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The article presents the course and results of research aimed at assessing the strength and practical usability of a furniture hinge additively manufactured from thermoplastic material. The research activities included: development of design assumptions, adoption of target geometry, creation of a 3D-CAD model, preliminary strength analysis in the FEM environment, prototype manufacturing using FFF method with thermoplastic material (pet-g), and conducting tests under conditions similar to real ones. The hinge geometry was based on typical market-available design solutions, while considering the specifics of the adopted manufacturing method. Strength analysis via FEM was conducted on the 3D-CAD model, allowing estimation of stress values and determination of the suitability of the developed geometry for testing on a real model. Subsequently, research models were produced using FFF technology with various infill patterns: linear 30%, hexagonal 30%, linear 60%, hexagonal 60%, and solid 100%. Bench tests were conducted to determine the maximum load-bearing capacity of the hinge under perpendicular loading to the axis and to assess hinge wear under conditions simulating real-life door usage. The results revealed that the hinge with solid infill safely carried a load of 160 kg without damage, while the hinge with hexagonal 30% infill exhibited the lowest load-bearing capacity, failing at 85 kg. To determine the hinge's durability, the clearance at two reference points on the doors was measured. [ABSTRACT FROM AUTHOR]

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]

This article describes a method of curve-fitting that involves splitting the curve into two (or more) and creating separate functions for each part. These functions are then concatenated via a linking function to create one overall function that better describes the original data than is otherwise achievable. The linking function is able to do this by separating the original two functions so that they are each active in only the relevant portion of the overall curve without the use of dummy variables. The final result is a continuous function in which it is straightforward to smooth the transition at the knot between the piecewise subfunctions. In addition, the piecewise subfunctions do not need to align at the knot since the degree of smoothing is readily controlled. All types of functions may be concatenated so that the method is flexible and relatively simple to apply. [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]

Rain‐harvesting behaviour represents an adaptation for water collection that has evolved in some species of iguanian reptiles inhabiting arid environments. To date, such behaviour has been observed only in members of the families Agamidae and Phrynosomatidae. A common set of integumentary features characterizes these rain‐harvesting species, including scale surface microstructures (SSMs), capillary channels and hinge joints. The influence of variations in these features on rain‐harvesting has been a subject of discussion for many decades. Nevertheless, a comprehensive comparative study of similarities and differences between harvesting and non‐harvesting species on a broader scale remains lacking. In this study, we classify scale surface microstructures into three categories: large hexagons (SSM1), smaller nested hexagons (SSM2) and hinge pits (SSM2H). As the first two SSM types are widespread, they do not appear to be directly linked to the adaptation for rain‐harvesting. Conversely, the presence or absence of hinge pits distinguishes harvesters from non‐harvesters. Additionally, channel hierarchy, width and structure determine the effectiveness of the rain‐harvesting architecture. Only Moloch horridus exhibits distinct integumentary features in comparison to other agamids and rain‐harvesting species. Ancestral character state reconstruction suggests that rain‐harvesting behaviour was likely absent in the ancestor of Iguanians, even though overlapping scales and SSM1 were present. Our findings illustrate that rain‐harvesting species have independently converged upon similar structural solutions to address their water acquisition challenges, building upon shared pre‐existing features. [ABSTRACT FROM AUTHOR]

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Hinge motion is observed in macrocyclic, mortise‐type molecular hinges using variable temperature NMR spectroscopy. The data is consistent with dynamic hinging from a folded‐to‐extended‐to‐folded enantiomeric state. Crystallographic and solution structures of the folded states are reported. Chemical shift predictions derived from crystallographic data corroborate fully revolute hinge motion. The rate of hinging is affected by steric congestion at the hinge axis. A macrocycle containing glycine, 1, hinges faster than one comprising aminoisobutyric acid, 2. The free energies of activation, ΔG≠, for 1 and 2 were determined to be 13.3±0.3 kcal/mol and 16.3±0.3 kcal/mol, respectively. This barrier is largely independent of solvent across those surveyed (CD3OD, CD3CN, DMSO‐d6, pyridine‐d5, D2O). Experiment and computation predict energy barriers that are consistent with disruption of an intramolecular network of hydrogen bonds. DFT calculations reveal a pathway for hinge motion. [ABSTRACT FROM AUTHOR]

