bluuebunny/crossref_metadata_2025 huggingface dataset:
Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5
Authors: Shukla Pradeep K. , Rao Roshan G. , Meena Avtar S. , Giorgianni Francesco , Lee Sue Chin , Raju Preeti , Shashikanth Nitesh , Shekhar Chandra , Beranova Sarka , Balazs Louisa , Tigyi Gabor , Gosain Ankush , Rao RadhaKrishna
Published: August 2023

Introduction

The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).

Methods

Adult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.

Results

Ionizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.

Conclusion

These data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.
Dynamic evaluation of blood immune cells predictive of response to immune checkpoint inhibitors in NSCLC by multicolor spectrum flow cytometry
Authors: Ma Weijie , Wei Sixi , Long Siqi , Tian Eddie C. , McLaughlin Bridget , Jaimes Maria , Montoya Dennis J. , Viswanath Varun R. , Chien Jeremy , Zhang Qianjun , Van Dyke Jonathan E. , Chen Shuai , Li Tianhong
Published: August 2023

Introduction

Immune checkpoint inhibitors (ICIs) only benefit a subset of cancer patients, underlining the need for predictive biomarkers for patient selection. Given the limitations of tumor tissue availability, flow cytometry of peripheral blood mononuclear cells (PBMCs) is considered a noninvasive method for immune monitoring. This study explores the use of spectrum flow cytometry, which allows a more comprehensive analysis of a greater number of markers using fewer immune cells, to identify potential blood immune biomarkers and monitor ICI treatment in non-small-cell lung cancer (NSCLC) patients.

Methods

PBMCs were collected from 14 non-small-cell lung cancer (NSCLC) patients before and after ICI treatment and 4 healthy human donors. Using spectrum flow cytometry, 24 immune cell markers were simultaneously monitored using only 1 million PBMCs. The results were also compared with those from clinical flow cytometry and bulk RNA sequencing analysis.

Results

Our findings showed that the measurement of CD4+ and CD8+ T cells by spectrum flow cytometry matched well with those by clinical flow cytometry (Pearson R ranging from 0.75 to 0.95) and bulk RNA sequencing analysis (R=0.80, P=1.3 x 10-4). A lower frequency of CD4+ central memory cells before treatment was associated with a longer median progression-free survival (PFS) [Not reached (NR) vs. 5 months; hazard ratio (HR)=8.1, 95% confidence interval (CI) 1.5–42, P=0.01]. A higher frequency of CD4-CD8- double-negative (DN) T cells was associated with a longer PFS (NR vs. 4.45 months; HR=11.1, 95% CI 2.2–55.0, P=0.003). ICIs significantly changed the frequency of cytotoxic CD8+PD1+ T cells, DN T cells, CD16+CD56dim and CD16+CD56- natural killer (NK) cells, and CD14+HLDRhigh and CD11c+HLADR + monocytes. Of these immune cell subtypes, an increase in the frequency of CD16+CD56dim NK cells and CD14+HLADRhigh monocytes after treatment compared to before treatment were associated with a longer PFS (NR vs. 5 months, HR=5.4, 95% CI 1.1-25.7, P=0.03; 7.8 vs. 3.8 months, HR=5.7, 95% CI 169 1.0-31.7, P=0.04), respectively.

Conclusion

Our preliminary findings suggest that the use of multicolor spectrum flow cytometry helps identify potential blood immune biomarkers for ICI treatment, which warrants further validation.
Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status
Authors: Lems Carlijn M. , Burger Gerhard A. , Beltman Joost B.
Published: August 2023

