bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pseudorabies virus upregulates low-density lipoprotein receptors to facilitate viral entry
Authors: Ma Ying-Xian , Chai Ya-Jing , Han Ya-Qi , Zhao Shi-Bo , Yang Guo-Yu , Wang Jiang , Ming Sheng-Li , Chu Bei-Bei 
Published: December 2023

ABSTRACT

Pseudorabies virus (PRV) is the causative agent of Aujeszky’s disease in pigs. The low-density lipoprotein receptor (LDLR) is a transcriptional target of the sterol-regulatory element-binding proteins (SREBPs) and participates in the uptake of LDL-derived cholesterol. However, the involvement of LDLR in PRV infection has not been well characterized. We observed an increased expression level of LDLR mRNA in PRV-infected 3D4/21, PK-15, HeLa, RAW264.7, and L929 cells. The LDLR protein level was also upregulated by PRV infection in PK-15 cells and in murine lung and brain. The treatment of cells with the SREBP inhibitor, fatostatin, or with SREBP2-specific small interfering RNA prevented the PRV-induced upregulation of LDLR expression as well as viral protein expression and progeny virus production. This suggested that PRV activated SREBPs to induce LDLR expression. Furthermore, interference in LDLR expression affected PRV proliferation, while LDLR overexpression promoted it. This indicated that LDLR was involved in PRV infection. The study also demonstrated that LDLR participated in PRV invasions. The overexpression of LDLR or inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to LDLR and targets it for lysosomal degradation, significantly enhanced PRV attachment and entry. Mechanistically, LDLR interacted with PRV on the plasma membrane, and pretreatment of cells with LDLR antibodies was able to neutralize viral entry. An
in vivo
study indicated that the treatment of mice with the PCSK9 inhibitor SBC-115076 promoted PRV proliferation. The data from the study indicate that PRV hijacks LDLR for viral entry through the activation of SREBPs.

IMPORTANCE
Pseudorabies virus (PRV) is a herpesvirus that primarily manifests as fever, pruritus, and encephalomyelitis in various domestic and wild animals. Owing to its lifelong latent infection characteristics, PRV outbreaks have led to significant financial setbacks in the global pig industry. There is evidence that PRV variant strains can infect humans, thereby crossing the species barrier. Therefore, gaining deeper insights into PRV pathogenesis and developing updated strategies to contain its spread are critical. This study posits that the low-density lipoprotein receptor (LDLR) could be a co-receptor for PRV infection. Hence, strategies targeting LDLR may provide a promising avenue for the development of effective PRV vaccines and therapeutic interventions.
Complete genome of
Flavobacterium pectinovorum
str. ZE23VCel01 obtained through Nanopore Q20+ chemistry
Authors: Serra Moncadas Lucas , Schnellmann Vanessa , Hofer Cyrill , Rain-Franco Angel , Andrei Adrian-Stefan 
Published: December 2023

ABSTRACT

This study reports the complete genome of
Flavobacterium pectinovorum
str. ZE23VCel01 isolated from a freshwater environment. By means of Nanopore Q20+ chemistry, the chromosome was assembled as a circular element with a length of 5.9 Mbp, a GC content of 33.58%, and a coverage of 122×.
Abh, AbrB3, and Spo0A play distinct regulatory roles during polymyxin synthesis in
Paenibacillus polymyxa
SC2
Authors: Cui Yanru , Zhao Dongying , Liu Kai , Mei Xiangui , Sun Shanshan , Du Binghai , Ding Yanqin 
Published: December 2023

ABSTRACT

Polymyxins exhibit antibacterial activity against various gram-negative bacteria. However, the regulatory mechanisms of polymyxin synthesis remain unclear. Here, Abh, AbrB3, and Spo0A of
Paenibacillus polymyxa
SC2 were found to bind to P

pmx

via DNA pull-down and electromagnetic mobility shift assays. Oxford Cup and liquid chromatography-mass spectrometry assays showed that antibacterial activity and polymyxin production increased in the Δ
abh
strain. Overexpression of
abh
and
abrB3
significantly decreased the antibacterial activity and polymyxin production. The transcription of
pmxA
determined via quantitative reverse transcription-PCR supported these results. Moreover, the mutation and complementation of
spo0A
revealed that Spo0A was an activator of polymyxin synthesis. Spo0A could bind to the
abh
promoter to activate
abh
expression. Spo0A could bind to the
abrB3
promoter to inhibit
abrB3
transcription and mitigate the inhibitory effect of AbrB3 on
abh
transcription.