Importin α is a nuclear transporter that binds to nuclear localization signals (NLSs), consisting of 7–20 positively charged amino acids found within cargo proteins. In addition to cargo binding, intramolecular interactions also occur within the importin α protein due to binding between the importin β-binding (IBB) domain and the NLS-binding sites, a phenomenon called auto-inhibition. The interactions causing auto-inhibition are driven by a stretch of basic residues, similar to an NLS, in the IBB domain. Consistent with this, importin α proteins that do not have some of these basic residues lack auto-inhibition; a naturally occurring example of such a protein is found in the apicomplexan parasite Plasmodium falciparum. In this report, we show that importin α from another apicomplexan parasite, Toxoplasma gondii, harbors basic residues (KKR) in the IBB domain and exhibits auto-inhibition. This protein has a long, unstructured hinge motif (between the IBB domain and the NLS-binding sites) that does not contribute to auto-inhibition. However, the IBB domain may have a higher propensity to form an α-helical structure, positioning the wild-type KKR motif in an orientation that results in weaker interactions with the NLS-binding site than a KRR mutant. We conclude that the importin α protein from T. gondii shows auto-inhibition, exhibiting a different phenotype from that of P. falciparum importin α. However, our data indicate that T. gondii importin α may have a low strength of auto-inhibition. We hypothesize that low levels of auto-inhibition may confer an advantage to these important human pathogens. [ABSTRACT FROM AUTHOR]

Purpose: Closing wedge distal femoral osteotomies (CWDFO) are attractive treatment options for unicompartmental knee osteoarthritis with coronal plane deformity. However, it has been traditionally associated with high rates of hinge fracture that can adversely impact recovery and patient outcomes. Appropriate siting of hinge point can be an effective method of reducing the incidence of hinge fractures. This study aims to illustrate a case series of CWDFO with low rates of hinge fracture utilising our preferred hinge point site. Methods: A retrospective study of a cohort of 39 CWDFO was performed between May 2019 and May 2022. Both medial and lateral CWDFO were included. The hinge point in all cases was placed at the level of the inferior margin of the metaphyseal flare, and inferior to the gastrocnemius origin, with a hinge thickness of 10 mm. Post-operative radiographs were obtained at 2, 4 and 8 weeks after surgery to assess for hinge fracture and union. Results: Thirty-nine cases of CWDFO were performed, consisting of eighteen cases of valgus malalignment that underwent medial CWDFO and twenty-one cases of varus malalignment that underwent lateral CWDFO. At surgery, the mean age was 47.6 (± 13.9) years and mean BMI was 29.4 (± 4.9). There were 23 men and 16 women. Three cases of hinge fractures occurred intraoperatively, translating into a hinge fracture rate of 7.69%. However, union was achieved in all three cases and all patients in this case series were able to progress to weight bear as tolerated at 2 months post-osteotomy. Conclusion: Distal placement of the hinge at the level of the inferior metaphyseal flare margin with the use of a hinge wire can greatly reduce the rates of hinge fracture in CWDFO. Level of evidence: Level III. [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]

Dirac semimetals (DSMs) are an important class of topological states of matter. Here, focusing on DSMs of band inversion type, we investigate their boundary modes from the effective model perspective. We show that in order to properly capture the boundary modes, k-cubic terms must be included in the effective model, which would drive an evolution of surface degeneracy manifold from a nodal line to a nodal point. Sizable k-cubic terms are also needed for better exposing the topological hinge modes in the spectrum. Using first-principles calculations, we demonstrate that this feature and the topological hinge modes can be clearly exhibited in β-CuI. We extend the discussion to magnetic DSMs and show that the time-reversal symmetry breaking can gap out the surface bands and hence is beneficial for the experimental detection of hinge modes. Furthermore, we show that magnetic DSMs serve as a parent state for realizing multiple other higher-order topological phases, including higher-order Weyl-point/nodal-line semimetals and higher-order topological insulators. [ABSTRACT FROM AUTHOR]