Epithelial-mesenchymal transition (EMT) and immune resistance mediated by Programmed Death-Ligand 1 (PD-L1) upregulation are established drivers of tumor progression. Their bi-directional crosstalk has been proposed to facilitate tumor immunoevasion, yet the impact of immunosuppression and spatial heterogeneity on the interplay between these processes remains to be characterized. Here we study the role of these factors using mathematical and spatial models. We first designed models incorporating immunosuppressive effects on T cells mediated via PD-L1 and the EMT-inducing cytokine Transforming Growth Factor beta (TGFβ). Our models predict that PD-L1-mediated immunosuppression merely reduces the difference in PD-L1 levels between EMT states, while TGFβ-mediated suppression also causes PD-L1 expression to correlate negatively with TGFβ within each EMT phenotype. We subsequently embedded the models in multi-scale spatial simulations to explicitly describe heterogeneity in cytokine levels and intratumoral heterogeneity. Our multi-scale models show that Interferon gamma (IFNγ)-induced partial EMT of a tumor cell subpopulation can provide some, albeit limited protection to bystander tumor cells. Moreover, our simulations show that the true relationship between EMT status and PD-L1 expression may be hidden at the population level, highlighting the importance of studying EMT and PD-L1 status at the single-cell level. Our findings deepen the understanding of the interactions between EMT and the immune response, which is crucial for developing novel diagnostics and therapeutics for cancer patients.
Case Report: Middle lobe syndrome: a rare presentation in eosinophilic granulomatosis with polyangiitis
Authors: Maranini Beatrice , Guzzinati Ippolito , Casoni Gian Luca , Ballotta Maria , Lo Monaco Andrea , Govoni Marcello
Published: August 2023

Background

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by necrotizing inflammation of small- and medium-sized blood vessels and the presence of circulating ANCA. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic ANCA-associated vasculitis, characterized by peripheral eosinophilia, neuropathy, palpable purpuras or petechiae, renal and cardiac involvement, sinusitis, asthma, and transient pulmonary infiltrates. Middle lobe syndrome (MLS) is defined as recurrent or chronic atelectasis of the right middle lobe of the lung, and it is a potential complication of asthma.

Case presentation

Herein, we describe a case of MLS in a 51-year-old woman, never-smoker, affected by EGPA, presenting exclusively with leukocytosis and elevated concentrations of acute-phase proteins, without any respiratory symptom, cough, or hemoptysis. Chest computed tomography (CT) imaging documented complete atelectasis of the middle lobe, together with complete obstruction of lobar bronchial branch origin. Fiberoptic bronchoscopy (FOB) revealed complete stenosis of the middle lobar bronchus origin, thus confirming the diagnosis of MLS, along with distal left main bronchus stenosis. Bronchoalveolar lavage (BAL) did not detect any infection. Bronchial biopsies included plasma cells, neutrophil infiltrates, only isolated eosinophils, and no granulomas, providing the hypothesis of vasculitic acute involvement less likely. First-line agents directed towards optimizing pulmonary function (mucolytics, bronchodilators, and antibiotic course) were therefore employed. However, the patient did not respond to conservative treatment; hence, endoscopic management of airway obstruction was performed, with chest CT documenting resolution of middle lobe atelectasis.

Conclusion

To the best of our knowledge, this is the first detailed description of MLS in EGPA completely resolved through FOB. Identification of MLS in EGPA appears essential as prognosis, longitudinal management, and treatment options may differ from other pulmonary involvement in AAV patients.
Analysis of the mechanisms regulating soluble PD-1 production and function in human NK cells
Authors: Mariotti Francesca Romana , Ingegnere Tiziano , Landolina Nadine , Vacca Paola , Munari Enrico , Moretta Lorenzo
Published: August 2023

NK cells represent important effectors that play a major role in innate defences against pathogens and display potent cytolytic activity against tumor cells. An array of surface receptors finely regulate their function and inhibitory checkpoints, such as PD-1, can dampen the immune response inducing an immunosuppressive state. Indeed, PD-1 expression in human NK cells correlated with impaired effector function and tumor immune evasion. Importantly, blockade of the PD-1/PD-L1 axis has been shown to reverse NK cell exhaustion and increase their cytotoxicity. Recently, soluble counterparts of checkpoint receptors, such as soluble PD-1 (sPD-1), are rising high interest due to their biological activity and ability to modulate immune responses. It has been widely demonstrated that sPD-1 can modulate T cell effector functions and tumor growth. Tumor-infiltrating T cells are considered the main source of circulating sPD-1. In addition, recently, also stimulated macrophages have been demonstrated to release sPD-1. However, no data are present on the role of sPD-1 in the context of other innate immune cell subsets and therefore this study is aimed to unveil the effect of sPD-1 on human NK cell function. We produced the recombinant sPD-1 protein and demonstrated that it binds PD-L1 and that its presence results in increased NK cell cytotoxicity. Notably, we also identified a pathway regulating endogenous sPD-1 synthesis and release in human NK cells. Secreted endogenous sPD-1, retained its biological function and could modulate NK cell effector function. Overall, these data reveal a pivotal role of sPD-1 in regulating NK-mediated innate immune responses.
Autoimmunity against laminin 332
Authors: Patzelt Sabrina , Schmidt Enno
Published: August 2023

