bluuebunny/crossref_metadata_2025 huggingface dataset:
An in silico micro-multiphysics agent-based approach for simulating bone regeneration in a mouse femur defect model
Authors: Kendall Jack J. , Ledoux Charles , Marques Francisco C. , Boaretti Daniele , Schulte Friederike A. , Morgan Elise F. , Müller Ralph
Published: December 2023

Bone defects represent a challenging clinical problem as they can lead to non-union. In silico models are well suited to study bone regeneration under varying conditions by linking both cellular and systems scales. This paper presents an in silico micro-multiphysics agent-based (micro-MPA) model for bone regeneration following an osteotomy. The model includes vasculature, bone, and immune cells, as well as their interaction with the local environment. The model was calibrated by time-lapsed micro-computed tomography data of femoral osteotomies in C57Bl/6J mice, and the differences between predicted bone volume fractions and the longitudinal in vivo measurements were quantitatively evaluated using root mean square error (RMSE). The model performed well in simulating bone regeneration across the osteotomy gap, with no difference (5.5% RMSE, p = 0.68) between the in silico and in vivo groups for the 5-week healing period – from the inflammatory phase to the remodelling phase – in the volume spanning the osteotomy gap. Overall, the proposed micro-MPA model was able to simulate the influence of the local mechanical environment on bone regeneration, and both this environment and cytokine concentrations were found to be key factors in promoting bone regeneration. Further, the validated model matched clinical observations that larger gap sizes correlate with worse healing outcomes and ultimately simulated non-union. This model could help design and guide future experimental studies in bone repair, by identifying which are the most critical in vivo experiments to perform.
Waste to Wealth: The power of food-waste anaerobic digestion integrated with lactic acid fermentation
Authors: Bühlmann Christopher H. , Mickan Bede S. , Tait Stephan , Batstone Damien J. , Bahri Parisa A.
Published: December 2023

Food waste (FW) costs the global economy $1 trillion annually and is associated with 8% of anthropogenic greenhouse gas emissions. Anaerobic digestion (AD) is an effective technology for recycling organic waste, including FW, for energy and nutrient recovery. Current major revenue streams for AD include the sale of biogas/power, gate fees, and digestate (fertiliser). However, subsidies provided by governments are a major profit driver for commercial facilities and are generally required for profitability, limiting its widespread adoption. Lactic acid (LA) is a high value intermediate of the AD process and literature evidence has indicated the recovery of LA can significantly boost the revenue generated from FW-AD. Moreover, FW fermentation naturally tends towards LA accumulation, promotion of LA producing bacteria, and inhibition of alternate competing microbes, making LA attractive for commercial production from FW. The integration of LA production and recovery into FW-AD could improve its economic performance and reduce the need for subsidy support, providing a platform for global adoption of the AD technology. However, challenges, such as 1) the low LA yield on FW, 2) seasonality of the FW composition, 3) unknown influence of LA recovery on downstream AD, and 4) impact of standard operational procedures for AD on upstream LA production, still exist making this focus area for future research. Even so, literature has shown the benefits of the LA-AD biorefinery, detailing improved process economics, increased FW utilisation, and elimination of subsidy support. Therefore, this review focuses on exploring the integrating LA production into AD by examining the current status of AD, LA integration strategies, challenges associated with LA production from FW, and identifies key challenges and considerations associated with downstream AD of fermented waste.
Modulation of redox reactivity of resazurin through host-guest complexation with Cucurbit[n]uril (n = 7, 8)
Authors: Liu Jia , He Su-Hang , Lambert Hugues , Lee Tung-Chun
Published: December 2023

Resazurin (Alamar Blue, RZ) is a widely utilized fluorescent probe for biological sensing, whose fluorescent intensity can be modulated by changing its redox states; thereby, electrochemical reactivity of RZ is of significance when designing a sensing assay. Herein, we report novel two-way electrochemical reactivity modulation of RZ using host-guest complexation with rigid molecular containers cucurbit[n]uril (CBn, n = 7, 8). The complexation between CBn and RZ is confirmed by 1H NMR measurements and supported by computational simulation, and the binding constants are determined via UV-vis titration. Notably, the voltametric data highlights that the redox reactivity of RZ can be activated or deactivated upon encapsulation by CB8 or CB7, respectively. This two-way reactivity modulation is hypothesized to be mediated by the difference in cavity volume that favors or hinders the approach of water molecules to the encapsulated reaction center during the reduction process. Despite the similar cavity size to CB, molecular containers such as cyclodextrins (CDs) exhibit considerably weaker modulation effects. Our approach can potentially be applied to other redox processes that involve proton transfer, and open new possibilities in supramolecular electrochemistry.
Genome-wide detection of Wolbachia in natural Aedes aegypti populations using ddRAD-Seq
Authors: Muharromah Atikah Fitria , Reyes Jerica Isabel L. , Kagia Ngure , Watanabe Kozo
Published: December 2023

Background

Wolbachia, an endosymbiotic bacterium, is globally used to control arboviruses because of its ability to block arboviral replication and manipulate the reproduction of Wolbachia host, Aedes aegypti. Polymerase chain reaction (PCR)-based Wolbachia detection has been recently reported from natural Ae. aegypti populations. However, due to the technical limitations of PCR, such as primer incompatibility, PCR-based assays are not sufficiently reliable or accurate. In this study, we examined double digestion restriction site-associated DNA sequencing (ddRAD-Seq) efficiency and limitations in Wolbachia detection and quantification in field-collected Ae. aegypti natural populations in Metro Manila, the Philippines, compared with PCR-based assays.

