Common Signal Research Articles

Ultra-high-resolution reflected-light imaging for dendrochronology

Dendroclimatic reconstructions play a key role in contextualizing recent climate change by improving our understanding of past climate variability. The Blue Intensity (BI) measurement technique is gaining prominence as a more accessible alternative to X-ray densitometry for producing climatically highly-sensitive tree-ring predictors. Nevertheless, accurately representing low-frequency trends and high-frequency extremes using scanner-based BI remains a challenge due to color biases and resolution limitations. Herein we introduce several methodological advances in sample surfacing, imaging, and image processing which yield measurement series analogous to BI from ultra-high-resolution (UHR; ∼74 700 dpi) images. Such series capture changes in tree-ring anatomical density by representing wood anatomical structure using binary (i.e., black-white) segmentation of sample images. We refer to this novel technique as Binary Surface Intensity (BSI). By utilizing a UHR system and entirely eliminating color and light intensity as variables, the most substantial drawbacks of scanner BI (i.e., discoloration and resolution biases) are bypassed, resulting in more accurate representations of low-frequency climatic trends and high-frequency extremes. Comparisons of several chronologies developed with the BSI and BI techniques, including a multiparameter dataset from Björklund et al. (2019), showed that BSI datasets outperform BI in terms of common signal (r-bar), but also contain strong climatic signals that can exceed those obtained from BI and X-ray density, and even match density datasets based on quantitative wood anatomy. However, measurement software advancements are still required to unlock the full potential of tree-ring parameters produced using the BSI technique. Ongoing development of this new technique will not only aid the attainment of long unbiased chronologies by overcoming color biases and resolution limitations, but also holds promise for unlocking UHR analyses of surface anatomical (sQWA) parameter datasets from reflected-light images. These advances will lead to more accurate tree-ring-based paleoclimatic reconstructions and could also serve a wider range of dendrochronological applications.

Prediction of shared gene signatures and biological mechanisms between polycystic ovary syndrome and asthma: Based on weighted gene coexpression network analysis.

Several clinical studies have shown an association between polycystic ovary syndrome (PCOS) and asthma; however, the molecular link between these conditions remains unclear. In this study, we conducted a reanalysis and repurposing of existing databases in order to depict the common key genes, related signaling pathways, and similarity of the immune microenvironment between PCOS and asthma. PCOS and asthma data sets were downloaded, and common signal pathways were identified by using gene set enrichment analysis. Identified common susceptibility genes were explored by intersecting the weighted gene coexpression network analysis module genes for both diseases. Then, we performed protein-protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses of the common susceptibility genes. Finally, we analyzed the immune environment of PCOS and asthma. We identified five hub genes, namely, MMP9, CDC42, CD44, CD19, and BCL2L1, and uncovered that these five hub genes showed a tendency to be upregulated in both PCOS and asthma and possessed good diagnostic ability. In addition, we revealed that both PCOS and asthma were significantly enriched in the FcεRI-mediated signaling pathway. Moreover, we found that both PCOS and asthma exhibited infiltration of similar types of immune cells, such as monocytes, suggesting that the two diseases have similar pathological features. PCOS and asthma share common causative genes with a similar immune environment. Taken together, we uncovered previously unsuspected traits for comprehensive diagnosis and treatment of PCOS and asthma in the future.

A Unified Rate-Splitting Framework for Secure Spectrum Sharing via Joint Precoding Optimization

To handle the security problem of cognitive radio (CR) systems, secondary users (SUs) are able to be designed to assist the primary user (PU) in secure transmission. To realize the spectrum sharing among CR users, we adopt the rate-splitting multiple access (RSMA) properly, with nonorthogonal multiple access (NOMA) and space division multiple access (SDMA) as its special cases. In this article, we set up a unified rate-splitting framework to guarantee the safe spectrum sharing through multiple multiaccess strategies, without the knowledge of wiretap channels. The precoding vectors at the transmitter are conjointly designed to boost the transmission of common stream, which is from both PU and SU. Besides, the private stream of the downlink CR system can be well secreted in the high-power common signal. As for NOMA and SDMA, when the message of SU is regarded as the friendly jamming signal, the security transmission requirement of PU can be similarly guaranteed via precoding design. Simulations validate that the rate-splitting framework we established can be effective in ensuring the spectrum sharing security for the secure users through RSMA, and the security for NOMA and SDMA is also able to be promoted through adjusting our designed framework.

