bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular characterization of baculovirus-induced chromatin marginalization and architectural alteration
Authors: Kong Xiangshuo , Chen Guanping , Li Conghui , Wu Xiaofeng 
Published: July 2023

AbstractTo facilitate rapid replication and assembly of progeny, baculovirus is known to manipulate the host nuclear microenvironment by inducing chromatin changes in localization and architecture. However, the molecular mechanisms underlying these changes remain unknown. Here, we revealed that the nuclear lamina (NL) protein Lamin A/C interacts with the heterochromatin protein 1 alpha (HP1a) and identified the middle region of HP1a as critical for this interaction. Suppression of Lamin A/C and HP1a expression resulted in a significant inhibition of chromatin marginalization mediated by baculovirus infection. Moreover, the heterochromatin modification H3K9me3, which is recognized and bound by HP1a, also participated in the process of chromatin marginalization. Our live-cell imaging and quantitative analysis unveiled a passive function of marginal chromatin, which involves the formation of a physical barrier that impedes the nuclear egress of the nucleocapsids. Furthermore, baculovirus-induced nuclear F-actin altered the steady-state of intranuclear actin pool, thus regulating the nucleosome disassembly. Overall, our findings illustrate the molecular mechanisms dictating chromatin marginalization and structural alterations during baculovirus infection, shedding new light on the potential function of marginalized chromatin in the origin of its biphasic life cycle.Author SummaryIn our previous study, we illustrated the organization and accessibility of chromatin marginalized by baculovirus infection through a combination of ATAC-seq and biochemical assays. Here, we further dissect the molecular mechanism underlying the baculovirus infection induced chromatin marginalization and disassembly. Specifically, baculovirus utilizes the Lamin A/C-HP1a-H3K9me3 axis to mediate chromatin marginalization at the nuclear periphery. When the interaction between Lamin A/C and HP1a is disrupted, the marginalization of chromatin is also affected. Furthermore, our single-virion tracking results indicate that the marginalized chromatin forms a physical barrier, impeding the nuclear export of nucleocapsids at the very late stage of infection. For the changes in chromatin architecture, we propose a model in which baculovirus infection induced nuclear F-actin compromises the dynamics of nuclear actin pool, which in turn promotes chromatin disassembly. Taken together, we provide a comprehensive understanding of molecular mechanism of baculovirus infection induced changes in chromatin localization and organization, which lay the foundation for studies on how DNA viruses manipulate the nuclear microenvironment.
An autophagy program that promotes T cell egress from the lymph node controls responses to immune checkpoint blockade
Authors: Houbaert Diede , Nikolakopoulos Apostolos Panagiotis , Meçe Odeta , Jacobs Kathryn , Roels Jana , Shankar Gautam , Agrawal Madhur , More Sanket , Ganne Maarten , Rillaerts Kristine , Boon Louis , Swoboda Magdalena , Nobis Max , Mourao Larissa , Bosisio Francesca , Vandamme Niels , Bergers Gabriele , Scheele Colinda LGJ , Agostinis Patrizia 
Published: July 2023

ABSTRACTLymphatic endothelial cells (LECs) lining the lymphatic vessels of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs control T cell dynamics under steady state and tumor-bearing conditions is lacking. Using intravital and high-resolution imaging combined with immune phenotyping, we show that LEC-specific deletion of the essential autophagy geneAtg5alters intranodal positioning of lymphocytes and accrues their persistence in the LNs, by increasing the availability of the main egress signal S1P. Single-cell RNA-sequencing of tumor-draining LNs from WT and ATG5LEC-KOmice unveils that loss of ATG5 remodels niche-specific LEC phenotypes, involved in molecular pathways regulating lymphocyte trafficking and LEC-T cell interactions. Functionally, loss of LEC-autophagy prevents recruitment of tumor-infiltrating T cells and NK cells and abrogates tumor regression in response to anti-PD-1 or anti-CTLA4-based immunotherapy. Thus, a unique LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics.Graphical Abstract
Understanding off-target growth defects introduced to influenza A virus by synonymous recoding
Authors: Sharp Colin P , Thompson Beth H , Tesla Blanka , Kurian Dominic , Simmonds Peter , Digard Paul , Gaunt Eleanor 
Published: July 2023

