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Abstract CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient’s age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR’s hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.

CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient's age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR's hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies. [ABSTRACT FROM AUTHOR]

Purpose: There is a high risk of increasing the posterior tibial slope (PTS) during medially opening‐wedge high tibial osteotomy (mowHTO). Most recently, the idea of intentional simultaneous coronal and sagittal correction, using uniplanar cutting techniques has emerged. This study aims to examine the influences of variable hinge positioning and osteotomy gap height on the sagittal and coronal plane. Methods: Twenty uniplanar mowHTOs were performed in standardised (left) solid‐foam proximal tibia models. In the different models, hinge position was rotated stepwise by 10°, between 90° (cutting straight medial to lateral) and 0° (cutting straight anterior to posterior) (n = 10). Additionally, gap heights of 5 and 10 mm were produced and analysed. Logistic regression analysis was performed to calculate a predictive regression formula for the relation between gap height, hinge rotation and the changes of medial proximal tibia angle (MPTA), medial and lateral PTS. Results: Between cutting angles of 90 and 20°, the MPTA was mainly influenced by the gap height (0.95° MPTA per 1 mm gap height), but not by the cutting angle. Between 20 and 0°, the MPTA was decreased by 3.6° per 10° of rotation, but not by the gap height. Between cutting angles of 90 and 10°, the PTS was increased linearly by 0.97° per 10° of rotation and by 0.61° per 1 mm gap height. Conclusion: In mowHTO with lateral hinge positions, the MPTA is mainly influenced by gap height. Changes of PTS can be avoided by a straight lateral hinge position. In posterior hinge locations (0‐20°), changes of MPTA are mainly caused by hinge rotation, but not by gap height. Level of Evidence: Level III, Case–control study. [ABSTRACT FROM AUTHOR]

Introduction: revision joint replacement surgery presents a surgical challenge. The use of rotating hinge prostheses is an option in patients with femorotibial bone defects, ligament insufficiency, or significant deformities. The aim of this study was to evaluate the clinical, functional, and radiological outcomes of a series of patients who underwent surgery using the GMK Hinge (Medacta®) rotational hinge model. Material and methods: a descriptive, retrospective, and analytical study was conducted on a series of 36 patients, with a mean age of 72.5 years (47-85), operated on by the same surgical team between January 2015 and January 2022. The etiology of revision was chronic infection in 38.9% of cases, instability in 33.3%, aseptic loosening in 19.4%, and stiffness in 8.4%. The Knee Society Score (KSS) and the Forgotten Joint Score (FJS) were used to assess functional outcomes. The degree of femorotibial bone defect was evaluated using the Anderson Orthopaedic Research Institute (AORI) classification. Postoperative complications are also recorded. Results: a total of 36 patients, 17 males and 19 females, were included, with a mean follow-up of 30 months (12-66). Twelve patients had type 1 defects, ten had 2A defects, ten had 2B defects, and two had type 3 defects on the femoral side, with the use of wedges required for asymmetrical defects (21 patients). The predominant tibial defect was type 1 without the need for wedges. The majority achieved a satisfactory outcome on the KSS scale (72.2 ± 9.4), with significant differences compared to the previous KSS (54.3 ± 8.9). A score of 31 (12-67) was also obtained on the FJS scale. Postoperative complications were present in 16.7% of patients. Conclusions: complex prosthetic revision surgery using a rotating hinge prosthesis represents a suitable therapeutic option, yielding appropriate clinical and functional outcomes, albeit not without complications. [ABSTRACT FROM AUTHOR]

Abstract Purpose There is a high risk of increasing the posterior tibial slope (PTS) during medially opening‐wedge high tibial osteotomy (mowHTO). Most recently, the idea of intentional simultaneous coronal and sagittal correction, using uniplanar cutting techniques has emerged. This study aims to examine the influences of variable hinge positioning and osteotomy gap height on the sagittal and coronal plane. Methods Twenty uniplanar mowHTOs were performed in standardised (left) solid‐foam proximal tibia models. In the different models, hinge position was rotated stepwise by 10°, between 90° (cutting straight medial to lateral) and 0° (cutting straight anterior to posterior) (n = 10). Additionally, gap heights of 5 and 10 mm were produced and analysed. Logistic regression analysis was performed to calculate a predictive regression formula for the relation between gap height, hinge rotation and the changes of medial proximal tibia angle (MPTA), medial and lateral PTS. Results Between cutting angles of 90 and 20°, the MPTA was mainly influenced by the gap height (0.95° MPTA per 1 mm gap height), but not by the cutting angle. Between 20 and 0°, the MPTA was decreased by 3.6° per 10° of rotation, but not by the gap height. Between cutting angles of 90 and 10°, the PTS was increased linearly by 0.97° per 10° of rotation and by 0.61° per 1 mm gap height. Conclusion In mowHTO with lateral hinge positions, the MPTA is mainly influenced by gap height. Changes of PTS can be avoided by a straight lateral hinge position. In posterior hinge locations (0‐20°), changes of MPTA are mainly caused by hinge rotation, but not by gap height. Level of Evidence Level III, Case–control study.