Methods

A total of 217 individuals Ae. aegypti were collected from Metropolitan Manila, Philippines. We separated it into 14 populations consisting of 7 female and male populations. We constructed a library for pool ddRAD-Seq per population and also screened for Wolbachia by PCR assays using wsp and 16S rRNA. Wolbachia density per population were measured using RPS17 as the housekeeping gene.

Results

From 146,239,637 sequence reads obtained, 26,299 and 43,778 reads were mapped across the entire Wolbachia genome (with the wAlbA and wAlbB strains, respectively), suggesting that ddRAD-Seq complements PCR assays and supports more reliable Wolbachia detection from a genome-wide perspective. The number of reads mapped to the Wolbachia genome per population positively correlated with the number of Wolbachia-infected individuals per population based on PCR assays and the relative density of Wolbachia in the Ae. aegypti populations based on qPCR, suggesting ddRAD-Seq-based semi-quantification of Wolbachia by ddRAD-Seq. Male Ae. aegypti exhibited more reads mapped to the Wolbachia genome than females, suggesting higher Wolbachia prevalence rates in their case. We detected 150 single nucleotide polymorphism loci across the Wolbachia genome, allowing for more accurate the detection of four strains: wPip, wRi, TRS of Brugia malayi, and wMel.

Conclusions

Taken together, our results demonstrate the feasibility of ddRAD-Seq-based Wolbachia detection from field-collected Ae. aegypti mosquitoes.
Epidemiological investigation of lower respiratory tract infections during influenza A (H1N1) pdm09 virus pandemic based on targeted next-generation sequencing
Authors: Li Xiaodan , Liu Yang , Li Minzhe , Bian Jing , Song Demei , Liu Chaoying
Published: December 2023

Background

Co-infection has been a significant contributor to morbidity and mortality in previous influenza pandemics. However, the current influenza A (H1N1) pdm09 virus pandemic, as the first major outbreak following the SARS-CoV-2 pandemic, may differ epidemiologically. Further investigation is necessary to understand the specific features and impact of this influenza A pandemic. Study design: We conducted a retrospective cohort study at a Chinese hospital between January and April 2023, focusing on patients with lower respiratory tract infections. Pathogen detection employed targeted next-generation sequencing (tNGS) on bronchoalveolar lavage fluid (BALF) or sputum samples.

Results

This study enrolled 167 patients with lower respiratory tract infections, and the overall positivity rate detected through tNGS was around 80%. Among them, 40 patients had influenza A (H1N1) pdm09 virus infection, peaking in March. In these patients, 27.5% had sole infections, and 72.5% had co-infections, commonly with bacteria. The frequently detected pathogens were Aspergillus fumigatus, SARS-CoV-2, and Streptococcus pneumoniae. For non-influenza A virus-infected patients, the co-infection rate was 36.1%, with 42.3% having SARS-CoV-2. Patients with influenza A virus infection were younger, had more females and diabetes cases. Among them, those with sole infections were older, with less fever and asthma but more smoking history. Regarding prognosis, compared to sole influenza A virus infection, co-infected patients demonstrated higher 21-day recovery rates and a higher incidence of heart failure. However, they exhibited lower proportions of respiratory failure, acute kidney failure, septic shock, and hospital stays lasting more than 10 days. Interestingly, patients with non-influenza A virus infection had a significantly lower 21-day recovery rate. Correlation analysis indicated that the 21-day recovery rate was only associated with influenza A (H1N1) pdm09 virus.

Conclusion

During the current pandemic, the influenza A (H1N1) pdm09 virus may have been influenced by the SARS-CoV-2 pandemic and did not exhibit a strong pathogenicity. In fact, patients infected with influenza A virus showed better prognoses compared to those infected with other pathogens. Additionally, tNGS demonstrated excellent detection performance in this study and showed great potential, prompting clinical physicians to consider its use as an auxiliary diagnostic tool.
Effectiveness of blood flow restriction versus traditional weight-bearing training in rehabilitation of knee osteoarthritis patients with MASLD: a multicenter randomized controlled trial
Authors: Hu Chengfang , Zhu Bin , Wang Yanmao , Yang Fei , Zhang Jun , Zhong Wanrun , Lu Shengdi , Luo Congfeng
Published: December 2023

To compare the reliability and effectiveness of blood blow restriction resistance training (BFR) versus traditional weight-bearing training (WB) in knee osteoarthritis (KOA) patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods

This multicenter randomized controlled trial was conducted from January 2021 to June 2022 at Shanghai Jiao Tong University affiliated Sixth People’s Hospital and The People’s Hospital of Mengla County. A total of 120 outpatients were recruited and randomized to perform WB (n=60) or BFR (n=60) resistance training protocols in accordance with standard recommended protocols for 12 weeks. Demographic data and Kellgren and Lawrence grading system scores were collected. Pain, range of motion (ROM), scaled maximal isotonic strength (10RM), self-reported function (KOOS), and 30-s chair sit-to-stand test results were assessed at weeks 1, 4, and 12.

Results

112 patients (57 in the WB group, 55 in the BFR group) completed the training programs and assessments. No significant intergroup demographic differences were noted. ROM and scaled 10RM significantly increased at the 4- and 12-week assessments and differed significantly between groups. The pain, ability of daily living and quality of life subscale in KOOS increased significantly at the 12-week assessment and differed significantly between groups, adjusted for baseline value. Significant and comparable increases in 30-s chair sit-to-stand test results were observed within and between study groups.

