bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversing myeloid-derived suppressor cells mediated immunosuppression via p38α inhibition enhances immunotherapy efficacy in triple negative breast cancer
Authors: Wang Qianyu , Li Shasha , Dai Yifei , Yu Xiankuo , Wang Yumei , Li Lu , Yang Ming , Lin Kequan , Shao Wei , Wang Haiyan , Wang Huili , Zhang Guanbin , Wang Dong 
Published: April 2023

AbstractInfiltration of myeloid-derived suppressor cells (MDSCs) leads to Immunosuppressive tumor microenvironment (TME), which is one of the major causes for low objective response rates of immune checkpoint blockade (ICB) therapy. Here, we report that chemical inhibition of p38α reverses this MDSC-induced immunosuppressive TME and improves the immunotherapy efficacy in triple negative breast cancer (TNBC). Firstly, by combining the tumor immunological phenotype (TIP) gene signature and high throughput sequencing based high throughput screening (HTS2), we identified that ponatinib significantly inhibits the expression of “cold” tumor associated chemokines CXCL1 and CXCL2 in cancer cells. This inhibition decreases the infiltration of MDSCs and consequently increased the accumulation of “hot” tumor associated T cells and NK cells and thus reverses the immunosuppressive TME. Then, by multiple preclinical models, we found that ponatinib significantly inhibits tumor growth in a TME-dependent manner and enhances the efficacy of anti-PD-L1 immunotherapy on TNBCin vivo. Notably, ponatinib exhibits no significant inhibition on immune cells in mouse spleens. Mechanistically, ponatinib directly inhibits the kinase activity of p38α, which results in the reduction of the phosphorylation of STAT1 at Ser727, and thus the decreased expression of CXCL1 and CXCL2 in cancer cells. Our study provided the therapeutic potential of combining p38α inhibition with ICB for the treatment of TNBC.
Novel expression of MHC II in DRG neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice
Authors: Whitaker Emily E. , Mecum Neal E. , Cott Riley C. , Goode Diana J. 
Published: April 2023

AbstractChemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+T cells are activated, and the extent cytokines released by CD4+T cells target DRG neurons are unknown. Here, we found novel expression of functional major histocompatibility complex II (MHCII) protein in DRG neurons, and CD4+T cells in close proximity to DRG neurons, together suggesting CD4+T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male mouse DRG regardless of PTX, while MHCII is induced in small nociceptive neurons in female DRG after PTX. Accordingly, reducing MHCII in small nociceptive neurons increased hypersensitivity to cold only in naïve male mice, but increased severity of PTX-induced cold hypersensitivity in both sexes. Collectively, our results demonstrate expression of MHCII on DRG neurons and a functional role during homeostasis and inflammation.Graphical abstractCreated withBiorender.comSummaryNovel expression of functional MHCII protein was detected on the surface of DRG neurons, suggesting a potential mechanism for CD4+T cell activation and targeted cytokine release. Reducing MHCII from a subpopulation of neurons known to contribute to CIPN increased the severity of PTX-induced cold hypersensitivity in female and male mice.
A high-throughput approach reveals distinct peptide charging behaviors in electrospray ionization mass spectrometry
Authors: Xu Allyn M. , Tang Lauren C. , Jovanovic Marko , Regev Oded 
Published: April 2023

AbstractElectrospray ionization is a powerful and prevalent technique used to ionize analytes in mass spectrometry. The distribution of charges that an analyte receives (charge state distribution, CSD) is an important consideration for interpreting mass spectra. However, due to an incomplete understanding of the ionization mechanism, the analyte properties that influence CSDs are not fully understood. Here, we employ a machine learning-based high-throughput approach and analyze CSDs of hundreds of thousands of peptides. Interestingly, half of the peptides exhibit charges that differ from what one would naively expect (number of basic sites). We find that these peptides can be classified into two regimes—undercharging and overcharging—and that these two regimes display markedly different charging characteristics. Strikingly, peptides in the overcharging regime show minimal dependence on basic site count, and more generally, the two regimes exhibit distinct sequence determinants. These findings highlight the rich ionization behavior of peptides and the potential of CSDs for enhancing peptide identification.
Study of the Effect of Intestinal Microbes on Obesity: A Bibliometric Analysis
Authors: Su Zehao , Tian Chenyu , Wang Guan , Guo Jingjing , Yang Xiaoyan 
Published: April 2023

