bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cell Predominant Response to AAV-Spike Protects hACE2 Mice from SARS-CoV-2 Pneumonia
Authors: Greer Christopher D. , Kasden Coral M. , Morales Leon , Lundgreen Kendall A. , Hicks Philip D. , Carpenter Lilia J. , Salas-Quinchucua Cristhian , Tichy Elisia D. , Maguire Albert M. , Hoffman Jennifer G. , Bailey Robin J. , Zhou Shangzhen , Luo Angela , Chomistek Steven J. , Kozyak Benjamin W. , Bridges Charles R. , Gordon Gilad S. , Tabin Geoffrey C. , Bates Paul F. , Osorio Jorge E. , Bennett Jean , Stedman Hansell H. 
Published: August 2021

AbstractPrevention of COVID-19 is widely believed to depend on neutralization of SARS-CoV-2 by vaccine-induced humoral immunity1,2, raising concern that emerging escape variants may perpetuate the pandemic3–6. Here we show that a single intramuscular injection of Adeno-Associated Virus-6 (AAV6) or AAV9 encoding a modified, N-terminal domain deleted (ΔNTD) spike protein induces robust cellular immunity and provides long-term protection in k18-hACE2 transgenic mice from lethal SARS-CoV-2 challenge, associated weight loss and pneumonia independent of vaccine-induced neutralizing humoral immunity. In both mice and macaques, vaccine-induced cellular immunity results in the clearance of transduced muscle fibers coincident with macrophage and CD8+ cytotoxic T cell infiltration at the site of immunization. Additionally, mice demonstrate a strong Type-1 polarized cellular immunophenotype and equivalent ex vivo T cell reactivity to peptides of wt and alpha (B.1.1.7) variant spike. These studies demonstrate not only that AAV6 and AAV9 can function as effective vaccine platforms, but also that vaccines can provide long-term efficacy primarily through the induction of cellular immunity. The findings may provide an alternative approach to containment of the evolving COVID-19 pandemic and have broader implications for the development of variant-agnostic universal vaccines against a wider range of pathogens.
Genome size drives morphological evolution in organ-specific ways
Authors: Itgen Michael W. , Siegel Dustin S. , Sessions Stanley K. , Mueller Rachel Lockridge 
Published: August 2021

AbstractMorphogenesis is an emergent property of biochemical and cellular interactions during development. Genome size and the correlated trait of cell size can influence these interactions through its effects on developmental rate and tissue geometry, ultimately driving the evolution of morphology. We tested the effects of genome size and body size evolution on heart and liver morphology using nine species of the salamander genus Plethodon (genome sizes 29.3–67 Gb). Our results show that whole organ size is determined by body size, whereas tissue structure changes dramatically with evolutionary increases in genome size. In the heart, increased genome size is correlated with a reduction of myocardia in the ventricle, yielding proportionally less force–producing mass and more empty space. In the liver, increased genome size is correlated with fewer and larger vascular structures, positioning hepatocytes farther from the circulatory vessels that transport key metabolites. Although these structural changes should have obvious impacts on organ function, their effects on organismal performance and fitness are likely negligible because low metabolic rates in salamanders relax selective pressure on key metabolic organ performance. Overall, this study reveals the effects of large genome and cell size on the developmental systems producing the heart and liver.
Distinct stage-specific transcriptional states of B cells in human tonsillar tissue
Authors: Espinoza Diego A. , Le Coz Carole , Romberg Neil , Bar-Or Amit , Li Rui 
Published: August 2021