Protein kinases are key regulators of cellular signaling and play a critical role in oncogenesis. Inhibitors of protein kinases are pursued by both industry and academia as a promising target for cancer therapy. Within the protein kinases, the ATP site has produced more than 40 FDA‐approved drugs. The ATP site is broadly composed of a hinge region, gatekeeper residues, DFG‐loop, ribose pocket, and other hydrophobic regions. The hinge region in the ATP site can be used for designing potent inhibitors. In this review, we discuss some representative studies that will highlight the interactions of heterocyclic compounds with hinge regions of different kinases like BRAF kinase, EGRF kinase, MAP kinase, and Mps1 kinase. [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]

The dynamics of exoskeleton model placed on a movable flying base of Flyboard Air type is considered. The impact of electric drive spinning rotors on the exoskeleton dynamics is examined. The importance of taking this impact into account in developing an operating mechanism is established. [ABSTRACT FROM AUTHOR]

The Structural Maintenance of Chromosome (SMC) protein is essential for various cellular processes, including chromosome organization, DNA repair, and genome stability. MksB, an alternative SMC protein present in prokaryotes, comprises a hinge dimerization domain and an ABC ATPase head domain linked by a coiled-coil arm. While hinge dimerization in bacterial and eukaryotic SMCs is attributed to conserved glycines, our study unveils the critical role of a novel KDDR motif located at a loop near the hinge dimer interface in Mycobacterium smegmatis MksB (MsMksB). We demonstrate the regulatory role of this motif in MsMksB dimerization and DNA binding activity. The K600D mutation in the KDDR motif induces MsMksB dimer-to-monomer conversion, highlighting the significance of this motif in MsMksB dimerization. Mass spectrometry-based mapping of the DNA binding site revealed the lysine's involvement in protein-DNA interaction. Monomers of the hinge domain lose DNA binding activity, and MsMksB single-arm mutants exhibit reduced DNA binding and ATPase activity, underscoring the importance of hinge-mediated dimerization in MsMksB function. Notably, the R603D mutant retains dimerization but shows compromised ATPase and DNA binding activities. Mutants with defective ATPase activity exhibit impaired DNA condensation in vivo. These findings provide novel regulatory insight into the mechanism of MksB dimerization and DNA binding, uncovering the fundamental processes of chromosome condensation and segregation., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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.

Introduction: Valgus high tibial osteotomy (HTO) is indicated for managing isolated medial knee osteoarthritis in a young patient with a metaphyseal deformity of the proximal tibia. In a medial opening HTO, maintaining the integrity of the lateral hinge is crucial for ensuring proper healing and correction retention. Using a locked plate to stabilize an HTO is common practice, allowing for earlier weight-bearing. The objective of this study was therefore to measure and track the mechanical load distribution on a locked fixation plate and the lateral hinge of an HTO using a finite element (FE) model simulating single-leg stance loading., Hypothesis: The working hypothesis was that during weight-bearing, the plate and the lateral hinge absorb stress asymmetrically, predominantly on the plate., Material and Methods: A numerical model of an HTO stabilized with a locked plate was developed based on the actual geometry of a healthy proximal tibia (using Autodesk Fusion 360 and Altair HyperWorks software). In this finite element simulation of loading, a mesh convergence study was conducted to optimize the accuracy of the numerical model results. The primary outcome measure was the maximum stress value in the affected areas (Von Mises stress, in MPa) of the plate and the lateral hinge., Results: The maximum stress intensity in the plate was approximately 20.29 MPa. The maximum stress intensity in the bony hinge was about 5.6 MPa. The results of the mesh convergence study for the hinge and the plate enabled defining the most suitable model for future FE studies: a 4 mm mesh for all model elements except for the high-stress area in the plate and the hinge, which were meshed with a 0.7 mm element size. This adaptation provided greater precision in the study., Discussion: There is a distribution and allocation of stress both on the plate and the hinge, underlining the significance of the plate and the absolute necessity of preserving the hinge. Predictably, the plate absorbs the majority of the load, more than three times that of the hinge., Conclusion: The hypothesis is confirmed; however, additional studies would be necessary to validate these numerical results: an experimental component on instrumented cadaveric bones, as well as comparative studies of different fixation plates., Level of Evidence: V, expert opinion; controlled laboratory study., (Copyright © 2024. Published by Elsevier Masson SAS.)

