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Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: There are various traditional landmarks used to estimate the femoral component version, yet none are widely accepted by direct anterior surgeons. The purpose of this study was to compare bony landmarks easily accessible to direct anterior surgeons and to estimate which one provides the best estimate of femoral component anteversion., Methods: A computed tomography database was used to identify 736 left entire-femur computed tomography scans. Seven visible anatomic landmarks were identified using a computer model in which a 45° virtual neck resection was made at 10 mm above the lesser trochanter. Thirteen axes, to reference the femoral stem position, were created between the 7 landmarks. Means and standard deviations (SDs) of angles between each axis and the transepicondylar axis (TEA) were compared for their precision., Results: The traditional lesser trochanter predicted anteversion from the TEA was 34.1° (SD 9.7°). Predicted anteversion from the TEA was 3.3° (SD 8.1°) when aligned from the center of the canal to the middle of the medial calcar; 14.0° (SD 8.1°) from the center of the canal to the anterior 1/3 of the medial calcar; and 24.8° (SD 8.5°) from the center of the canal to the most anterior point on the medial calcar., Conclusions: Compared to the lesser trochanter, 7 axes were more precise (lower SD) when predicting the version. Estimating the femoral component position, via simulated data, using 3 points along the medial calcar is a relatively precise and easily accessible tool for surgeons., (© 2024 The Authors.)

Purpose: The aim of this study was to describe the native trochlear orientation of non-arthritic knees in three planes and to quantify the relationship between trochlear and distal condylar anatomy across race and sex., Methods: Computed tomography scans of 1578 femora were included in this study. The mediolateral position of the trochlear sulcus, the distal trochlear sulcus angle (DTSA) the medial sulcus angle (MSA) and the lateral sulcus angle (LSA) as well as the mechanical lateral distal femoral angle (mLDFA) were measured relative to a standard reference coordinate system. Multiple linear regression analyses were performed to account for potential confounding variables., Results: The mediolateral position of the trochlear sulcus had minimal mean deviation of the sagittal femoral plane. The mean DTSA was 86.1° (SD 2.2°). Multilinear regression analysis found mLDFA, sex, and age all influence DTSA (p < 0.05), with mLDFA having by far the greatest influence (r 2  = 0.55). The medial facet of the trochlear sulcus was found to be flat proximally and more prominent distally. The lateral facet was relatively uniform throughout the arc., Conclusion: In non-arthritic knees, due to a strong positive correlation between the DTSA and the mLDFA, the trochlear sulcus is consistently orientated in the sagittal femoral plane regardless of distal condylar anatomy. Minor deviations from the sagittal plane occur in a lateral direction in the middle part and in a medial direction at the proximal and distal part of the trochlea. These findings have relevance regarding the biomimetic design of total knee implants., (© 2021. The Author(s).)

