bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systems Modeling Methodology for Estimation of Harm in the Automotive Accident Environment
Authors: Kuchar Alexandra C. , Greif Robert , Neat George W.
Published: November 2021

A systems modeling approach is presented for assessment of harm in the automotive accident environment. The methodology consists of parametric simulation of several controlled accident variables, with case results weighted by the relative frequency of each specific event. A hierarchy of models is proposed, consisting of a statistical model to define the accident environment and assign weighting factors for each crash situation case, and vehicle and occupant models for kinematic simulation of crash events. Head and chest injury results obtained from simulation are converted to harm vectors, in terms of probabilistic Abbreviated Injury Scale (AIS) distributions based on previously defined risk analyses. These harm vectors are weighted by each case’s probability as defined by the statistical model, and summed to obtain a total estimate of harm for the accident environment. The methodology is applied to a subset accident environment consisting of single- and two-vehicle frontal collisions among passenger cars and light trucks. The model is validated against injury field data, and is found to accurately reflect trends in distribution of injury severity while slightly underestimating moderate to severe injuries. The model is also exercised for variable sensitivity analyses, wherein the effects of light truck/car population mix are evaluated in terms of their impact on occupant harm within the subset accident environment.
Injury Assessment of the Portable Vehicle Arresting Barrier (PVAB)
Authors: Bir Cynthia , Atkinson Theresa
Published: November 2021

The Portable Vehicle Arresting Barrier (PVAB) was developed in an effort to promote area denial, enforce roadblocks, and improve security to a local area. A netting system is used to trap and stop a vehicle within 200 feet of the capture point. A kinetic effect assessment was conducted to determine whether occupant protection was affected by the capture event. The crashworthiness assessment of the PVAB was completed in two phases: a review of a “real world” crash database (NASS) and experimental testing with biomechanical surrogates (Hybrid III). The database review and the experimental testing show that capture with the PVAB system results in primarily minor injuries.
Raw Materials and Processing Issues in the Development of Vascugel, a Cell Therapy for Vascular Disease
Authors: Sigler James S.
Published: November 2021

Vascular arterial disease is the most common cause of death in the United States. Cardiovascular surgery such as coronary artery bypass graft surgery and therapies such as angioplasty and stenting are the current standard of care. However, a large number of these procedures fail due to a form of arterial disease known as restenosis. Restenosis is the re-narrowing of the treated blood vessel following vessel wall injury resulting in decreased blood flow. This re-narrowing occurs in large part because the smooth muscle cells in the wall of the vessel proliferate after the vessel is damaged. This proliferation occurs because the endothelial cells lining the inside of the vessel, which normally control proliferation, are damaged and can no longer provide the physiological function of keeping the underlying smooth muscle cells in a steady state. Of the approximately 1.5 million procedures per year, over 500,000 are coronary artery bypass graft surgeries (1996 and 1998 data from Medical Data International). Coronary artery bypass grafts experience restenosis at a 12 to 20% rate after one year.
Conditions for Cell Sorting, Mixing and Checkerboard Pattern Formation Determined Using Mechanics and Computer Simulations
Authors: Brodland G. W.
Published: November 2021

Sufficient conditions for the sorting of biological cells and necessary conditions for cell mixing and checkerboard pattern formation are derived using principles of mechanics and confirmed by computer simulations.
Spinal Cord Stress and Strain Predictions in a Ligamentous C5-C6 Segment
Authors: Scifert J. , Totoribe K. , Goel V. , Clark C. , Reinhardt J. , Bolinger L.
Published: November 2021

Several spinal disorders and traumatic loading situations are known to inflict damage to neurovascular components of the cervical spinal cord. Studies have shown that damage to the spinal cord can occur regardless of significant damage to surrounding structures. To understand the mechanics of spinal cord injury, one needs to quantify stresses and strains within the spinal cord and its components in response to exterrnal loads applied to the bony spine. Experimental studies can not address this issue. This study presents a Finite Element (FE) model to quantify the physiologic strains and stresses in the cervical spinal cord placed in the ligamentous C5-C6 motion segment, with loads applied to the bony segment and not the the cord itself, as have been done in experimental studies reported in the literature.
Magnetic Resonance Images of Tendon Microstructure
Authors: Israel Rajakumar , Atkinson Theresa
Published: November 2021

Tendon and ligament typically produce a weak signal during Magnetic Resonance Imaging (MRI). As a result only gross defects in the tissue could be detected. A method was recently developed to allow more detailed images of tendon structure to be obtained. This new method requires less than 2.5 minutes per scan and is therefore a reasonable method to utilize in a clinical setting to evaluate tendon or ligament injury and healing.
Impact of Thresholding Techniques on Micro-CT Image Based Computational Models of Trabecular Bone
Authors: Eichler Mark J. , Kim Chi Hyun , Müller Ralph , Guo X. Edward
Published: November 2021

Age-related bone fractures are mostly influenced by trabecular bone sites. Trabecular bone constantly adapts its bone volume fraction (BV/TV) and orientation, and thus its mechanical properties, to mechanical usage. Therefore, understanding the trabecular bone adaptation process and its consequences will contribute to the better understanding of the etiology of age-related fractures. Micro-computed tomography (micro-CT) is a relatively new method to quantify the complex three-dimensional (3D) trabecular bone architecture [1,2]. Finite element computational studies can be performed on these 3D microstructural images by converting each image voxel into an element [3,4,5]. Image thresholding techniques to segment bone voxels from bone marrow voxels have a major impact on the results of these models. However, the influence of different types of thresholding techniques on the mechanical properties of bone has not been examined carefully.
Interaction of Airflow With Viscoelastic Gel in Endotracheal Tubes
Authors: Hassan Amgad A. , Evrensel Cahit A. , Krumpe Peter E.
Published: November 2021