Detailed structural analysis of the formations of the Maksyutov eclogite–glaucophane–schist complex in the Southern Urals has been carried out. U–Pb (LA-ICP-MS) isotopic dates of detrital zircons from quartzites of the Yumaguzino and Karamala groups (tectonostratigraphic units) making up the complex were obtained. The data show that both groups are similar in age but differ in the facies formations that comprise the proximal (Yumaguzino Group) and distal (Karamala Group) regions of the Paleozoic margin of the Baltica paleocontinent. The alternation of these groups in the Maksyutov Complex is explained by their tectonic juxtaposition during the formation of the scaly-thrust structure of this complex. Formations of the Maksyutov Complex subsided in the subduction zone beneath the Magnitogorsk island arc and were subjected to fold deformations during the subsequent exhumation. Four deformation stages have been established during the structural evolution of the complex. The first stage is associated with the development of the southwest-vergent folds and sheath folds F1 and corresponds to the eduction of the formations of the Maksyutov metamorphic complex from the subduction zone of the Magnitogorsk island arc in the southwestern direction (in modern coordinates) in the middle of the Famennian–Late Devonian. The second stage manifests itself in the development of the southeast-vergent folds F2, which are most common in the Maksyutov Complex. This stage is associated with an oblique sinistral collision of the Magnitogorsk island arc with the Baltica margin in the Late Devonian. At the third deformation stage, the west-vergent folds F3 were formed, caused by movements during the Late Paleozoic continental collision in the Main Ural Fault Zone. Postcollisional shear movements at the fourth deformation stage, marked by the development of folds F4 with steeply dipping hinges, completed the main stage of the structural evolution of the region. [ABSTRACT FROM AUTHOR]

A spatial (3D) model of an exoskeleton with links of variable length is considered. The construction of a multi-link model is based on the analysis of a one-link model of with one fixed point in space and a two-link model of variable length. In connection with the difficulties arising in the construction of systems of differential equations of motion with a relatively large number of links that are associated with a long compilation time even when using modern computational systems and algorithms, a generalization for the mechanism for the case of an arbitrary finite number of links is considered and a high-speed method for constructing systems of differential equations of motion for the considered models of mechanisms is given. A five-link 3D model of an exoskeleton with of variable length that can be used to create a working exoskeleton or an anthropomorphic robot is presented. We propose a model with two solid weighty sections located at both ends of the link and a weightless section between them in the center of the link. Analytically synthesized trajectories of movement are obtained and the results of numerical simulation of the movement of a man-machine system in the form of a man in an exoskeleton are presented. Application of the proposed model allows one to reduce the load on the joints, increase strength, comfort and time of continuous use of the exoskeleton. [ABSTRACT FROM AUTHOR]