Background: Improved understanding of the morphological characteristics of knees with osteoarthritis (OA) and various deformities can enable personalized implant positioning and balancing in total knee arthroplasty in an effort to continue improving clinical outcomes and optimizing procedural value. Therefore, the purpose of this study was to outline morphological differences in the medial and lateral distal femur and proximal tibia associated with varus and valgus deformities in knee OA., Methods: A large computed tomography (CT) database was used to identify 1,158 knees, which were divided into normal and osteoarthritic groups; the latter was further divided on the basis of deformity into neutral, varus, and valgus subgroups. Morphological measurements included the non-weight-bearing hip-knee-ankle angle (nwHKA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), rotation of the posterior condylar axis (PCA) relative to the surgical transepicondylar axis (sTEA), ratio of medial to lateral posterior condylar offset, ratio of medial to lateral condylar radius, medial posterior slope (MPS), lateral posterior slope (LPS), medial coronal slope (MCS), and lateral coronal slope (LCS)., Results: Compared with the normal group, the OA group was in overall varus (nwHKA, -2.2° ± 5.0° compared with -0.2° ± 2.4°) and had a significantly smaller MPS (8.4° ± 4.0° compared with 9.2° ± 4.0°), larger LPS (9.2° ± 3.6° compared with 7.2° ± 3.3°), and smaller MCS (82.1° ± 4.3° compared with 83.9° ± 3.3°). Differences among the OA subgroups were also observed for the MCS and LCS. Compared with the normal group, the sTEA of the OA group was less externally rotated relative to the PCA (0.3° ± 1.5° compared with 1.2° ± 1.9°), and both the condylar offset ratio (1.01 ± 0.06 compared with 1.04 ± 0.07) and the condylar radius ratio (0.98 ± 0.07 compared with 1.03 ± 0.07) were smaller. Only the condylar radius ratio showed differences among the OA subgroups, with valgus deformity associated with a larger ratio., Conclusions: An analysis of CT scans of 965 healthy and 193 osteoarthritic knees revealed significant differences in PCA, condylar offset, and condylar radius as well as tibial slope in both the sagittal and coronal planes., Clinical Relevance: There is a strong need to evolve toward a more personalized treatment for osteoarthritic knees that utilizes implants and technology to help tailor total knee arthroplasty on the basis of the patient's morphologic characteristics., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G973)., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Since the introduction of the first total knee designs, a frequent design goal has been to reproduce normal knee motion. However, studies of many currently used total knee designs, have shown that this goal has not been achieved. We proposed that Guided Motion total knee designs, could achieve more anatomic motion than present standard designs., Methods: Several Guided Motion knees for application without cruciate ligaments were designed using a computer method where the bearing surfaces were generated by the motion required. A knee testing machine was constructed where physiological forces including compressive, shear and torque were applied during knee flexion. The neutral path of motion and the laxity about the neutral path were measured. This evaluation method was a modification of the ASTM standard Constraint Test., Results: The motions of the Guided Motion knees and a standard PS knee were compared with the anatomic motion of knee specimens determined in an earlier study The Guided Motion knees showed motion patterns which were closer to anatomic than the PS knee., Conclusions: The results provided justification for carrying out further evaluations of functional conditions, using either knee simulators or computer modelling. If anatomic motions could be reproduced in vivo, it is possible that clinical outcomes could be improved., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function., Results: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory., Conclusion: We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.

Background: The expression of heat shock protein gp96 is strongly correlated with the degree of tissue inflammation in ulcerative colitis and Crohn's disease, thereby leading us to the hypothesis that inhibition of expression via gp96-II peptide prevents intestinal inflammation., Methods: We employed daily injections of gp96-II peptide in two murine models of intestinal inflammation, the first resulting from five daily injections of IL-12/IL-18, the second via a single intrarectal application of TNBS (2,4,6-trinitrobenzenesulfonic acid). We also assessed the effectiveness of gp96-II peptide in murine and human primary cell culture., Results: In the IL-12/IL-18 model, all gp96-II peptide-treated animals survived until day 5, whereas 80% of placebo-injected animals died. gp96-II peptide reduced IL-12/IL-18-induced plasma IFNγ by 89%, IL-1β by 63%, IL-6 by 43% and tumor necrosis factor (TNF) by 70% compared to controls. The clinical assessment Disease Activity Index of intestinal inflammation severity was found to be significantly lower in the gp96-II-treated animals when compared to vehicle-injected mice. gp96-II peptide treatment in the TNBS model limited weight loss to 5% on day 7 compared with prednisolone treatment, whereas placebo-treated animals suffered a 20% weight loss. Histological disease severity was reduced equally by prednisolone (by 40%) and gp96-II peptide (35%). Mice treated with either gp96-II peptide or prednisolone exhibited improved endoscopic scores compared with vehicle-treated control mice: vascularity, fibrin, granularity, and translucency scores were reduced by up to 49% by prednisolone and by up to 30% by gp96-II peptide. In vitro , gp96-II peptide reduced TLR2-, TLR4- and IL-12/IL-18-induced cytokine expression in murine splenocytes, with declines in constitutive IL-6 (54%), lipopolysaccharide-induced TNF (48%), IL-6 (81%) and in Staphylococcus epidermidis -induced TNF (67%) and IL-6 (81%), as well as IL-12/IL-18-induced IFNγ (75%). gp96-II peptide reduced IL-1β, IL-6, TNF and GM-CSF in human peripheral blood mononuclear cells to a similar degree without affecting cell viability, whereas RANTES, IL-25 and MIF were twofold to threefold increased., Conclusion: gp96-II peptide protects against murine intestinal inflammation by regulating inflammation in vivo and in vitro , pointing to its promise as a novel treatment for inflammatory bowel disease.

Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) both cause an inflammatory response and hypoxia. Patients who have both conditions (overlap syndrome) have increased morbidity and mortality. This article aims to increase awareness of the potential effects that untreated OSA can have on COPD and the importance of treating patients with overlap syndrome.

