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Archaeological isotope studies have traditionally been anthropocentric, with animals analyzed either as proxies or as baseline data in human-focused studies of diet and behavior. However, the value of analyzing animals in their own right is becoming increasingly clear for understanding human-animal-environment relationships. This chapter presents the results of a multi-species, multi-isotope investigation of animal remains recovered from Fishbourne Roman Palace (Sussex, UK). This extraordinarily high-status site, located at the edge of the Roman Empire, appears to have been a node through which exotic animals and new cultural attitudes to the natural world entered Britain. Here, we show how isotope analysis can be used to explore these ideologies, and reconstruct changing relationships between people, animals, and their environments.

Aim There has been a global movement towards transformation of youth mental health services, but limited information on the core principles and characteristics of these new services is available. Jigsaw is one such service, established in Ireland in 2006, with the intent of creating change in Ireland's system of mental healthcare for 12-25 year olds. The aim of this paper is to describe the evolution of Jigsaw services, which are now firmly embedded in the Irish system of care for young people, and recognized internationally as an established service network. Methods This paper describes provides an up-to-date description of the Jigsaw service model, key areas of evolution that have shaped this model, and identifies future directions in service development. Results Key attributes of the Jigsaw service model including therapeutic service, scope of practice, youth mental health promotion, youth participation, and monitoring/evaluation are described in this paper. Information on key enablers (funding and governance/quality) and service providers is also included. Conclusions Information on the core principles and characteristics of youth mental health services is important. This paper addresses a gap in the literature by describing the Jigsaw service model, which continues to evolve so that it is responsive to the needs of young people.

Discover a fresh take on classical screw theory and understand the geometry embedded within robots and mechanisms with this essential text. The book begins with a geometrical study of points, lines, and planes and slowly takes the reader toward a mastery of screw theory with some cutting-edge results, all while using only basic linear algebra and ordinary vectors. It features a discussion of the geometry of parallel and serial robot manipulators, in addition to the reciprocity of screws and a singularity study. All 41 essential screw systems are unveiled, establishing the possible freedom twists and constraint wrenches for a kinematic joint. Familiarizing the reader with screw geometry in order to study the statics and kinematics of robots and mechanisms, this is a perfect resource for engineers and graduate students.

BACKGROUND Advancements in bioengineering have allowed bispecific Abs to develop with therapeutic applications in immuno-oncology. Here we describe a fully humanized bispecific t cell engager (BiTE) that binds the GBM-associated antigen interleukin 13 receptor alpha 2 (IL13Rα2) and the T Cell receptor CD3 epsilon (CD3ε) to elicit an anti-tumor immune response in patient-derived models of GBM. METHODS In vitro, BiTE-mediated activation of T Cells was assessed via flow cytometry as measurements of T cell activation markers CD25 and CD69 and cytokines IFNγ and TNFα. BiTE-directed T cell-mediated cytotoxicity was assessed in GBM 6 and GBM12patient-derived xenograft lines. In vivo, GBM6 patient-derived xenograft cells were intracranially implanted in NSG-MHC I/II DKO mice, reconstituted with HLA-matched donor peripheral blood lymphocytes (PBMC), and subsequently treated with 2.5 mg/kg BiTE via i.p. injection x 4 days/week of therapeutic BiTE for three weeks. Animals were followed for survival, and the brains of long-term survivors were analyzed for residual disease and T cell infiltration. RESULTS In vitro, BiTE potently activated T cells as determined by a high expression of CD25 and CD69 and the production of TNFα and IFNγ. BiTE also directed T cell-mediated cytotoxicity against GBM cells in a dose-dependent manner, with significant activity still seen in the low nanogram range. In vivo, BiTE significantly extended the survival of tumor-bearing animals in GBM6patient-derived xenograft models. Histological analysis of long-term surviving mice shows complete absence of tumor and robust presence of CD8+ T cells localized to the original site of tumor implantation. CONCLUSIONS Our data demonstrate the efficacy of humanized BiTE in patient-derived GBM models, and our results support the investigation of this novel therapeutic in a clinical trial setting.FUNDING: R01 NS122395-01 and R01 NS095642-01

