bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomechanical Evaluation of the Cross‐link Usage and Position in the Single and Multiple Segment Posterior Lumbar Interbody Fusion
Authors: Han Lin , Yang Haisong , Li Yongheng , Li Zhiyong , Ma Hongdao , Wang Chenfeng , Yuan Jincan , Zheng Luyu , Chen Qiang , Lu Xuhua
Published: September 2022

Objective

Previous studies have neither explored the usage of cross‐links nor investigated the optimal position of the cross‐links in posterior lumbar interbody fusion (PLIF). This study evaluates biomechanical properties of cross‐links in terms of different fixation segments and optimal position in single‐ and multi‐segment posterior lumbar interbody fusion.

Methods

Two finite element (FE) models of instrumented lumbosacral spine with single‐(L4/5) and multi‐segment (L3‐S1) PLIF surgery were simulated. On the basis of the two models, the benefits of the usage of cross‐links were assessed and compared with the status of no application of cross‐links. Moreover, the effects of position of cross‐links on multi‐segment PLIF surgery were studied in Upper, Middle, and Lower positions.

Results

No significant difference was found in the range of motion (ROM), intersegmental rotational angle (IRA) of adjacent segments, and intradiscal pressure (IDP) regardless of the usage of cross‐links in the single‐segment PLIF surgery, while the cross‐link increased the maximum von Mises stress in the fixation (MSF) under the axial rotation (53.65 MPa vs 41.42 MPa). In the multi‐segment PLIF surgery, the usage of cross‐links showed anti‐rotational advantages indicated by ROM (Without Cross‐link 2.35o, Upper, 2.24o; Middle, 2.26o; Lower, 2.30o) and IRA (Without Cross‐link 1.19o, Upper, 1.08o; Middle, 1.09o; Lower, 1.13o). The greatest values of MSF were found in without cross‐link case under the flexion, lateral bending, and axial rotation (37.48, 62.61, and 86.73 MPa). The application of cross‐links at the Middle and Lower positions had lower values of MSF (48.79 and 69.62 MPa) under the lateral bending and axial rotation, respectively.

Conclusion

The application of cross‐links was not beneficial for the single‐segment PLIF, while it was found highly advantageous for the multi‐segment PLIF. Moreover, the usage of cross‐links at the Middle or Lower positions resulted in a better biomechanical stability.
Economic costs of the Russia‐Ukraine war
Authors: Liadze Iana , Macchiarelli Corrado , Mortimer‐Lee Paul , Sanchez Juanino Patricia
Published: September 2022

The unprovoked and brutal invasion of Ukraine by Russia on 24 February 2022 is imposing a terrible human cost. In this paper, we use the National Institute Global Econometric Model (NiGEM) to quantify the impact of the war on the global economy. The war represents a massive cost, equivalent to 1% of global GDP in 2022, or about $1.5 trillion valued at purchasing power parity exchange rates (PPP), compared with our GDP forecast made at the beginning of 2022. Europe is the region affected most, given trade links its proximity to Ukraine and Russia and its reliance on energy and food supplies from those countries. GDP in Europe is expected to shrink by more than 1% in 2022 compared with our forecast at the beginning of 2022. In Western Europe, Germany will be worst affected, followed by France and Italy. GDP in ‘Developing Europe’, where Ukraine is the largest representative, is expected to shrink by 30%. The war will also add about 2% to global inflation in 2022 and 1% in 2023, compared with NIESR's inflation projection at the beginning of 2022.
Wind Load Similarity Relations for Parabolic Trough Collectors
Authors: Yang Moucun , Zhi Liming , Liu Huan , Zhu Yuezhao , Taylor Robert A.
Published: September 2022

Large-scale parabolic trough collectors (PTCs) are generally installed in flat, open areas. Their specific costs ($/m2) are dependent on wind load-based structural design factors. To help estimate these wind loads, validated numerical simulations were used to develop similarity relations for large-scale PTCs. First, similarity relations of wind pressure, force, and lift/drag coefficients were deduced between a full-sized model (FM) and a scaled-down experimental similarity model. Second, the wind loads on the similarity model were simulated with a computational model to analyze the pressure distributions and aerodynamic performance under different wind speeds and pitch angles. Third, the computational method was extended to compute wind loads on a LS-2 collector (a commercial-scale PTC designed by LUZ International Ltd). The numerical results had a close agreement with the experiment results, on the whole, achieving a mean relative error in the drag coefficients of 5.1%, 3.8% in the lift coefficients and 5.0% in the moment coefficients, which indicated that the simulation model was valid. Further, compared with the shear stress transport model for the atmospheric boundary layer (ABL) along with large eddy simulations for the ABL, the k–ɛ turbulence model has better accuracy. Finally, practical similarity equations were proposed which can be used to estimate the wind loads on a range of PTC designs in a wide range of conditions. The mean relative error of these practical similarity equations was found to be within 12.0%. Overall, this study reports a validated set of similarity equations that can be used to bypass costly numerical simulation and/or wind tunnel testing for the estimation of wind loads on the large-scale PTCs (e.g., the EuroTrough) installed in flat, open areas.
A New Evaluation Metric for Demand Response-Driven Real-Time Price Prediction Towards Sustainable Manufacturing
Authors: Yun Lingxiang , Li Lin
Published: September 2022