We studied the combined role of the medial meniscus in distributing load and providing stability. Ten normal knees were loaded in combinations of compressive and shear loading as the knee was flexed over a full range. A digital camera tracked the motion, from which femoral-tibial contacts were determined by computer modelling. Load transmission was determined from the Tekscan for the anterior horn, central body, posterior horn, and the uncovered cartilage in the centre of the meniscus. For the three types of loading; compression only, compression and anterior shear, compression and posterior shear; between 40% and 80% of the total load was transmitted through the meniscus. The overall average was 58%, the remaining 42% being transmitted through the uncovered cartilage. The anterior horn was loaded only up to 30 degrees flexion, but played a role in controlling anterior femoral displacement. The central body was loaded 10-20% which would provide some restraint to medial femoral subluxation. Overall the posterior horn carried the highest percentage of the shear load, especially after 30 degrees flexion when a posterior shear force was applied, where the meniscus was estimated to carry 50% of the shear force. This study added new insights into meniscal function during weight bearing conditions, particularly its role in early flexion, and in transmitting shear forces., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The purpose of this study was to determine if a horizontal cleavage lesion (HCL) of the posterior horn of the medial meniscus would result in changes to tibiofemoral contact mechanics, as measured by peak contact pressure and contact area, which can lead to cartilage degeneration. To study this, 10 cadaveric knees were tested in a rig where forces were applied (500 N Compression, 100 N shear, 2.5 Nm Torque) and the knee dynamically flexed from -5° to 135°, as peak contact pressure and contact area were recorded. After testing of the intact knee, a horizontal cleavage lesion was created arthroscopically and testing repeated. The Wilcoxon signed-rank test was used to determine if there were differences in peak contact pressure and contact area between the intact knee and that with the HCL. A statistically significant increase in peak contact pressure of 13%, on average, and a decrease in contact area of 6%, on average, was noted following the HCL. This suggests that a horizontal cleavage lesion will result in small but statistically significant changes in tibiofemoral contact mechanics which may lead to cartilage degeneration., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Motivation: Many secretory peptides are synthesized as inactive precursors that must undergo post-translational processing to become biologically active peptides. Attempts to predict natural peptides are limited by the low performance of proteolytic site predictors and by the high combinatorial complexity of pairing such sites. To overcome these limitations, we analyzed the site-wise evolutionary mutation rates of peptide hormone precursors, calculated using the Rate4Site algorithm., Results: Our analysis revealed that within their precursors, peptide residues are significantly more conserved than the pro-peptide residues. This disparity enables the prediction of peptides with a precision of ∼60% at a recall of 40% [receiver-operating characteristic curve (ROC) AUC 0.79]. Subsequently, combining the Rate4Site score with additional features and training a Random Forest classifier enable the prediction of natural peptides hidden within secreted human proteins at a precision of ∼90% at a recall of 50% (ROC AUC 0.96). The high performance of our method allows it to be applied to full secretomes and to predict naturally occurring active peptides. Our prediction on Homo sapiens revealed several putative peptides in the human secretome that are currently unannotated. Furthermore, the unique expression of some of these peptides implies a potential hormone function, including peptides that are highly expressed in endocrine glands., Availability and Implementation: A pseudocode is available in the SUPPLEMENTARY INFORMATION., Contact: doron.gerber@biu.ac.il or kliger@cgen.com, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Adenosine-to-inosine modification of RNA molecules (A-to-I RNA editing) is an important mechanism that increases transciptome diversity. It occurs when a genomically encoded adenosine (A) is converted to an inosine (I) by ADAR proteins. Sequencing reactions read inosine as guanosine (G); therefore, current methods to detect A-to-I editing sites align RNA sequences to their corresponding DNA regions and identify A-to-G mismatches. However, such methods perform poorly on RNAs that underwent extensive editing ("ultra"-editing), as the large number of mismatches obscures the genomic origin of these RNAs. Therefore, only a few anecdotal ultra-edited RNAs have been discovered so far. Here we introduce and apply a novel computational method to identify ultra-edited RNAs. We detected 760 ESTs containing 15,646 editing sites (more than 20 sites per EST, on average), of which 13,668 are novel. Ultra-edited RNAs exhibit the known sequence motif of ADARs and tend to localize in sense strand Alu elements. Compared to sites of mild editing, ultra-editing occurs primarily in Alu-rich regions, where potential base pairing with neighboring, inverted Alus creates particularly long double-stranded RNA structures. Ultra-editing sites are underrepresented in old Alu subfamilies, tend to be non-conserved, and avoid exons, suggesting that ultra-editing is usually deleterious. A possible biological function of ultra-editing could be mediated by non-canonical splicing and cleavage of the RNA near the editing sites., Competing Interests: The authors have declared that no competing interests exist.