MusicFace: Music-driven expressive singing face synthesis

It remains an interesting and challenging problem to synthesize a vivid and realistic singing face driven by music. In this paper, we present a method for this task with natural motions for the lips, facial expression, head pose, and eyes. Due to the coupling of mixed information for the human voice and backing music in common music audio signals, we design a decouple-and-fuse strategy to tackle the challenge. We first decompose the input music audio into a human voice stream and a backing music stream. Due to the implicit and complicated correlation between the two-stream input signals and the dynamics of the facial expressions, head motions, and eye states, we model their relationship with an attention scheme, where the effects of the two streams are fused seamlessly. Furthermore, to improve the expressivenes of the generated results, we decompose head movement generation in terms of speed and direction, and decompose eye state generation into short-term blinking and long-term eye closing, modeling them separately. We have also built a novel dataset, SingingFace, to support training and evaluation of models for this task, including future work on this topic. Extensive experiments and a user study show that our proposed method is capable of synthesizing vivid singing faces, qualitatively and quantitatively better than the prior state-of-the-art.

Blockade of Common Gamma Chain Cytokine Signaling with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, in Combination with Costimulatory Blockers Delayed Skin Graft Rejection in Mice

There is a current medical need to identify innovative maintenance therapies to prevent allograft rejection in solid organ transplantation. During transplant rejection, recipient immune cells identify a grafted organ as foreign and attack it: CD4 + T cells orchestrate transplant rejection by recruiting a range of effector cells responsible for the damage of rejection including CD8 + T cells, NK cells, B cells and macrophages. These pathogenic immune cell responses can be driven by cytokines of the common gamma chain (γ c) cytokine family (IL2, IL4, IL7, IL9, IL15, and IL21). γ c cytokines signal through their corresponding receptors, expressed primarily on immune cells, that share a common coreceptor, interleukin 2 receptor subunit gamma (IL2RG) that is required for signaling. To understand the role of γ c cytokines in driving transplant rejection, we generated REGN7257, a fully human IL2RG monoclonal antibody that inhibits γ c cytokine-induced signaling, and we tested its ability to suppress allogeneic immune cell responses in a mouse model of skin graft rejection when delivered as a monotherapy and in combination with mycophenolate mofetil (MMF) or T cell costimulatory pathway blockers. In this model, recipient B6/129 (mixed background) Il2rg hu/hu mice were transplanted with tail skin from BALB/cJ donor mice. Graft survival was analyzed using a log rank Mantel-Cox test to detect statistically significant differences across groups (*=p<0.033; **= p<0.002; ***=p<0.0002; ****=p<0.0001). In a mouse model of skin graft rejection, γ c cytokine signaling blockade with REGN7257 given as maintenance immunosuppression effectively improved overall graft survival (Median Survival Time [MST] IL2RG=13) compared to mice that received a control antibody (MST CTRL=9 [****vs IL2RG Ab]), and with similar efficacy to that observed with the calcineurin inhibitor tacrolimus (MST TAC=12.5 [**vs control, n.s. vs IL2RG Ab]). In treatment combination experiments, while monotherapy treatment with the antiproliferative agent MMF was not as efficient as REGN7257 at delaying skin graft rejection (MST MMF=10 [*vs control] and MST IL2RG=12 [*vs MMF]), simultaneous blockade of cell proliferation and γ c cytokine signaling conferred an advantage over monotherapies (MST MMF+IL2RG=15.5 [****vs control, **vs IL2RG Ab]). Similarly, induction therapy consisting of γ c cytokine signaling blockade followed by maintenance immunosuppression using the CTLA4-Ig fusion protein abatacept, significantly improved overall skin graft survival (MST IL2RG+CTLA4=19.5 [****vs control]) compared to REGN7257 induction only (MST IL2RG=11 [****vs control and combo]) or abatacept maintenance only (MST CTLA4=10 [*vs control, ****vs combo]). Finally, maintenance immunosuppression combining blocking of γc cytokine signaling together with blocking of both CD28 and CD40L costimulatory signals prolonged skin graft survival better than any combination therapies of only 2 pathway blockers (MST TRIPLE=26 [**vs control] and MST DOUBLE=16-21 [n.s.-** vs triple]). Overall, our study showed that γ c cytokine blockade could potentially be an alternative to calcineurin inhibitor-based regimens to prevent rejection by specifically targeting immune cells. Our data also highlighted the inherent complexity of effector mechanisms and pathways involved in allograft rejection and showed that prolonged allograft survival requires simultaneous blockade of multiple T cell activating signals, including inhibition of cytokine signaling and costimulatory signals. These data provide evidence of γ c cytokines as key drivers of allogeneic immune cell responses during acute transplant rejection, offering a potentially novel strategy for the management of transplant patients.