The clearance of mucus from endotracheal (ET) tubes by a simulated cough is studied experimentally. Cough is approximated as a pulse of 0.3-second duration. A viscoelastic gel, Locust Bean Gum (LBG)/Borax solution, is used as mucus simulant. The relationships between mucus rheology, tube diameter, clearance are examined. Tube diameters ranging from 6mm to 10mm are used in this study. The displacement of the mass center of the simulant drop (0.1 ml) is measured. Our investigation shows that, for the same average air speed in the ET tube, the displacement is increased with the decreasing diameter. The results also indicate that, although simulant with lower viscosity/elasticity ratio requires lower air velocity for initial movement of the simulant surface, its mass center moves a shorter distance compared to a simulant with higher viscosity/elasticity ratio if the air velocity is increased further.
Imaging and Measurement of the Separation Surface Between Converging Fluids of Differing Viscosity at a Microscopic Branch
Authors: Peach J. P. , Hitt D. L.
Published: November 2021

The mechanics of branching blood flow is of fundamental importance in understanding the nonuniform distribution of blood components within a microvascular network and, indeed, even within an individual vessel. The nonuniformity resulting from the branch can in turn impact microvascular flow impedance and oxygen transport processes. A construct known as the “separation surface” is often used to describe the flow at converging (venular) and diverging (arteriolar) branches. In the case of two converging flows, the separation surface identifies the portions of the flow in the outlet branch which originated from each of the two feeding branches. The reverse situation holds for a diverging branch. If the converging fluids are immiscible, then the separation surface is a persistent, physical surface within the flow. For converging blood flow, mixing occurs and the separation surface loses its definition with downstream position.
Parametric Meshing of Finite Element Models of Lumbar Spine
Authors: Kasra Mehran
Published: November 2021

In a finite element model, material properties, loading condition, and constraint condition can be changed easily as variable parameters. However, changing a finite element mesh representing different geometries may be a very difficult task, especially for a large and complicated model such as that of lumbar spine. In this case, changing the model geometry can be done easily, if it can be defined with mathematical functions and a set of geometrical parameters.
Underwater Shock Waves to Medicine
Authors: Takayama Kazuyoshi
Published: November 2021

Application of underwater shock waves to medicine is one of the most interesting research topics in shock wave research. The facility of disintegrating bladder stones by using spark generated shock waves was invented by Yutkin in 1950. Later his method was combined with an endoscope to disintegrate kidney stones.
Manufacturing of Functionally Graded Materials
Authors: Kahlen Franz-Josef , Kar Aravinda
Published: November 2021

Laser deposition of metal layers has been recognized in recent years as a one-step process to fabricate metal parts. A one-dimensional model was developed to calculate the plume temperature, process parameters and melt pool characteristics. The model accounts for the transmission of the laser beam through the plume, energy transfer in the molten phase and the Stefan conditions at the solid-liquid and liquid-vapor interfaces. The surface temperature at the molten surface is found to exceed the normal boiling temperature causing the pressure to be higher than one atmospheric pressure. The plume temperatures were found to be below the respective material’s ionization temperature. The calculated plume temperatures are in good agreement with the values obtained from the spectral data. Also, the model predictions for remelt layer depth, deposition height and plasma height compare well with experimental data. The authors have employed this one-step technique to create graded materials by varying the part’s composition from 100% stainless steel to a 100% nickel-based superalloy. Mechanical properties of these graded materials are measured and the effects of slow solidification rates are investigated.
Probabilistic Optimum Design of Aircraft Structures
Authors: Onyebueke Landon , Nnamani Ikechukwu
Published: November 2021

This paper discusses the application of probabilistic design methodology for the optimum design of aircraft structures. Material properties and loads are considered as stochastic data in formulating the optimization model for the design. The procedure accommodates various types of sensitivity analyses. Attention is focused on studies in which both the aerodynamic and structural designs are optimized simultaneously. Tradeoffs between drag and structural weight for aircraft wings are affected by two aerodynamic-structural interactions. First, structural weight affects the required lift and, thus drag. Second, structural deformations change the aerodynamic shape.

Design results obtained using the Monte Carlo simulation method, and the limit state function approach, are presented. The limit state function method applies the Most Probable Point (MPP) search approach. Some of the approximate methods that have been applied for the search are FORM, AMV, AIS, etc.
Development and Validation of the Small Punch Test for UHMWPE Used in Total Joint Replacements
Authors: Edidin A. A. , Kurtz S. M.
Published: November 2021

Around 500,000 total hip and knee arthroplasties are performed each year in the United States, with a comparable number performed annually throughout the rest of the world. Since its development in the 1960s, contemporary total joint arthroplasty has proven to be extremely successful in alleviating pain and restoring joint function. However, for a minority of patients, mechanical and biological sequelae emanating from the breakdown of the ultra-high molecular weight polyethylene (UHMPWE) bearings limit the longevity of the procedures.
A Probabilistic Approach to the Modeling of Coarse Grain Heat Affected Zone Fracture in A707 Steel Welds
Authors: Zhou J. , Soboyejo W. O.
Published: November 2021