INTRODUCTION Given the limited drug penetration across the blood-brain barrier (BBB), the therapeutic potential of new and existing therapies has not been fully exploited for the benefit of glioblastoma (GBM) patients. METHODS Here we employed a novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) that temporarily opens the BBB to deliver liposomal doxorubicin (DOX) and anti-PD-1 therapy (aPD-1) in mouse glioma models and 3 recurrent GBM patients. Immunological variables were evaluated in tumor and immune cells as well as efficacy in glioma-bearing mice treated with DOX delivered by LIPU. These included measurement of HLA ABC and HLA DR protein expression by tumor cells, microglia, and macrophages and IFN-g production by glioma-associated microglia and macrophages in mouse and human tumors. We also assessed efficacy of LIPU/MB enhanced combination therapy in glioma-bearing mice. RESULTS Upregulation of HLA ABC and HLA DR was observed in GBM cell lines at low concentrations of DOX. Tumor cells from GBM patients treated with DOX, aPD-1 and LIPU/MB showed increased expression of HLA ABC and HLA DR compared to paired pretreatment samples. In both mice and humans, LIPU/MB liposomal DOX increased absolute brain drug concentrations and elicited a specific IFN-g phenotype and MHC I expression in glioma-associated microglia and macrophages in mice and humans. Furthermore, LIPU/MB-mediated BBB opening increased brain concentrations of aPD-1 in mice and in peritumoral regions of GBM patients. Combined treatment with liposomal DOX and aPD-1 delivered with LIPU/MB resulted in long-term survival of glioma-bearing mice that relied on the activity of CD8+ T cells for its efficacy. CONCLUSIONS Overall, this translational study demonstrates the utility of LIPU/MB to stimulate intracranial immune responses in the context of treatment with DOX and aPD-1 for gliomas.

In children, diffuse midline gliomas retain poor outcomes, failing to have a durable response to conventional therapies. Immunotherapies hold promise, with the integration of the host's immune system fundamental to their design. Here, we describe a novel genetically engineered immunocompetent model that incorporates interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen, to evaluate the antitumor activity of IL13Rα2-CAR T cell and bispecific T cell engager (BiTE) therapies in preclinical studies. The RCAS-Tva delivery system was utilized to induce gliomagenesis through p53 loss and the constitutive expression of PDGFB and human IL13Rα2 in Nestin-Tva;p53fl/fl mice. Pups were injected with virus-producing DF1 cells, encoding either for RCAS-Cre and PDGFB+IL13Rα2 or RCAS-Cre and PDGFB. Kaplan-Meier survival curves established and compared tumor growth dynamics in both models. Tumor tissue was characterized through immunohistochemistry and H&E staining. Cell lines generated from tumor-bearing tissue were used for orthotopic injection and in vitro studies. Expression of PDGFB and IL13Rα2 was confirmed by flow cytometry and western blot. In both groups, de novo tumors developed without significant difference in median survival between RCAS:PDGFB (n=25, 40 days) and RCAS:PDGB+IL13Rα2 (n=32, 39 days). Tumors demonstrated characteristics of high-grade glioma such as infiltration, pseudopalisading necrosis, microvascular proliferation, high Ki-67 index, heterogenous IL13Rα2 expression, with notable presence of CD11b+ macrophages and low count of CD3+ T cells. Orthotopic tumors from developed cell lines were histologically similar to de novo tumors. Treatment of generated cell lines with IL13Rα2-targeting BiTE protein resulted in a loss of glioma cell viability and target-specific activation of T cells. Engineered de novo tumors possess histopathologic features common to diffused midline gliomas. IL13Rα2-positive cell lines derived from de novo tumors were responsive to targeted treatment, opening the opportunity for preclinical assessment of IL13Rα2-directed immunotherapies, with the potential for clinical translation.

Although mental health problems represent the largest burden of disease in young people, access to mental health care has been poor for this group. Integrated youth health care services have been proposed as an innovative solution. Integrated care joins up physical health, mental health and social care services, ideally in one location, so that a young person receives holistic care in a coordinated way. It can be implemented in a range of ways. A review of the available literature identified a range of studies reporting the results of evaluation research into integrated care services. The best available data indicate that many young people who may not otherwise have sought help are accessing these mental health services, and there are promising outcomes for most in terms of symptomatic and functional recovery. Where evaluated, young people report having benefited from and being highly satisfied with these services. Some young people, such as those with more severe presenting symptoms and those who received fewer treatment sessions, have failed to benefit, indicating a need for further integration with more specialist care. Efforts are underway to articulate the standards and core features to which integrated care services should adhere, as well as to further evaluate outcomes. This will guide the ongoing development of best practice models of service delivery.

Two problems are addressed in this paper. First, the mathematical model to perform the static analysis of an antiprism tensegrity structure subjected to a wide variety of external loads is presented. The virtual work approach is used to deduce the equilibrium equations and a method based on Newton’s Third Law is used to verify the numerical results. Two numerical examples are provided to demonstrate the use of the mathematical model, as well as the verification method. The second problem deals with the development of a mathematical model to perform the static analysis of a prestressed antiprism tensegrity structure subjected to an arbitrary length reduction of its connecting ties. Again, a virtual work approach is used to deduce the equilibrium equations and the numerical results are verified using a Newtonian approach. One example is provided to illustrate the mathematical model.