IMPORTANCE

Polymyxins are considered the last line of defense against multidrug-resistant bacteria. The regulatory mechanism of polymyxin synthesis is poorly studied in
Paenibacillus polymyxa
. In this study, we found that Abh and AbrB3 negatively regulated, whereas Spo0A positively regulated polymyxin synthesis in
P. polymyxa
SC2. In addition, a regulatory relationship between Abh, AbrB3, and Spo0A was revealed, which regulate polymyxin synthesis via multiple regulatory mechanisms in
P. polymyxa
.
‘COVID-19 is just another way to die…’: a qualitative longitudinal study of frontline COVID-19 response governance across Syria
Authors: Douedari Yazan , Alhaffar Mervat , Khanshor Ahmad , Alrashid Alhiraki Omar , Marzouk Manar , Howard Natasha 
Published: December 2023

IntroductionGovernance of COVID-19 responses has been challenging for all countries. Syria has been particularly challenged due to protracted multiparty conflict and debilitated health systems fragmented across different areas of control. To improve response governance, better understanding of frontline response policy implementation across the country is needed. This study thus explored perspectives of COVID-19 response governance among frontline healthcare providers over time and across major areas of control.MethodsWe used a qualitative longitudinal study design, conducting five rounds of remote semistructured interviews in Arabic (ie, approximately eight interviews each in March 2020, July 2020, September 2020, December 2020 and September 2021) with 14 purposively sampled public and private healthcare providers in the three main areas of control (ie, opposition-controlled area, Autonomous Administration-controlled area and al-Assad government-controlled area (GCA)). We conducted integrative thematic analysis in Arabic within and across geography and time.ResultsAlmost all participants across all areas and rounds expressed distrust of local health authorities and dissatisfaction with COVID-19 response governance. This was most apparent in initial rounds and in GCA. Response planning was identified as insufficient, non-participatory and non-transparent. Limited infrastructure and resources were the main challenges across time, though anticipated rapid virus spread and health systems’ collapse did not occur and participant optimism increased over time. Public adherence to prevention measures varied—initially weak due to general scepticism, increasing after first cases were confirmed and then fluctuating with case numbers and challenges of insecurity and misinformation. Perceptions of COVID-19 vaccination varied, with low uptake and hesitancy attributed to misinformation, disinformation and disinterest. Suggested improvements to COVID-19 response governance focused on strengthening health systems’ capacity and coordination.ConclusionThis is a unique longitudinal study of COVID-19 responses. Addressing transparency and misinformation should be a first step to improving public engagement and trust and thus response governance for health emergencies in Syria.
Impact of twice-a-day transcranial direct current stimulation intervention on cognitive function and motor cortex plasticity in patients with Alzheimer’s disease
Authors: Li Xingxing , Chen Lei , Yu Kunqiang , Zhuang Wenhao , Zhu Hui , Xu Wenqiang , Yan Hui , Qi Gangqiao , Zhou Dongsheng , Wu Shaochang 
Published: December 2023