The increasing industry energy demand highlights the urgency of demand response management, while the emerging smart manufacturing technologies pave the way for the implementation of real-time price (RTP)-based demand response management towards sustainable manufacturing. The demand response management requires scheduling of manufacturing systems based on RTP predictions, and thus the prediction quality can directly alter the effectiveness of demand response. However, since the general price prediction algorithms and prediction evaluation metrics are not specifically designed for RTP in demand response problems, a good RTP prediction obtained and evaluated by these algorithms and metrics may not be suitable for demand response scheduling. Therefore, in this study, the relationships between the effectiveness of demand response for manufacturing systems and evaluation results from six commonly used metrics are investigated. Meanwhile, a new metric called k-peak distance (KPD), considering the characteristics of the demand response problem, is proposed and compared with the other six metrics. Furthermore, an encoder-decoder long short-term memory recurrent neural network with KPD is proposed to provide better RTP prediction for manufacturing demand response problems. The case studies indicate that the proposed KPD metric shows a 1.8–3.6 times higher correlation with the demand response effectiveness compared to the other metrics. In addition, the production schedule based on the RTP prediction obtained from the proposed algorithm can improve the effectiveness of demand response by 23.4% on average.
Topology Optimization Design of Scramjet Structures With Forced Convective Heat Transfer on Unstructured Meshes
Authors: Duan Zhijian , Xie Gongnan , Li Xin
Published: September 2022

A topology optimization strategy with coupled fluid–solid interaction was proposed to maximize the cooling efficiency of a kind of structure applied for scramjets. The Galerkin finite element method (FEM) is used to solve the forced convective heat transfer, and the rational approximation of material properties (RAMP) method combined with the globally convergent method of moving asymptotes (GCMMA) method are used to solve the topological optimization models with different boundary conditions and objective functions. Examples are provided to demonstrate the validity and effectiveness of the optimization strategy. The optimal flow passages of scramjet structures are achieved successfully. Compared with a baseline structure with rectangular straight passages, the optimized flow passages significantly reduce the averaged bulk temperature and pressure loss, and the bulk temperature is more uniform to avoid the occurrence of concentrated high-temperature areas. With the Reynolds number changing from 1000 to 1750, the heat transfer performance of the three-dimensional topology-optimized structure increases by 16.79% to 20.82%.
Assessment of the Flow Field and Heat Transfer in a Vane Cooling System Using Magnetic Resonance Velocimetry, Thermochromic Liquid Crystals, and Computational Fluid Dynamics
Authors: Bruschewski Martin , Wüstenhagen Carolin , Domnick Clemens , Krewinkel Robert , Shiau Chao-Cheng , Grundmann Sven , Han Je-Chin
Published: September 2022

Computational fluid dynamics (CFD) is the standard tool in the turbomachinery industry to analyze and optimize internal cooling systems of turbine components, but the code applied has to be validated. This paper presents a combined experimental and numerical study on the flow field and heat transfer in a cooling system consisting of a three-pass serpentine with rib turbulators and trailing edge ejection. The cooling geometry is taken from a stator vane currently used in an industrial gas turbine and operates at a coolant inlet Reynolds number of 45,000. As an experimental technique, magnetic resonance velocimetry (MRV) was used to obtain the three-dimensional time-averaged velocity field of the isothermal flow. The measurements were conducted in a large-scale model and resulted in 3.2 million velocity vectors and measurement uncertainty of 6.1% of the bulk inlet velocity. The local wall heat transfer was measured in a separate experiment using thermochromic liquid crystals (TLC). These measurements yielded the distribution of the heat transfer coefficient on both the pressure and the suction side internal walls with a measurement uncertainty of 12%. The experimental data are used as a reference for the numerical study. In total, eight turbulence models are evaluated here, including one-equation, two-equation, algebraic and differential Reynolds stress models, and a scale adaptive simulation. The results show the differences between the velocity fields and the heat transfer coefficient distribution, allowing for the identification of the optimum turbulence model for this particular type of flow.
Scaling Flat Plate Overall Effectiveness Measurements
Authors: McNamara Luke J. , Fischer Jacob P. , Kernan Marta E. , Rutledge James L.
Published: September 2022

