bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans
Authors: Dodd John , Jordan Robert , Makhlina Marie , Barnett Keith , Roffel Ad , Spana Carl , Obr Alison , Dhingra Priyanka , Kayne Paul S. 
Published: February 2023

IntroductionPL8177 is a potent and selective agonist of the melanocortin 1 receptor (MC1R). PL8177 has shown efficacy in reversing intestinal inflammation in a cannulated rat ulcerative colitis model. To facilitate oral delivery, a novel, polymer-encapsulated formulation of PL8177 was developed. This formulation was tested in 2 rat ulcerative colitis models and evaluated for distribution, in vivo, in rats, dogs, and humans. MethodsThe rat models of colitis were induced by treatment with 2,4-dinitrobenzenesulfonic acid or dextran sulfate sodium. Single nuclei RNA sequencing of colon tissues was performed to characterize the mechanism of action. The distribution and concentration of PL8177 and the main metabolite within the GI tract after a single oral dose of PL8177 was investigated in rats and dogs. A phase 0 clinical study using a single microdose (70 µg) of [14C]-labeled PL8177 investigated the release of PL8177 in the colon of healthy men after oral administration.ResultsRats treated with 50 µg oral PL8177 demonstrated significantly lower macroscopic colon damage scores and improvement in colon weight, stool consistency, and fecal occult blood vs the vehicle without active drug. Histopathology analysis resulted in the maintenance of intact colon structure and barrier, reduced immune cell infiltration, and increased enterocytes with PL8177 treatment. Transcriptome data show that oral PL8177 50 µg treatment causes relative cell populations and key gene expressions levels to move closer to healthy controls. Compared with vehicle, treated colon samples show negative enrichment of immune marker genes and diverse immune-related pathways. In rats and dogs, orally administered PL8177 was detected at higher amounts in the colon vs upper GI tract. [14C]-PL8177 and the main metabolite were detected in the feces but not in the plasma and urine in humans. This suggests that the parent drug [14C]-PL8177 was released from the polymer formulation and metabolized within the GI tract, where it would be expected to exert its effect. ConclusionCollectively, these findings support further research into the oral formulation of PL8177 as a possible therapeutic for GI inflammatory diseases in humans.
Gut microbiota composition in patients with advanced malignancies experiencing immune-related adverse events
Authors: Liu Xinyu , Tang Hao , Zhou Qingyang , Zeng Yanlin , Lu Bo , Chen Dan , Li Yue , Qian Jiaming , Chen Minjiang , Zhao Jing , Xu Yan , Wang Mengzhao , Tan Bei 
Published: February 2023

IntroductionThe gut microbiota is implicated in the occurrence and severity of immune-related adverse events (irAEs), but the role it plays as well as its causal relationship with irAEs has yet to be established.MethodsFrom May 2020 to August 2021, 93 fecal samples were prospectively collected from 37 patients with advanced thoracic cancers treated with anti-PD-1 therapy, and 61 samples were collected from 33 patients with various cancers developing different irAEs. 16S rDNA amplicon sequencing was performed. Antibiotic-treated mice underwent fecal microbiota transplantation (FMT) with samples from patients with and without colitic irAEs.ResultsMicrobiota composition was significantly different in patients with and without irAEs (P=0.001) and with and without colitic-type irAEs (P=0.003). Bifidobacterium, Faecalibacterium, and Agathobacter were less abundant and Erysipelatoclostridium more abundant in irAE patients, while Bacteroides and Bifidobacterium were less abundant and Enterococcus more abundant in colitis-type irAE patients. Major butyrate-producing bacteria were also less abundant in patients with irAEs than those without (P=0.007) and in colitic vs. non-colitic irAE patients (P=0.018). An irAE prediction model had an AUC of 86.4% in training and 91.7% in testing. Immune-related colitis was more common in colitic-irAE-FMT (3/9) than non-irAE-FMT mice (0/9).ConclusionsThe gut microbiota is important in dictating irAE occurrence and type, especially for immune-related colitis, possibly by modulating metabolic pathways.
A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses via α-tocopherol component
Authors: Yoshioka Yuya , Kobiyama Kouji , Hayashi Tomoya , Onishi Motoyasu , Yanagida Yosuke , Nakagawa Takayuki , Hashimoto Masayuki , Nishinaka Anri , Hirose Jun , Asaoka Yoshiji , Tajiri Minako , Hayata Atsushi , Ishida Satoru , Omoto Shinya , Nagira Morio , Ishii Ken J. 
Published: February 2023

BackgroundAdjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models. However, the characteristics and mechanisms of the immune responses induced by A-910823 are not yet known.Methods and ResultsTo characterize A-910823, we compared the adaptive immune response profile enhanced by A-910823 with that of other adjuvants (AddaVax, QS21, aluminum salt-based adjuvants, and empty lipid nanoparticle [eLNP]) in a murine model. Compared with other adjuvants, A-910823 enhanced humoral immune responses to an equal or greater extent following potent T follicular helper (Tfh) and germinal center B (GCB) cell induction, without inducing a strong systemic inflammatory cytokine response. Furthermore, S-268019-b containing A-910823 adjuvant produced similar results even when given as a booster dose following primary administration of a lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) vaccine. Preparation of modified A-910823 adjuvants to identify which components of A-910823 play a role in driving the adjuvant effect and detailed evaluation of the immunological characteristics induced by each adjuvant showed that the induction of humoral immunity and Tfh and GCB cell induction in A-910823 were dependent on α-tocopherol. Finally, we revealed that the recruitment of inflammatory cells to the draining lymph nodes and induction of serum cytokines and chemokines by A-910823 were also dependent on the α-tocopherol component.ConclusionsThis study demonstrates that the novel adjuvant A-910823 is capable of robust Tfh cell induction and humoral immune responses, even when given as a booster dose. The findings also emphasize that α-tocopherol drives the potent Tfh-inducing adjuvant function of A-910823. Overall, our data provide key information that may inform the future production of improved adjuvants.
Pre-immunotherapy radiotherapy enhanced the efficacy of multi-line sintilimab in unresectable advanced esophageal squamous cell carcinoma
Authors: Xu Shuhui , Xu Xianxing , Zhu Hui 
Published: February 2023

BackgroundThe use of immunotherapy for the treatment of esophageal squamous cell carcinoma (ESCC) is gradually increasing. In this retrospective study, we evaluated the efficacy and explored potential factors of prognosis in multi-line sintilimab for unresectable advanced ESCC.MethodsAll pathological specimens were available from our Department of Pathology. We performed PD-L1 immunohistochemical staining of surgical or puncture specimens from 133 patients. We evaluated the efficacy of multi-line sintilimab and found potential factors according to multivariate analysis. We assessed the relationship between radiotherapy and immunotherapy, and according to whether patients had received radiotherapy within 3 months prior to immunotherapy, we attempted to analyze differences in progression-free survival (PFS) and overall survival (OS).ResultsA total of 133 patients were enrolled in this retrospective study between January 2019 and December 2021. The median follow-up was 16.1 months. All patients were treated with at least two cycles of sintilimab. Of all patients, a total of 74 experienced disease progression, with a median progression-free survival of 9.0 months (95% CI 7.701–10.299). We found that pre-immunotherapy radiotherapy was a possible predictor that affected the prognosis of multi-line sintilimab and that 3 months was a significant cutoff. A total of 128 patients (96.2%) had received radiotherapy prior to immunotherapy. Of those patients, 89 (66.9%) had received radiation therapy within 3 months prior to immunotherapy. PFS was considerably longer in patients who were treated within 3 months of radiotherapy than in patients who did not receive radiation therapy within 3 months of radiation therapy prior to immunotherapy (median progression-free survival 10.0 months [95% CI 8.030–11.970] vs. 5.0 months [95% CI 2.755–7.245]). Among all patients, the median overall survival was 14.9 months (95% CI 12.558–17.242). Overall survival was significantly longer in patients who had previously received radiotherapy within 3 months prior to immunotherapy than in those who had not (median overall survival 15.3 months [95% CI 13.724–16.876] vs. 12.2 months [10.001–14.399].ConclusionBased on this retrospective study, sintilimab is a significant option for patients with unresectable advanced ESCC who have been previously treated, and pre-immunotherapy radiotherapy within 3 months enhanced the efficacy.
Towards effective wildlife protection law for marine species in China: A stakeholders’ perspective
Authors: Kwan Kit Yue , Chen Ruifang , Wang Chun-Chieh , Lin Shuhao , Wu Lv , Xie Xiaoyong , Weng Zhaohong , Hu Menghong , Zhou Haichao , Wu Zhou , Fu Yijian , Zhen Wenquan , Yang Xin , Wen Yulong 
Published: February 2023