A probabilistic framework is presented for the modeling of the variability in crack-tip opening displacement (fracture toughness) during the fracture of coarse grained heat affected zones in A707 steel welds. The variability in inclusion distribution and fracture conditions is modeled using weak link statistics in physically-based fracture mechanics models that describe the fracture behavior in the lower-shelf and transition-temperature regimes. The models are used to explain the measured trends in experiments designed to explore the effects of heat input on crack-tip opening displacement. The implications of the results are also analyzed for the design of welded structures.
Laser Shock Peening for Fatigue Resistance
Authors: Clauer Allan H. , Lahrman David F.
Published: November 2021

Laser shock peening is developing into a commercial surface enhancement process for increasing the fatigue life of metal components. The process produces deep residual compressive stresses into treated surfaces which inhibit the initiation and propagation of fatigue cracks. The process has been particularly effective in increasing the resistance to foreign object damage in fan and compressor blades of aircraft gas turbine engines. However, the potential application of this process is much broader, encompassing automotive, tooling and dies, and others. Significant effort is being made to lower the cost and increase the throughput of the process, to make it an affordable process for many more applications. This describes the process and reviews the progress being made in the technology, both in material property enhancement and use of the process, and towards reducing cost and increasing throughput.
Mechanisms Controlling the Performance and Durability of Thermal Barrier Coatings
Authors: Mumm Daniel R. , Evans Anthony G.
Published: November 2021

Thermal protection systems based on ceramic thermal barrier coatings (TBCs) are used extensively to protect hot-section components in gas turbine engines. They comprise thermally insulating ceramic coatings, deposited on an aluminum-containing intermetallic bond coat (BC) that provides oxidation protection. A thin thermally-grown oxide (TGO layer forms between the TBC and BC during cyclic thermal exposure. Each of the system constituents evolves in service and all interact during thermal cycling to control the thermo-mechanical performance of the system. Exposed to thermal cycling conditions, TBC systems are susceptible to loss of adhesion and spalling failures. Multiple failure mechanisms exist, dependent upon differing thermal histoiy and processing approach for various coating systems. Coating failure is ultimately controlled by the large residual compression in the TGO and its role in amplifying the effects of imperfections in the vicinity of the TGO. The failure occurs through a process involving crack nucleation, propagation and coalescence events. For a particular commercial system, it is found that the TGO ‘ratchets’ into the bond coat with each thermal cycle, at an array of interfacial sites. The displacements induce strains in the superposed TBC that cause it to crack. The cracks extend laterally as the TGO ratcheting process proceeds, until the cracks from neighboring sites coalesce. Once this happens, the system fails by large scale buckling. It is shown that the displacements are ‘vectored’ by a lateral component of the growth strain in the TGO. The relative roles of bond coat visco-plasticity, initial interface morphology, and phase evolution are discuss. The behavior observed for this system is compared with predictions of a ratcheting model, as well as with the behavior observed for other commercial coating systems.
Growth and Failure of Oxide Irregularities During Thermal Cycling: Interactions Between Stress, Geometry and Oxide Formation
Authors: Begley M. R. , Ambrico J. M. , Jordan E. H.
Published: November 2021

In some oxide thin film systems, such thermal barrier coating systems (TBCs), thermal cycling leads to the development of geometric irregularities in the film. The evolution of these irregularities involves very large changes in aspect-ratio and often occurs rapidly over several hundreds of cycles. A key aspect of this behavior is the development of tensile stresses in the irregularity due to plastic yielding of the surrounding metal. These stresses can accelerate the elongation of the oxide (which translates into shape evolution of the irregularity) by various mechanisms, including enhanced oxide formation, inelastic stretching (creep) and failure of the oxide. An idealized analytical model consisting of a thin elastic shell embedded in an elastic-plastic matrix is used to explore the interactions between geometry, thermal strains, plasticity and oxide growth. Boundaries between purely elastic deformation, uni-directional yielding and reversed plasticity are shown to have a strong dependence on the size of the irregularity relative to the oxide thickness. For any given thermal strain, there is a critical aspect ratio of the irregularity that leads to maximum tensile stress in the oxide. The resulting closed-form solutions allow for quick and easy evaluations of various oxide-growth scenarios, including stress-dependent oxide formation. This talk will present the application of these models to TBC thermal cycling experiments, and discuss how stress-dependent oxide formation plays a role in the rapid evolution of these irregularities. A variety of oxide growth scenarios will be illustrated, and used to demonstrate that oxide failure and subsequent oxide formation in the cracked region is the most likely explanation for the rapid shape evolution seen in the experiments.
A DOT1B/Ribonuclease H2 Protein Complex Is Involved in R-Loop Processing, Genomic Integrity, and Antigenic Variation in Trypanosoma brucei
Authors: Eisenhuth Nicole , Vellmer Tim , Rauh Elisa T. , Butter Falk , Janzen Christian J.
Published: November 2021