Low temperature experiments are often performed on models of cooled turbine components in order to predict the temperature of the actual turbine component at engine conditions. Designing the scaled experiment properly takes care beyond simply matching the freestream Reynolds number. For instance, it is well known that for the overall effectiveness to match that at engine conditions, the Biot number of the experimental model must match that of the engine component. Somewhat less clear is the method by which one must scale the coolant flowrate. Widely used coolant flowrate parameters have generally been informed based on the results of adiabatic effectiveness experiments and it remains unclear how well these parameters also allow for matched overall effectiveness, which is highly dependent on internal cooling. In the present work, overall effectiveness distributions were measured on a flat plate with three rows of zero-degree compound angle 7-7-7 shaped holes. The influence of various thermodynamic gas properties was examined using several foreign gases as the coolant while matching coolant flowrate parameters M, I, and ACR. It is shown that the thermal conductivity of the coolant plays an outsized role in the overall effectiveness, but this is not accounted for with any of the traditional coolant flowrate parameters. With significant thermal conductivity variations possible between the coolant and freestream gas at both engine and experimental conditions, consideration of this effect is of vital importance to the experimentalist.
A new species of Allochaetophoridae (Acari: Tetranychoidea) from Iran
Authors: Bagheri Mohammad , Mohammad-Doustaresharaf Mojtaba
Published: September 2022

Allochaetophora urmiana sp. nov., a new species of the family Allochaetophoridae, is described and illustrated based on all instar stages (female, male, larva, protonymph and deutonymph). This is the second report of the family Allochaetophoridae for Iran and Asia, fourth for the world and first description of the protonymph stage. All specimens were collected from grassland in northwestern Iran. We also provide a key (based on the adult female and deutonymph) and a table of diagnostic characters for identification of all known species.
A Queer Cooptation of Sport: RuPaul’s Drag Race Contestants as Athletes in a Culture of Risk and Injury
Authors: St. Amant Niya
Published: September 2022

RuPaul’s Drag Race (RPDR) is a reality television show wherein drag queens compete for the title of America’s next drag superstar. This article contends that RPDR is sport and that the queens are contestants in a culture of risk wherein queens must be willing to play through pain, risk their bodies, and demonstrate emotional toughness to succeed. A hegemonic power structure exists on RPDR wherein judges, fans, and contestants reward queens willing to participate in the culture of risk and deem queens unwilling to participate as unworthy. Using a discourse analysis of Season 9, this article will demonstrate how the contestants on RPDR must conform to the traditional masculine and feminine gender norms commonly found in sporting contexts to garner success on and off the show.
The emergence of spontaneous coordinated epithelial rotation on cylindrical curved surfaces
Authors: Glentis Alexandros , Blanch-Mercader Carles , Balasubramaniam Lakshmi , Saw Thuan Beng , d’Alessandro Joseph , Janel Sebastien , Douanier Audrey , Delaval Benedicte , Lafont Frank , Lim Chwee Teck , Delacour Delphine , Prost Jacques , Xi Wang , Ladoux Benoit
Published: September 2022

Three-dimensional collective epithelial rotation around a given axis represents a coordinated cellular movement driving tissue morphogenesis and transformation. Questions regarding these behaviors and their relationship with substrate curvatures are intimately linked to spontaneous active matter processes and to vital morphogenetic and embryonic processes. Here, using interdisciplinary approaches, we study the dynamics of epithelial layers lining different cylindrical surfaces. We observe large-scale, persistent, and circumferential rotation in both concavely and convexly curved cylindrical tissues. While epithelia of inverse curvature show an orthogonal switch in actomyosin network orientation and opposite apicobasal polarities, their rotational movements emerge and vary similarly within a common curvature window. We further reveal that this persisting rotation requires stable cell-cell adhesion and Rac-1–dependent cell polarity. Using an active polar gel model, we unveil the different relationships of collective cell polarity and actin alignment with curvatures, which lead to coordinated rotational behavior despite the inverted curvature and cytoskeleton order.
Exosome-mediated delivery of Cas9 ribonucleoprotein complexes for tissue-specific gene therapy of liver diseases
Authors: Wan Tao , Zhong Jiafeng , Pan Qi , Zhou Tianhua , Ping Yuan , Liu Xiangrui
Published: September 2022

CRISPR-Cas9 gene editing has emerged as a powerful therapeutic technology, but the lack of safe and efficient in vivo delivery systems, especially for tissue-specific vectors, limits its broad clinical applications. Delivery of Cas9 ribonucleoprotein (RNP) owns competitive advantages over other options; however, the large size of RNPs exceeds the loading capacity of currently available delivery vectors. Here, we report a previously unidentified genome editing delivery system, named exosome
RNP
, in which Cas9 RNPs were loaded into purified exosomes isolated from hepatic stellate cells through electroporation. Exosome
RNP
facilitated effective cytosolic delivery of RNP in vitro while specifically accumulated in the liver tissue in vivo. Exosome
RNP
showed vigorous therapeutic potential in acute liver injury, chronic liver fibrosis, and hepatocellular carcinoma mouse models via targeting p53 up-regulated modulator of apoptosis (
PUMA
), cyclin E1 (
CcnE1
), and K (lysine) acetyltransferase 5 (
KAT5
), respectively. The developed exosome
RNP
provides a feasible platform for precise and tissue-specific gene therapies of liver diseases.
Poly(ADP-ribose) promotes toxicity of
C9ORF72
arginine-rich dipeptide repeat proteins
Authors: Gao Junli , Mewborne Quinlan T. , Girdhar Amandeep , Sheth Udit , Coyne Alyssa N. , Punathil Ritika , Kang Bong Gu , Dasovich Morgan , Veire Austin , DeJesus Hernandez Mariely , Liu Shuaichen , Shi Zheng , Dafinca Ruxandra , Fouquerel Elise , Talbot Kevin , Kam Tae-In , Zhang Yong-Jie , Dickson Dennis , Petrucelli Leonard , van Blitterswijk Marka , Guo Lin , Dawson Ted M. , Dawson Valina L. , Leung Anthony K. L. , Lloyd Thomas E. , Gendron Tania F. , Rothstein Jeffrey D. , Zhang Ke
Published: September 2022