Abstract Background The chimeric antigen receptor-expressing T (CAR-T) cells for cancer immunotherapy have obtained considerable clinical importance. CAR T cells need an optimized intracellular signaling domain to get appropriately activated and also for the proper antigen recognition, the length and composition of the extracellular spacer are critical factors. Results We constructed two third-generation nanobody-based VEGFR2-CARs containing either IgG1 hinge-CH2-CH3 region or hinge-only as long or short extracellular spacers, respectively. Both CARs also contained intracellular activating domains of CD28, OX40, and CD3ζ. The T cells from healthy individuals were transduced efficiently with the two CARs, and showed increased secretion of IL-2 and IFN-γ cytokines, and also CD69 and CD25 activation markers along with cytolytic activity after encountering VEGFR2+ cells. The VEGFR2-CAR T cells harboring the long spacer showed higher cytokine release and CD69 and CD25 expression in addition to a more efficient cytolytic effect on VEGFR2+ target cells. Conclusions The results demonstrated that the third-generation anti-VEGFR2 nanobody-based CAR T cell with a long spacer had a superior function and potentially could be a better candidate for solid tumor treatment.

This work aims to conduct theoretical and experimental studies on the energy and force parameters of the separation process, as well as the geometric accuracy of the separated tubular workpiece using the "eccentric twisting" method. A mathematical model of a device with a "crank-circular" mechanism for cutting pipes by "eccentric twisting" has been developed. The technological process of cutting pipes by "eccentric twisting" was simulated using the DEFORM-3D software package. The results of experimental studies are in good agreement with the theoretical data calculated using the proposed mathematical model and the specialized program DEFORM-3D. The maximum differences between the cutting torque values obtained theoretically and experimentally do not exceed 6%. For the industrial implementation of research results, a design of an installation with a wedge-hinged drive with a concave wedge in combination with a "crank-circular" mechanism for separating pipes by the "eccentric torsion" scheme is proposed.

Background: The chimeric antigen receptor-expressing T (CAR-T) cells for cancer immunotherapy have obtained considerable clinical importance. CAR T cells need an optimized intracellular signaling domain to get appropriately activated and also for the proper antigen recognition, the length and composition of the extracellular spacer are critical factors. Results: We constructed two third-generation nanobody-based VEGFR2-CARs containing either IgG1 hinge-CH2-CH3 region or hinge-only as long or short extracellular spacers, respectively. Both CARs also contained intracellular activating domains of CD28, OX40, and CD3ζ. The T cells from healthy individuals were transduced efficiently with the two CARs, and showed increased secretion of IL-2 and IFN-γ cytokines, and also CD69 and CD25 activation markers along with cytolytic activity after encountering VEGFR2+ cells. The VEGFR2-CAR T cells harboring the long spacer showed higher cytokine release and CD69 and CD25 expression in addition to a more efficient cytolytic effect on VEGFR2+ target cells. Conclusions: The results demonstrated that the third-generation anti-VEGFR2 nanobody-based CAR T cell with a long spacer had a superior function and potentially could be a better candidate for solid tumor treatment. [ABSTRACT FROM AUTHOR]

Background: There have been reports on the significant canal cross-sectional area (CSA) expansion difference between pre- and post-operation, but no comparison of CSA expansion between the hinge-side area (Area H) and the open-side area (Area O) has been reported. This study aimed to measure the spinal CSA expansion between Area H and Area O retrospectively after open-door laminoplasty using new titanium spacers and evaluated this common decompression procedure's effectiveness. Materials and Methods: This study included 27 patients diagnosed with cervical spondylotic radiculopathy or myelopathy, ossification of the posterior longitudinal ligament, and developmental canal stenosis from February 2021 to October 2022. The CSA difference between pre- and post-cervical laminoplasty (C4--C6 levels) was measured with cervical transverse computed tomography scan images. The CSA difference in Area H and Area O between pre- and post-laminoplasty was similarly calculated. Results: The spinal canal areas of each segment after open-door laminoplasty were significantly enlarged (P < 0.05). Area O was also significantly enlarged compared to that of Area H (P < 0.05). Conclusion: Area O was more enlarged than Area H, and both sides were statistically enlarged after open-door laminoplasty. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has demonstrated unprecedented success with high remission rates for heavily pretreated patients with hematological malignancies. The hinge connecting the extracellular antigen recognition unit to the transmembrane domain provides the length and flexibility of the CAR constructs and ensures that the CAR can reach the target antigen and mediate recognition and killing of target cells. The hinge can also include specific amino acid sequences to improve CAR expression, influence T cell proliferation, and facilitate CAR T cell detection, enrichment, and even elimination. Here, we report the generation of two novel hinge domains derived from the low-affinity p75 chain of the human nerve growth factor receptor (NGFR), termed N3 and N4, which, when incorporated into the CAR backbone, allow detection as well as high-grade enrichment of CAR T cells with GMP-compatible immunomagnetic reagents. After optimizing the MACS protocol for excellent CAR T cell purity and yield, we demonstrated that N3- and N4-hinged CAR T cells are as efficacious as their CD8-hinged counterparts in vitro against hematological blasts and also in vivo in the control of acute monocytic leukemia in an immunodeficient mouse xenograft model. Thus, both hinges could potentially be an integral part of future CAR designs and universally applicable in clinical applications.