AbstractBackgroundObesity is a serious public health problem. According to statistics, there are millions obese people worldwide. The intestinal microbiota is the microbiota that lives in the gastrointestinal tract of the human body and can interact with the external environment through diet. Probing and summarizing the relationship between intestinal microbes and obesity has important guiding significance for the accurate control of the research direction and expanding the choice of obesity treatment methods. We aimed to use bibliometrics to qualitatively and quantitatively analyze the published literature and to reveal the research hotspots and development trends in the effects of intestinal microbes on obesity research.MethodsWe obtained documents from the core collection of Web of Science (WoSCC) from 2013–2022 on February 2nd, 2023. Microsoft Excel, Biblioshiny R language software packages and CiteSpace were employed to collect publication data, analyze publication trends, and visualize relevant results.ResultsWe identified 8888 original research articles on the effects of intestinal microbes on obesity published between 2013 and 2022. China made the highest number of publications on the topic, with 3036 publications (34.16%), and the United States with 87065 citations made the greatest contribution. University of Copenhagen was the most prolific institution (209 publications). Patrice D. Cani published the most related articles (97 publications), whereas Peter J. Turnbaugh was cited the most frequently (3307 citations). Nutrients was the journal with the most studies (399 publications, 4.49%), and Nature was the most commonly co-cited journal (6446 citations). The burst keywords “obese patient” and “serum” recently appeared as research frontiers.ConclusionAlthough China has the largest number of publications, the United States, depending on its largest citations, has become the leader in the effects of intestinal microbes on obesity research. Current research hotspots focus on related mechanisms of the effects of intestinal microbes on obesity and therapeutic methods for obesity with intestinal microbes. Through diet, probiotic preparations and regulation of the intestinal flora, fecal microbe transplantation may have a significant impact on reducing the obesity epidemic. Considering the great potential and application prospects, intestinal microbe applications in obesity therapy will remain a research hotspot in the future.
Transposable Elements are differentially activated in cell lineages during the developing murine submandibular gland
Authors: Valdebenito-Maturana Braulio 
Published: April 2023

AbstractThe murine submandibular gland (SMG) is a model organ to study development, because it follows a branching morphogenesis pattern that is similar to that of lung, kidney, and other systems. It has been speculated that through its study, insights into regeneration and cancer could be obtained. Previously, using bulk RNA-Seq data, we reported that Transposable Elements (TEs) become activated during the SMG development. However, an outstanding question was as to whether their activity influenced different cell populations. Here, taking advantage of a single cell RNA-Seq atlas of the developing SMG, I studied TE expression to find out whether their activity can be recapitulated across its development, and if so, how they influenced cell types and cell fate specification. In this work, I found a total of 339 TEs that are markers of different cell populations, and then, through the modeling of the SMG development using Trajectory Inference methods, I found 2 TEs that could be potentially influencing differentiation processes. In sum, this short report reveals that TEs may be involved in the normal development of the SMG, and it highlights the importance of considering them in scRNA-Seq studies.
The Effect of Evaluating Self’s Emotions on Frontal Alpha Asymmetry
Authors: Ito Masato , Takahashi Toru , Kurihara Yuto , Osu Rieko 
Published: April 2023