Laminin 332 is a heterotrimeric structural protein of the basal membrane zone (BMZ) of the skin and adjacent mucosal tissues. The importance of laminin 332 for the structural integrity of the BMZ is demonstrated by mutations in any of the three genes encoding for its three chains causing variants of junctional epidermolysis bullosa. Autoimmunity against laminin 332 is observed in mucous membrane pemphigoid (MMP) and in the rare patients with orf-induced pemphigoid. MMP is an autoimmune blistering disease with predominant mucosal manifestations and autoantibodies against the BMZ of the skin and orifice-close mucous membranes. The main autoantigens of MMP are type XVII collagen (BP180) and laminin 332 targeted in about 80% and 10-20% of patients, respectively. An increasing number of studies has highlighted the association of anti-laminin 332 MMP and malignancies that can be revealed in about a quarter of these patients. This data has led to the recommendation of current guidelines to assay for anti-laminin 332 reactivity in all MMP patients. The present review focuses on anti-laminin 332 MMP describing clinical features, its pathophysiology, and detection of serum anti-laminin 332 IgG. In addition, the available data about the occurrence of malignancies in anti-laminin 332 MMP, the underlying tumor entities, and its biology are detailed.
Study on the adaptability and optimization of boom replacement methods for suspension bridges
Authors: Mu Yingna , Hu Qibing , Chen Changping , Tan Yanbin , Zheng Yanna , Liang Guoxuan
Published: August 2023

To ensure the safe operation of bridges, the study of methods and techniques for boom replacement has become a crucial aspect of the scientific maintenance of suspension bridges. This study focuses on analyzing the bridge responses and evaluating the applicability of three different boom replacement methods: single-point, three-point and five-point, using finite element calculations. A sea-crossing suspension bridge is taken as a case study to simulate the process of boom replacement using temporary booms. Consequently, the optimal replacement method for booms of varying lengths is determined. Meanwhile, this research proposes a quantitative basis for classifying boom lengths based on calculation data and analysis results to determine the suitable boom lengths for different replacement methods. Besides, a comparison of the relationship between the force transmission efficiency of temporary booms and boom length reveals that longer booms exhibit lower force transmission efficiency, with the efficiency decreasing at a faster rate as boom length increases. Overall, these findings provide a theoretical basis for the study of boom replacement in suspension bridges.
Analysis on intelligent deformation prediction of deep foundation pits with internal support based on optical fiber monitoring and the HSS model
Authors: Zhao Jie , Li Wenjie , Peng Yanli
Published: August 2023

With the continuous expansion of the city scale, while rapidly advancing foundation pit construction, it has become a top priority to prevent the potential safety hazards caused by efforts to catch up with deadlines. In this case, deep foundation pit monitoring can provide important technical support for the foundation pit design and construction safety. However, conventional foundation pit monitoring for point monitoring of structural characteristics cannot accurately locate local strains and related cracks, and cannot provide real-time monitoring of support structures, ordinary soil constitutive models cannot consider the strain hardening characteristics of soft soil. This paper aimed to analyze the characteristics of excavation deformation of a deep foundation pit with internal support in the Dalian Donggang Business District by combining the methods of optical fiber monitoring and finite element simulation. In this study, distributed optical fiber monitoring and routine monitoring were adopted to carry out the synchronous excavation monitoring of foundation pit support structures. The main monitoring objects were the deep horizontal displacement of the support piles and the surface settlement of the foundation pit. Moreover, the authors used the Plaxis finite element software based on the Hardening Soil-small (HSS) model to conduct the numerical simulation analysis, and the results were compared with two groups of the measured data of the deep foundation pit obtained from the aforementioned research. Additionally, in light of the SSA-BP neural network, the back-analysis method of HSS model parameters in the Dalian area is proposed. The findings show that, under the premise of selecting reasonable parameters, the results of finite element analysis of the HSS model, considering the small strain characteristics of the soil, demonstrate a high degree of fit with the actual deformation law of foundation pits, which proves the rationality of the model. Furthermore, it was verified that the distributed optical fiber monitoring has conspicuous advantages in terms of data continuity and accuracy in contrast to routine monitoring. The research results of this paper can provide reference for deformation monitoring and early warning regarding the support structures of deep foundation pits.
Development of a new prognostic index PNPI for prognosis prediction of CKD patients with pneumonia at hospital admission
Authors: Cai Xiao-Yu , Fan Jia-He , Cheng Yi-Chun , Ge Shu-Wang , Xu Gang
Published: August 2023

Background

The aim of this study was to investigate the relationship between pneumonia and chronic kidney disease (CKD), to elucidate potential risk factors, and to develop a new predictive model for the poor prognosis of pneumonia in CKD patients.