This roundtable paper is part of the project ‘Digitized Love and Intimacy on Hinge.’ It aims to investigate how digital dating apps reconfigure cultural attitudes to love and intimacy and, conversely, how said attitudes influence digital dating practices. The conversation is informed by (n)ethnographic usage of the app. As algorithms and affordances of dating applications can implicitly or explicitly privilege certain groups of users and exclude others, this conversation mainly aims to make sense of how Hinge’s interface – or ‘affordances’– facilitates the dating process and how inclusive and diverse the application’s affordances are. We discuss that there is a contradiction between what Hinge portrays itself to be and what it practically ends up being, partly because of its affordances. This roundtable highlights the need to study affordances as relational technologies and to take the perceptions, ideas, and interpretations of users seriously alongside the actual features and designs offered by applications.

Currently, the direction associated with the development of exoskeletons and anthropomorphic robots is experiencing rapid growth due to the increase in the computing power of microprocessors and the breakthrough development of the theory of control of complex systems, including electromechanical systems that simulate the biomechanics of the human musculoskeletal system. This paper presents a controlled mechatronic robotic model of the support leg of an anthropomorphic robot or exoskeleton with two moving links.GOAL. Mathematical modeling of the dynamics of the supporting leg of an exoskeleton or an anthropomorphic mechanism in the form of two moving links.METHODS. The main difference between the model presented in this study and those created earlier is the use of angles counted between links corresponding to the case of real operation of electric drives. To achieve the goal of the work, the methods of robotics, mathematical modeling, mechatronics, theoretical mechanics, the study of systems of ordinary differential equations, control theory, empirical data for the human musculoskeletal system were applied.RESULTS. For the model of the mechanism, a system of Lagrange equations of the second kind is written, direct and inverse problems of dynamics are solved for a given program control of the motion of a mechatronic robotic system. The results are presented graphically and as an animated visualization of the movement of the links. Calculations were carried out both without taking into account the dynamics of electric drives, and taking into account the rotation of the rotors of electric motors. It has been established that the influence of the dynamics of the rotor of the electric motor on the mechanism is significant.CONCLUSION. The developed methods for setting the program movement of the supporting leg of an exoskeleton or an anthropomorphic robot made it possible to solve direct and inverse problems of dynamics and establish the need to take into account the rotating rotor of an electric motor.

Doors are the most critical part in any structure as they may eventually fail first when subjected to extreme loads such as blasts. Blast resistant doors in a structure work as effective barriers against blast pressure thus making the entire structure safe. Accordingly, the need to provide blast resistant doors arises in important structures to endure blast pressure. Herein, the comparative performance of a three-hinged five-latched double leaf composite door subjected to blast loading is investigated using finite element analysis software LsDyna. The composite door consists of front and rear steel plates composed of armor steel and three different infill materials, i.e., polyurethane (PU) foam, aluminum syntactic foam with 200 μm cenosphere (Al200), or plain cement concrete (PC) are explored in this investigation. Comparative studies of these composite doors are performed by varying the thicknesses and types of infill material and blast-scaled distances. The peak deflection, permanent deflection, internal energy, and total energy are compared among the doors considered herein. Weight and cost analysis of the door are also considered to determine the most cost-effective solution. The numerical results show that the polyurethane core door illustrates better performance for 150 mm of core material. However, the plain concrete infill door and cenosphere aluminum alloy core door demonstrate enhanced performance for 100 mm core thickness at 0.15, 0.2, 0.3, and 0.4 m/kg1/3 scaled distances. [ABSTRACT FROM AUTHOR]

The space deployable structures based on shape memory polymer composites (SMPCs) possessed excellent self-deployable performance, which effectively avoided the impact and electromagnetic pulse (EMP) caused by the explosion of pyrotechnic devices. In this work, two types of self-driven curved hinges with different angles of 80° and 115° (Type 80 and Type 115) were designed based on SMPCs. The thermomechanical properties and time–temperature-dependent viscoelastic behaviors of SMPCs were systematically investigated. The three-point bending performance and cyclic shape memory performance of the developed hinges were also characterized. In addition, the deployment performances of Type 80 driven 350 g object under different heating powers were investigated in the environment of ± 70 °C and 103 Pa atmospheric pressure. A staircase-like heating strategy was proposed to achieve precise and controllable deployment under this environment. The developed self-driven curved hinges were expected to have tremendous application potential on the flap actuators and optical payload rotating platforms of the satellites. [ABSTRACT FROM AUTHOR]

BackgroundThe choice of trough position in Expansive open-door laminoplasty (EOLP) mostly relied on bony landmarks and surgeons’ experience. The present study was to validate the efficacy of the three-dimensional (3D) printed patient-specific drilling templates with the function of locating and depth control for EOLP.Materials and MethodsA single-center, prospective randomized controlled study was conducted on the patients who underwent unilateral EOLP from August 2019 to December 2020. The 3D printed patient-specific drilling template was fabricated and used in the template group. All the EOLP were performed by a senior surgeon and a junior surgeon. The clinical outcomes and radiographic results were evaluated.ResultsA total of 37 patients who completed the 12-month follow-up were analyzed. The clinical outcomes were significantly improved after surgery in both groups (P