BackgroundNon-invasive brain stimulation has improved cognitive functions in patients with Alzheimer’s disease (AD), and some studies suggest a close relationship between cognition and plasticity. However, the clinical benefits of transcranial direct current stimulation (tDCS) in patients still need to be evaluated.AimsThis study examined the role of tDCS in improving cognition and whether the improved cognition is related to altered cortical plasticity.Methods124 patients with AD were randomly assigned to active tDCS (n=63) or sham tDCS (n=61). The tDCS was applied at the dorsolateral prefrontal cortex for 30 treatment sessions across 6 weeks (5 days per week, 2 days off). The Mini-Mental State Examination and the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) were used for cognition evaluation at baseline, week 2 and week 6. The cortical plasticity was represented by motor-evoked potential (MEP) measured with an electromyogram.ResultsThe results showed that multiple courses of active tDCS can improve the cognitive functions of patients with AD, especially in the memory domain (word recall, recall of test instructions and word recognition). In addition, the damaged MEP level was enhanced following active treatment. In the active tDCS group, the improvements in ADAS-Cog total and subitem (word recall and word recognition) scores were negatively correlated with the enhancement of MEP.ConclusionsOur research indicates for the first time that twice-a-day tDCS may improve the cognitive function of patients with AD. This study also suggests that cognitive dysfunction may be related to impaired cortical plasticity, which warrants mechanistic investigations of the relationship between cognition and plasticity in the future.Trial registration numberChiCTR1900021067.
Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models
Authors: Phadke Manali S , Li Jiannong , Chen Zhihua , Rodriguez Paulo C , Mandula Jessica K , Karapetyan Lilit , Forsyth Peter A , Chen Y Ann , Smalley Keiran S M 
Published: December 2023

BackgroundAlthough the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap.MethodsWe used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination.ResultsThe anti-PD-1+CTLA-4 combination was associated with the infiltration of FOXP3+regulatory CD4+ cells (Tregs), fewer activated CD4+T cells and the accumulation of a subset of IFNγ secreting cytotoxic CD8+T cells, whereas the anti-PD-1+LAG-3 combination led to the accumulation of CD4+T helper cells that expressed CXCR4, TNFSF8, IL21R and a subset of CD8+T cells with reduced expression of cytotoxic markers. T cell depletion studies showed a requirement for CD4+T cells for the anti-PD-1+LAG-3 combination, but not the PD-1-CTLA-4 combination at both flank and brain tumor sites. In anti-PD-1+LAG-3 treated tumors, CD4+T cell depletion was associated with fewer activated (CD69+) CD8+T cells and impaired IFNγ release but, conversely, increased numbers of activated CD8+T cells and IFNγ release in anti-PD-1+CTLA-4 treated tumors.ConclusionsTogether these studies suggest that these two clinically relevant immune checkpoint inhibitor (ICI) combinations have differential effects on CD4+T cell polarization, which in turn, impacted cytotoxic CD8+T cell function. Further insights into the mechanisms of action/resistance of these clinically-relevant ICI combinations will allow therapy to be further personalized.
CXCL10 and Nrf2-upregulated mesenchymal stem cells reinvigorate T lymphocytes for combating glioblastoma
Authors: Mao Jiaji , Li Jianing , Chen Junwei , Wen Qin , Cao Minghui , Zhang Fang , Li Baoxun , Zhang Qinyuan , Wang Zhe , Zhang Jingzhong , Shen Jun 
Published: December 2023