Trypanosoma brucei
is a unicellular parasite that causes devastating diseases like sleeping sickness in humans and the “nagana” disease in cattle in Africa. Fundamental to the establishment and prolongation of a trypanosome infection is the parasite's ability to escape the mammalian host's immune system by antigenic variation, which relies on periodic changes of a protein surface coat.
Restraint of Fumarate Accrual by HIF-1α Preserves miR-27a-Mediated Limitation of Interleukin 10 during Infection of Macrophages by Histoplasma capsulatum
Authors: Evans Heather M. , Schultz Destiny F. , Boiman Adam J. , McKell Melanie C. , Qualls Joseph E. , Deepe George S.
Published: November 2021

Histoplasma capsulatumand relatedHistoplasmaspecies are intracellular fungal pathogens endemic to broad regions of the globe, including the Americas, Africa, and Asia. While most infections resolve with mild or no symptoms, failure of the host to control fungal growth produces severe disease.
CCR2 Signaling Restricts SARS-CoV-2 Infection
Authors: Vanderheiden Abigail , Thomas Jeronay , Soung Allison L. , Davis-Gardner Meredith E. , Floyd Katharine , Jin Fengzhi , Cowan David A. , Pellegrini Kathryn , Creanga Adrian , Pegu Amarendra , Derrien-Colemyn Alexandrine , Shi Pei-Yong , Grakoui Arash , Klein Robyn S. , Bosinger Steven E. , Kohlmeier Jacob E. , Menachery Vineet D. , Suthar Mehul S.
Published: November 2021

SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined.
Identifying crystal accumulation and melt extraction during formation of high-silica granite
Authors: Lu Tian-Yu , He Zhen-Yu , Klemd Reiner
Published: November 2021

High-silica (>70 wt% SiO2) magmas are usually believed to form via shallow crustal–level fractional crystallization of intermediate magmas. However, the broad applicability of this model is controversial, because the required crystal-melt separation processes have rarely been documented globally up to now. The ca. 50 Ma Nyemo composite pluton of the Gangdese batholith belt in southern Tibet, which comprises intrusive rocks with intermediate- to high-silica compositions (65–78 wt%), offers a unique opportunity for substantiating the coexistence of extracted melts and complementary silicic cumulates in one of Earth's most complete transcrustal silicic magmatic systems. The Nyemo pluton intrusive rocks exhibit similar zircon Hf isotopic compositional ranges (mean εHf(t) = +5.7 to +8.3), suggesting a common, non-radiogenic magma source with crustal assimilation in the deep crust. Yet, these rocks have distinct geochemical characteristics. High-silica miarolitic and rapakivi granites are strongly depleted in Ba, Sr, and Eu, and their zircon trace elements show extremely low Eu/Eu* and Dy/Yb. In contrast, monzogranite is relatively enriched in Ba and Sr with minor Eu anomalies, and the zircon trace elements are characterized by relatively high Eu/Eu* and Dy/Yb. Therefore, we propose that the high-silica granites represent highly fractionated melt extracted from a mush reservoir at unusually low storage pressure (∼99–119 MPa), and that the monzogranite constitutes the complementary residual silicic cumulates.
Testing local and extraregional sediment sources for the Late Cretaceous northern Nanaimo basin, British Columbia, using 40Ar/39Ar detrital K-feldspar thermochronology
Authors: Isava V. , Grove M. , Mahoney J.B. , Haggart J.W.
Published: November 2021

Detrital K-feldspar 40Ar/39Ar thermochronology was conducted on clastic sedimentary rock samples collected from northern exposures of the Upper Cretaceous Nanaimo Group on Vancouver Island and adjacent Gulf Islands of British Columbia to constrain the denudation history of the local Coast Mountains batholith source region and determine the origin of extraregional sediment supplied to the basin. Strata of the northern Nanaimo Group deposited between 86 and 83 Ma (Comox and Extension formations) exhibit a 130–85 Ma age distribution of detrital K-feldspar 40Ar/39Ar ages that lack age maxima. These are interpreted to have been sourced from the southwestern Coast Mountains batholith. Younger strata deposited between 83 and 72 Ma (Cedar District and De Courcy formations) yield a broader age range (150–85 Ma) with an age maximum near the depositional age. These results indicate focused denudation of deeper-seated rocks east of the Harrison Lake fault. The youngest units deposited after 72 Ma (Geoffrey, Spray, and Gabriola formations) primarily yield younger than 75 Ma detrital K-feldspar ages with pronounced age maxima near the depositional age. This sediment was sourced extraregionally relative to the Coast Mountains batholith.

We sought to constrain the origin of the extraregional sediment by measuring the thermal histories of 74 samples of basement rocks from throughout the Pacific Northwest, and by compiling a database of over 2400 biotite 40Ar/39Ar and K/Ar cooling ages from predominantly Cretaceous batholiths along the western North American margin. This analysis focused upon two previously proposed source regions: the Idaho batholith and the Mojave-Salina margin of southern California. The Nanaimo detrital K-feldspar 40Ar/39Ar age distributions favor the peraluminous Late Cretaceous Idaho batholith and its Proterozoic Belt-Purcell Supergroup sedimentary wall rock as the more likely source of the extraregional sediment and disfavor the Baja–British Columbia hypothesis for 2000–4000-km-scale translation of rocks along the margin during the Late Cretaceous.
Primary pulmonary angiosarcoma
Authors: Rana Muhammad Kashif , Rahman Owais , O’Brien Aiden
Published: November 2021