Conclusion

BFR training enhanced muscle strength, reduced pain, and improved daily living and sports activities in patients with KOA, compared to WB training alone. BFR should be recommended for rehabilitation in KOA individuals with MASLD.

Clinical trial registration number

ChiCTR2100042872.
Combined inflammatory parameters and tertiary lymphoid structure predict prognosis in patients with resectable non-small cell lung cancer treated with neoadjuvant chemoimmunotherapy
Authors: Xu Fuhao , Zhu He , Dong Yinjun , Li Li , Liu Ning , Yuan Shuanghu
Published: December 2023

Introduction

Neoadjuvant chemoimmunotherapy shows great potential for patients with non-small cell lung cancer (NSCLC), but no clear prognostic markers have been identified. This study investigates the correlation between inflammatory parameters and the expression of tertiary lymphoid structures (TLS) and the predictive ability of inflammatory parameters combined with TLS for disease-free survival (DFS) in patients with resectable NSCLC receiving neoadjuvant chemotherapy.

Materials and methods

We retrospectively analyzed the clinical data and hematological parameters of 117 patients with NSCLC who underwent neoadjuvant chemoimmunotherapy and radical surgery. TLS were evaluated by observing H&E stained and immunohistochemically stained tissue sections. Univariate chi-square and multifactor logistic analyses were used to determine the correlation between hematological parameters and TLS. The Kaplan–Meier method, univariate and multivariate Cox regression analysis and constructed nomogram models were used to assess the prognostic value of the investigated parameters on DFS. Receiver operating characteristic (ROC) curves analyses were used to compare the performances of the three models.

Results

After logistic analysis, it was found that platelet-to-lymphocyte ratio (PLR) ≤288.78 (odds ratio OR=0.122, P=0.009) was an independent predictor of high TLS expression. The Cox regression analyses showed that Histology (HR=0.205, P=0.002), systemic immune inflammation index (SII) (HR=2.758, P=0.042) and TLS (HR=0.057, P<0.05) were independent prognostic factors in patients with NSCLC. The combined SII-TLS model was better than the single-indicator model in assessing the 1-year and 18-months DFS rates in patients with NSCLC.

Conclusion

Our study showed that PLR was an independent predictor of TLS and that both TLS and SII predicted prognosis in patients with neoadjuvant chemoimmunotherapy-resectable NSCLC; however, combining SII and TLS to assess DFS was more accurate than using either parameter alone.
Distinct mast cell subpopulations within and around lymphatic vessels regulate lymph flow and progression of inflammatory-erosive arthritis in TNF-transgenic mice
Authors: Peng Yue , Kenney H. Mark , de Mesy Bentley Karen L. , Xing Lianping , Ritchlin Christopher T. , Schwarz Edward M.
Published: December 2023

Objective

Inflammatory-erosive arthritis is exacerbated by dysfunction of joint-draining popliteal lymphatic vessels (PLVs). Synovial mast cells are known to be pro-inflammatory in rheumatoid arthritis (RA). In other settings they have anti-inflammatory and tissue reparative effects. Herein, we elucidate the role of mast cells on PLV function and inflammatory-erosive arthritis in tumor necrosis factor transgenic (TNF-tg) mice that exhibit defects in PLVs commensurate with disease progression.

Methods

Whole mount immunofluorescent microscopy, toluidine blue stained histology, scanning electron microscopy, and in silico bioinformatics were performed to phenotype and quantify PLV mast cells. Ankle bone volumes were assessed by μCT, while corresponding histology quantified synovitis and osteoclasts. Near-infrared indocyanine green imaging measured lymphatic clearance as an outcome of PLV draining function. Effects of genetic MC depletion were assessed via comparison of 4.5-month-old WT, TNF-tg, MC deficient KitW-sh/W-sh (cKit-/-), and TNF-tg x cKit-/- mice. Pharmacological inhibition of mast cells was assessed by treating TNF-tg mice with placebo or cromolyn sodium (3.15mg/kg/day) for 3-weeks.

Results

PLVs are surrounded by MCT+/MCPT1+/MCPT4+ mast cells whose numbers are increased 2.8-fold in TNF-tg mice. The percentage of peri-vascular degranulating mast cells was inversely correlated with ICG clearance. A population of MCT+/MCPT1-/MCPT4- mast cells were embedded within the PLV structure. In silico single-cell RNA-seq (scRNAseq) analyses identified a population of PLV-associated mast cells (marker genes: Mcpt4, Cma1, Cpa3, Tpsb2, Kit, Fcer1a & Gata2) with enhanced TGFβ-related signaling that are phenotypically distinct from known MC subsets in the Mouse Cell Atlas. cKit-/- mice have greater lymphatic defects than TNF-tg mice with exacerbation of lymphatic dysfunction and inflammatory-erosive arthritis in TNF-tg x cKit-/- vs. TNF-Tg mice. Cromolyn sodium therapy stabilized PLV mast cells, increased TNF-induced bone loss, synovitis, and osteoclasts, and decreased ICG clearance.