ABSTRACTB cells within secondary lymphoid tissues encompass a diverse range of activation states and multiple maturation processes that reflect antigen recognition and transition through the germinal center (GC) reaction, in which mature B cells differentiate into memory and antibody-secreting cells (ASCs). Here, using single-cell RNA-seq, we identify distinct activation and maturation profiles of B cells within and outside the GC reaction in human secondary lymphoid tissue. In particular, we identify a distinct, previously uncharacterizedCCL4/CCL3chemokine-expressing B-cell population with an expression pattern consistent with BCR/CD40 activation. Furthermore, we present a computational method leveraging regulatory network inference and pseudotemporal modeling to identify upstream transcription factor modulation along the GC to ASC maturation axis. Our dataset provides valuable insight into the diverse functional profiles and maturation processes that B cells undergo within secondary lymphoid tissues and will be a useful resource on which to base further studies into the B-cell immune compartment.HighlightsscRNA-seq of human tonsillar B cells identifies distinct activation and maturation phenotypes.Identification of a chemokine-expressing B-cell population in the human tonsil with a BCR and CD40 co-stimulatory gene signature.Transcription factor regulatory network analysis identifies MYC and REL as predicted regulators of chemokine expression in the chemokine-expressing B-cell population.Trajectory inference with gene and regulatory network modeling implicates novel transcription factors in the GC-to-ASC transition.
Pseudotyped Bat Coronavirus RaTG13 is efficiently neutralised by convalescent sera from SARS-CoV-2 infected Patients
Authors: Cantoni Diego , Mayora-Neto Martin , Thakur Nazia , Elrefaey Ahmed ME , Newman Joseph , Vishwanath Sneha , Nadesalingam Angalee , Chan Andrew , Smith Peter , Castillo-Olivares Javier , Baxendale Helen , Charleston Bryan , Heeney Jonathan , Bailey Dalan , Temperton Nigel 
Published: August 2021

AbstractRaTG13 is a close relative of SARS-CoV-2, the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, sharing 96% sequence similarity at the genome-wide level. The spike receptor binding domain (RBD) of RaTG13 contains a large number of amino acid substitutions when compared to SARS-CoV-2, likely impacting affinity for the ACE2 receptor. Antigenic differences between the viruses are less well understood, especially whether RaTG13 spike can be efficiently neutralised by antibodies generated from infection with, or vaccination against, SARS-CoV-2. Using RaTG13 and SARS-CoV-2 pseudotypes we compared neutralisation using convalescent sera from previously infected patients as well as vaccinated healthcare workers. Surprisingly, our results revealed that RaTG13 was more efficiently neutralised than SARS-CoV-2. In addition, neutralisation assays using spike chimeras and mutants harbouring single amino acid substitutions within the RBD demonstrated that both spike proteins can tolerate multiple changes without dramatically reducing how efficiently they are neutralised. Moreover, introducing the 484K mutation into RaTG13 resulted in increased neutralisation, in contrast to the same mutation in SARS-CoV-2 (E484K). This is despite E484K having a well-documented role in immune evasion in variants of concern (VOC) such as B.1.351 (Beta). These results indicate that the immune-escape mutations found in SARS-CoV-2 VOCs might be driven by strong antibody pressures, and that the future spill-over of RaTG13 and/or related sarbecoviruses could be mitigated using current SARS-CoV-2-based vaccination strategies.
A Test of the Pioneer Factor Hypothesis
Authors: Hansen Jeffrey L , Cohen Barak A 
Published: August 2021

AbstractThe Pioneer Factor Hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (nonPFs) that activate batteries of silent genes. We tested the PFH by expressing the endodermal PF FoxA1 and nonPF Hnf4a in K562 lymphoblast cells. While co-expression of FoxA1 and Hnf4a activated a burst of endoderm-specific gene expression, we found no evidence for functional distinction between these two TFs. When expressed independently, both TFs bound and opened inaccessible sites, activated endodermal genes, and “pioneered” for each other, although FoxA1 required fewer copies of its motif to bind at inaccessible sites. A subset of targets required both TFs, but the mode of action at these targets did not conform to the sequential activity predicted by the PFH. From these results we propose an alternative to the PFH where “pioneer activity” depends not on the existence of discrete TF subclasses, but on TF binding affinity and genomic context.
Detection and phenotypic characterization of carbapenem non susceptible gram-negative bacilli isolated from clinical specimens
Authors: Abdeta Abera , Bitew Adane , Fentaw Surafel , Tsige Estifanos , Assefa Dawit , Lejisa Tadesse , Kefyalew Yordanos , Tigabu Eyasu 
Published: August 2021