Primary pulmonary angiosarcoma is a rare type of malignant vascular tumour with poor prognosis. Diagnosis is often late due to non-specific symptoms and low clinical suspicion for angiosarcoma. A 72-year-old man presented to hospital with a 6-month history of mild progressive dyspnoea, with associated cough, episodes of presyncope and weight loss. CT pulmonary angiogram (CTPA) was reported as a large saddle pulmonary embolism extending into both the right and left pulmonary arteries. Further Multidisciplinary team meeting (MDM) discussion, and review of CTPA and subsequent investigations revealed a large primary pulmonary artery sarcoma which was later confirmed histology. The patient was referred to the cardiothoracic surgeons and underwent left radical pneumonectomy.
Helcococcus kunzii, a skin-colonising microorganism with pathogenic capacity: a case of polymicrobial intracranial empyema
Authors: Mouro Margarida , Frade João , Chaves Catarina , Velez Jorge
Published: November 2021

Helcococcus kunziiis a Gram-positive anaerobic facultative coccus that colonises the skin. Human infection is rare, with very few cases being described in the literature. The authors present the case of a 17-year-old man, with a history of cholesteatoma, diagnosed with mastoiditis complicated by intracranial empyema. After urgent surgical drainage, Gram staining revealed a Gram-negative bacillus and a Gram-positive coccus. The latter exhibited fastidious growth, presented as small grey colonies in blood agar, and was afterwards identified asH. kunzii. The patient was started on intravenous antibiotics, switched to oral route after 8 weeks and fully recovered. To the best of our knowledge, this is the third case of an intracranial infection in whichH. kunziiis involved, two of them occurring in patients with cholesteatoma.
COVID-19 vaccine-associated subacute thyroiditis: an unusual suspect for de Quervain’s thyroiditis
Authors: Jeeyavudeen Mohammad Sadiq , Patrick Alan W , Gibb Fraser W , Dover Anna R
Published: November 2021

Subacute thyroiditis following vaccination is an uncommon presentation of thyrotoxicosis. As the world undertakes its largest immunisation campaign to date in an attempt to protect the population from COVID-19 infections, an increasing number of rare post vaccine side effects are being observed. We report a case of a middle-aged woman who presented with painful thyroid swelling following the second dose of the COVID-19 mRNA vaccine BNT162b2 (Pfizer–BioNTech) with clinical, biochemical and imaging features consistent with destructive thyrotoxicosis. Symptomatic management only was required for the self-limiting episode. Thyroiditis typically has a mild and self-limiting course and thus this observation should not deter people from vaccination, as COVID-19 infection has a far greater morbidity and mortality risk than thyroiditis.
216 Multiplex base editing of NK cell to enhance cancer immunotherapy
Authors: Wang Minjing , Kluesner Mitchell , Vázquez Patricia Claudio , Webber Beau , Moriarity Branden
Published: November 2021

Background

Natural killer (NK) cells have many unique features that have gained attention in cancer immunotherapy. NK cells can kill in antigen independent and dependent fashion, can be used as an allogeneic product, and perform antibody-dependent cell-mediated cytotoxicity (ADCC). However, NK cell function is regulated by many activating and inhibitory receptors, which cancer cells take advantage of to avoid being killed by NK cells. NK cells are also known for their technical and biological challenges which result in low editing efficiencies, compared to T cells and other immune cells.

Methods

Base editing (BE) is a CRISPR-Cas9 based genome editing technology that allows precise single base transitions. Previously, we reported a high efficiency method for multiplex engineering of T cells using BE and thus reasoned that applying similar concepts in NK cells may offer an opportunity to alter many genes simultaneously at higher efficiency through multiplex base editing. We thus selected a panel of genes bearing critical roles in NK cell function for immunotherapy, including inhibitory intracellular regulator AHR and CISH, inhibitory checkpoint receptor KLRG1, TIGIT, KLRC1, and PDCD1, and Fc receptor CD16A. CD16A is responsible for NK cell ADCC and is regulated via cleavage upon NK activation. Non-cleavable CD16A improves ADCC killing and can be achieved through single-base substitution with BE.

Results

Using the adenosine BE (ABE8e), we achieved multiplex editing (6 genes) rates up to 99% and 95% editing/knockout at DNA and protein levels, respectively. Notably, we assessed for reduction in editing efficiency when additional genes were targeted and found no significant reduction in editing efficiencies when targeting up to 6 genes simultaneously. Moreover, functional evaluation of non-cleavable CD16A NK cells revealed up to 35% increase of cytotoxicity against Raji cells.

Conclusions

We were able to achieve high multiplex editing efficiency in primary human NK cells using ABE8eand there was no significant decrease of editing efficiency as the number of gene of interest increases, up to 6 genes in total. Functional assay confirmed increased NK cell cytotoxicity against tumor cells. Our end goal is to achieve high efficiency multiplex editing in CAR-expressing NK cells to further improve NK cell activity and toxicity for cancer immunotherapy.

