bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activated tissue resident memory T-cells (CD8+CD103+CD39+) uniquely predict survival in left sided “immune-hot” colorectal cancers
Authors: Talhouni Shahd , Fadhil Wakkas , Mongan Nigel P. , Field Lara , Hunter Kelly , Makhsous Sogand , Maciel-Guerra Alexandre , Kaur Nayandeep , Nestarenkaite Ausrine , Laurinavicius Arvydas , Willcox Benjamin E. , Dottorini Tania , Spendlove Ian , Jackson Andrew M. , Ilyas Mohammad , Ramage Judith M. 
Published: May 2023

IntroductionCharacterization of the tumour immune infiltrate (notably CD8+ T-cells) has strong predictive survival value for cancer patients. Quantification of CD8 T-cells alone cannot determine antigenic experience, as not all infiltrating T-cells recognize tumour antigens. Activated tumour-specific tissue resident memory CD8 T-cells (TRM) can be defined by the co-express of CD103, CD39 and CD8. We investigated the hypothesis that the abundance and localization of TRM provides a higher-resolution route to patient stratification.MethodsA comprehensive series of 1000 colorectal cancer (CRC) were arrayed on a tissue microarray, with representative cores from three tumour locations and the adjacent normal mucosa. Using multiplex immunohistochemistry we quantified and determined the localization of TRM.ResultsAcross all patients, activated TRM were an independent predictor of survival, and superior to CD8 alone. Patients with the best survival had immune-hot tumours heavily infiltrated throughout with activated TRM. Interestingly, differences between right- and left-sided tumours were apparent. In left-sided CRC, only the presence of activated TRM (and not CD8 alone) was prognostically significant. Patients with low numbers of activated TRM cells had a poor prognosis even with high CD8 T-cell infiltration. In contrast, in right-sided CRC, high CD8 T-cell infiltration with low numbers of activated TRM was a good prognosis.ConclusionThe presence of high intra-tumoural CD8 T-cells alone is not a predictor of survival in left-sided CRC and potentially risks under treatment of patients. Measuring both high tumour-associated TRM and total CD8 T-cells in left-sided disease has the potential to minimize current under-treatment of patients. The challenge will be to design immunotherapies, for left-sided CRC patients with high CD8 T-cells and low activate TRM,that result in effective immune responses and thereby improve patient survival.
Peripheral nerve repair is associated with augmented cross-tissue inflammation following vascularized composite allotransplantation
Authors: Shah Ashti M. , Aral Ali Mubin , Zamora Ruben , Gharpure Nitin , El-Dehaibi Fayten , Zor Fatih , Kulahci Yalcin , Karagoz Huseyin , Barclay Derek A. , Yin Jinling , Breidenbach Warren , Tuder Dmitry , Gorantla Vijay S. , Vodovotz Yoram 
Published: May 2023

IntroductionVascularized composite allotransplantation (VCA), with nerve repair/coaptation (NR) and tacrolimus (TAC) immunosuppressive therapy, is used to repair devastating traumatic injuries but is often complicated by inflammation spanning multiple tissues. We identified the parallel upregulation of transcriptional pathways involving chemokine signaling, T-cell receptor signaling, Th17, Th1, and Th2 pathways in skin and nerve tissue in complete VCA rejection compared to baseline in 7 human hand transplants and defined increasing complexity of protein-level dynamic networks involving chemokine, Th1, and Th17 pathways as a function of rejection severity in 5 of these patients. We next hypothesized that neural mechanisms may regulate the complex spatiotemporal evolution of rejection-associated inflammation post-VCA.MethodsFor mechanistic and ethical reasons, protein-level inflammatory mediators in tissues from Lewis rats (8 per group) receiving either syngeneic (Lewis) or allogeneic (Brown-Norway) orthotopic hind limb transplants in combination with TAC, with and without sciatic NR, were compared to human hand transplant samples using computational methods.ResultsIn cross-correlation analyses of these mediators, VCA tissues from human hand transplants (which included NR) were most similar to those from rats undergoing VCA + NR. Based on dynamic hypergraph analyses, NR following either syngeneic or allogeneic transplantation in rats was associated with greater trans-compartmental localization of early inflammatory mediators vs. no-NR, and impaired downregulation of mediators including IL-17A at later times.DiscussionThus, NR, while considered necessary for restoring graft function, may also result in dysregulated and mis-compartmentalized inflammation post-VCA and therefore necessitate mitigation strategies. Our novel computational pipeline may also yield translational, spatiotemporal insights in other contexts.
Combined analysis of single-cell and bulk RNA sequencing reveals the expression patterns of circadian rhythm disruption in the immune microenvironment of Alzheimer’s disease
Authors: He Huiling , Yang Yingxia , Wang Lingxing , Guo Zeming , Ye Lichao , Ou-Yang Wanjiong , Yang Meili 
Published: May 2023