BackgroundLack of tumor-infiltrating T lymphocytes and concurrent T-cell dysfunction have been identified as major contributors to glioblastoma (GBM) immunotherapy resistance. Upregulating CXCL10 in the tumor microenvironment (TME) is a promising immunotherapeutic approach that potentially increases tumor-infiltrating T cells and boosts T-cell activity but is lacking effective delivery methods.MethodsIn this study, mesenchymal stem cells (MSCs) were transduced with a recombinant lentivirus encodingCxcl10,Nrf2(an anti-apoptosis gene), and a ferritin heavy chain (Fth) reporter gene in order to increase their CXCL10 secretion, TME survival, and MRI visibility. Using FTH-MRI guidance, these cells were injected into the tumor periphery of orthotopic GL261 and CT2A GBMs in mice. Combination therapy consisting of CXCL10-Nrf2-FTH-MSC transplantation together with immune checkpoint blockade (ICB) was also performed for CT2A GBMs. Thereafter, in vivo and serial MRI, survival analysis, and histology examinations were conducted to assess the treatments’ efficacy and mechanism.ResultsCXCL10-Nrf2-FTH-MSCs exhibit enhanced T lymphocyte recruitment, oxidative stress tolerance, and iron accumulation. Under in vivo FTH-MRI guidance and monitoring, peritumoral transplantation of CXCL10-Nrf2-FTH-MSCs remarkably inhibited orthotopic GL261 and CT2A tumor growth in C57BL6 mice and prolonged animal survival. While ICB alone demonstrated no therapeutic impact, CXCL10-Nrf2-FTH-MSC transplantation combined with ICB demonstrated an enhanced anticancer effect for CT2A GBMs compared with transplanting it alone. Histology revealed that peritumorally injected CXCL10-Nrf2-FTH-MSCs survived longer in the TME, increased CXCL10 production, and ultimately remodeled the TME by increasing CD8+T cells, interferon-γ+cytotoxic T lymphocytes (CTLs), GzmB+CTLs, and Th1 cells while reducing regulatory T cells (Tregs), exhausted CD8+and exhausted CD4+T cells.ConclusionsMRI-guided peritumoral administration of CXCL10 and Nrf2-overexpressed MSCs can significantly limit GBM growth by revitalizing T lymphocytes within TME. The combination application of CXCL10-Nrf2-FTH-MSC transplantation and ICB therapy presents a potentially effective approach to treating GBM.
Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion
Authors: Teagle Alexandra Rose , Castro-Sanchez Patricia , Brownlie Rebecca J , Logan Nicola , Kapoor Simran S , Wright David , Salmond Robert J , Zamoyska Rose 
Published: December 2023

BackgroundAdoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phosphotyrosine phosphatase non-receptor type 22 (PTPN22), which improves CD8+T cell antitumor efficacy in ACT. We tested whetherPtpn22KOcytolytic T cells (CTLs) were also more effective thanPtpn22WTCTL in controlling tumors in scenarios that favor T cell exhaustion.MethodsTumor control byPtpn22WTandPtpn22KOCTL was assessed following adoptive transfer of low numbers of CTL to mice with subcutaneously implanted MC38 tumors. Tumor infiltrating lymphocytes were isolated for analysis of effector functions. An in vitro assay was established to compare CTL function in response to acute and chronic restimulation with antigen-pulsed tumor cells. The expression of effector and exhaustion-associated proteins byPtpn22WTandPtpn22KOT cells was followed over time in vitro and in vivo using the ID8 tumor model. Finally, the effect of PD-1 and TIM-3 blockade onPtpn22KOCTL tumor control was assessed using monoclonal antibodies and CRISPR/Cas9-mediated knockout.ResultsDespite having improved effector function at the time of transfer,Ptpn22KOCTL became more exhausted thanPtpn22WTCTL, characterized by more rapid loss of effector functions, and earlier and higher expression of inhibitory receptors (IRs), particularly the terminal exhaustion marker TIM-3. TIM-3 expression, under the control of the transcription factor NFIL3, was induced by IL-2 signaling which was enhanced inPtpn22KOcells. Antitumor responses ofPtpn22KOCTL were improved following PD-1 blockade in vivo, yet knockout or antibody-mediated blockade of TIM-3 did not improve but further impaired tumor control, indicating TIM-3 signaling itself did not drive the diminished function seen inPtpn22KOCTL.ConclusionsThis study questions whether TIM-3 plays a role as an IR and highlights that genetic manipulation of T cells for ACT needs to balance short-term augmented effector function against the risk of T cell exhaustion in order to achieve longer-term protection.
Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway
Authors: Zheng Xufen , Luo Yuxiang , Xiong Yangjie , Liu Xiaoxiao , Zeng Chunling , Lu Xiaojing , Wang Xiaofang , Cheng Yumei , Wang Simin , Lan Haoqi , Wang Kai , Weng Zhonghui , Bi Wenbo , Gan Xinxin , Jia Xiaona , Wang Linhui , Wang Yuexiang 
Published: December 2023