Reference

Webber B, Lonetree C, Kluesner M, et al. Highly efficient multiplex human T cell engineering without double-strand breaks usingCas9 base editors. Nat Commun 2019;10:5222.
295 Tumor cell- intrinsic expression of FGFR3 drives anti-PDL-1 immunotherapy resistance in a murine bladder cancer model
Authors: Fleming-Trujillo Erica , Bloodworth Jeffrey , Fernald Anthony , Ramsland Aubrianna , Gajewski Thomas , Sweis Randy
Published: November 2021

Background

Immune checkpoint blockade therapy has recently shown efficacy in treating advanced urothelial bladder cancer and anti-PD-1/PD-L1 therapy is currently the standard of care. However, most patients do not respond to these drugs and resistance mechanisms remain elusive. The non-T cell-inflamed tumor microenvironment phenotype correlates with poor prognosis and immunotherapy resistance. We previously found that activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) were exclusive to non-T cell-inflamed bladder cancers. We investigated the impact of tumor cell-intrinsic FGFR3 activation on T cell infiltration and tumor responsiveness to anti-PD-1/PD-L1 in a murine model.

Methods

We developed a syngeneic transplantable murine bladder cancer model using the MB49 cell line engineered to express FGFR3 with either the activating G370C mutation (FGFR3-G370C), a kinase-dead mutation K508M (FGFR3-K508M), a truncating mutation resulting in a secreted receptor (FGFR3-sec), or control. Mice were injected subcutaneously into flank and size was measured every 3 days along with PD-L1 therapy (BioXcell clone 10F.9G2). Tumors, draining lymph nodes, and spleens were harvested at endpoint for flow cytometry.

Results

Tumors from mice inoculated with MB49-FGFR3-G370C cells showed diminished CD8+ T cell accumulation within the tumor and were resistant to anti-PD-L1 checkpoint blockade compared to MB49 controls. To determine if FGFR3-mediated immune resistance was dependent on FGFR3 kinase activity, MB49-FGFR3-K508M tumors were evaluated and unexpectedly found to be resistant to anti-PD-L1 treatment. Tumors with a secreted FGFR3 receptor (FGFR3-sec) retained responsiveness to anti-PD-L1 therapy.

Conclusions

In a murine bladder cancer model, FGFR3 activation led to relative T cell exclusion and resistance to immune checkpoint blockade. The mechanism of resistance was not dependent on receptor kinase activity. Further studies are ongoing to determine the biochemical mechanisms of FGFR3-mediated immunotherapy resistance in bladder cancer.
307 Interaction of anti-PD-1/PD-1 immunocomplexes with human FcRs: binding properties and functional implication
Authors: Daveri Elena , Luison Elena , Vallacchi Viviana , Vergani Barbara , Huber Veronica , Cova Agata , Leone Biagio Eugenio , Garassino Marina , Figini Mariangela , Rivoltini Licia
Published: November 2021

Background

Rescue of exhausted T cell immunity through the inhibition of PD-1/PD-L1 interaction is a pillar of immunotherapeutic anti-PD-1 monoclonal antibodies (mAbs), as Nivolumab and Pembrolizumab. Despite the IgG4 subclass, anti-PD-1 mAbs can bind different FcγRs and trigger immunosuppressive activity in FcR-expressing myeloid cells. This effect is evident when anti-PD-1 mAbs engage soluble PD-1 (sPD-1) forming a stable sPD-1-antiPD-1mAb immune complex (PD-1 IC). In the present study we dissect the process by investigating which of the FcγRs displays the highest affinity for monomeric or complexed Nivolumab. In addition, methods for detecting and quantifying PD-1 ICs in plasma of patients treated with PD-1 blockers mAbs are under development for clinical application.

Methods

By surface plasmon resonance (SRP) (BiacoreTM T200, Cytiva), the interaction of FcγRI/CD64, FcγRIIa/CD32a, FcγRIIb/CD32b, FcγRIIIa/CD16a and FcγRIIIb/CD16b with anti-PD1 Nivolumab and the corresponding PD-1-IC has been evaluated, and their cellular localization has been assessed by confocal microscopy. Further, sPD-1 and PD-1 IC has been determined by customized ELISAs and western blot approaches in plasma of anti-PD-1 mAb-treated patients.

Results

The binding of anti-PD1 and PD-1-IC occurred with all the FcγRs tested, albeit sensorgrams revealed diverse degrees of affinity. No major difference in the overall affinity of the monomeric anti-PD-1 versus PD-1 IC is observed for FcγRI/CD64, FcγRIIa/CD32a, FcγRIIb/CD32b. Instead, the dissociation phase was clearly slowest for PD-1 IC with respect to the monomeric mAb in FcγRIIIa/CD16a and FcγRIIIb/CD16b binding studies. Nevertheless, only PD-1 IC undergoes internalization when interacting with human FcγR+ myeloid cells in vitro, through pathways that does not appear to lead to lysosomal co-localization. Customized ELISA for PD-1 IC quantification has been developed to detect the complex after enrichment of plasma IgG4 by specific matrix. Data concerning the evaluation of PD-1 IC concentration in plasma of cancer patients treated with Nivolumab, will be presented.