AbstractBackgroundMulti-drug resistant, extremely drug-resistant, pan-drug resistant, carbapenem-resistant, and carbapenemase-producing gram-negative bacteria are becoming more common in health care settings and are posing a growing threat to public health.ObjectiveThe study was aimed to detect and phenotypically characterize carbapenem non susceptible gram-negative bacilli at Ethiopian Public Health Institute.Materials and methodsProspective cross-sectional study was conducted from June 30, 2019, to May 30, 2020, at the national reference laboratory of the Ethiopian Public Health Institute. Clinical samples were collected, inoculated, and incubated in accordance to standard protocol for each sample. Antimicrobial susceptibility testing was done using Kirby Bauer disk diffusion. Identification was done using the traditional biochemical method. Multidrug-resistant and extensively drug-resistant were classified using a standardized definition established by European Centers for Disease prevention and control and the United States Centers for Disease prevention and control experts. Carbapenemase production was confirmed by modified carbapenem inactivation and a simplified carbapenem inactivation method. Meropenem with EDTA was used to differentiate serine carbapenemase and Metallo β-lactamase.ResultsA total of 1337 clinical specimens were analyzed, of which 429-gram negative bacilli isolates were recovered. Out of 429 isolates 319, 74, and 36 were Enterobacterales, Acinetobacter species, and P. aeruginosa respectively. In our study, the prevalence of Multidrug-resistant, extensively drug-resistant, Carbapenemase-producing, and carbapenem non-susceptible Gram-negative bacilli were, 45.2%, 7.7%, 5.4%, and 15.4% respectively. Out of 66 isolates screened for Carbapenemase, 34.8% (23/66) were Carbapenemase enzyme producers. Ten out of twenty-three Carbapenemase-positive organisms were Metallo-beta-lactamase producers. Thirteen out of twenty-three isolates were serine carbapenemase producers. Three out of 13 serine Carbapenemase positive organisms were Klebsiella pneumoniae Carbapenemase.ConclusionThe finding from this study revealed a high prevalence of Multidrug-resistant, extremely drug-resistant, carbapenemase-producing gram-negative bacteria, particularly among Intensive care unit patients at the health facility level, this necessitates a robust laboratory-based antimicrobial resistance monitoring and infection prevention and control program.
Toxic SOD1 trimers are off-pathway in the formation of amyloid-like fibrils in ALS
Authors: Hnath Brianna , Dokholyan Nikolay V. 
Published: August 2021

AbstractAccumulation of insoluble amyloid fibrils is widely studied as a critical factor in the pathology of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Misfolded Cu, Zn superoxide dismutase (SOD1) was the first protein linked to ALS, and non-native SOD1 trimeric oligomers were recently linked to cytotoxicity, while larger oligomers were protective to cells. The balance between trimers and larger aggregates in the process of SOD1 aggregation is, thus, a critical determinant of potential therapeutic approaches to treat ALS. Yet, it is unknown whether these trimeric oligomers are a necessary intermediate for larger aggregate formation or a distinct off-pathway species competing with fibril formation. Depending on the on- or off-pathway scenario of trimer formation, we expect drastically different therapeutic approaches. Here, we show that the toxic SOD1 trimer is an off-pathway intermediate competing with protective fibril formation. We design mutant SOD1 constructs that remain in a trimeric state (super stable trimers) and show that stabilizing the trimeric SOD1 prevents formation of fibrilsin vitroand in a motor neuron like cell model (NSC-34). Using size exclusion chromatography we track the aggregation kinetics of purified SOD1 and show direct competition of trimeric SOD1 with larger oligomer and fibril formation. Finally, we show the trimer is structurally independent of both larger soluble oligomers and insoluble fibrils using circular dichroism spectroscopy and limited proteolysis.Significance StatementProtein aggregation into large insoluble species is a hallmark of many neurodegenerative diseases, but recent evidence suggests that smaller soluble aggregates are responsible for neuronal death. Depending on whether these toxic oligomers appear on- or off-pathway to larger aggregates, which is currently unknown, the strategies for pharmaceutic intervention would be drastically different. Here, we determine that stabilizing the trimeric form of SOD1 reduces larger aggregate formation while increasing toxicity to cells. Trimeric and larger aggregate concentrations have a strong negative correlation over time, and the structure of the trimer is significantly different from larger soluble and insoluble aggregates. Our findings show that formation of trimeric SOD1 is directly competing with that of larger aggregates.
Genetic editing of CISH enhances T cell effector programs independently of immune checkpoint cell surface ligand expression
Authors: Arthofer Elisa , Chakraborty Krishnendu , Viney Lydia , Johnson Matthew J , Webber Beau R. , Moriarity Branden S. , Lou Emil , Choudhry Modassir , Klebanoff Christopher A. , Henley Tom 
Published: August 2021