Chimeric Antigen Receptor T Cell Therapies Clinical Trials in Pediatric Oncology: A Retrospective Analysis from Clinicaltrials.Gov

Background: Chimeric Antigen Receptor (CAR) T-cell clinical trials are growing exponentially. Database analysis can help identify scientific trends and generate projections regarding potential approvals before the results of the studies are completed or published. This is particularly interesting in pediatric oncology, where available analyses from repository databases are scarce or not available. Because of that reason, we sought to analyze the clinical trial public records from entries related to CAR T-cell clinical studies in pediatric patients (18 years or younger) uploaded to the clinicaltrials.gov database. Methods: We query the available data from clinicaltrials.gov using the following keywords: “CAR T cell in pediatrics”, “CAR T cell and cancer”, “chimeric antigen receptor”, “CAR T AND tumor antigen”, 'CAR T cell antigens“, ”Tumor antigens targeted by CAR T cells“, ”engineered T cells“, ”modified T cell“, ”CAR T cells in Cancer“, ”CAR T cell therapy“, ”CAR T cell therapy AND Cancer“ (data cut off July-2023). The data were tabulated, and the trials that did not meet the search criteria were excluded manually. Data cleansing was performed using published scientific data, web search-based information, and patent databases. Results: We found 4297 results in the Clinicaltrials.gov platform; we excluded 3978 clinical trials that did not involve the pediatric population (<18 years) or CAR T-cell intervention. The final analysis included 319 clinical trials posted on the clinicaltrials.gov website by the cut-off date. 207 (64.9%) were conducted in China, 74 (23.2%) in the US, and 21 (6.5%) in Europe. Most CAR T-cell trials focused on hematological cancer (89%), followed by non-CNS solid tumors 8%, and CNS tumors 3%. The most frequent targets were CD19 (46%), CD7 (7%), followed by GD2, CD22, CD123, CD19 + CD22 and CD30. Most clinical trials did not report the construct generation used in their CAR T cell product (58%). Among the trials with that information, second-generation constructs (2G) were used in 32% of the studies, followed by 3G and 4G constructs (5% of studies each). Most clinical trials were in early stages of development, Phase 1 or 2 (75%). We observed a continuous increase in the number of clinical trials registered yearly, except for a small reduction in 2022 and 2021, probably related to COVID restrictions and challenges. Overall, the general trend predicts at least a 50% yearly increase in registered studies ( Figure 1). Similarly, to what is observed in adult clinical trials, the most common signaling domains are 2G CAR constructs expressing either CD28 or 4-1BB as costimulatory domains. Among those, 4-1BB being is the most popular choice. Conclusion: Our findings indicate a growing interest in the clinical development of CAR T-cell therapies applied to pediatric oncology. Most of these studies are in early phase I and II and focus primarily on hematological cancers using second-generation constructs targeting CD19. The is a steady increase in the number of studies registered each year that predicts future FDA approvals using CAR T-cell products.