Conclusions

Mast cells are required for normal lymphatic function. Genetic ablation and pharmacological inhibition of mast cells exacerbates TNF-induced inflammatory-erosive arthritis with decreased lymphatic clearance. Together, these findings support an inflammatory role of activated/degranulated peri-PLV mast cells during arthritic progression, and a homeostatic role of intra-PLV mast cells, in which loss of the latter dominantly exacerbates arthritis secondary to defects in joint-draining lymphatics, warranting investigation into specific cellular mechanisms.
Protective role of Cecropin AD against LPS-induced intestinal mucosal injury in chickens
Authors: Zhi Yan , Li Tingyu , Li Yaxuan , Zhang Tao , Du Mengze , Zhang Qian , Wang Xiangdong , Hu Ge
Published: December 2023

Introduction

Cecropin AD (CAD), a renowned antimicrobial peptide, has shown promising potential in treating various bacterial infections. This study investigates the protective effects of CAD against lipopolysaccharide (LPS)-induced intestinal adversities in chickens.

Methods

Sixty SPF-grade chicks were divided into groups and exposed to different dosages of CAD, followed by LPS administration. The study assessed the impact of CAD on intestinal mucosal injury markers, oxidative stress, and inflammation.

Results

LPS significantly increased Diamine oxidase (DAO) and D-lactate (D-LA) levels, both indicators of intestinal mucosal injury. CAD treatment substantially attenuated these elevations, particularly at higher dosages. Additionally, CAD markedly reduced oxidative stress in intestinal tissues, as shown by normalized antioxidant levels and decreased reactive oxygen species. Histological analysis supported these findings, showing better-preserved villi structures in CAD-treated groups. Furthermore, CAD significantly reduced IL-6 and IL-8 expression post-LPS stimulation and effectively regulated the NLRP3 inflammasome pathway, decreasing associated factors like NLRP3, Caspase-1, IL-1b, and IL-18.

Discussion

The study demonstrates CAD's therapeutic potential in alleviating LPS-induced intestinal injuries. The protective effects are primarily attributed to its anti-inflammatory and antioxidative actions and modulation of the NLRP3 inflammasome pathway.
A gut microbiome signature for HIV and metabolic dysfunction-associated steatotic liver disease
Authors: Martínez-Sanz Javier , Talavera-Rodríguez Alba , Díaz-Álvarez Jorge , Rosas Cancio-Suárez Marta , Rodríguez Juan Miguel , Alba Claudio , Montes María Luisa , Martín-Mateos Rosa , Burgos-Santamaría Diego , Moreno Santiago , Serrano-Villar Sergio , Sánchez-Conde Matilde
Published: December 2023

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as an increasingly recognized problem among people living with HIV (PLWH). The gut-liver axis is considered to be strongly implicated in the pathogenesis of MASLD. We aimed to characterize the gut microbiota composition in PLWH and MASLD and compare it with that of two control groups: PLWH without MASLD and individuals with MASLD without HIV infection.

Methods

We collected clinical data and stool samples from participants. Bacterial 16S rRNA genes were amplified, sequenced, and clustered into operational taxonomic unit. Alpha diversity was studied by Shannon and Simpson indexes. To study how different the gut microbiota composition is between the different groups, beta diversity estimation was evaluated by principal coordinate analysis (PCoA) using Bray-Curtis dissimilarity. To further analyze differences in microbiome composition we performed a linear discriminant analysis (LDA) effect size (LEfSe).

Results

We included 30 HIV+MASLD+, 30 HIV+MASLD- and 20 HIV-MASLD+ participants. Major butyrate producers, including Faecalibacterium, Ruminococcus, and Lachnospira dominated the microbiota in all three groups. Shannon’s and Simpson’s diversity metrics were higher among MASLD+ individuals (Kruskal-Wallis p = 0.047). Beta diversity analysis showed distinct clustering in MASLD-, with MASLD+ participants overlapping regardless of HIV status (ADONIS significance <0.001). MASLD was associated with increased homogeneity across individuals, in contrast to that observed in the HIV+NAFDL- group, in which the dispersion was higher (Permanova test, p value <0.001; ANOSIM, p value <0.001). MASLD but not HIV determined a different microbiota structure (HIV+MASLD- vs. HIV+MASLD+, q-value = 0.002; HIV-MASLD+ vs. HIV+MASLD+, q-value = 0.930; and HIV-MASLD+ vs. HIV+MASLD-, q-value < 0.001). The most abundant genera in MASLD- were Prevotella, Bacteroides, Dialister, Acidaminococcos, Alloprevotella, and Catenibacterium. In contrast, the most enriched genera in MASLD+ were Ruminococcus, Streptococcus, Holdemanella, Blautia, and Lactobacillus.

Conclusions

We found a microbiome signature linked to MASLD, which had a greater influence on the overall structure of the gut microbiota than HIV status alone.
Predicting the efficacy of glucocorticoids in pediatric primary immune thrombocytopenia using plasma proteomics
Authors: Cao Qingqing , Zhu Haiyan , Xu Wei , Zhang Rongrong , Wang Yun , Tian Zhaofang , Yuan Yufang
Published: December 2023

Objective

Primary immune thrombocytopenia (ITP) is the most common acquired autoimmune bleeding disorder among children. While glucocorticoids are the primary first-line treatment for ITP treatment, they prove ineffective in certain patients. The challenge of identifying biomarkers capable of early prediction regarding the response to glucocorticoid therapy in ITP persists. This study aimed to identify ideal biomarkers for predicting glucocorticoid efficacy in patients with ITP using plasma proteomics.

Methods

A four-dimensional data-independent acquisition approach was performed to determine the differentially expressed proteins in plasma samples collected from glucocorticoid-sensitive (GCS) (n=18) and glucocorticoid-resistant (GCR) (n=17) children with ITP treated with prednisone. The significantly differentially expressed proteins were selected for enzyme-linked immunosorbent assay validation in a cohort conprising 65 samples(30 healthy controls, 18 GCS and 17 GCR children with ITP). Receiver operating characteristics curves, calibration curves, and clinical decision curve analysis were used to determine the diagnostic efficacy of this method.