Conclusions

Despite the IgG4 subclass is expected to display the lowest binding affinity to Fcγs, we report here that anti-PD-1 therapeutic antibodies bind significantly to CD16, CD32 and CD64, particularly if stabilized in the IC form by engaging soluble PD-1. This evidence, if occurring in vivo, could introduce novel functional properties to these therapeutic agents, with potential detrimental effects on their clinical efficacy. Our findings imply that tools to antagonize PD-1-related exhaustion by Fc-null mAbs or non-mAb-based strategies could be preferred to engage full-fledged antitumor immune responses without unwanted effects related to FcR triggering.
377 Characterization of peripheral biomarkers of GS-1423, a first in class bifunctional anti-CD73-TGFβ receptor II- trap molecule, in a phase 1 dose escalation study in patients with advanced solid tumors
Authors: Zavodovskaya Marianna , Tolcher Anthony , Gordon Michael , Strauss James , Mahoney Kathleen , Yi Ping Cheng , Sorensen Rick , Yang Xiaoyun , Lin Kai-Wen , Li Biao , Seto Anna , Peach Matthew , Goddard Audrey , Chen Tianling , Jürgensmeier Juliane
Published: November 2021

Background

GS-1423 is a first-in-class bifunctional molecule comprised of an anti-CD73 antibody fused to the extracellular domain of TGFβ receptor II (TGFβRII). GS-1423 is designed to inhibit CD73-mediated adenosine production and neutralize active TGFβ within the tumor microenvironment. Dual antagonism of these 2 broadly immunosuppressive barriers is anticipated to facilitate productive anti-tumor immunity.

Methods

This open label Phase 1a study (NCT03954704) evaluated the safety, tolerability, and pharmacokinetics of GS-1423. Exploratory biomarkers included the evaluation of the inhibition of GS-1423 targets, i.e.CD73 and TGFβ, in the periphery. Biomarker assessments were performed in serial blood samples from patients receiving GS-1423 every two weeks (Q2W). Biomarker assays, unless otherwise stated, were custom built and qualified to measure the following: 1) TGF-beta 1/2/3 (Luminex, Bio-Rad) in platelet poor plasma, 2) CD73 target occupancy (TO) on B and CD8 T cells in whole blood, 3) free soluble CD73 (sCD73) not bound to GS-1423, and 4) sCD73 activity in platelet poor plasma. Biomarker values were plotted longitudinally by patient and by dose.

Results

A dose dependent decrease in TGF-beta 1/2/3 in plasma of patients was observed on treatment. There was no detectable TGFβ at the 20 mg/kg dose level and above at 2 hours post first dose and for the duration of the Q2W dosing interval. A dose dependent increase in CD73 TO on B and CD8 T cells was also observed with treatment, and complete TO was achieved at 20 mg/kg and above at 2 hours post first dose for the duration of the Q2W dosing interval. Free sCD73 decreased at 2 hours post first dose, while remaining above the lower limit of quantitation, and then increased above baseline after 24 hours post-dose at the 3 mg/kg dose level and above. The sCD73 activity in blood correlated with changes in free sCD73 levels.

Conclusions

Blood biomarker analyses of GS-1423 in patients with advanced solid tumors demonstrated undetectable soluble TGFβ1/2/3 and complete TO of CD73 on B and T cells at the 20 mg/kg dose level and above. The mechanism underlying the increase in sCD73 following GS-1423 treatment remains to be elucidated.

Ethics Approval

The study obtained ethics approval from the IRB/IEC and all participants gave informed consent before taking part in the study.
Urinary catheter management: what neurologists need to know
Authors: Clark Calum , Haslam Collette , Malde Sachin , Panicker Jalesh N
Published: November 2021

Patients with neurological disorders often have lower urinary tract dysfunction, manifesting as urinary retention or urinary incontinence, and so commonly use catheters. Neurologists should therefore be aware of the different types of catheters and appliances and their risks, benefits and complications. Clean intermittent self-catheterisation is preferable to an indwelling catheter; however, if this is not possible, then a suprapubic indwelling catheter is preferable to a urethral catheter for long-term management. We review the decision-making process when selecting catheters for neurological patients, the evidence base regarding the different options and how neurologists can recognise and address complications. We also discuss alternatives to catheterisation, such as non-invasive containment products and surgical treatments, and the indications for urological referral.
Circumventing tobacco control and safety policies to promote waterpipe use in smoking venues: the perspective of staff in waterpipe smoking venues
Authors: Lee Jung Jae , Yeung Karly Cheuk Yin , Wang Man Ping , Thorne Sally , Tong Henry Sau Chai , Lai Vienna
Published: November 2021

Objective

To understand Hong Kong waterpipe smoking (WPS) sales and promotion, including strategies to avoid policy enforcement, from the perspective of WPS venue staff.

Methods

Qualitative interviews and observations were guided by interpretive description. 20 WPS venue staff who were responsible for preparing and serving waterpipes to patrons and had worked at the bar for at least 3 months were recruited. In-depth semistructured interviews with WPS venue staff were conducted, in addition to covert and participant observations in 10 WPS venues in Hong Kong. Interpretive description involving constant comparative analysis of qualitative data was adopted to facilitate an inductive analytic approach to generate findings.

Results

Two primary themes emerged from analyses of interview and observation data: strategies to avoid law enforcement, and perceived health and safety concerns linked to working and smoking in waterpipe venues. The findings suggest that many Hong Kong venues may be failing to comply with tobacco control policies and developing strategies to circumvent law enforcement. Moreover, waterpipe preparation, allowance of WPS and burning of charcoal in indoor areas were perceived as negatively affecting the health and safety of staff and customers.