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in
C9ORF72
, play a critical role in
C9ORF72
-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.
The Transcriptional Regulator SpxA1 Influences the Morphology and Virulence of
Listeria monocytogenes
Authors: Cesinger Monica R. , Daramola Oluwasegun I. , Kwiatkowski Lucy M. , Reniere Michelle L.
Published: September 2022

Listeria monocytogenes
is a Gram-positive facultative anaerobe and an excellent model pathogen for investigating regulatory changes that occur during infection of a mammalian host. SpxA1 is a widely conserved transcriptional regulator that induces expression of peroxide-detoxifying genes in
L. monocytogenes
and is thus required for aerobic growth.
Calpain-1: a Novel Antiviral Host Factor Identified in Porcine Small Intestinal Mucus
Authors: Li Yuchen , Wang Xiuyu , Zhang En , Liu Ruiling , Yang Chengjie , Duan Ying , Jiang Yuqi , Yang Qian
Published: September 2022

Although the antiviral activity of the intestinal mucus was recognized 20 years ago, the antiviral active ingredients in the mucus are poorly understood. Currently, most research on antiviral molecules in the intestinal mucus remains limited to members of the mucin family.
Impacts of Menstruation, Community Type, and an Oral Yeast Probiotic on the Vaginal Microbiome
Authors: Oerlemans E. , Ahannach S. , Wittouck S. , Dehay E. , De Boeck I. , Ballet N. , Rodriguez B. , Tuyaerts I. , Lebeer S.
Published: September 2022

How to define and promote a healthy state of the vaginal microbiome is not well understood. Knowledge of which underlying factors shape the microbial community composition of the vagina and how to modulate them will contribute to vaginal disease prevention and improve fertility.
Supplemental Material: Evolution of the Bronson Hill arc and Central Maine basin, northern New Hampshire to western Maine: U-Pb zircon constraints on the timing of magmatism, sedimentation, and tectonism
Authors: Eusden J. Dykstra , al. et
Published: September 2022

Table S1: Analysis of primary and secondary standards 
Risk factors for prolonged recovery from concussion in young patients
Authors: Cuff Steven , Maki Aaron , Feiss Robyn , Young Julie , Shi Junxin , Hautmann Amanda , Yang Jingzhen
Published: September 2022

Objectives

For young patients sustaining concussion, assessing recovery is vital in determining safe return to play. Identifying risk factors may aid clinicians in recognising patients at risk for prolonged recovery. The study objective is to identify risk factors for prolonged (>28 days) and extended (>90 days) recovery (defined as symptom duration) and analyse how these risk factors differ between the two groups.

Methods

We retrospectively analysed electronic health record data (n=4937) among patients aged 10–18 years collected at Nationwide Children’s Hospital Sports Medicine concussion clinics between 1 July 2012 and 30 June 2019. Data collected included patient demographics, comorbidities (eg, prior psychiatric diagnoses, prior concussions) and injury characteristics (eg, loss of consciousness, injury setting). We examined patient risk factors for prolonged (>28 days) and/or extended (>90 days) recovery using modified Poisson regression models.

Results

Factors associated with increased risk of prolonged recovery from concussion included prior concussions (adjusted risk ratio (ARR) 1.19, 95% CI 1.02 to 1.38) for two concussions (ARR 1.36, 95% CI 1.14 to 1.61), for >3, and higher initial symptom score (ARR 2.57, 95% CI 2.34 to 2.83) for postconcussion symptom (PCS) scores 21–60 (ARR 2.89, 95% CI 2.54 to 3.29), for PCS>60. Risk factors for extended recovery included history of concussion (ARR 1.50, 95% CI 1.09 to 2.06) for two concussions (ARR 1.75, 95% CI 1.17 to 2.62), for >3 and older age (15–18 years, ARR 1.11, 95% CI 1.05 to 1.18). Additionally, comorbid attention deficit hyperactivity disorder increased risk of prolonged recovery (ARR 1.14, 95% CI 1.01 to 1.29) while anxiety increased risk for extended recovery (ARR 1.47, 95% CI 1.10 to 1.95).