Results

47 differentially expressed proteins (36 up-regulated and 11 down-regulated) were identified in the GCR group compared with the GCS group. The significantly differentially expressed proteins myosin heavy chain 9 (MYH9) and fetuin B (FETUB) were selected for enzyme-linked immunosorbent assay validation. The validation results were consistent with the proteomics analyses. Compared with the GCS group, the GCR group exhibited a significantly reduced the plasma concentration of MYH9 and elevated the plasma concentration of FETUB. Furthermore, the receiver operating characteristics curves, calibration curves, and clinical decision curve analysis demonstrated good diagnostic efficacy of these validated biomarkers.

Conclusion

This study contributes to the establishment of objective biological indicators for precision therapy in children with ITP. More importantly, the proteins MYH9 and FETUB hold potential as a foundation for making informed decisions regarding alternative treatments for drugresistant patients, thereby preventing treatment delays.
Systemic sclerosis is a risk factor of incident psoriasis: results from a nationwide cohort study
Authors: Kwon Oh Chan , Han Kyungdo , Park Min-Chan
Published: December 2023

Objective

Although the co-existence of systemic sclerosis (SSc) and psoriasis (PsO) has been reported, the risk relationship between the two diseases remains unclear. We aimed to assess whether SSc is associated with the risk of incident PsO.

Methods

From the Korean National Health Insurance Service database, 4,933 patients with SSc and 24,665 age- and sex-matched controls were selected. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident PsO were estimated using multivariable Cox proportional hazard models adjusted for known risk factors of PsO. Further, we selected individuals whose health check-up data were available (2,355 patients with SSc and 11,775 age- and sex-matched controls). In this population, we further adjusted for additional risk factors of PsO using the health check-up data.

Results

In the analysis of 4,933 patients with SSc and 24,665 age- and sex-matched controls, incidence rates of PsO in patients with SSc and controls were 10.26 and 3.20 per 1,000 person-years, respectively. After adjusting for risk factors of PsO, patients with SSc had a significantly higher risk of incident PsO (adjusted HR: 3.055 [95% CI: 2.597, 3.594]). Moreover, in the analysis of individuals who had health check-up data, additional risk factors of PsO were further adjusted; the result also showed that patients with SSc have a significantly higher risk of incident PsO (adjusted HR: 2.820 [95% CI: 2.207, 3.603]).

Conclusion

Patients with SSc had a 3-fold higher risk of developing incident PsO than controls, independent of known risk factors of PsO.
Exosomes in lung cancer metastasis, diagnosis, and immunologically relevant advances
Authors: Zhao Jianhua , Li Xiwen , Liu Lele , Zhu Zhen , He Chunyan
Published: December 2023

Lung cancer is a chronic wasting disease with insidious onset and long treatment cycle. Exosomes are specialized extracellular vesicles, at first exosomes were considered as a transporter of cellular metabolic wastes, but recently many studies have identified exosomes which contain a variety of biologically active substances that play a role in the regulation of cellular communication and physiological functions. Exosomes play an important role in the development of lung cancer and can promote metastasis through a variety of mechanisms. However, at the same time, researchers have also discovered that immune cells can also inhibit lung cancer through exosomes. In addition, researchers have discovered that some specific miRNAs in exosomes can be used as markers for early diagnosis of lung cancer. Engineering exosomes may be one of the strategies to enhance the clinical translational application of exosomes in the future, for example, strategies such as modifying exosomes to enhance targeting or utilizing exosomes as carriers for drug delivery have been explored. but more studies are needed to verify the safety and efficacy. This article reviews the latest research on exosomes in the field of lung cancer, from the mechanism of lung cancer development, the functions of immune cell-derived exosomes and tumor-derived exosomes, to the early diagnosis of lung cancer.
A chimeric influenza virus vaccine expressing fusion protein epitopes induces protection from human metapneumovirus challenge in mice
Authors: Chongyu Tian , Guanglin Lei , Fang Sun , Zhuoya Deng , Hao Yang , Cong Li , Xinyu Li , Wei He , Lingyun Tan , Yan Niu , Penghui Yang
Published: December 2023

Human metapneumovirus (HMPV) is a common virus associated with acute respiratory distress syndrome in pediatric patients. There are no HMPV vaccines or therapeutics that have been approved for prevention or treatment. In this study, we constructed a novel recombinant influenza virus carrying partial HMPV fusion protein (HMPV-F), termed rFLU-HMPV/F-NS, utilizing reverse genetics, which contained (HMPV-F) in the background of NS segments of influenza virus A/PuertoRico/8/34(PR8). The morphological characteristics of rFLU-HMPV/F-NS were consistent with the wild-type flu virus. Additionally, immunofluorescence results showed that fusion proteins in the chimeric rFLU-HMPV/F-NS could work well, and the virus could be stably passaged in SPF chicken embryos. Furthermore, intranasal immunization with rFLU-HMPV/F-NS in BALB/c mice induced robust humoral, mucosal and Th1-type dominant cellular immune responses in vivo. More importantly, we discovered that rFLU-HMPV/F-NS afforded significant protective efficacy against the wild-type HMPV and influenza virus challenge, with significantly attenuated pathological changes and reduced viral titers in the lung tissues of immunized mice. Collectively, these findings demonstrated that chimeric recombinant rFLU-HMPV/F-NS as a promising HMPV candidate vaccine has potentials for the development of HMPV vaccine.
Rapid identification of enteric bacteria from whole genome sequences using average nucleotide identity metrics
Authors: Lindsey Rebecca L. , Gladney Lori M. , Huang Andrew D. , Griswold Taylor , Katz Lee S. , Dinsmore Blake A. , Im Monica S. , Kucerova Zuzana , Smith Peyton A. , Lane Charlotte , Carleton Heather A.
Published: December 2023