Conclusions

The study provides preliminary evidence indicating the ineffectiveness of current tobacco control policy on WPS. Due to its risks to health and safety, and the need to sustain tobacco control efforts for their intended purpose, waterpipe-specific regulations and stricter surveillance on waterpipe sales and promotion are urgently required.
Dynamics of charged test particles around quantum-corrected Schwarzschild black holes
Authors: Gao Bo , Deng Xue-Mei
Published: November 2021

We investigate neutral and charged test particles’ motions around quantum-corrected Schwarzschild black holes immersed in an external magnetic field. Taking the innermost stable circular orbits of neutral timelike particles into account, we find that the black holes can mimic different ranges of the Kerr black hole’s spin |a/M| from 0.15 to 0.99. Our analysis of charged test particles’ motions suggests that the values of the angular momentumland the energy$$E^{2}$$E2are slightly higher than Schwarzschild black holes. The allowed regions of the$$(l,E^{2})$$(l,E2)demonstrate that the critical energy$$E^{2}_{c}$$Ec2divides the charged test particle’s bounded trajectory into three types. With the help of a Monte Carlo method, we study the charged particles’ probabilities of falling into the black holes and find that the probability density function againstldepends on the signs of the particles’ charges. Finally, the epicyclic frequencies of the charged particles are considered with respect to the observed twin peak quasi-periodic oscillations frequencies. Our results might provide hints for distinguishing quantum-corrected Schwarzschild black holes from Schwarzschild ones by using the dynamics of charged test particles around the strong gravitational field.
Universes as big data
Authors: He Yang-Hui
Published: November 2021

In this paper, we briefly overview how, historically, string theory led theoretical physics first to precise problems in algebraic and differential geometry, and thence to computational geometry in the last decade or so, and now, in the last few years, to data science. Using the Calabi–Yau landscape — accumulated by the collaboration of physicists, mathematicians and computer scientists over the last four decades — as a starting-point and concrete playground, we review some recent progress in machine-learning applied to the sifting through of possible universes from compactification, as well as wider problems in geometrical engineering of quantum field theories. In parallel, we discuss the program in machine-learning mathematical structures and address the tantalizing question of how it helps doing mathematics, ranging from mathematical physics, to geometry, to representation theory, to combinatorics and to number theory.
Heterogeneous traffic flow model under connected vehicles environment considering cyberattacks
Authors: Lin Lizhen , Ge Hongxia , Cheng Rongjun
Published: November 2021

Under the Vehicle-to-Vehicle (V2V) environment, connected vehicles (CVs) can share the traveling information with each other to keep the traffic flow stable. However, the open network cooperation environment makes CVs vulnerable to cyberattacks, which leads to changes in driving behavior. The existing theories divide cyberattacks into three types: bogus information, replay/delay and collusion cyberattacks. In addition, the mixed flow consisting of truck and car is a common form of road traffic. In order to clarify the potential impact of cyberattacks on mixed traffic flow, this paper proposes an extended car-following model considering cyberattacks under CVs environment. Subsequently, the stability of the model is analyzed theoretically, and the stability condition of the model is obtained. The numerical simulation is carried out and the result shows that the cyberattacks lead to different degrees of traffic behavior hazards such as queue time extension, congestion and even rear end collision. Among them, cooperative attack is the most serious.
Meteorites that produce K-feldspar-rich ejecta blankets correspond to mass extinctions
Authors: Pankhurst M.J. , Stevenson C.J. , Coldwell B.C.
Published: November 2021

Meteorite impacts load the atmosphere with dust and cover the Earth's surface with debris. They have long been debated as a trigger of mass extinctions throughout Earth history. Impact winters generally last <10
0
years, whereas ejecta blankets persist for 10
3
–10
5
years. We show that only meteorite impacts that emplaced ejecta blankets rich in K-feldspar (Kfs) correlate to Earth system crises (
n
 = 11,
p
 < 0.000005). Kfs is a powerful ice-nucleating aerosol, yet is normally rare in atmospheric dust mineralogy. Ice nucleation plays an important part in cloud microphysics, which modulates the global albedo. A conceptual model is proposed whereby the anomalous presence of Kfs post impact is posited to have two key effects on cloud dynamics: (1) Kfs reduces the average albedo of mixed-phase clouds, which leads to a hotter climate; and (2) Kfs weakens the cloud albedo feedback mechanism, which increases climate sensitivity. These mechanisms offer an explanation as to why this otherwise benign mineral is correlated so strongly with mass extinction events: every Kfs-rich ejecta blanket corresponds to a severe extinction episode over the last 600 myr. This model may also explain why many kill mechanisms only variably correlate with extinction events through geological time: they coincide with these rare periods of climate destabilization by atmospheric Kfs.

Supplementary material
: Extended Fig. 1 from main text is available at
https://doi.org/10.6084/m9.figshare.c.5690646
Topological Magnons: A Review
Authors: McClarty Paul A.
Published: November 2021

At sufficiently low temperatures, magnetic materials often enter correlated phases hosting collective, coherent magnetic excitations such as magnons or triplons. Drawing on the enormous progress on topological materials of the past few years, recent research has led to new insights into the geometry and topology of these magnetic excitations. Berry phases associated with magnetic dynamics can lead to observable consequences in heat and spin transport, whereas analogs of topological insulators and semimetals can arise within magnon band structures from natural magnetic couplings. Magnetic excitations offer a platform to explore the interplay of magnetic symmetries and topology, drive topological transitions using magnetic fields, examine the effects of interactions on topological bands, and generate topologically protected spin currents at interfaces. In this review, we survey progress on all these topics, highlighting aspects of topological matter that are unique to magnon systems and the avenues yet to be fully investigated.