Modulation of cell cycle increases CRISPR-mediated homology-directed DNA repair

BackgroundGene knock‐in (KI) in animal cells via homology‐directed repair (HDR) is an inefficient process, requiring a laborious work for screening from few modified cells. HDR tends to occur in the S and G2/M phases of cell cycle; therefore, strategies that enhance the proportion of cells in these specific phases could improve HDR efficiency.ResultsWe used various types of cell cycle inhibitors to synchronize the cell cycle in S and G2/M phases in order to investigate their effect on regulating CRISPR/Cas9-mediated HDR. Our results indicated that the four small molecules—docetaxel, irinotecan, nocodazole and mitomycin C—promoted CRISPR/Cas9-mediated KI with different homologous donor types in various animal cells. Moreover, the small molecule inhibitors enhanced KI in animal embryos. Molecular analysis identified common signal pathways activated during crosstalk between cell cycle and DNA repair. Synchronization of the cell cycle in the S and G2/M phases results in CDK1/CCNB1 protein accumulation, which can initiate the HDR process by activating HDR factors to facilitate effective end resection of CRISPR-cleaved double-strand breaks. We have demonstrated that augmenting protein levels of factors associated with the cell cycle via overexpression can facilitate KI in animal cells, consistent with the effect of small molecules.ConclusionSmall molecules that induce cell cycle synchronization in S and G2/M phases promote CRISPR/Cas9-mediated HDR efficiency in animal cells and embryos. Our research reveals the common molecular mechanisms that bridge cell cycle progression and HDR activity, which will inform further work to use HDR as an effective tool for preparing genetically modified animals or for gene therapy.

Meta-Analysis of Antioxidant Mutants Reveals Common Alarm Signals for Shaping Abiotic Stress-Induced Transcriptome in Plants.

Aims: Reactive oxygen species (ROS) are key regulators of plant growth, development, and stress tolerance. Stress-induced changes in ROS levels trigger multilevel signaling. However, the precise mechanisms by which ROS signals are translated into changes in gene expression remain poorly defined. Focusing on six key antioxidant enzymes, we performed a meta-analysis of transcriptome data available in public databases to analyze ROS-mediated control of nuclear gene expression. Results: An information-guided pipeline was developed, which identified 19 putative transcription factors (TFs), as components in a "common alarm signal cascade" pathway following perception of changes in ROS levels. Crucially, 30%-35% of the abiotic stress transcriptome signatures had binding sites for common alarm signal-transcription factors (CAS-TFs) in their promoter regions. Furthermore, Phloem Early Dof 2 (PEAR2), DNA binding with one finger 5.8 (DOF5.8), and Obf-Binding Protein 3 (OBP3) were identified as top-ranked TFs on the basis of a cumulative DAPseq (DNA-affinity purification sequencing) score on the promoters of selected genes regulating core pathways of salt, drought, heat, and cold stress tolerance. Innovation: This study identifies a set of CAS-TFs that may play a major role in shaping the transcriptome of abiotic stress-induced ROS signaling. Ranking analysis identified PEAR2, DOF5.8, and OBP3 as the top-ranked CAS-TFs that regulated known markers of abiotic stress tolerance. Conclusion: The current findings suggest a major role of ROS in the abiotic stress signaling and also identify a set of TFs that take part in the signaling. Taken together, these findings suggested that the common alarm signal cascade underpins broad-range tolerance against multistress conditions. The identification of associated ROS-responsive CAS-TFs may provide novel targets for crop improvement.

COVID-19 ORF3a Viroporin-Influenced Common and Unique Cellular Signaling Cascades in Lung, Heart, and the Brain Choroid Plexus Organoids with Additional Enriched MicroRNA Network Analyses for Lung and the Brain Tissues

COVID-19 ORF3a Viroporin-Influenced Common and Unique Cellular Signaling Cascades in Lung, Heart, and the Brain Choroid Plexus Organoids with Additional Enriched MicroRNA Network Analyses for Lung and the Brain Tissues

A large meta-analysis identifies genes associated with anterior uveitis

Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27. We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p = 1.03e-196) and ERAP1 (OR = 0.86, p = 1.1e-08), and find IPMK (OR = 9.4, p = 4.42e-09) and IDO2 (OR = 3.61, p = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p = 2.7e-08), risk genes IPMK and IDO2, and several additional candidate risk genes, including ADGFR5, STXBP2, and ACHE. Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease.