Conclusion

Overall, risk factors for prolonged recovery differ somewhat from risk factors for extended recovery. For patients who present to clinic with concussion, mental health is an important consideration which may impact the timeline for symptom recovery.
Molecular characterisation of Hb Akron [β52 (D3) Asp→Val] combined with thalassaemia in a Chinese family
Authors: He Sheng , Wang Bolian , Yi Shang , Huang Zhenyan , Liang Lifang , Peng Zhenren , Song Pengshu , Chen Biyan , Chen Faqin , Wei Hongwei
Published: September 2022

Aims

Hb Akron (HBB:c.158A>T) is a rare β-chain variant and many characteristics about its clinical features still remain unclear. In this study, we aimed to explore the molecular and haematological characterisations of previously undescribed states for Hb Akron associated with different forms of thalassaemia.

Methods

Haematology and genetic analysis were performed in 9 members from a Chinese Zhuang ethnic family.

Results

Hb Akron in various combinations with β0-thalassaemia and α0-thalassaemia were identified and characterised. Simple heterozygote for Hb Akron is asymptomatic, while the compound heterozygotes of Hb Akron associated with the β0-thalassaemia mutation generates a more severe haematological phenotype than Hb Akron or β0-thalassaemia mutation seen in isolation. The specific peak of Hb Akron appears at Zone D (195–225 s) in the state of heterozygote and compound heterozygote on haemoglobin capillary electrophoresis device, and the reduction of Hb Akron level in heterozygotes is proportional to the degree of α-globin gene deficiency.

Conclusions

We have for the first time described the genetic and haematological characteristics of Hb Akron combined with different thalassaemia mutations, which will provide useful information for genetic counselling and prenatal diagnostic service of this mutation in a population with high prevalence of thalassaemia.
Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer
Authors: Zhu Xudong , Liang Rongpu , Lan Tianyun , Ding Dongbing , Huang Shengxin , Shao Jun , Zheng Zongheng , Chen Tufeng , Huang Yong , Liu Jianpei , Pathak Janak L , Wei Hongbo , Wei Bo
Published: September 2022

Background

Onco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression.

Methods

CD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages.

Results

CRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155+TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. CD155+macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-β-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155–⁄–bone marrow transplantation in wild-type mice, as well as CD155– macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155+TAMs.

Conclusions

These findings indicated that CD155+TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155+TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.
FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer
Authors: Liu Jiaxin , Wei Lingyun , Hu Nan , Wang Dong , Ni Juan , Zhang Sha , Liu Hongbing , Lv Tangfeng , Yin Jie , Ye Mingxiang , Song Yong
Published: September 2022

Background

Activation of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been extensively described as a pivotal mechanism to escape immune surveillance and elicits suppressive effect on antitumor immunity. Blockade of the PD-1/PD-L1 interaction by checkpoint inhibitors has been shown to result in tumor shrinkage and prolong patient survival. However, regulatory machinery for PD-1/PD-L1 expression is largely unknown.

Methods

We used bioinformatic tools and biochemical methods to investigate the significance of F-box and WD repeat domain containing 7 (FBW7) in regulating PD-1 protein stability. By generating a panel of FBW7 and PD-1 encoding plasmids, we expressed FBW7 and PD-1 or their mutants to performed immunoprecipitation and immunoblotting assays. The efficacy of cotargeting FBW7 to enhance antitumor immunity was evaluated in C57BL/6J mice. These laboratory findings were further validated in tumor samples obtained from patients with non-small cell lung cancer (NSCLC).

Results

We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. Cotargeting FBW7 accelerates PD-1 protein degradation and enhances antitumor immunity in vivo. Moreover, we demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7. Higher expression of FBW7 characterizes a ‘hot’ tumor microenvironment and confers more favorable responses to PD-1 blockade therapy.

Conclusions

This study highlights the critical role of FBW7 in determining PD-1 protein stability. FBW7 ubiquitinates PD-1 in a phosphorylation-dependent manner, as a consequence, leading to PD-1 protein degradation and cytotoxic lymphocytes infiltrating the tumor microenvironment. Screening FBW7 status would predict clinical response to anti-PD-1 immunotherapy in patients with NSCLC, and targeting FBW7 is a promising strategy to enhance antitumor immunity.
Generation andin vivovalidation of an IL-12 fusion protein based on a novel anti-human FAP monoclonal antibody
Authors: Nadal Lisa , Peissert Frederik , Elsayed Abdullah , Weiss Tobias , Look Thomas , Weller Michael , Piro Geny , Carbone Carmine , Tortora Giampaolo , Matasci Mattia , Favalli Nicholas , Corbellari Riccardo , Di Nitto Cesare , Prodi Eleonora , Libbra Chiara , Galeazzi Simone , Carotenuto Claudiopietro , Halin Cornelia , Puca Emanuele , Neri Dario , De Luca Roberto
Published: September 2022

Background

In this study, we describe the generation of a fully human monoclonal antibody (named ‘7NP2’) targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.

Methods

7NP2 was isolated from a synthetic antibody phage display library and was improved by one round of mutagenesis-based affinity maturation. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin (IL)-12 was generated and the anticancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. Furthermore, the safety of the fully human product (named IL12-7NP2) was evaluated inCynomolgusmonkeys.