Identification of enteric bacteria species by whole genome sequence (WGS) analysis requires a rapid and an easily standardized approach. We leveraged the principles of average nucleotide identity using MUMmer (ANIm) software, which calculates the percent bases aligned between two bacterial genomes and their corresponding ANI values, to set threshold values for determining species consistent with the conventional identification methods of known species. The performance of species identification was evaluated using two datasets: the Reference Genome Dataset v2 (RGDv2), consisting of 43 enteric genome assemblies representing 32 species, and the Test Genome Dataset (TGDv1), comprising 454 genome assemblies which is designed to represent all species needed to query for identification, as well as rare and closely related species. The RGDv2 contains six Campylobacter spp., three Escherichia/Shigella spp., one Grimontia hollisae, six Listeria spp., one Photobacterium damselae, two Salmonella spp., and thirteen Vibrio spp., while the TGDv1 contains 454 enteric bacterial genomes representing 42 different species. The analysis showed that, when a standard minimum of 70% genome bases alignment existed, the ANI threshold values determined for these species were ≥95 for Escherichia/Shigella and Vibrio species, ≥93% for Salmonella species, and ≥92% for Campylobacter and Listeria species. Using these metrics, the RGDv2 accurately classified all validation strains in TGDv1 at the species level, which is consistent with the classification based on previous gold standard methods.
Faecalibacterium prausnitzii promotes intestinal epithelial IL-18 production through activation of the HIF1α pathway
Authors: Fagundes Raphael R. , Bravo-Ruiseco Gabriela , Hu Shixian , Kierans Sarah J. , Weersma Rinse K. , Taylor Cormac T. , Dijkstra Gerard , Harmsen Hermie J. M. , Faber Klaas Nico
Published: December 2023

Introduction

Intestinal epithelial cells produce interleukin-18 (IL-18), a key factor in promoting epithelial barrier integrity. Here, we analyzed the potential role of gut bacteria and the hypoxia-inducible factor 1α (HIF1α) pathway in regulating mucosal IL18 expression in inflammatory bowel disease (IBD).

Methods

Mucosal samples from patients with IBD (n = 760) were analyzed for bacterial composition, IL18 levels and HIF1α pathway activation. Wild-type Caco-2 and CRISPR/Cas9-engineered Caco-2-HIF1A-null cells were cocultured with Faecalibacterium prausnitzii in a “Human oxygen-Bacteria anaerobic” in vitro system and analyzed by RNA sequencing.

Results

Mucosal IL18 mRNA levels correlated positively with the abundance of mucosal-associated butyrate-producing bacteria, in particular F. prausnitzii, and with HIF1α pathway activation in patients with IBD. HIF1α-mediated expression of IL18, either by a pharmacological agonist (dimethyloxallyl glycine) or F. prausnitzii, was abrogated in Caco-2-HIF1A-null cells.

Conclusion

Butyrate-producing gut bacteria like F. prausnitzii regulate mucosal IL18 expression in a HIF1α-dependent manner that may aid in mucosal healing in IBD.
From adhesion complex to signaling hub: the dual role of dystroglycan
Authors: Sciandra Francesca , Bozzi Manuela , Bigotti Maria Giulia
Published: December 2023

Dystroglycan (DG) is a transmembrane protein widely expressed in multiple cells and tissues. It is formed by two subunits, α− and β-DG, and represents a molecular bridge between the outside and the inside of the cell, which is essential for the mechanical and structural stability of the plasma membrane. The α-subunit is a cell-surface protein that binds to the extracellular matrix (ECM) and is tightly associated with the plasma membrane via a non-covalent interaction with the β-subunit, which, in turn, is a transmembrane protein that binds to the cytoskeletal actin. DG is a versatile molecule acting not only as a mechanical building block but also as a modulator of outside–inside signaling events. The cytoplasmic domain of β-DG interacts with different adaptor and cytoskeletal proteins that function as molecular switches for the transmission of ECM signals inside the cells. These interactions can modulate the involvement of DG in different biological processes, ranging from cell growth and survival to differentiation and proliferation/regeneration. Although the molecular events that characterize signaling through the ECM-DG-cytoskeleton axis are still largely unknown, in recent years, a growing list of evidence has started to fill the gaps in our understanding of the role of DG in signal transduction. This mini-review represents an update of recent developments, uncovering the dual role of DG as an adhesion and signaling molecule that might inspire new ideas for the design of novel therapeutic strategies for pathologies such as muscular dystrophy, cardiomyopathy, and cancer, where the DG signaling hub plays important roles.
Human neural stem cells restore spatial memory in a transgenic Alzheimer’s disease mouse model by an immunomodulating mechanism
Authors: Chen Kevin S. , Noureldein Mohamed H. , McGinley Lisa M. , Hayes John M. , Rigan Diana M. , Kwentus Jacquelin F. , Mason Shayna N. , Mendelson Faye E. , Savelieff Masha G. , Feldman Eva L.
Published: December 2023

Introduction

Stem cells are a promising therapeutic in Alzheimer’s disease (AD) given the complex pathophysiologic pathways involved. However, the therapeutic mechanisms of stem cells remain unclear. Here, we used spatial transcriptomics to elucidate therapeutic mechanisms of human neural stem cells (hNSCs) in an animal model of AD.