Method

We conducted a retrospective observational study of CKD patients admitted to Tongji Hospital between June 2012 and June 2022. Demographic information, comorbidities or laboratory tests were collected. Applying univariate and multivariate logistic regression analyses, independent risk factors associated with a poor prognosis (i.e., respiratory failure, shock, combined other organ failure, and/or death during hospitalization) for pneumonia in CKD patients were discovered, with nomogram model subsequently developed. Predictive model was compared with other commonly used pneumonia severity scores.

Result

Of 3,193 CKD patients with pneumonia, 1,013 (31.7%) met the primary endpoint during hospitalization. Risk factors predicting poor prognosis of pneumonia in CKD patients were selected on the result of multivariate logistic regression models, including chronic cardiac disease; CKD stage; elevated neutrophil to lymphocyte ratio (NLR) and D-dimer; decreased platelets, PTA, and chloride iron; and significant symptom presence and GGO presentation on CT. The nomogram model outperformed other pneumonia severity indices with AUC of 0.82 (95% CI: 0.80, 0.84) in training set and 0.83 (95% CI: 0.80, 0.86) in testing set. In addition, calibration curve and decision curve analysis (DCA) proved its efficiency and adaptability.

Conclusion

We designed a clinical prediction model PNPI (pneumonia in nephropathy patients prognostic index) to assess the risk of poor prognosis in CKD patients with pneumonia, which may be generalized after more external validation.
Impact of occupational pesticide exposure on the human gut microbiome
Authors: Gois Milla F. Brandao , Fernández-Pato Asier , Huss Anke , Gacesa Ranko , Wijmenga Cisca , Weersma Rinse K. , Fu Jingyuan , Vermeulen Roel C. H. , Zhernakova Alexandra , Lenters Virissa C. , Kurilshikov Alexander
Published: August 2023

The rising use of pesticides in modern agriculture has led to a shift in disease burden in which exposure to these chemicals plays an increasingly important role. The human gut microbiome, which is partially responsible for the biotransformation of xenobiotics, is also known to promote biotransformation of environmental pollutants. Understanding the effects of occupational pesticide exposure on the gut microbiome can thus provide valuable insights into the mechanisms underlying the impact of pesticide exposure on health. Here we investigate the impact of occupational pesticide exposure on human gut microbiome composition in 7198 participants from the Dutch Microbiome Project of the Lifelines Study. We used job-exposure matrices in combination with occupational codes to retrieve categorical and cumulative estimates of occupational exposures to general pesticides, herbicides, insecticides and fungicides. Approximately 4% of our cohort was occupationally exposed to at least one class of pesticides, with predominant exposure to multiple pesticide classes. Most participants reported long-term employment, suggesting a cumulative profile of exposure. We demonstrate that contact with insecticides, fungicides and a general “all pesticides” class was consistently associated with changes in the gut microbiome, showing significant associations with decreased alpha diversity and a differing beta diversity. We also report changes in the abundance of 39 different bacterial taxa upon exposure to the different pesticide classes included in this study. Together, the extent of statistically relevant associations between gut microbial changes and pesticide exposure in our findings highlights the impact of these compounds on the human gut microbiome.
Influencing factors and mechanism of Cr(VI) reduction by facultative anaerobic Exiguobacterium sp. PY14
Authors: Huang Yunhong , Tang Jie , Zhang Bei , Long Zhong-Er , Ni Haiyan , Fu Xueqin , Zou Long
Published: August 2023