Results

Biodistribution analysis in tumor-bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conductedin vivo, showing a potent antitumor activity in immunocompetent and immunodeficient mouse models of cancer, both as single agent and in combination with immune checkpoint inhibitors. The fully human product was tolerated when administered to non-human primates.

Conclusions

The results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.
Ethics of care challenge to advance directives for dementia patients
Authors: Choi William Jinwoong
Published: September 2022

Advance directives for withholding life-saving treatment are controversial for dementia patients whose previously expressed wishes conflict with their currently expressed desires. To illustrate this ethical dilemma, McMahan conceives a hypothetical case in which an intellectually proud creative woman signs an advance directive stipulating her refusal to receive life-saving treatment if she contracts a fatal condition with dementia. However, when she develops dementia and forgets this advance directive, she contracts pneumonia and now expresses a desire to live. In response to such dilemmas, scholars like Norman Cantor have defended the moral authority of advance directives by giving credence to one’s prior competent wishes over one’s current incompetent preferences. I argue that their arguments, which are rooted in the principle of respect for autonomy, operate under ableist assumptions about incompetent persons and exclude other important features of respect. I propose an ethics of care model as an alternative moral approach that reconceptualises respect as a matter of caring about people’s contemporaneous interests, even if they are not competently conceived. It fosters the virtues of care by encouraging healthcare providers to recognise dementia patients as legitimate narrative agents capable of authoring their own evolving life story. I argue that the ethics of care model not only provides an ethical defence of the creative woman’s current incompetent desire to live despite her advance directive, but also vindicates our moral intuitions about what it means to demonstrate respect to dementia patients.
Different humoral but similar cellular responses of patients with autoimmune inflammatory rheumatic diseases under disease-modifying antirheumatic drugs after COVID-19 vaccination
Authors: Andreica Ioana , Blazquez-Navarro Arturo , Sokolar Jan , Anft Moritz , Kiltz Uta , Pfaender Stephanie , Vidal Blanco Elena , Westhoff Timm , Babel Nina , Stervbo Ulrik , Baraliakos Xenofon
Published: September 2022

Objectives

The effect of different modes of immunosuppressive therapy in autoimmune inflammatory rheumatic diseases (AIRDs) remains unclear. We investigated the impact of immunosuppressive therapies on humoral and cellular responses after two-dose vaccination.

Methods

Patients with rheumatoid arthritis, axial spondyloarthritis or psoriatic arthritis treated with TNFi, IL-17i (biological disease-modifying antirheumatic drugs, b-DMARDs), Janus-kinase inhibitors (JAKi) (targeted synthetic, ts-DMARD) or methotrexate (MTX) (conventional synthetic DMARD, csDMARD) alone or in combination were included. Almost all patients received mRNA-based vaccine, four patients had a heterologous scheme. Neutralising capacity and levels of IgG against SARS-CoV-2 spike-protein were evaluated together with quantification of activation markers on T-cells and their production of key cytokines 4 weeks after first and second vaccination.

Results

92 patients were included, median age 50 years, 50% female, 33.7% receiving TNFi, 26.1% IL-17i, 26.1% JAKi (all alone or in combination with MTX), 14.1% received MTX only. Although after first vaccination only 37.8% patients presented neutralising antibodies, the majority (94.5%) developed these after the second vaccination. Patients on IL17i developed the highest titres compared with the other modes of action. Co-administration of MTX led to lower, even if not significant, titres compared with b/tsDMARD monotherapy. Neutralising antibodies correlated well with IgG titres against SARS-CoV-2 spike-protein. T-cell immunity revealed similar frequencies of activated T-cells and cytokine profiles across therapies.

Conclusions

Even after insufficient seroconversion for neutralising antibodies and IgG against SARS-CoV-2 spike-protein in patients with AIRDs on different medications, a second vaccination covered almost all patients regardless of DMARDs therapy, with better outcomes in those on IL-17i. However, no difference of bDMARD/tsDMARD or csDMARD therapy was found on the cellular immune response.
Towards tobacco-free retailers: feasibility of an intervention encouraging retailers to stop selling tobacco in Tasmania
Authors: Smith Abby L , Mihrshahi Seema , Martin-Gall Veronica A , Brkic Marina , Veitch Mark G , Freeman Becky
Published: September 2022

Background

Despite calls for greater emphasis on tobacco supply reduction strategies, limited evidence of interventions (regulatory and non-regulatory) to reduce tobacco retailer numbers exists. This study investigated the feasibility of a real-world, non-regulatory intervention to encourage low volume tobacco retailers to stop selling, in a jurisdiction with a tobacco retailer licensing system.

Intervention

Between December 2018 and 2019, low volume tobacco retailers (n=164) were exposed to multiple intervention elements (eg, postcard and letter mail-out, onsite visit) focused on the business benefits of stopping selling, in the lead up to their tobacco licence expiry date. The intervention was delivered in Tasmania, Australia in a region characterised by socioeconomic disadvantage, high smoking rates and density of tobacco retailers.