This paper investigates the soft-finger contact by presenting the contact with a set of line springs based on screw theory, reveals the rotational effects, and identifies the stiffness properties of the contact. An elastic model of a soft-finger contact is proposed and a generalized contact stiffness matrix is developed by applying the congruence transformation and by introducing stiffness mapping of the line springs in translational directions and rotational axes. The effective stiffnesses along these directions and axes are hence obtained and the rotational stiffnesses are revealed. This helps create a screw representation of a six-dimensional soft-finger contact and produce an approach of analyzing and synthesizing a robotic grasp without resorting to the point contact representation. The correlation between the rotational stiffness, the number of equivalent point contacts and the number of equivalent contours is given and the stiffness synthesis is presented with both modular and direct approaches. The grasp thus achieved from the stiffness analysis contributes to both translational and rotational restraint and the stiffness matrix so developed is proven to be symmetric and positive definite. Case studies are presented with a two-soft-finger grasp and a three-soft-finger grasp. The grasps are analyzed with a general stiffness matrix which is used to control the fine displacements of a grasped object by changing the preload on the contact.

Two types of trusses were optimized using the simple, yet powerful, mathematical technique of employing line geometry as defined by the mathematicians Plucker and Grassmann. The key benefit to this design methodology is simplicity. Multiple-node designs were analyzed, with particular focus placed on the triangular truss. The methodology is based on a geometric stability criterion called the quality index. This approach allowed for a simple equation to be created that identifies the optimal geometry based on the exterior angles and the number of sides. Trusses with single and double connecting points are considered using the quality index. An example of a double connection truss is the triangular truss. In this case, each node (either on the top or the base) has two structural elements connecting to the other nodes. It is shown that there are optimal design criteria for the upper, lower, and separation dimensions. These optimal geometric designs yield conical trusses. Further consideration of the 3-3 truss produced a closed-form solution. This equation holds significant potential for truss designs, providing a clear comparison between single and double connections.

This paper presents a methodology whereby the payload weight of a serial manipulator can be determined from a minimum set of sensor data, i.e., joint angle and joint torque measurements. The particular manipulator geometry that is analyzed is a four degree-of-freedom serial chain that is commonly used in excavator systems. It was quite remarkable that a relatively simple solution was obtained for the payload weight considering that there are a total of nine unknown moments and cross moments of inertia of the payload together with the unknown location of the center of mass. Example calculations are presented. © 2003 Wiley Periodicals, Inc.

This paper emphasizes the role of mathematical techniques that the Catastrophe Theory has recently provided as powerful tools for both the control and the design of compliant systems whose behavior is governed by a potential function. The problem of the identification of absolutely safe working areas as regards the stability of the equilibrium is addressed. An application example of such a theory to the stability analysis of a planar mechanism equipped with flexural pivots is carried out for the first time.

A review of a family of tensegrity structures that self-deploy from a stowed or packed configuration is presented. In the packed configuration, the mechanism is of a cylindrical form with the struts lying side by side. Such structures may be applied in the deployment of antennas in space and in the rapid deployment of shelters or tents. This family of structures evolved from a study of in-parallel platforms with compliant legs or connectors. A number of relevant references are cited.

This paper uses screw algebra to derive relatively simple and explicit expressions for the complex motion-invariant rotational first- and second-order geometric influence coefficients for a planar multi-loop mechanism in terms of reciprocal products of screws and differential screws. The concept of the differential screws is presented and used as an effective tool in characterizing the second-order geometric influence coefficients. Furthermore, the geometrical interpretation of both the screw product and the reciprocal product of screws in two-dimensional space is presented and implemented to simplify the formulation. It is believed that this is the first time to be able to derive the motion-invariant geometric influence coefficients of multi closed-loop mechanisms in explicit and relatively simple forms. The use of the geometric influence coefficients eases the kinematic and dynamic modelling problems of mechanisms. The derived simple expressions for geometric influence coefficients are then implemented to drive the angular velocity-squared/acceleration ratio of the output link. If the single-degree of freedom (dof) planar multi-loop mechanism is running with constant input velocity this ratio becomes motion-invariant too. An illustrative example is presented. This technique has the potential of being extended to cover other spatial and spherical mechanisms as well as multi-degree of freedom multi-loop mechanisms. It could also be extended to derive simple expressions for the translational geometric influence coefficients.

