bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular mimicry between tumor associated antigens and microbiota-derived epitopes
Authors: Ragone Concetta , Manolio Carmen , Mauriello Angela , Cavalluzzo Beatrice , Buonaguro Franco M. , Tornesello Maria Lina , Tagliamonte Maria , Buonaguro Luigi 
Published: July 2022

Abstract
Background
The gut microbiota profile is unique for each individual and are composed by different bacteria species according to individual birth-to-infant transitions. In the last years, the local and systemic effects of microbiota on cancer onset, progression and response to treatments, such as immunotherapies, has been extensively described. Here we offer a new perspective, proposing a role for the microbiota based on the molecular mimicry of tumor associated antigens by microbiome-associated antigens.

Methods
In the present study we looked for homology between published TAAs and non-self microbiota-derived epitopes. Blast search for sequence homology was combined with extensive bioinformatics analyses.

Results
Several evidences for homology between TAAs and microbiota-derived antigens have been found. Strikingly, three cases of 100% homology between the paired sequences has been identified. The predicted average affinity to HLA molecules of microbiota-derived antigens is very high (< 100 nM). The structural conformation of the microbiota-derived epitopes is, in general, highly similar to the corresponding TAA. In some cases, it is identical and contact areas with both HLA and TCR chains are indistinguishable. Moreover, the spatial conformation of TCR-facing residues can be identical in paired TAA and microbiota-derived epitopes, with exactly the same values of planar as well as dihedral angles.

Conclusions
The data reported in the present study show for the first time the high homology in the linear sequence as well as in structure and conformation between TAAs and peptides derived from microbiota species of the Firmicutes and the Bacteroidetes phyla, which together account for 90% of gut microbiota. Cross-reacting CD8+ T cell responses are very likely induced. Therefore, the anti-microbiota T cell memory may turn out to be an anti-cancer T cell memory, able to control the growth of a cancer developed during the lifetime if the expressed TAA is similar to the microbiota epitope. This may ultimately represent a relevant selective advantage for cancer patients and may lead to a novel preventive anti-cancer vaccine strategy.
Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain
Authors: Peng Zhuang , Peng Sha , Lin Kangguang , Zhao Bin , Wei Lai , Tuo Qinhui , Liao Duanfang , Yuan Tifei , Shi Zhe 
Published: July 2022

Abstract
Background
Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect.

Methods
In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain–blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated.

Results
We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response.

Conclusions
Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.
NOX2-mediated reactive oxygen species are double-edged swords in focal cerebral ischemia in mice
Authors: Yingze Ye , Zhihong Jian , Tong Jin , Yina Li , Zhi Zeng , Xu Zhang , Xiaoxing Xiong , Lijuan Gu 
Published: July 2022

AbstractBackgroundReactive oxygen species (ROS) often promote acute brain injury after stroke, but their roles in the recovery phase have not been well studied. We tested the hypothesis that ROS activity mediated by NADPH oxidase 2 (NOX2) contributes to acute brain injury but promotes functional recovery during the delayed phase, which is linked with neuroinflammation, autophagy, angiogenesis, and the PI3K/Akt signaling pathway.MethodsWe used the NOX2 inhibitor apocynin to study the role of NOX2 in brain injury and functional recovery in a middle cerebral artery occlusion (MCAO) stroke mouse model. Infarct size, neurological deficits and behavior were evaluated on days 3, 7, 10 and 14 after reperfusion. In addition, dynamic NOX2-induced ROS levels were measured by dihydroethidium (DHE) staining. Autophagy, inflammasomes, and angiogenesis were measured by immunofluorescence staining and western blotting. RNA sequencing was performed, and bioinformatics technology was used to analyze differentially expressed genes (DEGs), as well as the enrichment of biological functions and signaling pathways in ischemia penumbra at 7 days after reperfusion. Then, Akt pathway-related proteins were further evaluated by western blotting.ResultsOur results showed that apocynin injection attenuated infarct size and mortality 3 days after stroke but promoted mortality and blocked functional recovery from 5 to 14 days after stroke. DHE staining showed that ROS levels were increased at 3 days after reperfusion and then gradually declined in WT mice, and these levels were significantly reduced by the NOX2 inhibitor apocynin. RNA-Seq analysis indicated that apocynin activated the immune response under hypoxic conditions. The immunofluorescence and western blot results demonstrated that apocynin inhibited the NLRP3 inflammasome and promoted angiogenesis at 3 days but promoted the NLRP3 inflammasome and inhibited angiogenesis at 7 and 14 days after stroke, which was mediated by regulating autophagy activation. Furthermore, RNA-Seq and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that apocynin injection resulted in PI3K–Akt signaling pathway enrichment after 7 days of MCAO. We then used an animal model to show that apocynin decreased the protein levels of phosphorylated PI3K and Akt and NF-κB p65, confirming that the PI3K–Akt–NF-κB pathway is involved in apocynin-mediated activation of inflammation and inhibition of angiogenesis.ConclusionsNOX2-induced ROS production is a double-edged sword that exacerbates brain injury in the acute phase but promotes functional recovery. This effect appears to be achieved by inhibiting NLRP3 inflammasome activation and promoting angiogenesis via autophagy activation.
PPP2R5D promotes hepatitis C virus infection by binding to viral NS5B and enhancing viral RNA replication
Authors: Anwar Muhammad Ikram , Li Ni , Zhou Qing , Chen Mingxiao , Hu Chengguang , Wu Tao , Chen Haihang , Li Yi-Ping , Zhou Yuanping 
Published: July 2022