BackgroundCancer immunotherapies can induce durable tumor regression, but most patients do not respond.SETD2mutation has been linked to the efficacy of immune checkpoint inhibitors (ICIs) immunotherapy. The functional importance of the SETD2 inactivation and how to modulate immunotherapy response remains unclear.MethodsTo explore the function of SETD2 in immunotherapy, knockout and subsequent functional experiments were conducted. Bulk RNA-seq, ATAC-seq, Chip-seq and single-cell RNA-seq were performed to dissect the mechanism and explore the immune microenvironment of mouse tumor. Flow cytometry was used to assess cell surface antigen and intratumoral T cell levels.ResultsWe comprehensively determine the effect of SETD2 inactivation in ICIs therapy and elucidate the mechanistic impact on tumor immunity. Murine syngeneic tumors harboringSetd2inactivation are sensitive to ICIs. By bulk and single-cell RNA-seq, we further reveal that SETD2 inactivation reprograms intratumoral immune cells and inflames the tumor microenvironment, which is characterized by high infiltration of T cells and enhanced antigen presentation to activate CD8+T cell-mediated killing. Mechanistically, via an integrated multiomics analysis using ATAC-seq, ChIP-seq and RNA-seq, we demonstrate that SETD2 inactivation reducesNR2F1transcription by impairing H3K36me3 deposition and chromatin accessibility, which activates the STAT1 signaling pathway to promote chemokines and programmed cell death protein-1 (PD-1) expression and enhance antigen presentation. All these regulatory mechanisms synergistically promote the effects of anti-programmed cell death ligand 1 immunotherapy inSetd2-knockout syngeneic mouse models. The SETD2-NR2F1-STAT1 regulatory axis is conserved in human and murine cancers. Finally, cancer patients harboringSETD2mutations who received ICIs show increased durable clinical benefits and survival.ConclusionsThese findings provide novel insights into the biology of SETD2 inactivation regulation and reveal a new potential therapeutic biomarker for ICIs immunotherapy in various refractory cancers.
A Conflict-Resilient Lock-Free Linearizable Calendar Queue
Authors: Marotta Romolo , Ianni Mauro , Pellegrini Alessandro , Quaglia Francesco 
Published: December 2023

In the last two decades, great attention has been devoted to the design of non-blocking and linearizable data structures, which enable exploiting the scaled-up degree of parallelism in off-the-shelf shared-memory multi-core machines. In this context, priority queues are highly challenging. Indeed, concurrent attempts to extract the highest-priority item are prone to create detrimental thread conflicts that lead to abort/retry of the operations. In this article, we present the first priority queue that jointly provides: (i) lock-freedom and linearizability; (ii) conflict resiliency against concurrent extractions; (iii) adaptiveness to different contention profiles; and (iv) amortized constant-time access for both insertions and extractions. Beyond presenting our solution, we also provide proof of its correctness based on an assertional approach. Also, we present an experimental study on a 64-CPU machine, showing that our proposal provides performance improvements over state-of-the-art non-blocking priority queues.
Myeloid Cells Pave the Metastatic Road in Breast Cancer
Authors: Michaud Daniel E. , Guerriero Jennifer L. 
Published: December 2023

Abstract
Current immunotherapeutic approaches are tailored towards biomarkers and mechanisms presented in the primary tumor microenvironment, yet few are designed against targets that arise in the metastatic site. In a recent Cancer Discovery article, Yofe and colleagues spatially and temporally mapped the evolving breast tumor metastatic environment within the lung at single-cell resolution to identify immunologic cell types and mechanisms underlying the formation of metastatic nodules. The authors identified myeloid cell, monocyte, and neutrophil phenotypes as the most significant differences between the primary tumor and metastatic site. The authors also revealed the existence of a metastasis-specific population of macrophages expressing Trem2 in both human and murine models that exhibit immunosuppressive features. Interestingly, Trem2+ macrophages are enriched at the invasive border of metastatic nodules compared with the metastatic core, suggesting they play an exclusionary role within the site. Characterization of the premetastatic lung in conjunction with pseudotime lineage analysis revealed that Fn1+ monocytes precede metastasis formation and are the likely source of Trem2+ macrophages in developed nodules. This study supports the characterization of metastatic immune microenvironments to identify novel immunotherapeutic targets that may not exist within the primary site but play a significant role in patient outcome.