AbstractIn this research to assess emotions from biometric signals, participants are asked to evaluate the emotions they subjectively experienced in order to confirm whether the assumed emotions were actually elicited. However, the evaluation of emotions is not routinely performed in daily life, and it is possible that this evaluation may alter biological signals. In fMRI studies, evaluation has been shown to activate the amygdala, which is said to be related to emotional expression. However, electroencephalography (EEG) studies do not take into consideration the effects of such evaluations, and it is unclear how these evaluations affect emotion-related brain activity observed in EEG. We hypothesized that emotion evaluations would amplify emotions and c alter Frontal Alpha Asymmetry (FAA), which has been shown to be related to emotional pleasantness and unpleasantness. We suspect this is because in order to evaluate one’s emotions, one must pay attention to one’s internal state, and this self-focused attention has been found to enhance the subjective emotional experience. We measured a 29-channel EEG when presented with unpleasant and highly arousing images from the International Affective Picture System (IAPS) from 40 healthy male and female participants. The results revealed that FAA was significantly lower in the condition in which participants rated their own emotions compared to the condition in which they did not. Similar to fMRI studies, this result indicates that emotion-related brain activity is amplified on an EEG. This paper provides a cautionary note regarding the use of such evaluations in EEG emotion estimation studies.
Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A
Authors: Prior Robert , Silva Alessio , Vangansewinkel Tim , Idkowiak Jakub , Tharkeshwar Arun Kumar , Hellings Tom P. , Michailidou Iliana , Vreijling Jeroen , Loos Maarten , Koopmans Bastijn , Vlek Nina , Straat Nina , Agaser Cedrick , Kuipers Tom , Michiels Christine , Rossaert Elisabeth , Verschoren Stijn , Vermeire Wendy , de Laat Vincent , Dehairs Jonas , Eggermont Kristel , van den Biggelaar Diede , Bademosi Adekunle T. , Meunier Frederic A. , vandeVen Martin , Van Damme Philip , Mei Hailiang , Swinnen Johannes V. , Lambrichts Ivo , Baas Frank , Fluiter Kees , Wolfs Esther , Den Bosch Ludo Van 
Published: April 2023

AbstractDuplication ofPMP22causes Charcot-Marie-Tooth disease type 1A (CMT1A) and is known to disrupt the lipid metabolism in myelinating Schwann cells by unknown mechanisms. By using two CMT1A mouse models overexpressing humanPMP22, we discovered thatPMP22dose-dependently downregulates genes that are involved in lipid and cholesterol metabolism. Lipidomic analysis on CMT1A mouse sciatic nerves confirmed lipid metabolic abnormalities primarily associated with cholesterol and sphingolipids. We observed similar lipidomic profiles and downregulation of genes associated with lipid metabolism in human CMT1A patient induced pluripotent stem cell-derived Schwann cell precursors (iPSC-SCPs). We confirmed these findings by demonstrating altered lipid raft dynamics and plasma membrane fluidity in CMT1A iPSC-SCPs. Additionally, we identified impaired cholesterol incorporation in the plasma membrane due to altered lipid storage homeostasis in CMT1A iPSC-SCPs, which could be modulated by changing the lipid composition of the cell culture medium. These findings suggest that PMP22 plays a role in regulating the lipid composition of the plasma membrane and lipid storage homeostasis. Targeting lipid metabolism may hold promise as a potential treatment for CMT1A patients.Graphical abstractHighlightsPMP22copy number causes a dose-dependent suppression of cholesterol and lipid biosynthesis in peripheral nerves of CMT1A miceLipid composition is altered in the sciatic nerves of CMT1A mice and in the membranes of patient derived iPSC-SCPs, with a significant reduction in sphingolipidsCMT1A iPSC-SCPs show decreased plasma membrane lipids required for regulating lipid raft dynamics, membrane fluidity, and membrane orderLipid storage misregulation is key in the pathogenesis of CMT1A
α-synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells
Authors: Hurley Michael J , Menozzi Elisa , Koletsi Sofia , Bates Rachel , Gegg Matthew E , Chau Kai-Yin , Blottière Hervé M , Macnaughtan Jane , Schapira Anthony H V 
Published: April 2023

AbstractBackgroundCaudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson disease (PD) pathogenesis, but the underlying mechanisms remain unknown. Intestinal enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in PD patients and these alterations can trigger α-synuclein pathology in animal models.ObjectiveHere we investigated the effect of toll-like receptor (TLR) and free fatty acid receptor (FFA2/3) agonists on α-synuclein levels in mouse STC-1 enteroendocrine cells.MethodsSTC-1 cells were treated with TLR and FFA2/3 agonists alone and in combination with selective antagonists. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and ELISA. And the level of α-synuclein and tumour necrosis factor (TNF) mRNA was measured by quantitative RT-PCR.ResultsTLR and FFA receptor agonists significantly increased intracellular and extracellular α-synuclein levels and antagonists significantly reduced these effects. TLR and FFA receptor agonists also significantly increased TNF transcription and this was inhibited by corresponding antagonists.ConclusionsElevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in STC-1 cells. Here we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in PD gut dysbiosis might facilitate accumulation and transmission of α-synuclein pathology from the gut to the brain.
Community structure and temporal dynamics of SARS-CoV-2 epistatic network allow for early detection of emerging variants with altered phenotypes
Authors: Mohebbi Fatemeh , Zelikovsky Alex , Mangul Serghei , Chowell Gerardo , Skums Pavel 
Published: April 2023

AbstractThe emergence of viral variants with altered phenotypes is a public health challenge underscoring the need for advanced evolutionary forecasting methods. Given extensive epistatic interactions within viral genomes and known viral evolutionary history, efficient genomic surveillance necessitates early detection of emerging viral haplotypes rather than commonly targeted single mutations. Haplotype inference, however, is a significantly more challenging problem precluding the use of traditional approaches.Here, using SARS-CoV-2 evolutionary dynamics as a case study, we show that emerging haplotypes with altered transmissibility can be linked to dense communities in coordinated substitution networks, which become discernible significantly earlier than the haplotypes become prevalent. From these insights, we develop a computational framework for inference of viral variants and validate it by successful early detection of known SARS-CoV-2 strains. Our methodology offers greater scalability than phylogenetic lineage tracing and can be applied to any rapidly evolving pathogen with adequate genomic surveillance data.
Quantitative relations among causality measures with applications to pulse-output nonlinear network reconstruction
Authors: Tian Zhong-qi K. , Chen Kai , Li Songting , McLaughlin David W. , Zhou Douglas 
Published: April 2023

AbstractThe causal connectivity of a network is often inferred to understand the network function. It is arguably acknowledged that the inferred causal connectivity relies on the causality measure one applies, and it may differ from the network’s underlying structural connectivity. However, the interpretation of causal connectivity remains to be fully clarified, in particular, how causal connectivity depends on causality measures and how causal connectivity relates to structural connectivity. Here, we focus on nonlinear networks with pulse signals as measured output,e.g., neural networks with spike output, and address the above issues based on four intensively utilized causality measures,i.e., time-delayed correlation coefficient, time-delayed mutual information, Granger causality, and transfer entropy. We theoretically show how these causality measures are related to one another when applied to pulse signals. Taking the simulated Hodgkin-Huxley neural network and the real mouse brain network as two illustrative examples, we further verify the quantitative relations among the four causality measures and demonstrate that the causal connectivity inferred by any of the four well coincides with the underlying network structural connectivity, therefore establishing a direct link between the causal and structural connectivity. We stress that the structural connectivity of networks can be reconstructed pairwise without conditioning on the global information of all other nodes in a network, thus circumventing the curse of dimensionality. Our framework provides a practical and effective approach for pulse-output network reconstruction.Significance StatementInferring network connectivity is a key challenge in many diverse scientific fields. We investigate networks with pulse signal as measured output and solve the above reverse-engineering issue by establishing a direct link between the network’s causal connectivity and structural connectivity. Here, the causal connectivity can be inferred by any one of the four causality measures,i.e., time-delayed correlation coefficient, time-delayed mutual information, Granger causality, and transfer entropy. We analytically reveal the relationship among these four measures and show that they are equally effective to fully reconstruct the network connectivity pairwise. Our work provides a practical framework to reconstruct the structural connectivity in general pulse-output nonlinear networks or subnetworks.
A broadly protective CHO cell expressed recombinant spike protein subunit vaccine (IMT-CVAX) against SARS-CoV-2
Authors: Jitender  , Kumar B. Vikram , Singh Sneha , Verma Geetika , Kumar Reetesh , Mishra Pranaya M. , Kumar Sahil , Nagaraj Santhosh K. , Nag Joydeep , Joy Christy M. , Nikam Bhushan , Singh Dharmendra , Pooja  , Kalidas Nidhi , Singh Shubham , Mumtaz  , Bhardwaj Ashwani K. , Mankotia Dhananjay S. , Ringe Rajesh P. , Gupta Nimesh , Tripathi Shashank , Mishra Ravi P.N. 
Published: April 2023