ABSTRACTCpG dinucleotides are under-represented in the genomes of most RNA viruses. Synonymously increasing CpG content of a range of RNA viruses reliably causes replication defects due to the recognition of CpG motifs in RNA by cellular Zinc-finger Antiviral Protein (ZAP). Prior to the discovery of ZAP as a CpG sensor, we described an engineered influenza A virus (IAV) enriched for CpGs in segment 5 that displays the expected replication defects. However, we report here that this CpG-high (‘CpGH’) mutant is not attenuated by ZAP. To understand this, we sought to uncover the alternative attenuation mechanism(s). IAV segment 5 encodes NP, a component of the viral RNA replication complex. Unexpectedly, while CpG enrichment resulted in depleted segment 5 transcript and NP protein abundance, this did not impair viral polymerase activity. A pair of nucleotide changes, introduced as compensatory changes to maintain base frequencies, were instead found to be responsible for the replication defect. These mutations resulted in the encoding of a stretch of eight consecutive adenosines (8A), a phenomenon not seen in natural IAV isolates. Sequencing experiments revealed evidence of viral polymerase slippage at this site, resulting in the production of aberrant peptides and type I interferon induction. When the nucleotides in either of these two positions were restored to wildtype sequence, no viral attenuation was seen, despite the 86 extra CpGs encoded by this virus. Conversely, when these two adenosines were introduced into wildtype virus (thereby introducing the 8A tract), viral attenuation, polymerase slippage, aberrant peptide production and type I interferon induction were apparent. That a single nucleotide change can offset the growth defects in a virus designed to have a formidable barrier to wild-type reversion highlights the importance of understanding the processes underlying viral attenuation. The lessons from this study will inform improved recoding designs in the future.
Interaction with the membrane-anchored protein CHIC2 constrains the ubiquitin ligase activity of CHIP
Authors: Callahan M.D. , Hodul M. , Carroll E.C. , Ravalin M. , Nadel C.M. , de Silva A.R.I. , Cupo A.R. , McDermott L.E. , Nix J.C. , Page R.C. , Kao A.W. , Gestwicki J.E. 
Published: July 2023

AbstractMaintenance of cellular health requires the proper regulation of E3 ubiquitin ligases. The E3 ligase CHIP is canonically regulated by its interactions with the molecular chaperones Hsp70 and Hsp90, which focus CHIP’s ubiquitination activity on misfolded proteins. Here, we report a chaperone-independent interaction of CHIP with the membrane-anchored protein CHIC2, which strongly attenuates CHIP’s ligase activity. We show that CHIC2 outcompetes abundant, cytosolic chaperones through its exquisite CHIP selectivity, rather than through enhanced affinity. In proteomic experiments, we find that CHIC2 knockout phenocopies CHIP knockout in certain cell types, implying that chaperone-independent interactions can sometimes predominate CHIP’s functions. Furthermore, loss of the CHIP-CHIC2 interaction induces neurodegeneration and shortens lifespan inC. elegans, demonstrating that formation of this chaperone-independent complex is important in animals. We propose that CHIC2 attenuates CHIP activity at the membrane, offering a novel mechanism by which this ubiquitin ligase can be regulated.
BISoN: A Bayesian framework for inference of social networks
Authors: Hart Jordan , Weiss Michael Nash , Franks Daniel , Brent Lauren 
Published: July 2023

Abstract

Animal social networks are often constructed from point estimates of edge weights. In many contexts, edge weights are inferred from observational data, and the uncertainty around estimates can be affected by various factors. Though this has been acknowledged in previous work, methods that explicitly quantify uncertainty in edge weights have not yet been widely adopted and remain undeveloped for many common types of data. Furthermore, existing methods are unable to cope with some of the complexities often found in observational data, and do not propagate uncertainty in edge weights to subsequent statistical analyses.