Immunotherapy including chimeric antigen receptor (CAR) T cell therapy has revolutionized modern cancer therapy and has achieved remarkable remission and survival rates for several malignancies with historically dismal outcomes. The hinge of the CAR connects the antigen binding to the transmembrane domain and can be exploited to confer features to CAR T cells including additional stimulation, targeted elimination or detection and enrichment of the genetically modified cells. For establishing a novel hinge derived from human CD34, we systematically tested CD34 fragments of different lengths, all containing the binding site of the QBend-10 monoclonal antibody, in a FMC63-based CD19 CAR lentiviral construct. A final construct of 99 amino acids called C6 proved to be the best candidate for flow cytometry-based detection of CAR T cells and >95% enrichment of genetically modified T cells on MACS columns. The C6 hinge was functionally indistinguishable from the commonly used CD8α hinge in vitro as well as in in vivo experiments in NSG mice. We also showed that the C6 hinge can be used for a variety of different CARs and mediates high killing efficacy without unspecific activation by target antigen-negative cells, thus making C6 ideally suited as a universal hinge for CARs for clinical applications.

Biotherapeutics are exposed to common transition metal ions such as Cu(II) and Fe(II) during manufacturing processes and storage. IgG1 biotherapeutics are vulnerable to reactive oxygen species (ROS) generated via metal-catalyzed oxidation reactions. Exposure to these metal ions can lead to potential changes to structure and function, ultimately influencing efficacy, potency, and potential immunogenicity of the molecules. Here, we stress four biotherapeutics of the IgG1 subclass (trastuzumab, trastuzumab emtansine, anti-NaPi2b, and anti-NaPi2b-vc-MMAE) with two common pharmaceutically relevant metal-induced oxidizing systems, Cu(II)/ ascorbic acid and Fe(II)/ H2O2, and evaluated oxidation, size distribution, carbonylation, Fc effector functions, antibody-dependent cellular cytotoxicity (ADCC) activity, cell anti-proliferation and autophaghic flux. Our study demonstrates that the extent of oxidation was metal ion-dependent and site-specific, leading to decreased FcγRIIIa and FcRn receptor binding and subsequently potentially reduced bioactivity, though antigen binding was not affected to a great extent. In general, the monoclonal antibody (mAb) and corresponding antibody-drug conjugate (ADC) showed similar impacts to product quality when exposed to the same metal ion, either Cu(II) or Fe(II). Our study clearly demonstrates that transition metal ion binding to therapeutic IgG1 mAbs and ADCs is not random and that oxidation products show unique structural and functional ramifications. A critical outcome from this study is our highlighting of key process parameters, route of degradation, especially oxidation (metal catalyzed or via ROS), on the CH1 and Fc region of full-length mAbs and ADCs.Abbreviations: DNPH 2,4-dinitrophenylhydrazine; ADC Antibody drug conjugate; ADCC Antibody-dependent cellular cytotoxicity; CDR Complementary determining region; DTT Dithiothreitol; HMWF high molecular weight form; LC-MS Liquid chromatography–mass spectrometry; LMWF low molecular weight forms; MOA Mechanism of action; MCO Metal-catalyzed oxidation; MetO Methionine sulfoxide; mAbs Monoclonal antibodies; MyBPC Myosin binding protein C; ROS Reactive oxygen species; SEC Size exclusion chromatography

This article examines the nonlinear vibrations of a thin-walled structure such as a cylindrical shell interacting with the ground. On the basis of the seismodynamic theory of underground structures, the nature of the movement of the structure is revealed depending on the stiffness coefficient and rheological properties of the soil, as well as on the frequency of external influences. When solving specific problems, seismic waves in the form of a sinusoid are considered. Nonlinear integro-differential equations describing the vibrations of structures laid in the ground are solved approximately in the following sequence: - The method of decomposition of displacements in rad by coordinate functions is applied, which are selected depending on the boundary conditions. Using the approximate Bubnov-Galerkin method, the original nonlinear integro-differential equations in partial derivatives of the fourth order are reduced to ordinary equations of the second order; - The obtained nonlinear integro-differential equations are solved by the averaging method, as well as numerically. - The nature of the change in stress and amplitude of oscillation in time in an elastic and viscoelastic shell at different coefficients of soil stiffness was obtained. [ABSTRACT FROM AUTHOR]

T cell engager (TCE) antibodies have emerged as promising cancer therapeutics that link cytotoxic T-cells to tumor cells by simultaneously binding to CD3E on T-cells and to a tumor-associated antigen (TAA) expressed by tumor cells. We previously reported a novel bispecific format, the IgG-like Fab x sdAb-Fc (also known as half-IG_VH-h-CH2-CH3), combining a conventional antigen-binding fragment (Fab) with a single domain antibody (sdAb). Here, we evaluated this Fab x sdAb-Fc format as a T-cell redirecting bispecific antibody (TbsAbs) by targeting mEGFR on tumor cells and mCD3E on T cells. We focused our attention specifically on the hinge design of the sdAb arm of the bispecific antibody. Our data show that a TbsAb with a shorter hinge of 23 amino acids (TbsAb.short) showed a significantly better T cell redirected tumor cell elimination than the TbsAb with a longer, classical antibody hinge of 39 amino acids (TbsAb.long). Moreover, the TbsAb.short form mediated better T cell-tumor cell aggregation and increased CD69 and CD25 expression levels on T cells more than the TbsAb.long form. Taken together, our results indicate that already minor changes in the hinge design of TbsAbs can have significant impact on the anti-tumor activity of TbsAbs and may provide a new means to improve their potency. [ABSTRACT FROM AUTHOR]