Blocking conformational changes in biologically active proteins holds therapeutic promise. Inspired by the susceptibility of viral entry to inhibition by synthetic peptides that block the formation of helix-helix interactions in viral envelope proteins, we developed a computational approach for predicting interacting helices. Using this approach, which combines correlated mutations analysis and Fourier transform, we designed peptides that target gp96 and clusterin, 2 secreted chaperones known to shift between inactive and active conformations. In human blood mononuclear cells, the gp96-derived peptide inhibited the production of TNFalpha, IL-1beta, IL-6, and IL-8 induced by endotoxin by >80%. When injected into mice, the peptide reduced circulating levels of endotoxin-induced TNFalpha, IL-6, and IFNgamma by >50%. The clusterin-derived peptide arrested proliferation of several neoplastic cell lines, and significantly enhanced the cytostatic activity of taxol in vitro and in a xenograft model of lung cancer. Also, the predicted mode of action of the active peptides was experimentally verified. Both peptides bound to their parent proteins, and their biological activity was abolished in the presence of the peptides corresponding to the counterpart helices. These data demonstrate a previously uncharacterized method for rational design of protein antagonists.

We put forward a theoretical model for the morphological transitions of templated mesoporous materials. These materials consist of a mixture of surfactant molecules and inorganic compounds which evolve dynamically upon mixing to form different morphologies depending on the composition and conditions at which mixing occurs. Our theoretical analysis is based on the assumption that adsorption of the inorganic compounds onto mesoscopic assemblies of surfactant molecules changes the effective interactions between the surfactant molecules, consequently lowering the spontaneous curvature of the surfactant layer and inducing morphological changes in the system. On the basis of a mean field phase diagram, we are able to follow the trajectories of the system starting with different initial conditions, and predict the final morphology of the product. In a typical scenario, the reduction in the spontaneous curvature leads first to a smooth transition from compact spherical micelles to elongated worm-like micelles. In the second stage, the layer of inorganic material coating the micelles gives rise to attractive inter-micellar interactions that eventually induce a collapse of the system into a closely packed hexagonal array of coated cylinders. Other pathways may lead to different structures including disordered bicontinuous and ordered cubic phases. The model is in good qualitative agreement with experimental observations.

The phase behavior of charged rods in the presence of interrod linkers is studied theoretically as a model for the equilibrium behavior underlying the organization of actin filaments by linker proteins in the cytoskeleton. The presence of linkers in the solution modifies the effective interrod interaction and can lead to interfilament attraction. Depending on the composition and physical properties of the system, such as linker-binding energies, filaments will orient either perpendicular or parallel to each other, leading to network-like or bundled structures. We show that such a system can have one of three generic phase diagrams, one dominated by bundles, another by networks, and the third containing both bundle and network-like phases. The first two diagrams can be found over a wide range of interaction energies, whereas the third diagram occurs only for a narrow range. These results provide theoretical understanding of the classification of linker proteins as bundling proteins or crosslinking proteins. In addition, they suggest possible mechanisms by which the cell may control cytoskeletal morphology.

Using molecular dynamics simulations we examine the effective interactions between two like-charged rods as a function of angle and separation. In particular, we determine how the competing electrostatic repulsions and multivalent-ion-induced attractions depend upon concentrations of simple and multivalent salts. We find that with increasing multivalent salt, the stable configuration of two rods evolves from isolated rods to aggregated perpendicular rods to aggregated parallel rods; at sufficiently high concentration, additional multivalent salt reduces the attraction. Monovalent salt enhances the attraction near the onset of aggregation and reduces it at a higher concentration of multivalent salt.

Following recent x-ray diffraction experiments by Wong, Li, and Safinya on biopolymer gels, we apply Onsager excluded volume theory to a nematic mixture of rigid rods and strong " pi/2" cross-linkers obtaining a long-ranged, highly anisotropic depletion attraction between the linkers. This attraction leads to breakdown of the percolation theory for this class of gels, to breakdown of Onsager's second-order virial method, and to formation of heterogeneities in the form of raftlike ribbons.