Methods

hNSCs were transplanted into the fimbria fornix of the hippocampus using the 5XFAD mouse model. Spatial memory was assessed by Morris water maze. Amyloid plaque burden was quantified. Spatial transcriptomics was performed and differentially expressed genes (DEGs) identified both globally and within the hippocampus. Subsequent pathway enrichment and ligand-receptor network analysis was performed.

Results

hNSC transplantation restored learning curves of 5XFAD mice. However, there were no changes in amyloid plaque burden. Spatial transcriptomics showed 1,061 DEGs normalized in hippocampal subregions. Plaque induced genes in microglia, along with populations of stage 1 and stage 2 disease associated microglia (DAM), were normalized upon hNSC transplantation. Pathologic signaling between hippocampus and DAM was also restored.

Discussion

hNSCs normalized many dysregulated genes, although this was not mediated by a change in amyloid plaque levels. Rather, hNSCs appear to exert beneficial effects in part by modulating microglia-mediated neuroinflammation and signaling in AD.
Approaches and considerations of studying neuronal ensembles: a brief review
Authors: Davidson Cameron J. , Mascarin Alixandria T. , Yahya Majd A. , Rubio F. Javier , Gheidi Ali
Published: December 2023

First theorized by Hebb, neuronal ensembles have provided a framework for understanding how the mammalian brain operates, especially regarding learning and memory. Neuronal ensembles are discrete, sparsely distributed groups of neurons that become activated in response to a specific stimulus and are thought to provide an internal representation of the world. Beyond the study of region-wide or projection-wide activation, the study of ensembles offers increased specificity and resolution to identify and target specific memories or associations. Neuroscientists interested in the neurobiology of learning, memory, and motivated behavior have used electrophysiological-, calcium-, and protein-based proxies of neuronal activity in preclinical models to better understand the neurobiology of learned and motivated behaviors. Although these three approaches may be used to pursue the same general goal of studying neuronal ensembles, technical differences lead to inconsistencies in the output and interpretation of data. This mini-review highlights some of the methodologies used in electrophysiological-, calcium-, and protein-based studies of neuronal ensembles and discusses their strengths and weaknesses.
Positive impact of the Therasuit method on gross motor function of children with autism spectrum disorder: Case series
Authors: Baptista Pedro Porto Alegre , Furtado Ana Carolina Azevedo , Fernandes Tiótrefis Gomes , Freire Júnior Renato Campos , Lima Cristiana Freitas Miranda , Mendonça Ayrles Silva Gonçalves Barbosa
Published: December 2023

The Therasuit method is a valuable physiotherapeutic method to improve the gross motor function of children with neuromotor disorders. This series of case studies investigates the effect of the Therasuit method on the gross motor function of children with autism spectrum disorder (ASD). Therasuit method is a therapeutic intervention that involves the use of a therapeutic suit attached to a cage to stimulate gross motor skills, muscle strengthening, stretching, task training, and balance, which is a positive intervention for other neurodevelopmental disorders. The study was conducted with nine male children (42.1 + 4.1 months old) with ASD who received the Therasuit protocol for 4 weeks (20 sessions). The Gross Motor Function Measure (GMFM-88) was used to assess the children’s gross motor function before and after the Therasuit method intervention. In dimension B, several skills showed improvement, including transfer to sitting, lean forward and return, trunk rotation without support, and transfer from sitting to all four stances. In dimension C, an increase was observed in skills such as being prone to all four stance transfers and reaching above the shoulders. In dimension D, maximum scores were achieved in skills such as pulling to stand on a large bench without assistance. The dimensions with the greatest impairment were D and E, corresponding to gross motor skills in orthostasis and dynamic skills in orthostasis, respectively. The findings suggest that the Therasuit method is a promising resource for treating motor impairments in children with ASD. However, further studies with a larger sample size, an adequate control condition, and random assignment of participants would be needed to provide stronger evidence of the method’s effectiveness in this population.
Safety, efficacy, and impact on gut microbial ecology of a Bifidobacterium longum subspecies infantis LMG11588 supplementation in healthy term infants: a randomized, double-blind, controlled trial in the Philippines
Authors: Capeding Maria Rosario Z. , Phee Loudhie Cyd M. , Ming Chang , Noti Mario , Vidal Karine , Le Carrou Gilles , Frézal A. , Moll Janne Marie , Vogt Josef Korbinian , Myers Pernille Neve , Nielsen Bjørn Henrik , Boulangé Claire L. , Samuel Tinu Mary , Berger Bernard , Cercamondi Colin Ivano
Published: December 2023

Introduction

Bifidobacterium longum subspecies infantis (B. infantis) may play a key role in infant gut development. This trial evaluated safety, tolerability, and efficacy of B. infantis LMG11588 supplementation.

Methods

This randomized, placebo-controlled, double-blind study conducted in the Philippines included healthy breastfed and/or formula-fed infants (14–21 days old) randomized for 8 weeks to a control group (CG; n = 77), or any of two B. infantis experimental groups (EGs): low (Lo-EG; 1*108 CFU/day; n = 75) or high dose (Hi-EG; 1.8*1010 CFU/day; n = 76). Primary endpoint was weight gain; secondary endpoints included stooling patterns, gastrointestinal symptoms, adverse events, fecal microbiome, biomarkers, pH, and organic acids.