Adaptive structures based on fiber-rubber composites with integrated Shape Memory Alloys are promising candidates for active deformation tasks in the fields of soft robotics and human-machine interactions. Solid-body hinges improve the deformation behavior of such composite structures. Textile technology enables the user to develop reinforcement fabrics with tailored properties suited for hinged actuation mechanisms. In this work, flat knitting technology is used to create biaxially reinforced, multilayer knitted fabrics with hinge areas and integrated Shape Memory Alloy wires. The hinge areas are achieved by dividing the structures into sections and varying the configuration and number of reinforcement fibers from section to section. The fabrics are then infused with silicone, producing a fiber-rubber composite specimen. An existing simulation model is enhanced to account for the hinges present within the specimen. The active deformation behavior of the resulting structures is then tested experimentally, showing large deformations of the hinged specimens. Finally, the simulation results are compared to the experimental results, showing deformations deviating from the experiments due to the developmental stage of the specimens. Future work will benefit from the findings by improving the deformation behavior of the specimens and enabling further development for first applications. [ABSTRACT FROM AUTHOR]

The study is focused on mesostructural folded parageneses of the Taldyk antiform (a.k.a. Taldyk block) located in the East Mugodzhar zone. The sequence of their formation is established; the structural evolution of the study area is investigated, and four stages of deformation are identified. The NW-trending folds F1 with SE-vergence formed during the first stage of deformation, DI. The geodynamics and timeline of this stage remain unclear. The W-E-trending folds F2 with E-vergence are related to tectonic movements that took place at stage DII. In the western limb of the antiform, stage DII is evidenced by folds overturned towards the south-east. In the eastern limb, folds plunge to the east and northeast. These fold structures are probably related to the Devonian subduction-obduction processes. At stage DIII, thrusting of the Taldyk antiform over the West Mugodzhar zone and folding F3 with W-vergence is related to the Ural continental collision in the Late Paleozoic, which completed the geodynamic evolution of the Ural paleo-ocean. At stage DIV, postcollisional shearing is evidenced by folds F4 with steeply dipping hinges, which completed the structural evolution of the study area.

Curved multi-frame box-girder bridges with hinges are widely used in the United States due to the large spanning capacity, construction simplification and construction cost economy. This type of bridge frequently has the characteristics of column height asymmetry, adjacent bridge frames vibrating discrepancy. The combination of curved shape and random seismic excitation angles could aggravate the irregularity of the structural seismic response. In this study, an OpenSees model is established for an example bridge, and the hinge is taken as a key component to observe. The impacts of seismic excitation angles and column height layouts on fragility are investigated through the comparison of the fragility curves. The conclusions list the most unfavorable seismic excitation angles corresponding to the fragilities of bridge system, plug-type concrete elements in hinges, hinge restrainers, columns, abutment bearings as well as the secondary components, respectively. The symmetrical column height layout is proved to be beneficial to mitigate the damage risks of restrainers in intermediate hinges and reduce the fragility of the bridge system. This study can provide a reference for the rapid assessment of the fragile position and damage degree of bridges through structural configuration and shape, as well as the seismic excitation angle. [ABSTRACT FROM AUTHOR]

Objective. The objective of the study is to determine the requirements for various devices of hydraulic reclamation machines, which are widely used in the construction of canals and drains, to maintain a given slope, as well as the calculation of the executive mechanism that serves to eliminate the oscillating movement of the working body relative to the line of the specified slope.Methods. A mathematical description of the vibrations of the working body for caterpillar hydraulic reclamation machines with mounted working bodies is given.Results. The article presents the results of research to identify the main factors affecting the oscillations of the working body of caterpillar reclamation machines. As a result of theoretical and experimental studies, it was found that when a caterpillar machine with a rigid undercarriage crosses single and multiple irregularities, the movement of the cutting edge of the rigidly mounted working body is graphically depicted by sinusoidal curves. The obtained dependencies allow conducting calculations of the automatic system of maintaining the specified slope and establish the area of stable modes of system operation. A geometric method for optimizing the hinge linkage of the working body of trenchless pipelayer is presented.Conclusion. The proposed methods of improving the performance of caterpillar hydraulic reclamation machines with mounted working bodies when moving on uneven ground surfaces can be used to create a wide class of mounted earthmoving machines, both with passive and active working bodies.