BackgroundCircadian rhythm disruption (CRD) represents a critical contributor to the pathogenesis of Alzheimer’s disease (AD). Nonetheless, how CRD functions within the AD immune microenvironment remains to be illustrated.MethodsCircadian rhythm score (CRscore) was utilized to quantify the microenvironment status of circadian disruption in a single-cell RNA sequencing dataset derived from AD. Bulk transcriptome datasets from public repository were employed to validate the effectiveness and robustness of CRscore. A machine learning-based integrative model was applied for constructing a characteristic CRD signature, and RT-PCR analysis was employed to validate their expression levels.ResultsWe depicted the heterogeneity in B cells, CD4+ T cells, and CD8+ T cells based on the CRscore. Furthermore, we discovered that CRD might be strongly linked to the immunological and biological features of AD, as well as the pseudotime trajectories of major immune cell subtypes. Additionally, cell–cell interactions revealed that CRD was critical in the alternation of ligand-receptor pairs. Bulk sequencing analysis indicated that the CRscore was found to be a reliable predictive biomarker in AD patients. The characteristic CRD signature, which included 9 circadian‐related genes (CRGs), was an independent risk factor that accurately predicted the onset of AD. Meanwhile, abnormal expression of several characteristic CRGs, including GLRX, MEF2C, PSMA5, NR4A1, SEC61G, RGS1, and CEBPB, was detected in neurons treated with Aβ1-42 oligomer.ConclusionOur study revealed CRD-based cell subtypes in the AD microenvironment at single-cell level and proposed a robust and promising CRD signature for AD diagnosis. A deeper knowledge of these mechanisms may provide novel possibilities for incorporating “circadian rhythm-based anti-dementia therapies” into the treatment protocols of individualized medicine.
Delayed diagnosis of pneumonia in the emergency department: factors associated and prognosis
Authors: Bouam Maria , Binquet Christine , Moretto Florian , Sixt Thibault , Vourc’h Michèle , Piroth Lionel , Ray Patrick , Blot Mathieu 
Published: May 2023

IntroductionWhether a delayed diagnosis of community-acquired pneumonia (CAP) in the emergency department (ED) is associated with worse outcome is uncertain. We sought factors associated with a delayed diagnosis of CAP in the ED and those associated with in-hospital mortality.MethodsRetrospective study including all inpatients admitted to an ED (Dijon University Hospital, France) from 1 January to 31 December 2019, and hospitalized with a diagnosis of CAP. Patients diagnosed with CAP in the ED (n = 361, early diagnosis) were compared with those diagnosed later, in the hospital ward, after the ED visit (n = 74, delayed diagnosis). Demographic, clinical, biological and radiological data were collected upon admission to the ED, as well as administered therapies and outcomes including in-hospital mortality.Results435 inpatients were included: 361 (83%) with an early and 74 (17%) with a delayed diagnosis. The latter less frequently required oxygen (54 vs. 77%; p &lt; 0.001) and were less likely to have a quick-SOFA score ≥ 2 (20 vs. 32%; p = 0.056). Absence of chronic neurocognitive disorders, of dyspnea, and of radiological signs of pneumonia were independently associated with a delayed diagnosis. Patients with a delayed diagnosis less frequently received antibiotics in the ED (34 vs. 75%; p &lt; 0.001). However, a delayed diagnosis was not associated with in-hospital mortality after adjusting on initial severity.ConclusionDelayed diagnosis of pneumonia was associated with a less severe clinical presentation, lack of obvious signs of pneumonia on chest X-ray, and delayed antibiotics initiation, but was not associated with worse outcome.
Multimorbidity and adverse longitudinal outcomes among patients attending chronic outpatient medical care in Bahir Dar, Northwest Ethiopia
Authors: Eyowas Fantu Abebe , Schneider Marguerite , Alemu Shitaye , Getahun Fentie Ambaw 
Published: May 2023