Long-term growth and xylem hydraulic responses of Albizia procera (Roxb.) Benth. to climate in a moist tropical forest of Bangladesh

Climate change is a serious concern around the world, particularly in tropical regions including Bangladesh. Yet, how tree growth and hydraulic behavior of Bangladeshi native tree species changed in response to past climate variability and changes have not been adequately understood. We developed the first ring-width and vessel chronologies of Albizia procera (Roxb.) Benth. from a moist tropical forest of Bangladesh (Rema-Kalenga Wildlife Sanctury, RKWS) to analyze the impact of inter-annual climate variability on tree growth and xylem hydraulic traits. The chronologies contained common environmental signals as shown by the values of expressed population signal (EPS) and other statistical parameters. Climate-growth analysis showed that maximum temperature (Tmax) favored tree growth at the end of the wet season (November). Among the vessel and hydraulic trait chronologies, number of vessels (NV) had significant positive relation with May minimum temperature (Tmin) and vessel density (VD) had a negative relationship with April Tmin. Precipitation had a negative relation with vessel density (VD), and the potential specific hydraulic conductivity (KS). Relative humidity (RH) and vapour pressure deficit (VPD) had contrasting effects on vessel and hydraulic traits. On a regional scale, the ring-width index and vessel chronologies were correlated with both gridded land surface temperature and precipitation, but during different periods of the year. Linear mixed effect modeling revealed significant positive relationships between VD and Tmax implying a good acclimation potential of this tree to rising temperature. However, the absence of the generally expected trade-off between VD and DH calls for further studies on the hydraulic functions of this species in moist tropical forests.

BIOM-39. GENETIC VARIANTS ASSOCIATED WITH DISTANT RECURRENCE IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD THERAPY

Abstract Infiltrative growth is a hallmark of glioblastoma and is a major factor in therapeutic failure. Genetic variants predictive of distant recurrence may serve as novel treatment targets. The aim is to identify genetic variants associated with distance recurrence in glioblastoma patients. METHODS: From a prospective cohort of consecutive, non-selected glioblastoma patients administered standard therapy between 2016-2021 at Rigshospitalet, all patients with a genomic tumor profile were included. Distant recurrence was defined as a new contrast-enhancing tumor > 2 cm from the initial lesion. Tumor tissue was analyzed by RNA- and DNA-sequencing (WES or WGS). Genetic variants were defined as pathogenic and likely-pathogenic variants based on genomic reports. Predefined candidate biomarkers included: i) the most common genetic variants in the cohort (mutational frequency > 2%), ii) the number of reported variants per sample, and iii) groups of genetic variants according to the common signaling pathways. Candidates were screened for association with time to distant recurrence using univariate Cox regression analysis. Biomarkers with p < 0.20 were considered for multivariate analysis adjusted for known prognostic factors with death as the competing risk. RESULTS: A total of 236 patients were included, and 208 patients (88%) were evaluable for recurrence pattern. Distant recurrence was observed in 40 patients (19%). Patients with distant and local recurrence showed no difference in progression-free survival (p = 0.58), while distant recurrence tended to have a poor overall survival (OS, p = 0.09). The OS from time of first recurrence was significantly poorer for patients with distant recurrence compared to local recurrence (p = 0.01) with a median OS of 7.2 months (95%CI: 5.9-8.5) and 10.9 months (95%CI: 9.8-12). The median frequency of called gene variants was 4 (range 0-11) per sample. CONCLUSION: Patients with distant recurrence have a poor prognosis. Final analyses will be presented.