The hinge, a key component of deployable space mechanism, has a significant influence on the precision of the whole mechanism. Hysteresis is one of the uncontrollable factors affecting the precision of the hinge. However, much work so far has focused on the equivalent model of hysteresis, which is far from the actual situation. In this paper, the hysteresis model of the general rotary hinge was established via the finite element method (ABAQUS/Standard 6.14-4). The correctness of the model was verified by experiments, and the loss factor was defined to measure the size of hysteresis. The response surface method was then used to establish the response surface of the hysteresis loss factor of the general rotary hinge. Results show that the hinge was optimised. By comparing the response surfaces of the two types of hinges, the modified hinge can effectively reduce hysteresis loss factor. Importantly, the repeatability of the hinge can be effectively improved by reducing hysteresis loss factor through repeatability experiments. Using this method, the response surface of the hinge's hysteresis loss factor can be established accurately, and the hysteresis loss factor can be reduced through optimal design to improve the precision of the hinge. This method can provide reference and guidance for the hinge design of the high-precision deployable mechanism.

T cell engager (TCE) antibodies have emerged as promising cancer therapeutics that link cytotoxic T-cells to tumor cells by simultaneously binding to CD3E on T-cells and to a tumor-associated antigen (TAA) expressed by tumor cells. We previously reported a novel bispecific format, the IgG-like Fab x sdAb-Fc (also known as half-IG_VH-h-CH2-CH3), combining a conventional antigen-binding fragment (Fab) with a single domain antibody (sdAb). Here, we evaluated this Fab x sdAb-Fc format as a T-cell redirecting bispecific antibody (TbsAbs) by targeting mEGFR on tumor cells and mCD3E on T cells. We focused our attention specifically on the hinge design of the sdAb arm of the bispecific antibody. Our data show that a TbsAb with a shorter hinge of 23 amino acids (TbsAb.short) showed a significantly better T cell redirected tumor cell elimination than the TbsAb with a longer, classical antibody hinge of 39 amino acids (TbsAb.long). Moreover, the TbsAb.short form mediated better T cell-tumor cell aggregation and increased CD69 and CD25 expression levels on T cells more than the TbsAb.long form. Taken together, our results indicate that already minor changes in the hinge design of TbsAbs can have significant impact on the anti-tumor activity of TbsAbs and may provide a new means to improve their potency.

Essential genes cannot be deleted from the genome; therefore, temperature-sensitive (ts) mutants and cold-sensitive (cs) mutants are very useful to discover functions of essential genes in model organisms such as Schizosaccharomyces pombe and Saccharomyces cerevisiae. To isolate ts/cs mutants for essential genes of interest, error-prone mutagenesis (or random mutagenesis) coupled with in vitro selection has been widely used. However, this method often introduces multiple silent mutations, in addition to the mutation responsible for ts/cs, with the result that one cannot discern which mutation is responsible for the ts/cs phenotype. In addition, the location of the responsible mutation introduced is random, whereas it is preferable to isolate ts/cs mutants with single amino acid substitutions, located in a targeted motif or domain of the protein of interest. To solve these problems, we have developed a method to isolate ts/cs mutants with single amino acid substitutions in targeted regions using site-directed mutagenesis. This method takes advantage of the empirical fact that single amino acid substitutions (L/S -> P or G/A -> E/D) often cause ts or cs. Application of the method to condensin and cohesin hinge domains was successful: ∼20% of the selected single amino acid substitutions turned out to be ts or cs. This method is versatile in fission yeast and is expected to be broadly applicable to isolate ts/cs mutants with single amino acid substitutions in targeted regions of essential genes. 11 condensin hinge ts mutants were isolated using the method and their responsible mutations are broadly distributed in hinge domain. Characterization of these mutants will be very helpful to understand the function of hinge domain.

The human IgG3 subclass is conspicuously absent among the formats for approved monoclonal antibody therapies and Fc fusion protein biologics. Concern about the potential for rapid degradation, reduced plasma half-life, and increased immunogenicity due to marked variation in allotypes has apparently outweighed the potential advantages of IgG3, which include high affinity for activating Fcγ receptors, effective complement fixation, and a long hinge that appears better suited for low abundance targets. This review aims to highlight distinguishing features of IgG3 and to explore its functional role in the immune response. We present studies of natural immunity and recombinant antibody therapies that elucidate key contributions of IgG3 and discuss historical roadblocks that no longer remain clearly relevant. Collectively, this body of evidence motivates thoughtful reconsideration of the clinical advancement of this distinctive antibody subclass for treatment of human diseases.Abbreviations: ADCC - Antibody-Dependent Cell-mediated CytotoxicityADE – Antibody-dependent enhancementAID – Activation-Induced Cytidine DeaminaseCH – Constant HeavyCHF – Complement factor HCSR – Class Switch RecombinationEM - Electron MicroscopyFab – Fragment, antigen bindingFc – Fragment, crystallizableFcRn – Neonatal Fc ReceptorFcγR – Fc gamma ReceptorHIV – Human Immunodeficiency VirusIg - ImmunoglobulinIgH – Immunoglobulin Heavy chain geneNHP – Non-Human Primate

Adaptive structures based on fiber-rubber composites with integrated Shape Memory Alloys are promising candidates for active deformation tasks in the fields of soft robotics and human-machine interactions. Solid-body hinges improve the deformation behavior of such composite structures. Textile technology enables the user to develop reinforcement fabrics with tailored properties suited for hinged actuation mechanisms. In this work, flat knitting technology is used to create biaxially reinforced, multilayer knitted fabrics with hinge areas and integrated Shape Memory Alloy wires. The hinge areas are achieved by dividing the structures into sections and varying the configuration and number of reinforcement fibers from section to section. The fabrics are then infused with silicone, producing a fiber-rubber composite specimen. An existing simulation model is enhanced to account for the hinges present within the specimen. The active deformation behavior of the resulting structures is then tested experimentally, showing large deformations of the hinged specimens. Finally, the simulation results are compared to the experimental results, showing deformations deviating from the experiments due to the developmental stage of the specimens. Future work will benefit from the findings by improving the deformation behavior of the specimens and enabling further development for first applications.