ABSTRACTPD-1 acts as a negative regulator of T cell-mediated immune responses in the setting of persistent antigen expression, including cancer and chronic pathogen infections. Antibody-mediated blockade of the PD-1/PD-L1 axis benefits a subset of patients with highly immunogenic malignancies; however, many patients fail to respond due to a requirement for expression of the cell surface ligand PD-L1 within the tumor microenvironment. CISH is a member of a new class of intra-cellular immune checkpoint molecules that function downstream of the T cell receptor to regulate antigen-specific effector functions, including reactivity to cancer neoantigens. Herein, we employed multiplex CRISPR editing of primary human T cells to systematically compare the function of CISH deletion relative to PDCD1 (the gene encoding PD-1) and/or VSIG9 (the gene encoding TIGIT) in a model of neoantigen-mediated cancer cell cytolysis. PD-1 and TIGIT disruption enhanced cytolytic activity exclusively in the setting of high PD-L1 expression. In contrast, CISH inactivation enhanced antigen-specific cytolysis of tumor cells regardless of PD-L1 expression, including outperforming PD-1 and TIGIT disruption even in the presence of high PD-L1 tumor cells. Furthermore, we observed a synergistic increase in tumor cell killing when CISH and PD-1 or TIGIT are inactivated in combination, supporting the notion that these immune checkpoints regulate non-redundant pathways of T cell activation. Together, these data demonstrate that the intra-cellular immune checkpoint protein CISH can potentially enhance anti-tumor responses against a broad range of cancer types regardless of PD-L1 biomarker status.
Research on optimization of assembly line based on product scheduling and just-in-time feeding of parts
Authors: Zhang Hui , Li Xiyang , Kan Za , Zhang Xiaohai , Li Zhiyong 
Published: August 2021

Purpose
Reducing production auxiliary time is the key to improve the efficiency of the existing mixed-flow assembly line. This paper proposes a method combining improved genetic algorithm (GA) and Flexsim software. It also investigates mixed-flow assembly line scheduling and just-in-time (JIT) parts feeding scheme to reduce waste in production while taking the existing hill-drop mixed-flow assembly line as an example to verify the effectiveness of the method.

Design/methodology/approach
In this research, a method is presented to optimize the efficiency of the present assembly line. The multi-objective mathematical model is established based on the objective function of the minimum production cycle and part consumption balance, and the solution model is developed using multi-objective GA to obtain the mixed flow scheduling scheme of the hill-drop planter. Furthermore, modeling and simulation with Flexsim software are investigated along with the contents of line inventory, parts transportation means, daily feeding times and time points.

Findings
Theoretical analysis and simulation experiments are carried out in this paper while taking an example of a hill-drop planter mixed-flow assembly line. The results indicate that the method can effectively reduce the idle and overload of the assembly line, use the transportation resources rationally and decrease the accumulation of the line inventory.