We introduce a unified Bayesian framework for modelling social networks based on observational data. This framework, which we call BISoN, can accommodate many common types of observational social data, can capture confounds and model effects at the level of observations and is fully compatible with popular methods used in social network analysis.

We show how the framework can be applied to common types of data and how various types of downstream statistical analyses can be performed, including non‐random association tests and regressions on network properties.

Our framework opens up the opportunity to test new types of hypotheses, make full use of observational datasets, and increase the reliability of scientific inferences. We have made both an R package and example R scripts available to enable adoption of the framework.
FLT3‐directed UniCAR T‐cell therapy of acute myeloid leukaemia
Authors: Peschke J. C. , Bergmann R. , Mehnert M. , Gonzalez Soto K. E. , Loureiro L. R. , Mitwasi N. , Kegler A. , Altmann H. , Wobus M. , Máthé D. , Szigeti K. , Feldmann A. , Bornhäuser M. , Bachmann M. , Fasslrinner F. , Arndt C. 
Published: July 2023

SummaryAdaptor chimeric antigen receptor (CAR) T‐cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T‐cell therapy in myeloid malignancies. The adaptor CAR T‐cell platform ‘UniCAR’ is currently under early clinical investigation. Recently, the first proof of concept of a well‐tolerated, rapidly switchable, CD123‐directed UniCAR T‐cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti‐tumour responses, underlining the need to further design alternative AML‐specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS‐like tyrosine kinase 3 (FLT3)‐directed UniCAR T‐cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half‐life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3‐specific UniCAR T cells for the therapy of AML.
Comparison of mortality of brachycephalic dogs undergoing partial staphylectomy using conventional incisional, carbon dioxide laser, or bipolar vessel sealing device
Authors: Jones Sarah A. , Kennedy Shawn C. 
Published: July 2023

AbstractObjectiveTo compare mortality of dogs undergoing partial staphylectomy using conventional incisional, carbon dioxide (CO2) laser, and bipolar vessel sealing device (BVSD) techniques for the treatment of brachycephalic obstructive airway syndrome (BOAS).Study designRetrospective multicenter cohort study.AnimalsA total of 606 client‐owned English bulldogs, French bulldogs, and pugs.MethodsMedical records from 2011 to 2021 were reviewed for signalment, history, surgical technique, length of hospitalization, and complications. Multivariate statistical analysis was performed to compare odds of mortality between the three techniques of staphylectomy.ResultsThe overall mortality rate was 24/606 (4.0%). Of those 24 dogs, staphylectomy was performed with BVSD technique in 13 cases, with CO2 laser in nine, and using conventional incisional technique in two. Nine dogs were graded II or III laryngeal collapse, 14 were graded I, and one was unknown. BVSD technique was associated with mortality prior to discharge compared to the other two techniques (OR = 6.0, 95% CI: 1.3–28.4, p = .023). No differences were detected between conventional incisional and CO2 laser techniques. Concurrent higher grade (stage II or III) laryngeal collapse was independently associated with mortality prior to discharge (OR = 4.6, 95% CI: 1.8–11.8, p = .002).ConclusionThe use of BVSD and grade of laryngeal collapse were associated with a higher risk of perioperative mortality.Clinical significanceClinical studies using a randomized trial design should be conducted to further determine the putative influence of surgical instrumentation in the perioperative mortality rate following multilevel surgery in dogs with BOAS.
El debate de la sucesión del Líder Supremo en Irán: la influencia de los P?sd?r?n en el imaginario político post ‘Al? Jameneh??
Authors: Garduño García Moíses 
Published: July 2023