Curved multi-frame box-girder bridges with hinges are widely used in the United States due to the large spanning capacity, construction simplification and construction cost economy. This type of bridge frequently has the characteristics of column height asymmetry, adjacent bridge frames vibrating discrepancy. The combination of curved shape and random seismic excitation angles could aggravate the irregularity of the structural seismic response. In this study, an OpenSees model is established for an example bridge, and the hinge is taken as a key component to observe. The impacts of seismic excitation angles and column height layouts on fragility are investigated through the comparison of the fragility curves. The conclusions list the most unfavorable seismic excitation angles corresponding to the fragilities of bridge system, plug-type concrete elements in hinges, hinge restrainers, columns, abutment bearings as well as the secondary components, respectively. The symmetrical column height layout is proved to be beneficial to mitigate the damage risks of restrainers in intermediate hinges and reduce the fragility of the bridge system. This study can provide a reference for the rapid assessment of the fragile position and damage degree of bridges through structural configuration and shape, as well as the seismic excitation angle.

A domain that is often neglected in the assessment of chimeric antigen receptor (CAR) functionality is the extracellular spacer module. However, several studies have elucidated that membrane proximal epitopes are best targeted through CARs comprising long spacers, while short spacer CARs exhibit highest activity on distal epitopes. This finding can be explained by the requirement to have an optimal distance between the effector T cell and target cell. Commonly used long spacer domains are the CH2-CH3 domains of IgG molecules. However, CARs containing these spacers generally show inferior in vivo efficacy in mouse models compared to their observed in vitro activity, which is linked to unspecific Fcγ-Receptor binding and can be abolished by mutating the respective regions. Here, we first assessed a CAR therapy targeting membrane proximal CD20 using such a modified long IgG1 spacer. However, despite these mutations, this construct failed to unfold its observed in vitro cytotoxic potential in an in vivo model, while a shorter but less structured CD8α spacer CAR showed complete tumor clearance. Given the shortage of well-described long spacer domains with a favorable functionality profile, we designed a novel class of CAR spacers with similar attributes to IgG spacers but without unspecific off-target binding, derived from the Sialic acid-binding immunoglobulin-type lectins (Siglecs). Of five constructs tested, a Siglec-4 derived spacer showed highest cytotoxic potential and similar performance to a CD8α spacer in a CD20 specific CAR setting. In a pancreatic ductal adenocarcinoma model, a Siglec-4 spacer CAR targeting a membrane proximal (TSPAN8) epitope was efficiently engaged in vitro, while a membrane distal (CD66c) epitope did not activate the T cell. Transfer of the TSPAN8 specific Siglec-4 spacer CAR to an in vivo setting maintained the excellent tumor killing characteristics being indistinguishable from a TSPAN8 CD8α spacer CAR while outperforming an IgG4 long spacer CAR and, at the same time, showing an advantageous central memory CAR T cell phenotype with lower release of inflammatory cytokines. In summary, we developed a novel spacer that combines cytotoxic potential with an advantageous T cell and cytokine release phenotype, which make this an interesting candidate for future clinical applications.

A domain that is often neglected in the assessment of chimeric antigen receptor (CAR) functionality is the extracellular spacer module. However, several studies have elucidated that membrane proximal epitopes are best targeted through CARs comprising long spacers, while short spacer CARs exhibit highest activity on distal epitopes. This finding can be explained by the requirement to have an optimal distance between the effector T cell and target cell. Commonly used long spacer domains are the CH2-CH3 domains of IgG molecules. However, CARs containing these spacers generally show inferior in vivo efficacy in mouse models compared to their observed in vitro activity, which is linked to unspecific Fcγ-Receptor binding and can be abolished by mutating the respective regions. Here, we first assessed a CAR therapy targeting membrane proximal CD20 using such a modified long IgG1 spacer. However, despite these mutations, this construct failed to unfold its observed in vitro cytotoxic potential in an in vivo model, while a shorter but less structured CD8α spacer CAR showed complete tumor clearance. Given the shortage of well-described long spacer domains with a favorable functionality profile, we designed a novel class of CAR spacers with similar attributes to IgG spacers but without unspecific off-target binding, derived from the Sialic acid-binding immunoglobulin-type lectins (Siglecs). Of five constructs tested, a Siglec-4 derived spacer showed highest cytotoxic potential and similar performance to a CD8α spacer in a CD20 specific CAR setting. In a pancreatic ductal adenocarcinoma model, a Siglec-4 spacer CAR targeting a membrane proximal (TSPAN8) epitope was efficiently engaged in vitro , while a membrane distal (CD66c) epitope did not activate the T cell. Transfer of the TSPAN8 specific Siglec-4 spacer CAR to an in vivo setting maintained the excellent tumor killing characteristics being indistinguishable from a TSPAN8 CD8α spacer CAR while outperforming an IgG4 long spacer CAR and, at the same time, showing an advantageous central memory CAR T cell phenotype with lower release of inflammatory cytokines. In summary, we developed a novel spacer that combines cytotoxic potential with an advantageous T cell and cytokine release phenotype, which make this an interesting candidate for future clinical applications. [ABSTRACT FROM AUTHOR]