Abstract 14573: Dissecting Genetic Determinants Underlying Cardioskeletal Phenotypes Induced by Myopalladin Mutation in Murine Genetic Reference Population of Hybrid BXD Strains

Introduction: Mutations in myopalladin ( MYPN) gene are associated with cardiomyopathies (CM) and skeletal myopathies (SM). This study is aimed to identify Mypn -induced cardioskeletal phenotypes in a murine genetic reference population (GRP) and uncover common genetic mechanisms underlying the development of CM and SM. Hypothesis: Mypn induces common molecular signaling in cardiac and skeletal muscles. Methods: Pearson correlation between cardiac function and expression of Mypn in gastrocnemius muscles was performed in 40 mouse BXD recombinant inbred strains derived from C57BL/6J and DBA/2J parental mice. A causal Mypn-Q526X mutation was introduced to BXDs by crossing with MypnWT/Q526X knock-in mice and this generated F1 hybrid mutant (BXDQ526X) and wild type (BXDWT) strains. Cardiac (morphology, function by echo) and skeletal muscle (muscle mass, strength) phenotypes and transcriptomics (RNA-seq) were assessed in 3- and 6-month-old hybrid mice (N=5). Results: Skeletal muscle expression of Mypn was significantly associated with heart rate (HR) and heart mass (HM) in BXDs, while it was negatively associated with interventricular septum (IVS) thickness, indicating BXD strains with higher skeletal muscle Mypn expression had faster HR, higher HM but thinner IVS. Varied phenotypes in ejection fraction (EF%), ventricular volume and hypertrophy were found among BXD Q526X mice; BXD51 Q526X , BXD48 Q526X and BXD69 Q526X strains had significantly higher EF%, while some mutant mice showed EF% decrease compared to their respective BXD WT littermates. Many mutant lines displayed significantly reduced skeletal muscle strength or mass. Overt SM-related signs (rear limb deformity, restricted movement, waddling) were seen in BXD78 Q526X , while we found overlapping CM/SM traits in BXD51 Q526X mice. Conclusions: In this study, common Mypn -induced molecular signaling in cardiac and skeletal muscles is identified. Introduction of the Mypn -Q526X mutation into the diverse genetic background of BXD GRP exposed CM- and SM-related phenotypes in hybrid lines. The most susceptible lines with overt and overlapping CM/SM phenotypes will be useful to identify common genes, networks and pathways involved in CM and SM using systems genetics methods.

Genetic deficiency of the transcription factor NFAT1 confers protection against fibrogenic responses independent of immune influx.

Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple profibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor nuclear factor of activated T cells 1 (NFAT1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key profibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/--deficient mice subjected to bleomycin injury demonstrated improved survival and protection from lung fibrosis and collagen deposition as compared with bleomycin-injured wild-type (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WT→WT and Nfat1-/-→WT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibroprotection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/platelet-derived growth factor receptor alpha (PDGFRα)pos MCs demonstrated decreased MC numbers, proliferation [↓ cyclin D1 and 5-ethynyl-2'-deoxyuridine (EdU) incorporation], myofibroblast differentiation [↓ α-smooth muscle actin (α-SMA)], and survival (↓ Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed using pharmacological and genetic inhibition. Our findings identify NFAT1 as a critical mediator of profibrotic processes, contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.NEW & NOTEWORTHY Idiopathic pulmonary fibrosis (IPF) is a fatal disease with hallmarks of fibroblastic foci and exuberant matrix deposition, unknown etiology, and ineffective therapies. Several profibrotic/proinflammatory pathways are implicated in accelerating tissue remodeling toward a honeycombed end-stage disease. NFAT1 is a transcriptional factor activated in IPF tissues. Nfat1-deficient mice subjected to chronic injury are protected against fibrosis independent of immune influxes, with suppression of profibrotic mesenchymal phenotypes including proliferation, differentiation, resistance to apoptosis, and autotaxin-related migration.