Results

Non-inferiority in weight gain was demonstrated for Hi-EG and Lo-EG vs. CG. Overall, probiotic supplementation promoted mushy-soft stools, fewer regurgitation episodes, and increased fecal acetate production, which was more pronounced in the exclusively breastfed infants (EBF) and positively correlated with B. infantis abundance. In EBF, fecal pro-inflammatory cytokines (IL-1 beta, IL-8) were reduced. Strain-level metagenomic analysis allowed attributing the increased abundance of B. infantis in EGs versus CG, to LMG11588 probiotic colonization. Colonization by autochthonous B. infantis strains was similar between groups.

Discussion

B. infantis LMG11588 supplementation was associated with normal infant growth, was safe and well-tolerated and promoted a Bifidobacterium-rich microbiota driven by B. infantis LMG11588 colonization without disturbing the natural dispersal of autochthonous B. infantis strains. In EBF, supplementation stimulated microbial metabolic activity and beneficially modulated enteric inflammation.
Metformin: update on mechanisms of action on liver diseases
Authors: Ruan Gaoyi , Wu Fangquan , Shi Dibang , Sun Hongxia , Wang Fangyan , Xu Changlong
Published: December 2023

Substantial attention has been paid to the various effects of metformin on liver diseases; the liver is the targeted organ where metformin exerts its antihyperglycemic properties. In non-alcoholic fatty liver disease (NAFLD), studies have shown that metformin affects the ATP/AMP ratio to activate AMPK, subsequently governing lipid metabolism. The latest research showed that low-dose metformin targets the lysosomal AMPK pathway to decrease hepatic triglyceride levels through the PEN2-ATP6AP1 axis in an AMP-independent manner. Metformin regulates caspase-3, eukaryotic initiation factor-2a (eIF2a), and insulin receptor substrate-1 (IRS-1) in palmitate-exposed HepG2 cells, alleviating endoplasmic reticulum (ER) stress. Recent observations highlighted the critical association with intestinal flora, as confirmed by the finding that metformin decreased the relative abundance of Bacteroides fragilis while increasing Akkermansia muciniphila and Bifidobacterium bifidum. The suppression of intestinal farnesoid X receptor (FXR) and the elevation of short-chain fatty acids resulted in the upregulation of tight junction protein and the alleviation of hepatic inflammation induced by lipopolysaccharide (LPS). Additionally, metformin delayed the progression of cirrhosis by regulating the activation and proliferation of hepatic stellate cells (HSCs) via the TGF-β1/Smad3 and succinate-GPR91 pathways. In hepatocellular carcinoma (HCC), metformin impeded the cell cycle and enhanced the curative effect of antitumor medications. Moreover, metformin protects against chemical-induced and drug-induced liver injury (DILI) against hepatotoxic drugs. These findings suggest that metformin may have pharmacological efficacy against liver diseases.
Perioperative dexamethasone in high-grade gliomas: the short-term benefits and long-term harms
Authors: Mistry Akshitkumar M.
Published: December 2023

Dexamethasone has been commonly given to patients with a presumed new GBM in relatively large doses (6-16 mg daily for 1-2 weeks) since the 1960s without any rigorous evidence. This treatment with dexamethasone before the diagnosis and adjuvant therapy makes GBM patients unique compared to other newly diagnosed cancer patients. While dexamethasone may be beneficial, recent studies suggest that this potent immunosuppressant with pleiotropic effects is harmful in the long term. This perspective article summarizes the disadvantages of perioperative dexamethasone from multiple facets. It concludes that these growing data mandate rigorously testing the benefits of using perioperative dexamethasone.
A comprehensive review of Shengdeng in Tibetan medicine: textual research, herbal and botanical distribution, traditional uses, phytochemistry, and pharmacology
Authors: Ma Jing , Li Qiuyue , Wang Ting , Lu Hanyu , Liu Jia , Cai Rangji , Zhang Yi , Zhang Jing , Xie Xiaolong , Su Jinsong
Published: December 2023

“Shengdeng”, a group of Tibetan medicines with diverse biological origins, has long been utilized in Tibet for the treatment of rheumatoid arthritis. It showcases remarkable efficacy in alleviating rheumatism, reducing swelling, and relieving pain. This study aimed to clarify the plant species used as “Shengdeng” and summarize their botanical distribution, traditional uses, phytochemistry, and pharmacology to promote its utilization and development. “Shengdeng” is derived from a remarkable collection of 14 plant species belonging to six distinct families. Extensive phytochemical investigations have led to the identification of 355 chemical constituents within “Shengdeng”. Pharmacological studies conducted on “Shengdeng” have revealed a wide range of beneficial properties, including antioxidant, anticancer, antimicrobial, antiviral, antiparasitic, anti-inflammatory, and anti-arthritic activities. Notably, flavonoids and triterpenoids emerge as the predominant groups among these constituents, contributing to the therapeutic potential and diverse applications of “Shengdeng”. The present review provides a concise summary of the recent advancements in textual research concerning the herbal and botanical distribution, traditional uses, phytochemistry, and pharmacological activities of “Shengdeng”. It is crucial to note that future research on “Shengdeng” should prioritize the analysis of its active ingredients and the establishment of rigorous quality standards. These aspects are essential for ensuring consistency, efficacy, and safety in its clinical application.