response to the need to improve joint stability and reduce risk of dislocation. However, data suggests larger femoral heads are associated with higher joint failure rates. For cemented implants, ensuring the continued integrity of the cement mantle is key to long term fixation. This paper describes an investigation into the effect of variation in femoral head size on stresses in the acetabular cement mantle and pelvic bone. Three commonly used femoral head sizes: 28, 32, and 36 mm diameter were investigated. The study was undertaken using a finite element model validated using surface strains obtained from Digital Image Correlation (DIC) during experimentation on a composite hemipelvis implanted with a cemented all-polyethylene acetabular cup. Following validation, the models were used to investigate stresses in the pelvic bone and acetabular cement mantle resulting from two loading scenarios; an average weight subject (700 N) and an overweight subject (1,000 N) undertaking a single leg stand. We found that the highest peak stresses occurred in the anterosuperior and posterosuperior regions of the bone-cement interface, in the line of action of the load, where debonding usually initiates. Stress on the cortical bone-cement interface increased with femoral head diameter by up to 9% whilst stresses in the trabecular bone remained relatively invariant. Our findings may help to explain higher joint failure rates associated with larger femoral heads. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2966-2977, 2018.

Evaluation of the performance of three tenodesis techniques for the treatment of scapholunate instability: flexion-extension and radial-ulnar deviation.

Chronic scapholunate ligament (SL) injuries are difficult to treat and can lead to wrist dysfunction. Whilst several tendon reconstruction techniques have been employed in the management of SL instability, SL gap reappearance after surgery has been reported. Using a finite element model and cadaveric study data, we investigated the performance of the Corella, scapholunate axis (SLAM) and modified Brunelli tenodesis (MBT) techniques. Scapholunate dorsal and volar gap and angle were obtained following virtual surgery undertaken using each of the three reconstruction methods with the wrist positioned in flexion, extension, ulnar deviation and radial deviation, in addition to the ulnar-deviated clenched fist and neutral positions. From the study, it was found that, following simulated scapholunate interosseous ligament rupture, the Corella technique was better able to restore the SL gap and angle close to the intact ligament for all wrist positions investigated, followed by SLAM and MBT. The results suggest that for the tendon reconstruction techniques, the use of multiple junction points between scaphoid and lunate may be of benefit. Graphical abstract The use of multiple junction points between scaphoid and lunate may be of benefit for tendon reconstruction techniques.

Analysis of tenodesis techniques for treatment of scapholunate instability using the finite element method.

Chronic scapholunate ligament (SL) injury is a common disorder affecting the wrist. Despite advances in surgical techniques used to treat this injury, SL gap re-emergence may occur postoperatively. This paper presents an investigation into the performance of the Corella, schapolunate axis (SLAM), and modified Brunelli tenodesis (MBT) surgical reconstruction techniques used to treat scapholunate instability. Finite element (FE) models were used to undertake virtual surgery, and the resulting scapholunate (SL) gap and angle obtained using the 3 techniques were compared. The Corella technique was found to achieve the SL gap and angle closest to the intact (ligament) wrist, restoring SL gap and angle to within 5.6% and 0.6%, respectively. The MBT method resulted in an SL gap least close to the intact. The results of our study indicate that the contribution of volar scapholunate interosseous ligament to scapholunate stability could be important.

Changes in the stress in the femoral head neck junction after osteochondroplasty for hip impingement: a finite element study.

The surgical treatment of femoroacetabular impingement (FAI) often involves femoral osteochondroplasty. One risk of this procedure is fracture of the femoral neck. We developed a finite element (FE) model to investigate the relationship between depth of resection and femoral neck stress. CT data were used to obtain the geometry of a typical cam-type hip, and a 3D FE model was constructed to predict stress in the head-neck after resection surgery. The model accounted for the forces acting on the head and abductor muscular forces. Bone resection was performed virtually to incremental resection depths. The stresses were calculated for five resection depths and for five different activities (i) standing on one leg (static case); (ii) two-to-one-to-two leg standing; (iii) normal walking; (iv) walking down stairs; and (v) a knee bend. In general, both the average Von Mises stresses and the area of bone that yielded significantly increased at a resection depth of ≥10 mm. The knee bend and walking down stairs demonstrated the highest stresses. The FE model predicts that fracture is likely to occur in the resection area first following removal of a third (10 mm) or more of the diameter of the femoral neck. We suggest that when surgeons perform osteochondroplasty for hip impingement, the depth of resection should be limited to 10 mm.

Hyperdigraph-theoretic analysis of the EGFR signaling network: initial steps leading to GTP:Ras complex formation.

We construct an algebraic-combinatorial model of the SOS compartment of the EGFR biochemical network. A Petri net is used to construct an initial representation of the biochemical decision making network, which in turn defines a hyperdigraph. We observe that the linear algebraic structure of each hyperdigraph admits a canonical set of algebraic-combinatorial invariants that correspond to the information flow conservation laws governing a molecular kinetic reaction network. The linear algebraic structure of the hyperdigraph and its sets of invariants can be generalized to define a discrete algebraic-geometric structure, which is referred to as an oriented matroid. Oriented matroids define a polyhedral optimization geometry that is used to determine optimal subpaths that span the nullspace of a set of kinetic chemical reaction equations. Sets of constrained submodular path optimizations on the hyperdigraph are objectively obtained as a spanning tree of minimum cycle paths. This complete set of subcircuits is used to identify the network pinch points and invariant flow subpaths. We demonstrate that this family of minimal circuits also characteristically identifies additional significant biochemical reaction pattern features. We use the SOS Compartment A of the EGFR biochemical pathway to develop and demonstrate the application of our algebraic-combinatorial mathematical modeling methodology.

A computational model for the identification of biochemical pathways in the krebs cycle.

We have applied an algorithmic methodology which provably decomposes any complex network into a complete family of principal subcircuits to study the minimal circuits that describe the Krebs cycle. Every operational behavior that the network is capable of exhibiting can be represented by some combination of these principal subcircuits and this computational decomposition is linearly efficient. We have developed a computational model that can be applied to biochemical reaction systems which accurately renders pathways of such reactions via directed hypergraphs (Petri nets). We have applied the model to the citric acid cycle (Krebs cycle). The Krebs cycle, which oxidizes the acetyl group of acetyl CoA to CO(2) and reduces NAD and FAD to NADH and FADH(2), is a complex interacting set of nine subreaction networks. The Krebs cycle was selected because of its familiarity to the biological community and because it exhibits enough complexity to be interesting in order to introduce this novel analytic approach. This study validates the algorithmic methodology for the identification of significant biochemical signaling subcircuits, based solely upon the mathematical model and not upon prior biological knowledge. The utility of the algebraic-combinatorial model for identifying the complete set of biochemical subcircuits as a data set is demonstrated for this important metabolic process.