Articulators are instruments that aimed to reproduce the range of jaw movements. The first instrument designs were attempts to duplicate anatomic relations or reproduce functional movements of the anatomy. They were able to preserve centric position only. More sophisticated articulating instruments evolved as more was learned about the anatomy, mandibular movements, and mechanical principles. Over time, interest for articulators progressed. Articulators became adjustable, and they attempted to reproduce jaw movements of each patient by reproducing the anatomy of temporomandibular joints (TMJ's) and related structures. Part I of the article has discussed evolution of articulators beginning from the 18th century till 1940. A history of articulators from 1940 till today is discussed in the present article.

One of the objectives of prosthetic dentistry is to restore teeth in harmony with temporo-mandibular joints. Articulator is a device that allows an operator to fabricate a restoration that will be physiologically and psychologically successful. But how much do we really know about the origin of articulators? First articulator designs attempted to duplicate anatomic relationships and functional movements. More sophisticated articulators evolved as more new knowledge about anatomy, mandibular movements and mechanical principles were obtained. The aim of this article was to describe the origin, history and evolution of articulators through the years. For this article, an electronic search was performed across three databases (Science Direct, PubMed and Google Scholar) for relevant citations. Keywords such as articulators, history, early articulators were used alone and in combination for the search. The option of “related articles” was also utilized. Finally, search was performed on the review articles and the most relevant papers were selected.

The article presents an original classification and typing of theoretically possible realizations of layout diagrams containing parallel structure mechanisms that provide the basis for the implementation of the algorithm for calculating the mechanism geometric parameters. The mechanism is embedded in a pattern corresponding to this layout diagram and assigned initial data. The given classification can significantly reduce the time spent on the initial stage of designing mechanisms of parallel structure.

Spatial mechanisms of various types are widely used in technology. Most of them have one or two ball pairs, the presence of which reduces the service life of the device (ball pairs are difficult to protect from dust and dirt. They are more difficult to manufacture and have a lower loadbearing capacity than rotational pairs). Replacing ball pairs with rotary ones, designed, for example, with standard bearings, will greatly simplify and reduce the cost of their manufacturing technology, increase the service life and expand the area of practical application. The difficulty and complexity of creating fivelink and six-link mechanisms and devices with a special structure lies in the fact that the usual combination of links fails to achieve their operability (with rotatable links). Theoretically, this mechanism has been studied by many foreign and Russian scientists. However, Kazan scientists were the first to form and put into practice spatial mechanisms with rotational pairs. The paper presents synthesis and analysis of the spatial five-link mechanism by the degree of irregularity, axial displacement, elliptical law and by the reproduction of a linear function. The mechanism provides intensification and energy saving of mixing, separation, torque transmission of various drives.

The article considers regularities of the influence of forces of viscous resistance generated by the damper device in the cylindrical hinges of the nodes connect the links of the crane-manipulator units mobile transport-technological ma-chines. The specified effect is considered on the efficiency of the damping of oscillations of the metal in the process of operation, due to the presence of increased clearances due to wear of the holes of the hinge eyes. It is shown that the force of viscous resistance should be considered in addition to the generated damping devices forces of elastic resis-tance, as the latter determine the effectiveness of damping in general. The main role of forces of viscous resistance is the dissipation of energy of an oscillatory turning movement of the mating parts of the metal structures due to oscilla-tory displacement of the hinge pin within the hinge gap until the complete decay of oscillations. Considered in relation to the crane-manipulator installing mobile transport-technological machines AST-4-A the effect of the action of forces of viscous resistance is almost not observed when the coefficient of viscous damping less than 0.01 MN∙s/m, in the range 0,01...0,05 MN∙s/m this influence begins to manifest itself more and more noticeable, in the range of 0,05...0,4 MN∙s/m has a lot of damping vibrational displacement of the hinge pin within the gap, while the coefficient of viscous damping more than 0.4 MN∙s/m oscillatory process becomes aperiodic with an almost complete attenuation in the range of one oscillation of the hinged finger.

A variety of Fc domain engineering approaches for abrogating the effector functions of mAbs exists. To address some of the limitations of the current Fc domain silencing approaches, we are exploring a less commonly considered option which relies on the deletion of the hinge. Removal of the hinge domain in humanized IgG1 and IgG4 mAbs obliterates their ability to bind to activating human Fc gamma receptors I and IIIA, while leaving their ability to engage their target antigen intact. Deletion of the hinge also reduces binding to the Fc neonatal receptor, although Fc engineering allows partial recovery of affinity. Engineering of the CH3 domain, stabilizes hinge deleted IgG4s and prevents Fab arm exchange. The faster clearing properties together with the pacified Fc make modality of the hinge deleted mAb an appealing solution for therapeutic and diagnostic applications.