Microbial reduction is an effective way to deal with hexavalent chromium [Cr(VI)] contamination in the environment, which can significantly mitigate the biotoxicity and migration of this pollutant. The present study investigated the influence of environmental factors on aqueous Cr(VI) removal by a newly isolated facultative anaerobic bacterium, Exiguobacterium sp. PY14, and revealed the reduction mechanism. This strain with a minimum inhibitory concentration of 400 mg/L showed the strongest Cr(VI) removal capacity at pH 8.0 because of its basophilic nature, which was obviously depressed by increasing the Cr(VI) initial concentration under both aerobic and anaerobic conditions. In contrast, the removal rate constant for 50 mg/L of Cr(VI) under anaerobic conditions (1.82 × 10−2 h−1) was 3.3 times that under aerobic conditions. The co-existence of Fe(III) and Cu(II) significantly promoted the removal of Cr(VI), while Ag(I), Pb(II), Zn(II), and Cd(II) inhibited it. Electron-shuttling organics such as riboflavin, humic acid, and anthraquinone-2,6-disulfonate promoted the Cr(VI) removal to varying degrees, and the enhancement was more significant under anaerobic conditions. The removal of aqueous Cr(VI) by strain PY14 was demonstrated to be due to cytoplasmic rather than extracellular reduction by analyzing the contributions of different cell components, and the end products existed in the aqueous solution in the form of organo-Cr(III) complexes. Several possible genes involved in Cr(VI) metabolism, including chrR and chrA that encode well-known Chr family proteins responsible for chromate reduction and transport, respectively, were identified in the genome of PY14, which further clarified the Cr(VI) reduction pathway of this strain. The research progress in the influence of crucial environmental factors and biological reduction mechanisms will help promote the potential application of Exiguobacterium sp. PY14 with high adaptability to environmental stress in Cr(VI) removal in the actual environment.
Association of the LEP gene with immune infiltration as a diagnostic biomarker in preeclampsia
Authors: Chen Shaorong , Ke Yumin , Chen Weihong , Wu Sijia , Zhuang Xuanxuan , Lin Qiuya , Shi Qirong , Wu Zhuna
Published: August 2023

Objective: Preeclampsia (PE) is a serious condition in pregnant women and hence an important topic in obstetrics. The current research aimed to recognize the potential and significant immune-related diagnostic biomarkers for PE.

Methods: From the Gene Expression Omnibus (GEO) data sets, three public gene expression profiles (GSE24129, GSE54618, and GSE60438) from the placental samples of PE and normotensive pregnancy were downloaded. Differentially expressed genes (DEGs) were selected and determined among 73 PE and 85 normotensive control pregnancy samples. The DEGs were used for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA). The candidate biomarkers were identified by the least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) analysis. The receiver operating characteristic curve (ROC) was applied to evaluate diagnostic ability. For further confirmation, the expression levels and diagnostic value of biomarkers in PE were verified in the GSE75010 data set (80 PE and 77 controls) and validated by qRT-RCR, Western blot, and immunohistochemistry (IHC). The CIBERSORT algorithm was used to calculate the compositional patterns of 22 types of immune cells in PE.

Results: In total, 15 DEGs were recognized. The GO and KEGG analyses revealed that the DEGs were enriched in the steroid metabolic process, receptor ligand activity, GnRH secretion, and neuroactive ligand−receptor interaction. The recognized DEGs were primarily implicated in cell-type benign neoplasm, kidney failure, infertility, and PE. Gene sets related to hormone activity, glycosylation, multicellular organism process, and response to BMP were activated in PE. The LEP gene was distinguished as a diagnostic biomarker of PE (AUC = 0.712) and further certified in the GSE75010 data set (AUC = 0.850). The high expression of LEP was associated with PE in clinical samples. In addition, the analysis of the immune microenvironment showed that gamma delta T cells, memory B cells, M0 macrophages, and regulatory T cells were positively correlated with LEP expression (P < 0.05).

Conclusion:LEP expression can be considered to be a diagnostic biomarker of PE and can offer a novel perspective for future studies regarding the occurrence and molecular mechanisms of PE.
Dietary fatty acids differentially impact phagocytosis, inflammatory gene expression, and mitochondrial respiration in microglial and neuronal cell models
Authors: Butler Michael J. , Mackey-Alfonso Sabrina E. , Massa Nashali , Baskin Kedryn K. , Barrientos Ruth M.
Published: August 2023