BackgroundMultimorbidity is becoming more prevalent in low-and middle-income countries (LMICs). However, the evidence base on the burden and its longitudinal outcomes are limited. This study aimed to determine the longitudinal outcomes of patients with multimorbidity among a sample of individuals attending chronic outpatient non communicable diseases (NCDs) care in Bahir Dar, northwest Ethiopia.MethodsA facility-based longitudinal study was conducted among 1,123 participants aged 40+ attending care for single NCD (n = 491) or multimorbidity (n = 633). Data were collected both at baseline and after 1 year through standardized interviews and record reviews. Data were analyzed using Stata V.16. Descriptive statistics and longitudinal panel data analyzes were run to describe independent variables and identify factors predicting outcomes. Statistical significance was considered at p-value &lt;0.05.ResultsThe magnitude of multimorbidity has increased from 54.8% at baseline to 56.8% at 1 year. Four percent (n = 44) of patients were diagnosed with one or more NCDs and those having multimorbidity at baseline were more likely than those without multimorbidity to develop new NCDs. In addition, 106 (9.4%) and 22 (2%) individuals, respectively were hospitalized and died during the follow up period. In this study, about one-third of the participants had higher quality of life (QoL), and those having higher high activation status were more likely to be in the higher versus the combined moderate and lower QoL [AOR1 = 2.35, 95%CI: (1.93, 2.87)] and in the combined higher and moderate versus lower level of QoL [AOR2 = 1.53, 95%CI: (1.25, 1.88)].ConclusionDeveloping new NCDs is a frequent occurrence and the prevalence of multimorbidity is high. Living with multimorbidity was associated with poor progress, hospitalization and mortality. Patients having a higher activation level were more likely than those with low activation to have better QoL. If health systems are to meet the needs of the people with chronic conditions and multimorbidity, it is essential to understand diseases trajectories and of impact of multimorbidity on QoL, and determinants and individual capacities, and to increase their activation levels for better health improve outcomes through education and activation.
Treatment of liver fibrosis in hepatolenticular degeneration with traditional Chinese medicine: systematic review of meta-analysis, network pharmacology and molecular dynamics simulation
Authors: Yang Xulong , Wang Tiancheng , Tang Yiping , Shao Yawen , Gao Yaqin , Wu Peng 
Published: May 2023

BackgroundTraditional Chinese medicine (TCM) is widely used in the clinical treatment of hepatolenticular degeneration (HLD) and liver fibrosis (LF). In the present study, the curative effect was assessed using meta-analysis. The possible mechanism of TCM against LF in HLD was investigated using network pharmacology and molecular dynamics simulation.MethodsFor literature collection, we searched several databases, including PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP) and Wan Fang database until February 2023, and the Review Manager 5.3 was used to analyze the data. Network pharmacology and molecular dynamics simulation were used to explore the mechanism of TCM in treating LF in HLD.ResultsThe results of the meta-analysis revealed that the addition of Chinese herbal medicine (CHM) in treating HLD resulted in a higher total clinical effective rate than western medicine alone [RR 1.25, 95% CI (1.09, 1.44), p = 0.002]. It not only has a better effect on liver protection [Alanine aminotransferase: SMD = −1.20, 95% CI (−1.70, −0.70), p &lt; 0.00001; Aspartate aminotransferase: SMD = −1.41, 95% CI (−2.34, −0.49), p = 0.003; Total bilirubin: SMD = −1.70, 95% CI (−3.36, −0.03), p = 0.05] but also had an excellent therapeutic effect on LF through four indexes [Hyaluronic acid: SMD = −1.15, 95% CI (−1.76, −0.53), p = 0.0003; Procollagen peptide III: SMD = −0.72, 95% CI (−1.29, −0.15), p = 0.01; Collagen IV: SMD = −0.69, 95% CI (−1.21, −0.18), p = 0.008; Laminin: SMD = −0.47, 95% CI (−0.95, 0.01), p = 0.06]. Concurrently, the liver stiffness measurement decreased significantly [SMD = −1.06, 95% CI (−1.77, −0.36), p = 0.003]. The results of network pharmacological experiments and molecular dynamics simulation indicate that the three high-frequency TCMs (Rhei Radix Et Rhizoma-Coptidis Rhizoma-Curcumae Longae Rhizoma, DH-HL-JH) primarily act on the core targets (AKT1, SRC, and JUN) via the core components (rhein, quercetin, stigmasterol, and curcumin), regulate the signal pathway (PI3K-Akt, MAPK, EGFR, and VEGF signaling pathways), and play a role of anti-LF.ConclusionMeta-analysis indicates that TCM is beneficial in treating HLD patients and improving LF. The present study successfully predicts the effective components and potential targets and pathways involved in treating LF for the three high-frequency CHMs of DH-HL-JH. The findings of the present study are hoped to provide some evidence support for clinical treatment.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier: CRD42022302374.
House ammonia exposure causes alterations in microbiota, transcriptome, and metabolome of rabbits
Authors: Li Keyao , Pang Shuo , Li Zhechen , Ding Xiaoning , Gan Yating , Gan Qianfu , Fang Shaoming 
Published: May 2023