Originality/value
The method of combining improved GA and Flexsim software was used here for the first time intuitively and efficiently to study the balance of existing production lines and JIT feeding of parts. Investigating the production scheduling scheme provides a reference for the enterprise production line accompanied by the quantity allocation of transportation tools, the inventory consumption of the spare parts along the line and the utilization rate of each station to reduce the auxiliary time and apply practically.
Investigation of mechanical and corrosion behavior of laser hybrid weld joint of 2205 duplex stainless steel
Authors: Zheng Chuanbo , Zhang Cheng , Wang Xiao Yong , Gu Jie 
Published: August 2021

Purpose
Duplex stainless steel is composed of equal amounts of austenite and ferrite, which has excellent corrosion resistance and strength. However, after the metal was welded, the ratio of austenite and ferrite in the joint is unbalanced, and secondary phase precipitates are produced, which is also an important cause of pitting corrosion in the joint.

Design/methodology/approach
This paper aims to study the mechanical and corrosion behavior of welded joints, by adjusting the welding parameters of laser hybrid welding, dual heat sources are used to weld 2205 duplex stainless steel. The two-phase content of different parts of the welded joint is measured to study the influence of the ratio of the two-phase on the mechanical and corrosion properties of the joint.

Findings
The ratio of austenite and ferrite in different welded joints has an obvious difference, and from top to bottom, the austenite content decreased gradually, and the ferrite content increased gradually. The harmful phases are precipitated in the middle and lower part of the joint. The strength of welded joints is slightly lower than that of base metal. At the same time, the fracture analysis shows that some ferrite phases are affected by the precipitate in the grain and produce quasi-cleavage fracture. The corrosion results show that the corrosion resistance of the welded joints is lower than that of the base metal, and the concentration of chloride ions affects the corrosion resistance.

Originality/value
In this paper, the authors use the influence of different welding processes on the two-phase ratio of the joint to further study the influence of the microstructure on the corrosion resistance and mechanical properties of the weld.
Based on minimum fuel consumption mode integrated optimal control of fixed-wing UAV flight propulsion system
Authors: Li Yong , Han Feifei , Zhang Xinzhe , Peng Kai , Dang Li 
Published: August 2021

Purpose
In this paper, with the goal of reducing the fuel consumption of UAV, the engine performance optimization is studied and on the basis of aircraft/engine integrated control, the minimum fuel consumption optimization method of engine given thrust is proposed. In the case of keeping the given thrust of the engine unchanged, the main fuel flow of the engine without being connected to the afterburner is optimally controlled so as to minimize the fuel consumption.

Design/methodology/approach
In this study, the reference model real-time optimization control method is adopted. The engine reference model uses a nonlinear real-time mathematical model of a certain engine component method. The quasi-Newton method is adopted in the optimization algorithm. According to the optimization variable nozzle area, the turbine drop-pressure ratio corresponding to the optimized nozzle area is calculated, which is superimposed with the difference of the drop-pressure ratio of the conventional control plan and output to the conventional nozzle controller of the engine. The nozzle area is controlled by the conventional nozzle controller.

Findings
The engine real-time minimum fuel consumption optimization control method studied in this study can significantly reduce the engine fuel consumption rate under a given thrust. At the work point, this is a low-altitude large Mach work point, which is relatively close to the edge of the flight envelope. Before turning on the optimization controller, the fuel consumption is 0.8124 kg/s. After turning on the optimization controller, you can see that the fuel supply has decreased by about 4%. At this time, the speed of the high-pressure rotor is about 94% and the temperature after the turbine can remain stable all the time.

Practical implications
The optimal control method of minimum fuel consumption for the given thrust of UAV is proposed in this paper and the optimal control is carried out for the nozzle area of the engine. At the same time, a method is proposed to indirectly control the nozzle area by changing the turbine pressure ratio. The relevant UAV and its power plant designers and developers may consider the results of this study to reach a feasible solution to reduce the fuel consumption of UAV.

Originality/value
Fuel consumption optimization can save fuel consumption during aircraft cruising, increase the economy of commercial aircraft and improve the combat radius of military aircraft. With the increasingly wide application of UAVs in military and civilian fields, the demand for energy-saving and emission reduction will promote the UAV industry to improve the awareness of environmental protection and reduce the cost of UAV use and operation.