The consumption of diets high in saturated fatty acids and/or refined carbohydrates are associated with neuroinflammation, cognitive dysfunction, and neurodegenerative disease. In contrast, diets high in polyunsaturated fatty acids are associated with anti-inflammatory and neuroprotective effects. We have previously shown that high fat diet (HFD) consumption increases saturated fatty acids and decreases polyunsaturated fatty acids in the hippocampus. We have further shown that HFD elicits exaggerated neuroinflammation and reduced synaptic elements, and results in robust memory deficits in aged rats. Here, we examined the impact of palmitate, an abundant dietary saturated fat, on a variety of cellular responses in BV2 microglia and HippoE-14 neurons, and the extent to which the omega-3 fatty acid, docosahexaenoic acid (DHA), would buffer against these responses. Our data demonstrate that DHA pretreatment prevents or partially attenuates palmitate-induced alterations in proinflammatory, endoplasmic reticulum stress, and mitochondrial damage-associated gene expression in both cell types. Furthermore, we show that synaptoneurosomes isolated from aged, HFD-fed mice are engulfed by BV2 microglia at a faster rate than synaptoneurosomes isolated from aged, chow-fed mice, suggesting HFD alters signaling at synapses to hasten their engulfment by microglia. Consistent with this notion, we found modest increases in complement proteins and a decrease in CD47 protein expression on synaptoneurosomes isolated from the hippocampus of aged, HFD-fed mice. Interestingly, palmitate reduced BV2 microglial phagocytosis, but only of synaptoneurosomes isolated from chow-fed mice, an effect that was prevented by DHA pretreatment. Lastly, we measured the impact of palmitate and DHA on mitochondrial function in both microglial and neuronal cell models using the Seahorse XFe96 Analyzer. These data indicate that DHA pretreatment does not mitigate palmitate-induced reductions in mitochondrial respiration in BV2 microglia and HippoE-14 neurons, suggesting DHA may be acting downstream of mitochondrial function to exert its protective effects. Together, this study provides evidence that DHA can ameliorate the negative impact of palmitate on a variety of cellular functions in microglia- and neuron-like cells.
ReplaceNet: real-time replacement of a biological neural circuit with a hardware-assisted spiking neural network
Authors: Hwang Sangwoo , Hwang Yujin , Kim Duhee , Lee Junhee , Choe Han Kyoung , Lee Junghyup , Kang Hongki , Kung Jaeha
Published: August 2023

Recent developments in artificial neural networks and their learning algorithms have enabled new research directions in computer vision, language modeling, and neuroscience. Among various neural network algorithms, spiking neural networks (SNNs) are well-suited for understanding the behavior of biological neural circuits. In this work, we propose to guide the training of a sparse SNN in order to replace a sub-region of a cultured hippocampal network with limited hardware resources. To verify our approach with a realistic experimental setup, we record spikes of cultured hippocampal neurons with a microelectrode array (in vitro). The main focus of this work is to dynamically cut unimportant synapses during SNN training on the fly so that the model can be realized on resource-constrained hardware, e.g., implantable devices. To do so, we adopt a simple STDP learning rule to easily select important synapses that impact the quality of spike timing learning. By combining the STDP rule with online supervised learning, we can precisely predict the spike pattern of the cultured network in real-time. The reduction in the model complexity, i.e., the reduced number of connections, significantly reduces the required hardware resources, which is crucial in developing an implantable chip for the treatment of neurological disorders. In addition to the new learning algorithm, we prototype a sparse SNN hardware on a small FPGA with pipelined execution and parallel computing to verify the possibility of real-time replacement. As a result, we can replace a sub-region of the biological neural circuit within 22 μs using 2.5 × fewer hardware resources, i.e., by allowing 80% sparsity in the SNN model, compared to the fully-connected SNN model. With energy-efficient algorithms and hardware, this work presents an essential step toward real-time neuroprosthetic computation.
BRCA1 heterozygosity promotes DNA damage-induced senescence in a sex-specific manner following repeated mild traumatic brain injury
Authors: Leung Emily , Taskina Daria , Schwab Nicole , Hazrati Lili-Naz
Published: August 2023