IntroductionAs one of the megadiverse countries, the effectiveness of wildlife protection in China is of great significance to global biodiversity conservation. With continued evolution and revisions, China’s Wildlife Protection Law has listed over 140 marine species; however, it is still inclined toward terrestrial animals.MethodsTo narrow the gap between compliance and enforcement, we collected 1,309 effective responses from various coastal cities of China through an anonymous online questionnaire survey, to investigate their exposure, understanding and attitudes toward Wildlife Protection Law for marine species (mWPL).ResultsMost respondents demonstrated an overall good understanding about the context, necessity and effectiveness of mWPL. The fisher communities were found to be more aware of the dissemination and implementation of mWPL. However, they understood less of the penal system, and exhibited negative attitudes toward the necessity and punishment of the legislation, probably due to the conflicts between resource utilizations and legislative interventions. The participants also indicated that seahorses, horseshoe crabs and corals were commonly subjected to illegal exploitations.DiscussionWhile most respondents suggested greater fines, tighter laws and better public enforcement, we advocate the exploration of bottom-up options such as community engagement and environmental education to improve compliance and implementation of mWPL for the benefit of marine wildlife conservation in China.
Stability, phonon calculations, electronic structure, and optical properties of a VO2(M) nanostructure: A comprehensive density functional theory study
Authors: Mohebbi Elaheh , Pavoni Eleonora , Mencarelli Davide , Stipa Pierluigi , Laudadio Emiliano , Pierantoni Luca 
Published: February 2023

This work aimed to precisely evaluate the physical properties of vanadium dioxide (M), particularly the optical characteristics. We employed different exchange-correlation functionals to determine the phase stability, band gap properties, and optical characteristics of an experimentally recognized monoclinic VO2(M) polymorph. The calculations not only correctly interpreted the VO2(M) origin but also predicted other optical properties including the extinction coefficient (k) and refractive index (n), which have not been reported in experimental measurements. Phonon dispersion calculations confirmed the presence of negative frequencies for acoustic modes in the phononic curves. When the HSE functional correctly reproduced the experimental band gap, here for the first time, our calculations based on PBE and PBEsol yielded non-zero electronic bandgaps of 0.23 and 0.15 eV for bulk VO2(M). Our predictions showed that semi-local functionals can adequately predict the semiconductor properties of VO2(M) and performed better than all previously reported theoretical works on nulled band gaps. In addition to the better prediction of the peak position in the absorption spectra with HSE hybrid functional, this method also reasonably well described the static dielectric constant of 7.54, showing an excellent match to the experimental values. In general, the results of this study reveal that hybrid functionals yield superior outcomes compared to semi-local functionals for optical properties of a VO2(M) polymorph. Our results suggest that the PBEsol + HSE approach allows the efficient characterization of smart materials for electronic and optoelectronic applications.
Antibiofilm effect of melittin alone and in combination with conventional antibiotics toward strong biofilm of MDR-MRSA and -Pseudomonas aeruginosa
Authors: Mirzaei Rasoul , Esmaeili Gouvarchin Ghaleh Hadi , Ranjbar Reza 
Published: February 2023