AbstractProtective immunity induced by COVID-19 vaccines is mediated mainly by spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we report the development of a recombinant prefusion stabilized SARS-CoV-2 spike protein-subunit-based COVID-19 vaccine produced in the mammalian cell line. The gene encoding ectodomain (ECD) of the spike protein was engineered and cloned into Freedom pCHO 1.0, a mammalian expression vector, and subsequently expressed in the Chinese Hamster Ovary suspension cell line (CHO-S). The recombinant S protein ectodomain (hereafter referred to as IMT-CVAX) was purified using a combination of tangential flow filtration and liquid chromatography. Biochemical and biophysical characterization of IMT-CVAX was done to ensure its vital quality attributes. Intramuscular immunization of mice with two doses of adjuvanted IMT-CVAX elicited a strong anti-Spike IgG response. In pseudovirus-based assays, IMT-CVAX– immune mice sera exhibited a broad-spectrum neutralization of several SARS-CoV-2 variants of concern (VoCs). Golden Syrian Hamster immunized with IMT-CVAX provided excellent protection against SARS-CoV-2 infection, and, hamster immune sera neutralized the live SARS-CoV-2 virus. The adjuvanted IMT-CVAX induced robust Tfh-cells response and germinal center (GC) reaction in human ACE2 receptor-expressing transgenic mice. The findings of this study may pave the way for developing next-generation protein subunit-based vaccines to combat the existing SARS-CoV-2 and its emerging VoCs. The IMT-CVAX is produced using a scalable process and can be used for large-scale vaccine production in an industrial setup.
nanoCLAMP potently neutralizes SARS-CoV-2 and protects K18-hACE2 mice from infection
Authors: Pagneux Quentin , Garnier Nathalie , Fabregue Manon , Sharkaoui Sarah , Mazzoli Sophie , Engelmann Ilka , Boukherroub Rabah , Strecker Mary , Cruz Eric , Ducos Peter , Zarubica Ana , Suderman Richard , Szunerits Sabine 
Published: April 2023

AbstractIntranasal treatments, combined with vaccination, has the potential to slow mutational evolution of virusues by reducing transmission and replication. Here we illustrate the development of a SARS-CoV-2 receptor binding domain (RBD) nanoCLAMP and demonstrate its potential as an intranasally administered therapeutic. A multi-epitope nanoCLAMP was made by fusing a pM affinity single-domain nanoCLAMP (P2710) to alternate epitope binding nanoCLAMP, P2609. The resulting multimerised nanoCLAMP P2712 had sub-pM affinity for the Wuhan and South African (B.1.351) RBD (KD< 1 pM), and decreasing affinity for the Delta (B.1.617.2) and Omicron (B.1.1.529) variants (86 pM and 19.7 nM, respectively). P2712 potently inhibited ACE2:RBD interaction, suggesting its utility as a therapeutic. With an IC50= 0.4 ± 0.1 nM obtained from neutralization experiments using pseudoviral particles as well as patient cultured SARS-CoV-2 samples, nanoCLAMP P2712 protected K18-hACE2 mice from SARS-CoV-2 infection, reduced viral loads in the lungs and brains, and reduced associated upregulation of inflammatory cytokines and chemokines. Together, our findings warrant further investigation into the development of nanoCLAMPs as effective intranasally delivered COVID19 therapeutics.