IntroductionPollutant gas emissions in the current production system of the livestock industry have negative influences on environment as well as the health of farm staffs and animals. Although ammonia (NH3) is considered as the primary and harmful gas pollutant in the rabbit farm, less investigation has performed to determine the toxic effects of house ammonia exposure on rabbit in the commercial confined barn.MethodsIn this study, we performed multi-omics analysis on rabbits exposed to high and low concentration of house ammonia under similar environmental conditions to unravel the alterations in nasal and colonic microbiota, pulmonary and colonic gene expression, and muscular metabolic profile.Results and discussionThe results showed that house ammonia exposure notably affected microbial structure, composition, and functional capacity in both nasal and colon, which may impact on local immune responses and inflammatory processes. Transcriptome analysis indicated that genes related to cell death (MCL1, TMBIM6, HSPB1, and CD74) and immune response (CDC42, LAMTOR5, VAMP8, and CTSB) were differentially expressed in the lung, and colonic genes associated with redox state (CAT, SELENBP1, GLUD1, and ALDH1A1) were significantly up-regulated. Several key differentially abundant metabolites such as L-glutamic acid, L-glutamine, L-ornithine, oxoglutaric acid, and isocitric acid were identified in muscle metabolome, which could denote house ammonia exposure perturbed amino acids, nucleotides, and energy metabolism. In addition, the widespread and strong inter-system interplay were uncovered in the integrative correlation network, and central features were confirmed by in vitro experiments. Our findings disclose the comprehensive evidence for the deleterious effects of house ammonia exposure on rabbit and provide valuable information for understanding the underlying impairment mechanisms.
Association of residual feed intake with intestinal microbiome and metabolome in laying period of ducks
Authors: Sun Hanxue , Xu Wenwu , Gu Tiantian , Sun Jing , Li Chengfeng , Chen Li , Tian Yong , Li Guoqin , Lu Lizhi , Zeng Tao 
Published: May 2023

IntroductionResidual feed intake (RFI) is a indicator to evaluate animal feed. This experiment was explored to study the relationship between intestinal microbiome and metabolome of ducks with different residual feed intake during laying period.MethodsA total of 300 Shaoxing ducks aged 42 weeks were randomly selected and fed a diet of 60 d. At the end of the trial, 20 samples were selected according to the phenotype of RFI and divided into two groups (HRFI and LRFI). The cecal microbiota composition was explored by 16S ribosomal RNA gene sequencing and rectal metabolomics uses liquid chromatography-mass spectrometry (LC–MS) to identify the composition of metabolites in a non-targeted manner.ResultsResults show feed intake and feed conversion ratio in the group HRFI were significantly higher than those in the group LRFI (p &lt; 0.05). Chao1 indices were higher in the group LRFI than in the HRFI (p &lt; 0.05), Shannon and Simpson indices were higher in the group LRFI than in the HRFI (p &lt; 0.01). After linear discriminant analysis effect size (p &lt; 0.05, LDA score &gt; 3), Rikenellaceae, Rikenellaceae_RC9_gut_group, Lactobacillales and Ruminococcus_2, etc. were significantly enriched in the group LRFI at the genus level, while Prevotellaceae_NK3B31_group and Bacteria were significantly enriched in the group HRFI. After LC–MS analysis we found 338 metabolic difference products and 10 metabolic pathways, including the ABC transporter system, cysteine and methionine metabolism, arginine and proline metabolism, and vitamin B6 metabolism, were identified to be associated with the significantly differentially expressed between the groups LRFI and HRFI (p &lt; 0.05). We hypothesize that the difference between ducks with different RFIs is mainly due to the fact that ducks with LRFI have more SCFAs-producing bacteria in their gut microorganisms, which regulate the RFI of animals. This process we found that Phascolarctobaterium and Anaerobiospirillum may provide energy for ABC transporter system by producing SCFAs, and regulate RFI to improve feed utilization efficiency.DiscussionThese results revealed the relationship between microbiome and metabonomics in laying ducks with different RFI, and provided theoretical basis for further study on the relationship between them.
Transcriptomic analyses reveal the potential antibacterial mechanism of citral against Staphylococcus aureus
Authors: Liao Zedong , Lin Keshan , Liao Weijiang , Xie Ying , Yu Guoqing , Shao Yan , Dai Min , Sun Fenghui 
Published: May 2023