Abstract
Background
Hepatitis C virus (HCV) infection increased the risk of hepatocellular carcinoma. Identification of host factors required for HCV infection will help to unveil the HCV pathogenesis. Adaptive mutations that enable the replication of HCV infectious clones could provide hints that the mutation-carrying viral protein may specifically interact with some cellular factors essential for the HCV life cycle. Previously, we identified D559G mutation in HCV NS5B (RNA dependent RNA polymerase) important for replication of different genotype clones. Here, we searched for the factors that potentially interacted with NS5B and investigated its roles in HCV infection.

Methods
Wild-type-NS5B and D559G-NS5B of HCV genotype 2a clone, J6cc, were ectopically expressed in hepatoma Huh7.5 cells, and NS5B-binding proteins were pulled down and identified by mass spectrometry. The necessity and mode of action of the selected cellular protein for HCV infection were explored by experiments including gene knockout or knockdown, complementation, co-immunoprecipitation (Co-IP), colocalization, virus infection and replication, and enzymatic activity, etc.

Results
Mass spectrometry identified a number of cellular proteins, of which protein phosphatase 2 regulatory subunit B’delta (PPP2R5D, the PP2A regulatory B subunit) was one of D559G-NS5B-pulled down proteins and selected for further investigation. Co-IP confirmed that PPP2R5D specifically interacted with HCV NS5B but not HCV Core and NS3 proteins, and D559G slightly enhanced the interaction. NS5B also colocalized with PPP2R5D in the endoplasmic reticulum. Knockdown and knockout of PPP2R5D decreased and abrogated HCV infection in Huh7.5 cells, respectively, while transient and stable expression of PPP2R5D in PPP2R5D-knockout cells restored HCV infection to a level close to that in wild-type Huh7.5 cells. Replicon assay revealed that PPP2R5D promoted HCV replication, but the phosphatase activity and catalytic subunit of PP2A were not affected by NS5B.

Conclusions
PPP2R5D interactes with HCV NS5B and is required for HCV infection in cultured hepatoma cells through facilitating HCV replication.
Association between haemoglobin A1c and all-cause and cause-specific mortality in middle-aged and older Koreans: a prospective cohort study
Authors: Song Bo Mi , Lee Jung Hyun , Woo Hae Dong , Cho Mi Jin , Kim Sung Soo 
Published: July 2022

Abstract
Background
This study aimed to examine associations between haemoglobin A1c (HbA1c) levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans.

Methods
Using 16 years of follow-up data from the Korean Genome and Epidemiology Study, we analysed 9294 individuals aged 40–69 years with no history of cardiovascular disease (CVD) or cancer. Participants were divided into a known diabetes group and five groups categorized by HbA1c levels (< 5.0%, 5.0–5.4%, 5.5–5.9%, 6.0–6.4%, and ≥ 6.5%). Hazard ratios (HRs) for all-cause and cause-specific mortality associated with HbA1c levels were calculated using a conventional and a time-dependent Cox proportional hazards model. Restricted cubic spline models were fitted to investigate the relationship between continuous HbA1c levels and mortality among people without known diabetes. Subgroup analyses were performed for age, sex, smoking, hypertension, liver diseases, and red blood cell counts.