Este artículo aborda el debate de la sucesión de ‘Al? Jamen?? como Líder Supremo en Irán. Se pretende demostrar que el cargo político más importante de la República Islámica lo ostentará un personaje que actúe a favor de los intereses de los P?sd?r?n y no a favor del principio del “más docto” que, constitucionalmente, es el prioritario y más deseable para tener el cargo. Los candidatos de los P?sd?r?n deberán competir con los candidatos provenientes de otros centros de poder importantes en Irán tales como la Asamblea de Expertos o las redes informales del propio ‘Al? Jameneh??, actores que, con sus propias fichas, intentarán imponer a aquel ??atollah que mejor se adecúe a sus intereses en la coyuntura actual iraní. AbstractThis paper discusses the succession of ‘Al? Khamenei as a Supreme Leader in Iran. It shows that the most important political Office of the Islamic Republic will be held by people acting in favor of the interests of the P?sd?r?n rather than supporters of "the most learned" principle which, legally, is the most desirable requirement to have the office. So, P?sd?r?n´s candidates will have to compete with those who come from other centers of power in Iran such as r???ni??t, and the informal networks of 'Al? Jameneh??, actors who, with their own means, will try to impose one ??atollah that responds to their political and economical interests in the current context of the Iranian politics.
In vitro and in silico evaluation of the anti-amyloid and anti-inflammatory properties of curcumin and a V (IV) – curcumin complex in LPS-stimulated primary rat neurons-microglia mixed cultures
Authors: Katsipis Georgios , Lavrentiadou Sophia , Geromichalos George D. , Tsantarliotou Maria , Halevas Eleftherios , Litsardakis George , Pantazaki Anastasia A. 
Published: July 2023

Abstract

Lipopolysaccharides (LPS) of Gram-negative bacteria are mediators of neuroinflammation and neurodegeneration that have been detected in close association with aggregations of brain amyloid beta (Aβ) and microtubule-associated protein tau (MAPT). LPS induce the release of cytokines by microglia, the residing immune cells of the brain, and mediate the upregulation of inducible nitric oxide synthase (iNOS) – a mechanism associated with amyloidosis and MAPT destabilization. Curcumin is a natural product possessing several medicinal effects; however, its pharmaceutical exploitation is hindered by low bioavailability. V-Cur, a novel hemocompatible Vanadium (IV)-curcumin complex with higher solubility and pharmaceutical activity than curcumin, has been employed in the present study. Mixed cultures of primary rat brain neurons and microglia stimulated LPS presented increased levels of amyloid precursor protein (APP), an effect inhibited by either curcumin or V-Cur. V-Cur was also proved a more potent inhibitor of amyloid aggregation than curcumin, by both insulin aggregation assay and in silico studies. Cell stimulation with LPS increased full-length, inactivated, and total iNOS levels, and the inflammation markers IL-1β and TNF-α. Both curcumin and V-Cur alleviated these effects, with V-Cur reducing iNOS levels more than curcumin, whereas curcumin and V-Cur increased the MAPT levels in LPS-stimulated cells. Complementary insights into possible bioactivity mechanisms of both curcumin and V-Cur were provided by in silico molecular docking calculations on iNOS, TNF-α, IL-1β, Aβ1−42, APP and Aβ fibrils. This study renders curcumin-based compounds a promising anti-inflammatory intervention that may be proven a strong tool in the effort to mitigate neurodegenerative disease pathology and neuroinflammatory conditions.
Practice and Outcomes of Endotracheal Intubation in the Emergency Department at National Referral Hospital: An Experience from Bhutan
Authors: Tshering Ugyen , Wangdi Sherab , LeVine Shankar , Tenzin Karma , Choeda Tshering , Yeshi Sonam 
Published: July 2023