BackgroundThe emergence of multi-drug resistant Staphylococcus aureus (S. aureus) has posed a challenging clinical problem for treating its infection. The development of novel or new antibacterial agents becomes one of the useful methods to solve this problem, and has received more attention over the past decade. Citral is reported to have antibacterial activity against S. aureus, but its mechanism is yet entirely clear.MethodsTo reveal the antibacterial mechanism of citral against S. aureus, comparative transcriptomic analysis was carried out to analyze the gene expression differences between the citral-treated and untreated groups. The changes of protein, adenosine triphosphate (ATP) and reactive oxygen species (ROS) content in S. aureus caused by citral were also examined.ResultsSix hundred and fifty-nine differentially expressed genes were obtained according to the comparative transcriptomic analysis, including 287 up-regulated genes and 372 down-regulated genes. The oxidoreductase activity and fatty acid degradation pathway were enriched in up-regulated genes, and ribosome and S. aureus infection pathway were enriched in down-regulated genes. Meanwhile, physiological trials revealed a decline in ATP and protein levels, but an increase in ROS content within the citral-treated group. Thus, it can be inferred that the antibacterial effects of citral against S. aureus were likely due to its ability to decrease ATP content by down-regulating ATP synthase genes (atpD and atpG), reduce protein content, induce cell membrane and cell wall damages, accumulate ROS, and down-regulate virulence factor genes to reduce pathogenicity.ConclusionThese findings revealed the antibacterial mechanism of citral was likely a type of multi-target mode that affected multiple molecular processes in S. aureus, which lays the groundwork for further exploitation of citral as a therapeutic candidate against S. aureus infections.
Serum cortisol is negatively related to hippocampal volume, brain structure, and memory performance in healthy aging and Alzheimer’s disease
Authors: Dronse Julian , Ohndorf Anna , Richter Nils , Bischof Gérard N. , Fassbender Ronja , Behfar Qumars , Gramespacher Hannes , Dillen Kim , Jacobs Heidi I. L. , Kukolja Juraj , Fink Gereon R. , Onur Oezguer A. 
Published: May 2023

ObjectiveElevated cortisol levels have been frequently reported in Alzheimer’s disease (AD) and linked to brain atrophy, especially of the hippocampus. Besides, high cortisol levels have been shown to impair memory performance and increase the risk of developing AD in healthy individuals. We investigated the associations between serum cortisol levels, hippocampal volume, gray matter volume and memory performance in healthy aging and AD.MethodsIn our cross-sectional study, we analyzed the relationships between morning serum cortisol levels, verbal memory performance, hippocampal volume, and whole-brain voxel-wise gray matter volume in an independent sample of 29 healthy seniors (HS) and 29 patients along the spectrum of biomarker-based AD.ResultsCortisol levels were significantly elevated in patients with AD as compared to HS, and higher cortisol levels were correlated with worse memory performance in AD. Furthermore, higher cortisol levels were significantly associated with smaller left hippocampal volumes in HS and indirectly negatively correlated to memory function through hippocampal volume. Higher cortisol levels were further related to lower gray matter volume in the hippocampus and temporal and parietal areas in the left hemisphere in both groups. The strength of this association was similar in HS and AD.ConclusionIn AD, cortisol levels are elevated and associated with worse memory performance. Furthermore, in healthy seniors, higher cortisol levels show a detrimental relationship with brain regions typically affected by AD. Thus, increased cortisol levels seem to be indirectly linked to worse memory function even in otherwise healthy individuals. Cortisol may therefore not only serve as a biomarker of increased risk for AD, but maybe even more importantly, as an early target for preventive and therapeutic interventions.