Results
During a median follow-up period of 15.7 years, there were 944 deaths, including 185 deaths from CVD, 359 from cancer, and 125 from all external causes. Compared with participants with HbA1c levels of 5.5–5.9%, multivariate-adjusted HRs and 95% confidence intervals for all-cause death of participants with levels < 5.0%, 5.0–5.4%, 6.0–6.4%, and ≥ 6.5% and participants with known diabetes were 1.84 (1.35–2.51), 1.13 (0.95–1.34), 1.30 (1.04–1.62), 1.37 (0.97–1.93), and 2.03 (1.70–2.44), respectively. The risk of cancer mortality was significantly increased in HbA1c < 5.0% (HR, 2.21; 95% CI 1.42–3.44) and known diabetes (HR, 1.60; 95% CI 1.18–2.15). When we performed diverse subgroup analyses, low HbA1c levels at baseline were strongly associated with mortality in participants with liver diseases.

Conclusions
We found U-shaped associations between HbA1c levels at baseline and over time and all-cause mortality in middle-aged and older Koreans. Additionally, the risk of cancer mortality increased both in low and high HbA1c groups, but CVD mortality increased only in high HbA1c group. In particular, people with liver diseases and low HbA1c levels had a high risk of all-cause mortality. Therefore, more careful management of these groups is suggested to identify any deteriorating health conditions.

Graphical abstract
Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis
Authors: Zhang Wenlong , He Xin , Yin Haoli , Cao Wenmin , Lin Tingsheng , Chen Wei , Diao Wenli , Ding Meng , Hu Hao , Mo Wenjing , Zhang Qing , Guo Hongqian 
Published: July 2022

Abstract
Background
Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies.

Methods
Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1.

Results
Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo.

Conclusions
This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.
The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density
Authors: Ward Sarah V. , Burton Anya , Tamimi Rulla M. , Pereira Ana , Garmendia Maria Luisa , Pollan Marina , Boyd Norman , dos-Santos-Silva Isabel , Maskarinec Gertraud , Perez-Gomez Beatriz , Vachon Celine , Miao Hui , Lajous Martín , López-Ridaura Ruy , Bertrand Kimberly , Kwong Ava , Ursin Giske , Lee Eunjung , Ma Huiyan , Vinnicombe Sarah , Moss Sue , Allen Steve , Ndumia Rose , Vinayak Sudhir , Teo Soo-Hwang , Mariapun Shivaani , Peplonska Beata , Bukowska-Damska Agnieszka , Nagata Chisato , Hopper John , Giles Graham , Ozmen Vahit , Aribal Mustafa Erkin , Schüz Joachim , Van Gils Carla H. , Wanders Johanna O. P. , Sirous Reza , Sirous Mehri , Hipwell John , Kim Jisun , Lee Jong Won , Dickens Caroline , Hartman Mikael , Chia Kee-Seng , Scott Christopher , Chiarelli Anna M. , Linton Linda , Flugelman Anath Arzee , Salem Dorria , Kamal Rasha , McCormack Valerie , Stone Jennifer 
Published: July 2022

Abstract
Background
Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk.

Methods
Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche.

Results
In pooled analyses, later age at menarche was associated with higher per cent density (β√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (β√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (β√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (β√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups.

Conclusions
In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.
Clinical risk factors for admission with Pseudomonas and multidrug-resistant Pseudomonas community-acquired pneumonia
Authors: Idigo Adeniyi J. , Wells J. Michael , Brown Matthew L. , Wiener Howard W. , Griffin Russell L. , Cutter Gary , Shrestha Sadeep , Lee Rachael A. 
Published: July 2022

Abstract
Background
Microbial etiology for community-acquired pneumonia (CAP) is evolving with pathogens known for high CAP mortality e.g., Pseudomonas species. Chronic obstructive pulmonary disease (COPD) patients are at risk for hospitalization for CAP. Understanding regional patterns and risk factors for multidrug-resistant (MDR) Pseudomonas acquisition has implications for antimicrobial stewardship.

Objectives
To evaluate the regional epidemiology of MDR Pseudomonas CAP and its association with COPD.

Methods
We queried the electronic medical records of the University of Alabama at Birmingham Healthcare System to identify patients hospitalized for CAP with Pseudomonas positive respiratory samples between 01/01/2013–12/31/2019. Log binomial regression models were used to examine associations between COPD diagnosis and risk of Pseudomonas/MDR Pseudomonas CAP.