Abstract

Background:
Airway management is a critical skill required in the Emergency Department (ED). We conducted an observational airway registry-based study to report the practice and outcome of endotracheal intubations in the ED at a national hospital in Thimphu.
Methods:
All patients who were intubated in the ED and recorded on the registry data form between May 2020 to November 2022 were studied. Variables such as indications, type of physician performing intubations, success rate, complications, medications, and disposition were captured. Descriptive analysis was presented in frequency and proportions.
Results:
There were a total of 336 intubations during the study period.
First pass success rate was 87.80% and complication rate was 19.64%. 40 patients (11.90%) needed a second attempt and only 1 patient required a third attempt. Most intubations were performed by emergency medicine (EM) residents (54.17%), followed by medical officers (37.8%). Emergency Physician (EP) performed the least number of intubations, 27 (8.04%). 64.5% (n=217) patients received positive pressure ventilations during preoxygenation and 119 (35.42%) did not.
Conclusion:
Physicians working in the ED are the primary airway provider. First pass success rate was 87.80%. 40 patients (11.90%) needed a second attempt and only 1 patient required a third attempt.
B7-H6 promotes the killing activity of NK cells against cervical cancer through the downstream ERK pathway of NKp30
Authors: Guo Ruimeng , Chai Ou , Li Changying , Xu Yanying , Guo XueWang , Liu Xueying , Xu Yu 
Published: July 2023

Abstract
OBJECTIVE
As a ligand of NKp30, B7 homolog 6 (B7-H6) is involved in the immune regulation of various tumors. The aim of this study was to clarify the effect of B7-H6 expressed in HeLa cells on NK cell killing function.
METHODS
The expression of B7H6 was changed in HeLa cells using short hairpin RNA. Furthermore the effect of B7-H6 on the killing function of NK cell was analyzed after cell co-culture. Flow cytometry was used to detect NKp30 expression, degranulation function, perforin (PFP) and Granzyme B (GZMB) secretion function of NK cells. Enzyme-linked immunosorbent assay (ELISA) was used to detect interferon-γ (INF-γ) production function. The cytotoxicity of NK-92 cells was determined using the CytoTox 96 Non-Radio active Cytotoxicity Assay. Western blotting (WB) detection was used to detect the ERK phosphorylation level in NK cells.
RESULTS
When NK-92 cells co-cultivated with HeLa cells with different expression levels of B7-H6, the expression of NKp30, NK-92 cell killing rate, PFP and INF-γ production, and degranulation function were correspondingly changed in NK cells, but there is no effcet on GZMB production. After cell co-culture, ERK phosphorylation level in NK cells was increased gradually with the up-regulation of B7-H6 expression.
CONCLUSIONS
B7-H6 can enhance the killing function of NK cells to HeLa cells by activating the NKp30 downstream ERK signaling pathway.
A systematic assessment of Leishmania donovani infection in domestic and wild animal reservoir hosts of zoonotic Visceral Leishmaniasis
Authors: Pandey Ramendra Pati 
Published: July 2023

Abstract

Background
Leishmaniasis is a neglected disease with a global spread that affects both domestic and wild animals in addition to people. Leishmania donovani is the suspected anthroponotic cause of VL in India, where it is an endemic disease. The reservoir hosts play a crucial role in the life cycle of the Leishmania parasite. The complicated connection between the pathogen, vector, and reservoir exhibits geographical and temporal diversity. Human-to-human and, to a lesser extent, human-to-animal transmission is the principal mechanism for the maintenance of anthroponotic diseases.
Scope and approach
A deliberate, systematic search was conducted on PubMed, Science Direct, and Google Scholar using keywords such as "Leishmania donovani," "zoonotic visceral leishmaniasis," and "wild animal reservoir for leishmania donovani." 530 potentially significant references were obtained from these 507 were disallowed due to copy avoidance, irrelevant titles, research publications from nations other than India, or modified compositions. The remaining 20 investigations were later rejected because they did not meet the criteria for inclusion. Finally 3 research papers with 867 goats, 161 cattles, 106 chickens, 26 sheep, 3 buffaloes, 406 dogs and 309 rats were reported.
Conclusion
According to the review, goats are the epidemic's primary host and possible reservoir in several regions of India. In the endemic regions of the disease, some species of rodents along with the canines appear to be maintaining the L. donovani transmission cycle.