The octahedral manipulator is a "3-3" device that is fully in parallel. It has a linear actuator on each of its six legs. The legs connect an equilateral platform triangle to a similar base triangle in a zigzag pattern between vertices. Our proposed quality index takes a maximum value of 1 at a central symmet rical configuration that is shown to correspond to the maxi mum value of the determinant of the 6 x 6 Jacobian matrix of the manipulator. This matrix is none other than that of the nor malized line coordinates of the six leg-lines; for its determi nant to be a maximum, the platform triangle is found to be half of the size of the base triangle, and the perpendicular distance between platform and base is equal to the side of the platform triangle. When the manipulator is actuated so that the octahedron departs from this central configuration, the determinant al ways diminishes, and, as is well known, it becomes zero when a special configuration is reached (the platform then gain ing one or more uncontrollable freedoms). Our quality index λ, 0 ≤ λ ≤ 1, is a constructive measure of acceptable design proportions. The double-spherical joints (there are six) are the source of the critical practical difficulties. Kinematic substitutions can circumvent this problem, but often there is no reasonable alternative to accepting a reduction of maximum quality index through separation by fairly short distances of some or all of the double-ball joints. Too great a separation easily leads too far toward generality; any fully-in-parallel manipulator of more general proportions should be tested for quality against our octahedral form simply because no different form can be superior to a well-designed octahedron from the points of view of structural soundness and ability to apply both forces and controlled displacements to the end-effector platform.

An optimization approach to computing the boundaries of the workspaces of planar manipulators is presented. This numerical method consists of finding a suitable radiating point in the output coordinate space and then determining the points of intersection of a representative pencil of rays, emanating from the radiating point, with the boundary of the accessible set. This is done by application of a novel constrained optimization approach that has the considerable advantage that it may easily be automated. The method is illustrated by its application to two planar mechanisms, namely a planar Stewart platform and a planar redundantly controlled serial manipulator. In addition to the exterior boundaries of the workspace, interior curves that represent configurations at which controllability and mobility may be limited, are also mapped. The optimization methodology, implemented here for the planar case, may readily be extended to spatial Stewart platforms. [S1050-0472(00)00304-4]

A stability analysis is performed for the planar two-spring system using catastrophe theory. Basic elements of catastrophe theory are outlined and applied to the two-spring system to give catastrophe locus plots showing where a change in stability occurs. The method used for the two-spring yields a stability analysis without having to solve the inverse analysis. The inverse analysis for the two-spring system is used to illustrate system equilibrium positions before, dur ing, and after a change in stability.

This contribution presents a closed-form solution for the location of the acceleration center of a rigid body subjected to spatial motion. Moreover, all the special cases are deduced and analyzed by a systematic analysis of the conditions under which the closed-form solution cannot be computed. Finally, the results obtained here are compared with those previously published.

A reverse force analysis of a spatial three-spring system is presented which determines equilibrium positions when an external force is applied. The system consists of three linear springs, each of which is attached to the ground via pivots which form a triangular base. The three springs are joined at a common pivot at the other end, thus forming a tetrahedron. A known force is applied at the common pivot. The multiple equilibrium positions are computed by deriving and solving a 22nd degree polynomial in a single spring length. The degree of this polynomial is verified in the Appendix independently of the analysis, using geometry. Following this, corresponding pairs of the remaining two spring lengths are computed, which determine the multiple equilibrium positions. These results have been verified by numerical examples. The symbolic computation was performed by the computer algebra system MATHEMATICA.

It is well known that the velocity of the end effector of a serial chain can be written as a linear combination of the screws that represent, with respect to an arbitrary coordinate system, the kinematic pairs that join the end effector with the body used as the reference frame. In this paper, it is shown that the acceleration of a point in the end effector of the serial chain can be expressed in terms of the direction and moment parts of the same screw coordinates.; Further, is if the angular velocity of the end effector vanishes, then its acceleration can be written as a relatively simple expression involving only the complete screw coordinates themselves and their Lie products. Thus, the present work can be regarded in one sense as an extension of screw theory into the acceleration analysis of linkages. Furthermore, since the equations obtained here are tensorial, the present work can be also regarded as a step toward a coordinate free dynamic analysis, as suggested by Chevallier [Mech. Mach. Theory 26, 613–627 (1991)].

This paper presents a critical analysis of the metric of rigid body displacements obtained from the so-called kinematic mapping. It is shown that this metric is not suitable for finite rigid bodies. The paper also addresses the metrics obtained for the planar group, as it can be regarded as a subgroup of the group of all rigid body displacements, which is denoted here as the Euclidean group. Finally, the paper proposes some metrics for the set of spatial and planar displacements for a finite rigid body, undergoing a finite displacement.