Methods

For this mixed-methods study we collected data through implementation records on 164 retailers and postintervention interviews with 21 retailers to explore intervention implementation, awareness, acceptability, usefulness and actions taken.

Results

Retailers were able to recall the intervention, specifically messages focused on the business-related reasons to stop selling tobacco. Of the 107 retailers that the project officer spoke with onsite or via telephone, the majority (72%) accepted phase I components. The intervention introduced some retailers to the concept of ending tobacco sales, which made them stop and consider this option. Of the 164 retailers exposed to the intervention, 18 (11%) retailers ended tobacco sales.

Conclusion

Our study suggests that a non-regulatory intervention targeting low volume retailers to end tobacco sales may help to reduce the retail availability of tobacco.
Longitudinal bidirectional association between youth electronic cigarette use and tobacco cigarette smoking initiation in Thailand
Authors: Patanavanich Roengrudee , Worawattanakul Methavee , Glantz Stanton
Published: September 2022

Introduction

This study quantifies the longitudinal association between e-cigarette use and subsequent conventional cigarette initiation and vice versa among Thai youths.

Methods

Data from a longitudinal survey of 6045 Thai seventh grade students with baseline in 2019 and the 12-month follow-up in 2020 were analysed using complex survey multivariate logistic regressions to assess whether e-cigarette use was associated with subsequent cigarette smoking (ever, current and dual product users at follow-up) among baseline never smokers.

Results

Consistent with prior findings from other countries, among those who had never smoked cigarettes at baseline, ever e-cigarette users were more likely to try cigarette smoking (adjusted OR 4.44; 95% CI 2.23 to 8.86; p<0.001), or become dual users (adjusted OR 5.31; 95% CI 2.63 to 10.74; p<0.001) 1 year later. Baseline current e-cigarette users were more likely to become ever smokers (adjusted OR 5.37; 95% CI 1.82 to 15.90; p=0.005), current smokers (OR 3.92; 95% CI 1.69 to 9.14; p=0.003) and dual product users (adjusted OR 6.96; 95% CI 1.54 to 31.38; p=0.015) at the 12-month follow-up than non-e-cigarette users. Similarly, among never e-cigarette users at baseline, ever cigarette smoking were more likely to try e-cigarettes (adjusted OR 3.38; 95% CI 1.66 to 6.88; p=0.002), currently use e-cigarettes (adjusted OR 2.75; 95% CI 1.47 to 5.13; p=0.003) and currently use both e-cigarettes and cigarettes (adjusted OR 4.87; 95% CI 2.92 to 8.13; p<0.001) at the follow-up than never smokers. Among never e-cigarette users at baseline, current-cigarette smoking were more likely to try e-cigarettes (adjusted OR 6.21; 95% CI 2.58 to 14.95; p<0.001), currently use e-cigarettes (adjusted OR 2.80; 95% CI 1.27 to 6.14; p=0.014) and currently use both e-cigarettes and cigarettes (adjusted OR 7.70; 95% CI 3.45 to 17.19; p<0.001) at the follow-up than never smokers.

Conclusions

This longitudinal study in Asian low-income and middle-income countries supports the prospective association of youth e-cigarette use with subsequent smoking initiation and youth cigarette use with subsequent e-cigarette initiation that is similar to that observed in high-income Western countries.
Relative and quasi-entropies in semifinite von Neumann algebras
Authors: Łuczak Andrzej , Podsędkowska Hanna , Wieczorek Rafał
Published: September 2022

We prove that Araki’s relative entropy equals Umegaki’s information between normal states on semifinite von Neumann algebras, as well as derive formulae for quasi-entropies and Rényi’s relative entropy in semifinite von Neumann algebras, generalizing thus the results known in finite dimension. Our investigations rest on a thorough analysis of the relative modular operator in such an algebra.
Study of nonstatic anisotropic axial structures through perturbation
Authors: Bhatti M. Z. , Yousaf Z. , Yousaf M.
Published: September 2022

This work is related to the stability of a nonstatic, very restricted class of axially symmetric cosmic matter configuration under the influence of modified gravitational theory (AGT) with a realistic model in anisotropic conditions. We construct dynamically modified equations, continuity equations, mass functions and collapse equations in the scenario of considered AGT. We continue our analysis under the influence of f(R,T) gravity along with a minimally coupled gravitational function of the form [Formula: see text], where [Formula: see text] indicates constant entity. In this gravitational model, f is a function of Ricci scalar invariant R and the trace of the stress–energy tensor T. This gravitational function gives significant findings only for [Formula: see text], and both belong to the set of positive real numbers and also [Formula: see text]. We establish expressions of an adiabatic index, i.e. stiffness parameter of fluid [Formula: see text] utilizing relevant perturbation technique with the help of collapse equation in Newtonian [Formula: see text] and post-Newtonian [Formula: see text] domains. We consider the particular form of metric as well as material functions in [Formula: see text] and [Formula: see text] eras, and impose some constraints on physical quantities (i.e. pressure, density, mass, etc.) to carry out the stable behavior of a considered restricted geometry.
Polyfunctions over commutative rings
Authors: Specker Ernst , Hungerbühler Norbert , Wasem Micha
Published: September 2022