IntroductionMultidrug-resistant (MDR) pathogens are being recognized as a critical threat to human health if they can form biofilm and, in this sense, biofilm-forming MDR-methicillin resistant Staphylococcus aureus (MRSA) and -Pseudomonas aeruginosa strains are a worse concern. Hence, a growing body of documents has introduced antimicrobial peptides (AMPs) as a substitute candidate for conventional antimicrobial agents against drug-resistant and biofilm-associated infections. We evaluated melittin’s antibacterial and antibiofilm activity alone and/or in combination with gentamicin, ciprofloxacin, rifampin, and vancomycin on biofilm-forming MDR-P. aeruginosa and MDR-MRSA strains.MethodsAntibacterial tests [antibiogram, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC)], anti-biofilm tests [minimum biofilm inhibition concentration (MBIC), and minimum biofilm eradication concentration (MBEC)], as well as synergistic antibiofilm activity of melittin and antibiotics, were performed. Besides, the influence of melittin alone on the biofilm encoding genes and the cytotoxicity and hemolytic effects of melittin were examined.ResultsMIC, MBC, MBIC, and MBEC indices for melittin were in the range of 0.625–5, 1.25–10, 2.5–20, and 10–40 μg/ml, respectively. The findings found that the combination of melittin AMP with antibiotics was synergistic and fractional biofilm inhibitory concentration index (FBICi) for most tested concentrations was &lt;0.5, resulting in a significant reduction in melittin, gentamicin, ciprofloxacin, vancomycin, and rifampin concentrations by 2–256.4, 2–128, 2–16, 4–64 and 4–8 folds, respectively. This phenomenon reduced the toxicity of melittin, whereby its synergist concentration required for biofilm inhibition did not show cytotoxicity and hemolytic activity. Our findings found that melittin decreased the expression of icaA in S. aureus and LasR in P. aeruginosa genes from 0.1 to 4.11 fold for icaA, and 0.11 to 3.7 fold for LasR, respectively.ConclusionOverall, the results obtained from our study show that melittin alone is effective against the strong biofilm of MDR pathogens and also offers sound synergistic effects with antibiotics without toxicity. Hence, combining melittin and antibiotics can be a potential candidate for further evaluation of in vivo infections by MDR pathogens.
Comparative metagenomic analysis reveals rhizosphere microbial community composition and functions help protect grapevines against salt stress
Authors: Wang Bo , Wang Xicheng , Wang Zhuangwei , Zhu Kefeng , Wu Weimin 
Published: February 2023

IntroductionSoil salinization is a serious abiotic stress for grapevines. The rhizosphere microbiota of plants can help counter the negative effects caused by salt stress, but the distinction between rhizosphere microbes of salt-tolerant and salt-sensitive varieties remains unclear.MethodsThis study employed metagenomic sequencing to explore the rhizosphere microbial community of grapevine rootstocks 101-14 (salt tolerant) and 5BB (salt sensitive) with or without salt stress.Results and DiscussionCompared to the control (treated with ddH2O), salt stress induced greater changes in the rhizosphere microbiota of 101-14 than in that of 5BB. The relative abundances of more plant growth-promoting bacteria, including Planctomycetes, Bacteroidetes, Verrucomicrobia, Cyanobacteria, Gemmatimonadetes, Chloroflexi, and Firmicutes, were increased in 101-14 under salt stress, whereas only the relative abundances of four phyla (Actinobacteria, Gemmatimonadetes, Chloroflexi, and Cyanobacteria) were increased in 5BB under salt stress while those of three phyla (Acidobacteria, Verrucomicrobia, and Firmicutes) were depleted. The differentially enriched functions (KEGG level 2) in 101-14 were mainly associated with pathways related to cell motility; folding, sorting, and degradation functions; glycan biosynthesis and metabolism; xenobiotics biodegradation and metabolism; and metabolism of cofactors and vitamins, whereas only the translation function was differentially enriched in 5BB. Under salt stress, the rhizosphere microbiota functions of 101-14 and 5BB differed greatly, especially pathways related to metabolism. Further analysis revealed that pathways associated with sulfur and glutathione metabolism as well as bacterial chemotaxis were uniquely enriched in 101-14 under salt stress and therefore might play vital roles in the mitigation of salt stress on grapevines. In addition, the abundance of various sulfur cycle-related genes, including genes involved in assimilatory sulfate reduction (cysNC, cysQ, sat, and sir), sulfur reduction (fsr), SOX systems (soxB), sulfur oxidation (sqr), organic sulfur transformation (tpa, mdh, gdh, and betC), increased significantly in 101-14 after treatment with NaCl; these genes might mitigate the harmful effects of salt on grapevine. In short, the study findings indicate that both the composition and functions of the rhizosphere microbial community contribute to the enhanced tolerance of some grapevines to salt stress.
Longitudinal changes in participant and informant reports of subjective cognitive complaints are associated with dementia risk
Authors: Numbers Katya , Lam Ben C. P. , Crawford John D. , Kochan Nicole A. , Sachdev Perminder S. , Brodaty Henry 
Published: February 2023