Exploring the molecular mechanism underlying the psoriasis and T2D by using microarray data analysis

Although a large number of evidence has identified that psoriasis is significantly correlated with type 2 diabetes (T2D), the common molecular mechanism of its occurrence remains unclear. Our study aims to further elucidate the mechanism of the occurrence of this complication. We obtained the gene expression data of psoriasis (GSE30999) and T2D (GSE28829) from the Gene Expression Omnibus (GEO) dataset. Then the common differentially expressed genes (DEGs) of T2D and psoriasis were identified. After that, we performed three types of analyses about these DEGs, including functional enrichment analysis, protein–protein interaction (PPI) network and module manufacture, hub genes identification and co-expression analysis. 132 common DEGs (14 upregulated genes and 118 downregulated genes) were identified for subsequent a series of analyses. Function enrichment analysis demonstrated that Rap1 signaling pathway, PI3K-Akt signaling pathway, and cGMP-PKG signaling pathway may play a significant role in pathogenesis of psoriasis and T2D. Finally, 3 important hub genes were selected by utilizing cytoHubba, including SNRPN, GNAS, IGF2. Our work reveals the potential common signaling pathways of psoriasis and T2D. These Hub genes and common signaling pathways provide insights for further investigation of molecular mechanism about psoriasis and T2D.

Differential expression of serum miR-486 and miR-25 in ulcerative colitis and Crohn’s disease: Correlations with disease activity, extent, and location

Novel reliable biomarkers of inflammatory bowel disease (IBD) are clinically imperative due to potential limitations of endoscopic techniques. MicroRNAs (miRNAs) have emerged as non-invasive biomarkers of IBD; however, the full disease-specific miRNAs signature for IBD subtypes remains elusive. We evaluated the diagnostic role of circulating miR-486 and miR-25 in IBD patients and their potential ability to discriminate IBD subtypes; ulcerative colitis (UC) and Crohn’s disease (CD). Sixty UC patients, 60 CD patients, and 60 healthy controls were recruited. Serum miRNA expression was determined using RT-qPCR. Bioinformatics was employed for target gene and protein-protein interaction (PPI) network analyses. Serum miR-486 was upregulated in CD patients, but didn’t change in UC patients compared to controls. Conversely, serum miR-25 was decreased in both CD and UC patients compared to controls. Only miR-486 was differentially expressed between UC and CD patients. Receiver-operating characteristic analysis revealed that serum miR-486 was superior in CD diagnosis (AUC=0.945) and significantly distinguished CD and UC patients, whereas miR-25 showed discriminative potential for both UC and CD from controls. In the multivariate logistic analysis only miR-486 was associated with the risk of CD diagnosis. Serum miR-486 was correlated with CD activity index and location of disease in CD patients, whereas miR-25 was correlated with the type/extent of UC. PPI network analysis revealed common target genes and signaling pathways for both miRNAs. Conclusively, serum miR-486 and miR-25 might serve as new biomarkers of IBD, with serum miR-486 could be employed in risk stratification of IBD subtypes and has the ground for clinical utility in CD diagnosis, whereas miR-25 has potential for UC and CD diagnosis.

Adaptation to bile and anaerobicity limits Vibrio cholerae phage adsorption.

Vibrio cholerae is the bacterial pathogen responsible for cholera, a diarrheal disease that impacts people in areas without access to potable water. In regions that lack such infrastructure, cholera represents a large proportion of disease outbreaks. Bacteriophages (phages, viruses that infect bacteria) have recently been examined as potential therapeutic and prophylactic agents to treat and prevent bacterial disease outbreaks like cholera due to their specificity and stability. This work examines the interaction between V. cholerae and vibriophages in consideration for a cholera prophylaxis regimen (M. Yen, L. S. Cairns, and A. Camilli, Nat Commun 8:14187, 2017, https://doi.org/10.1038/ncomms14187) in the context of stimuli found in the intestinal environment. We discover that common signals in the intestinal environment induce cell surface modifications in V. cholerae that also restrict some phages from binding and initiating infection. These findings could impact considerations for the design of phage-based treatments, as phage infection appears to be limited by bacterial adaptations to the intestinal environment.

Synthetic and Natural Bioactive Molecules in Balancing the Crosstalk among Common Signaling Pathways in Alzheimer's Disease: Understanding the Neurotoxic Mechanisms for Therapeutic Intervention.