Introduction: Every month, Sports National Institute (ISN) in Malaysia received around 3 to 4 cases associated with anterior cruciate ligament (ACL) injury involving athletes in hockey, kick volleyball and netball. Knee orthosis is one of treatment method and has been shown to support lower limb joint mechanics, which may protect the ACL injury for becoming worst. In this paper, an investigation was conducted to evaluate the performance of existing knee orthosis for treating ACL injury. Methods: Ten participants which have been grouped into two; six ACL patients (Group 1) and four healthy subjects (Group 2), where they took part in two bracing conditions; 1) with hinge (Brace 1) and 2) sleeve with bilateral hinges (Brace 2). A non-braced condition was included as a baseline measure. Three-dimensional kinematics data were used to calculate knee joint motions. Results: From the findings of ACL subjects, the knee flexion in non-braced condition (49.9°) has high value than others two braces, in which Brace 1 (40.9°) is less value than Brace 2 (44.6°). This shows the Brace 2 have higher degree of freedom than Brace 1. Other than that, the comfortability assessment found that Brace 2 is the most favourable options by participants in terms of less slippage and comfortless condition. Conclusion: In conclusion, the Brace 2 give best performance during dynamic balance activity in individuals who benefit from high degree of freedom and less slippage issue. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to examine the radiological features of hinge fracture occurring at the distal medial femoral cortex in knees undergoing biplanar lateral closed-wedge distal femoral osteotomy (LCW-DFO) in double-level osteotomy (DLO) based on pre- and postoperative CT image analyses. It was hypothesised that medial hinge fractures in LCW-DFO would occur with a similar incidence to that in high tibial osteotomy, and its occurrence would affect the clinical/radiological outcomes and induce unintended change in alignment depending on the fracture type (direction of the fracture). Methods: A consecutive series of 36 knees (31 patients) with primary varus osteoarthritis undergoing DLO comprised the study population. The mean age at surgery was 62.0 ± 5.9 years. Presence of hinge fracture was assessed on radiographs and CT images at 1 week. The fracture type was classified depending on the direction of the fracture line: crack propagation in line with the osteotomy (type 1) and fractures extending proximally (type 2) or distally (type 3) from the tip of the wedge. Computer-assisted assessments of bony limb alignment and bony geometry were conducted on a full-length weight-bearing radiograph and CT images using image analysis software. In addition, subjective clinical results were evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS). Radiological and clinical follow-up results at 1 and 2 years were compared to the preoperative data, while comparative analysis was made between the subjects with and without a hinge fracture. Results: Postoperative image examinations revealed type 1 and 2 medial femoral hinge fractures in 4 and 7 knees, while no type 3 fracture was identified in the study population. Consequently, the overall incidence of the hinge fracture was 30.6% (11 of the 36 knees). Four of those 11 fractures (36.4%) could not be detected on plain radiographs. CT image analysis for three-dimensional bony geometry showed greater increase in internal rotation of the distal bony segment (increased femoral antetorsion by 9.5° on average) after surgery compared to the knees without a hinge fracture (P = 0.01). Clinical evaluation using the KOOS at 2 years showed no significant difference between the groups with and without hinge fractures. Conclusion: In LCW-DFO, medial femoral hinge fractures occurred in 30.6% of the cases. Knees with type 1 hinge fracture exhibited significantly greater increase in femoral antetorsion as compared to those without hinge fracture. In this case series, postoperative weight-bearing protocol was delayed for knees with hinge fracture. Consequently, surgical results were not affected by the occurrence of hinge fracture for up to 2 years. Level of evidence: IV (case series) [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.

A mathematical model of a spacecraft (SC) with an arbitrary number of large flexible structural (appendages) elements (LFSEs) is developed, implemented, and verified. The SC model obtained based on the general equations of dynamics is written in generalized coordinates. It allows three types of articulation between the LFSEs and the SC's body: cantilever, and with the help of one-step and two-step hinges. Due to the procedure used in the derivation of the equations of motion, the proposed model allows us to change the number of LFSEs and types of articulation without rewriting the equations of motion in symbolic form, which makes it comfortable for software implementation. [ABSTRACT FROM AUTHOR]

Duncan Pritchard's Epistemic Angst promises a novel solution to the closure-based sceptical problem that, unlike more traditional solutions, does not entail revising our fundamental epistemological commitments. In order to do this, it appeals to a Wittgensteinian account of rational evaluation, the overarching theme of which is that it neither makes sense to doubt nor to believe in our anti-sceptical hinge commitments. The purpose of this paper is to show that the argument for the claim that there can be no rational basis to believe our anti-sceptical hinge commitments relies upon an implicit assumption about rational support that I label The Pritchensteinian Rational Grounds Principle. I argue that, insofar as this principle is intended to apply to closure-style inferences, it leads to irrational doxastic attitudes. I consider a seemingly plausible modification of the principle that would avoid this result but show that this modified principle faces serious problems of its own. [ABSTRACT FROM AUTHOR]