BackgroundIndividuals with subjective cognitive complaints (SCCs) are at an increased risk of dementia. Questions remain about participant-reported versus informant-reported SCCs as indicators of future dementia and about longitudinal changes in participant-and informant-reported SCCs and risk of incident dementia.MethodParticipants were 873 older adults (M = 78.65-years; 55% female) and 849 informants from the Sydney Memory and Ageing Study. Comprehensive assessments occurred biennially, and clinical diagnoses were made by expert consensus for 10-years. SCCs were participants’ and informants’ responses to a single binary question concerning their/the participant’s memory decline (Yes/No) over the first 6-years. Categorical latent growth curve analyses, using the logit transformation, were used to model SCC change over time. Associations of initial propensity to report SCCs at baseline, and change in propensity to report SCCs over time, with dementia risk were examined using Cox regression.Results70% of participants reported SCCs at baseline, with a proportional increase in the odds of reporting by 11% for each additional year in the study. In contrast, 22% of informants reported SCCs at baseline, with a proportional increase by 30% in the odds of reporting per year. Participants’ initial level of (p = 0.007), but not change in SCC reporting (p = 0.179), was associated with risk of dementia controlling for all covariates. Both informants’ initial level of (p &lt; 0.001), and change in (p &lt; 0.001), SCCs significantly predicted incident dementia. When modelled together, informants’ initial level of, and change in, SCCs were still independently associated with increased dementia risk (p’s &lt; 0.001).ConclusionThese data suggest that informants’ initial impressions, and increased reporting, of SCCs appear to be uniquely prognostic of future dementia compared to participants’, even based on a single SCC question.
High plasma complement C4 levels as a novel predictor of clinical outcome in intracerebral hemorrhage
Authors: Wu Moxin , Chen Kai , Jiang Min , Xie Fusheng , Cao Xianming , Chen Liang , Chen Zhiying , Yin Xiaoping 
Published: February 2023

ObjectiveThe complement cascade is activated and contributes to the brain injury after intracerebral hemorrhage (ICH). Complement component 4 (C4), an important component of complement cascade, has been associated with severity of neurological impairment that occurs during ICH. However, the correlation of plasma complement C4 levels with hemorrhagic severity and clinical outcome in ICH patients has not been reported.Materials and methodsThis study is a monocentric, real-world, cohort study. In this study, we measured the plasma complement C4 levels of 83 ICH patients and 78 healthy controls. The hematoma volume, the National Institutes of Health Stroke Scale (NIHSS) score, the Glasgow Coma Scale (GCS) score, and the permeability surface (PS) were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma complement C4 levels to hemorrhagic severity and clinical outcomes. The contribution of complement C4 to secondary brain injury (SBI) was assessed by changes in plasma C4 levels between admission and at day 7 after ICH.ResultsThere was a significant elevation of plasma complement C4 levels in ICH patients than in healthy controls (40.48 ± 1.07 vs. 35.25 ± 0.60, p &lt; 0.0001), and the plasma complement C4 levels were closely related to the hemorrhagic severity. Moreover, plasma complement C4 levels of patients were positively correlated with the hematoma volume (r = 0.501, p &lt; 0.001), NIHSS score (r = 0.362, p &lt; 0.001), the GCS score (r = −0.490, p &lt; 0.001), and PS (r = 0.683, p = 0.045) following ICH. Logistic regression analysis also confirmed that patients with high plasma complement C4 levels show a poor clinical outcome after ICH (p &lt; 0.001). Meanwhile, the elevated plasma levels at day 7 after ICH indicated the correlation of complement C4 with SBI (p &lt; 0.01).ConclusionPlasma complement C4 levels are significantly elevated in ICH patients and positively correlated with the illness severity. Thus, these findings highlight the importance of complement C4 in brain injury after ICH and provide a novel predictor of clinical outcome for this disease.