The structure and function of the brain greatly rely on different signaling pathways. The wide variety of biological processes, including neurogenesis, axonal remodeling, the development and maintenance of pre- and postsynaptic terminals, and excitatory synaptic transmission, depends on combined actions of these molecular pathways. From that point of view, it is important to investigate signaling pathways and their crosstalk in order to better understand the formation of toxic proteins during neurodegeneration. With recent discoveries, it is established that the modulation of several pathological events in Alzheimer's disease (AD) due to the mammalian target of rapamycin (mTOR), Wnt signaling, 5'-adenosine monophosphate activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and sirtuin 1 (Sirt1, silent mating-type information regulator 2 homologue 1) are central to the key findings. These include decreased amyloid formation and inflammation, mitochondrial dynamics control, and enhanced neural stability. This review intends to emphasize the importance of these signaling pathways, which collectively determine the fate of neurons in AD in several ways. This review will also focus on the role of novel synthetic and natural bioactive molecules in balancing the intricate crosstalk among different pathways in order to prolong the longevity of AD patients.

A Fourier-based explanation of 1D-CNNs for machine condition monitoring applications

Neural networks (NN) have generated extensive interest in the field of machine condition monitoring (MCM). Many applications are however adapting structures and approaches from fields where NNs are highly established (e.g., image classification). This is done despite many neural network layers presenting strong similarities to signal processing steps that are well established in MCM. This paper aims at providing a mathematical analysis of typical NN architectures and layers, with specific attention to similarities to common signal processing steps such as filtering, downsampling, and enveloping. The set of strong analogies between NN and traditional MCM tools enables this work to provide MCM-specific guidelines for the design and tuning of NN architectures for MCM-specific applications. Most MCM applications are often characterised by periodic and cyclostationary signals, a situation not frequently encountered in many other NN applications. Hence, the Fourier-based explanation of the typical NN layers will be specific to the solution of typical MCM problems (e.g., diagnostics of gears and bearings). The study is aligned with the current trends of explainable AI and physics informed neural networks (PINN), in the sense that it aims at producing mathematical rules for a rational design of the network, drawing on the expertise accumulated in decades of signal processing for MCM. This is however done without upsetting traditional NN architectures, but rather trying to provide clear reasons for the setting of network parameters. The analytical work will be verified with numerical tests, which will also enable practical considerations, and by application of the suggested guidelines to the popular Case Western Reserve University (CWRU) experimental dataset.

Cytokines as drivers: Unraveling the mechanisms of epithelial-mesenchymal transition in COVID-19 lung fibrosis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like other viruses, can induce proliferation of myofibroblasts and even lead to fibrosis in the lung. Epithelial-mesenchymal transition (EMT) is thought to play an essential role in the pathogenesis of Coronavirus disease 19 (COVID-19). EMT is originally a critical process that regulates the development of different tissues in the embryo, but in inflammatory situations, EMT tries to be activated again to control inflammation or even heal inflammatory damage. However, in pathological situations, such as chronic viral infections (e.g., COVID-19) or pulmonary fibrosis initiation, this benign healing transforms into sinister nature, pushing the lung into the fibrotic process. Notably, the cytokines released by inflammatory cells and the chronic inflammatory microenvironment shared by fibrotic cells promote each other as critical factors in the induction of pathological EMT. In the induction of SARS-CoV-2 virus, cytokines are an essential mediator of EMT transformation, and a summary of whether COVID-19 patients, during the infection phase, have many persistent inflammatory mediators (cytokines) that are a causative factor of EMT has not yet appeared.The following common signaling drivers, including Transforming growth factor beta (TGF-β), cytokines, Notch signaling pathway, Wnt and hypoxia signaling pathways, drive the regulation of EMT. In this review, we will focus on 3 key EMT signaling pathways: TGF-β, Leucine zipper transcription factor like 1 (LZTFL1) and the common interleukin family expressed in the lung. TGF-β-induced SNAIL and LZTFL1 were identified as regulatory EMT in COVID-19. For cytokines, the interleukin family is a common inducer of EMT and plays an essential role in the formation of the microenvironment of fibrosis. We sought to demonstrate that cytokines act as "communicators" and build the "microenvironment" of fibrosis together with EMT as a "bridge" to induce EMT in fibrosis. The mechanisms utilized by these two pathways could serve as templates for other mesenchymal transformations and provide new potential therapeutic targets.