Results
Cohort consisted of 913 culture positive CAP cases aged 59-year (IQR:48–68), 61% (560) male, 60% (547) white, 65% (580) current/past smokers, and 42% (384) COPD. Prevalence of Pseudomonas CAP in culture positive CAP was 18% (167), MDR Pseudomonas CAP in Pseudomonas CAP was 22% (36), and yearly incidence of MDR Pseudomonas CAP was stable (p = 0.169). COPD was associated with Pseudomonas CAP (RR 1.39; 95% CI 1.01, 1.91; p = 0.041) but not with MDR Pseudomonas CAP (0.71; 95% CI 0.35, 1.45; p = 0.349). Stroke (RR 2.64; 95% CI 1.51, 4.61; p = 0.0006) and use of supplemental oxygen (RR 2.31; 95% CI 1.30, 4.12; p = 0.005) were associated with MDR Pseudomonas CAP.

Conclusion
Incidence of MDR Pseudomonas CAP was stable over time. COPD was associated with Pseudomonas CAP but not with MDR Pseudomonas CAP. Larger cohort studies are needed to confirm findings.
Effects of the substitution of cow’s milk with soymilk on the micronutrients, microbial, and sensory qualities of yoghurt
Authors: Otolowo Dupe T. , Omosebi Omolola M. , Araoye Kudirat T. , Ernest Temiloluwa E. , Osundahunsi Oluwatooyin F. 
Published: July 2022

AbstractThe consumption of imported dairy products is high especially in developing countries including Nigeria where little or no milk is produced locally which makes the products expensive, out of reach to common consumers and also inconvenient for lactose intolerance and vegans. Soymilk, as plant-based milk was substituted for cow’s milk in parts and in whole for the production of yoghurt and the effect of substitution was evaluated on the minerals, vitamins, microbial, and sensory properties of the products using the established methods. Significant differences (p < 0.05) exits among the yoghurt samples in the micronutrient contents. The soymilk substitution produced yoghurts with trace/macro mineral contents’ range of 0.14–28.50 mg/100 g and vitamin contents (ranged 0.02–0.43 mg/100 g) that were of comparable range of values with the yoghurt made with 100% cow’s milk (0.21–29.60 mg/100 g minerals and 0.05–0.58 mg/100 g vitamins). Generally, no significant difference (p < 0.05) was observed in most of the sensory attributes evaluated (range 8.00–8.01) in the entire samples (except in the 100% soymilk yoghurt). The microbial analysis proved the safety of the entire products for consumption. These showed the positive effect of substituting soymilk for cow’s milk at all the levels used, thus, the lactose intolerance and vegans can find alternative to dairy yoghurt in the 100% soymilk substitution and enjoy the functional health benefits of yoghurt. Also, the total dependence on importation of dairy milk and cost of production of composited milk yoghurt could be reduced to improve the nation’s economy and make the product economically accessible to common man.
Graphical abstract
Nutritional management and maize variety combination effectively control Striga asiatica in southern Africa
Authors: Mutsvanga Simbarashe , Gasura Edmore , Setimela Peter S. , Nyakurwa Cacious S. , Mabasa Stanford 
Published: July 2022

AbstractMaize (Zea mays L.) is an important staple food crop in sub-Saharan Africa (SSA) and contributes significantly to food security. Due to Striga, maize yield loss is estimated between 20 and 80% forcing some farmers to abandon their land therefore threatening food security. Many strategies have been applied to combat Striga infested fields to improve maize yields but alternative feasible approaches are still required. This study aimed at determining effects of phosphorus (P) and maize variety on Striga asiatica germination and attachment. A factorial experiment of eight P levels (0, 10, 20, 30, 40, 50, 60 and 70 kg ha−1), six maize varieties and Striga (inoculated and non-inoculated) in a 4 × 24 α-lattice design with three replications was set in a glasshouse at the University of Zimbabwe. A similar experiment was set under laboratory conditions using agar gel plates to determine S. asiatica germination using a complete randomized design with three replications. Adding P (at 40 kg ha−1) to soil infected with Striga, significantly (p < 0.05) reduced Striga counts and haustorial root attachments in all varieties with CV4 and R201 supporting lowest numbers. P also significantly (p < 0.05) improved plant height, chlorophyll content, leaf, cob, total biomasses and grain yield across all maize genotypes. Cultivar CV4 produced the highest grain yield under Striga attack. Furthermore, cultivars CV4 and CV1 had significantly (p < 0.05) lowest Striga seed maximum germination distance and percentages at zero P. Application of P reduced Striga germination, attachments and emergence in all varieties and increased tolerance of maize varieties.