A function [Formula: see text], where [Formula: see text] is a commutative ring with unit element, is called polyfunction if it admits a polynomial representative [Formula: see text]. Based on this notion, we introduce ring invariants which associate to [Formula: see text] the numbers [Formula: see text] and [Formula: see text], where [Formula: see text] is the subring generated by [Formula: see text]. For the ring [Formula: see text] the invariant [Formula: see text] coincides with the number theoretic Smarandache or Kempner function [Formula: see text]. If every function in a ring [Formula: see text] is a polyfunction, then [Formula: see text] is a finite field according to the Rédei–Szele theorem, and it holds that [Formula: see text]. However, the condition [Formula: see text] does not imply that every function [Formula: see text] is a polyfunction. We classify all finite commutative rings [Formula: see text] with unit element which satisfy [Formula: see text]. For infinite rings [Formula: see text], we obtain a bound on the cardinality of the subring [Formula: see text] and for [Formula: see text] in terms of [Formula: see text]. In particular we show that [Formula: see text]. We also give two new proofs for the Rédei–Szele theorem which are based on our results.
Reverse ∗-Jordan type maps on Jordan ∗-algebras
Authors: Ferreira Ruth N. , Ferreira Bruno L. M. , Costa Bruno Tadeu , da Silva Andre Vanderlinde
Published: September 2022

Let [Formula: see text] and [Formula: see text] be two ∗-Jordan algebras with identities [Formula: see text] and [Formula: see text], respectively, and [Formula: see text] a nontrivial ∗-idempotent in [Formula: see text]. In this paper, we study the characterization of multiplicative ∗-Jordan-type maps. In particular, we provide a characterization in the case of unital prime associative algebra endowed with an involution.
On generators and defining relations of quantum affine superalgebra Uq(𝔰𝔩̂m|n)
Authors: Lin Hongda , Yamane Hiroyuki , Zhang Honglian
Published: September 2022

Two presentations of quantum affine superalgebras were introduced by Yamane in [On defining relations of affine Lie superalgebras and affine quantized universal enveloping superalgebras, Publ. Res. Inst. Math. Sci. 35 (1999) 321–390], which were called Drinfeld–Jimbo realization and Drinfeld realization. Drinfeld realization contains infinite sequences of generators and relations. In this paper, we consider the Drinfeld realization of quantum affine superalgebra [Formula: see text] associated to type [Formula: see text] and define a simple algebra [Formula: see text] generated by only a finite part of these sequences of quantum affine superalgebra [Formula: see text]. We show that the algebra [Formula: see text] is isomorphic to the quantum affine superalgebra [Formula: see text]. Using the above isomorphism, we prove there exists an isomorphism between the two realizations.
Pre-train, Prompt, and Predict: A Systematic Survey of Prompting Methods in Natural Language Processing
Authors: Liu Pengfei , Yuan Weizhe , Fu Jinlan , Jiang Zhengbao , Hayashi Hiroaki , Neubig Graham
Published: September 2022

This article surveys and organizes research works in a new paradigm in natural language processing, which we dub “prompt-based learning.” Unlike traditional supervised learning, which trains a model to take in an input

x

and predict an output

y

as
P
(

y|x

), prompt-based learning is based on language models that model the probability of text directly. To use these models to perform prediction tasks, the original input

x

is modified using a
template
into a textual string
prompt

x′

that has some unfilled slots, and then the language model is used to probabilistically fill the unfilled information to obtain a final string

x̂

, from which the final output

y

can be derived. This framework is powerful and attractive for a number of reasons: It allows the language model to be
pre-trained
on massive amounts of raw text, and by defining a new prompting function the model is able to perform
few-shot
or even
zero-shot
learning, adapting to new scenarios with few or no labeled data. In this article, we introduce the basics of this promising paradigm, describe a unified set of mathematical notations that can cover a wide variety of existing work, and organize existing work along several dimensions, e.g., the choice of pre-trained language models, prompts, and tuning strategies. To make the field more accessible to interested beginners, we not only make a systematic review of existing works and a highly structured typology of prompt-based concepts but also release other resources, e.g., a website
NLPedia–Pretrain
including constantly updated survey and paperlist.
The Four Horsemen of an Ailing Software Project
Authors: Neville-Neil George V.
Published: September 2022

KV has talked about various measures of software quality in past columns, but perhaps falling software quality is one of the most objective measures that a team is failing. This Pestilence, brought about by the low morale engendered in the team by War and Famine, is a clear sign that something is wrong. In the real world, a diseased animal can be culled so that disease does not spread and become a pestilence over the land. Increasing bug counts, especially in the absence of increased functionality, is a sure sign of a coming project apocalypse.