Emerging evidence suggests cellular senescence, as a consequence of excess DNA damage and deficient repair, to be a driver of brain dysfunction following repeated mild traumatic brain injury (rmTBI). This study aimed to further investigate the role of deficient DNA repair, specifically BRCA1-related repair, on DNA damage-induced senescence. BRCA1, a repair protein involved in maintaining genomic integrity with multiple roles in the central nervous system, was previously reported to be significantly downregulated in post-mortem brains with a history of rmTBI. Here we examined the effects of impaired BRCA1-related repair on DNA damage-induced senescence and outcomes 1-week post-rmTBI using mice with a heterozygous knockout for BRCA1 in a sex-segregated manner. Altered BRCA1 repair with rmTBI resulted in altered anxiety-related behaviours in males and females using elevated zero maze and contextual fear conditioning. Evaluating molecular markers associated with DNA damage signalling and senescence-related pathways revealed sex-specific differences attributed to BRCA1, where females exhibited elevated DNA damage, impaired DNA damage signalling, and dampened senescence onset compared to males. Overall, the results from this study highlight sex-specific consequences of aberrant DNA repair on outcomes post-injury, and further support a need to develop sex-specific treatments following rmTBI.
Does serum neurofilament light help predict accelerated cognitive ageing in unimpaired older adults?
Authors: Collins Jessica M. , Bindoff Aidan D. , Roccati Eddy , Alty Jane E. , Vickers James C. , King Anna E.
Published: August 2023

Introduction

Neurofilament light (NfL) is a blood biomarker of neurodegeneration. While serum NfL levels have been demonstrated to increase with normal ageing, the relationship between serum NfL levels and normal age-related changes in cognitive functions is less well understood.

Methods

The current study investigated whether cross-sectional serum NfL levels measured by single molecule array technology (Simoa®) mediated the effect of age on cognition, measured by a battery of neuropsychological tests administered biannually for 8 years, in a cohort of 174 unimpaired older adults (≥50 years) from the Tasmanian Healthy Brain Project. Mediation analysis was conducted using latent variables representing cognitive test performance on three cognitive domains - episodic memory, executive function, and language (vocabulary, comprehension, naming). Cognitive test scores for the three domains were estimated for each participant, coincident with blood collection in 2018 using linear Bayesian hierarchical models.

Results

Higher serum NfL levels were significantly positively associated with age (p < 0.001 for all domains). Cognitive test scores were significantly negatively associated with age across the domains of executive function (p < 0.001), episodic memory (p < 0.001) and language (p < 0.05). However, serum NfL levels did not significantly mediate the relationship between age and cognitive test scores across any of the domains.

Discussion

This study adds to the literature on the relationship between serum NfL levels and cognition in unimpaired older adults and suggests that serum NfL is not a pre-clinical biomarker of ensuing cognitive decline in unimpaired older adults.
Rapid identification of α-glucosidase inhibitors from Poria using spectrum-effect, component knock-out, and molecular docking technique
Authors: Ma Changyang , Lu Jie , Ren Mengjie , Wang Qiuyi , Li Changqin , Xi Xuefeng , Liu Zhenhua
Published: August 2023

Instruction

Poria (Poria cocos) is known for its health-promoting effects and is consumed as a food due to its potential hypoglycemic activity. However, the composition of Poria is complex, and the bioactive compounds that inhibit α-glucosidase are not clear.

Methods

In this study, the fingerprint of the Poria methanol extract characterized by high-performance liquid chromatography (HPLC) and the model of the corresponding spectrum-effect relationship for α-glucosidase was first established to screen the active compounds from Poria. Then, the predicted bioactive compounds were knocked out and identified using mass spectrometry. Finally, the potential binding sites and main bonds of each compound with α-glucosidase were studied using molecular docking.

Results

The results have shown that at least 11 compounds from Poria could inhibit α-glucosidase effectively. Moreover, eight individual compounds, i.e., poricoic acid B (P8), dehydrotumulosic acid (P9), poricoic acid A (P10), polyporenic acid C (P12), 3- epidehydrotumulosic acid (P13), dehydropachymic acid (P14), 3-O-acetyl-16α-hydroxytrametenolic acid (P21), and pachymic acid (P22), were identified, and they exhibited effective inhibitory activity against α-glucosidase.

Discussion

The possible inhibitory mechanism of them based on molecular docking showed that the binding sites are mainly found in the rings A, B, and C of these compounds, and C-3 C-16 and side chains of C-17, with the phenylalanine, arginine, tyrosine, histidine, and valine of α-glucosidase. The main interactions among them might be alkyl and hydrogen bonds, which theoretically verified the inhibitory activity of these compounds on α-glucosidase. The achievements of this study provided useful references for discovering bioactive compounds with hypoglycemic effects from Poria.
Associations between composite dietary antioxidant index and estimated 10-year atherosclerotic cardiovascular disease risk among U.S. adults
Authors: Zhang Jia , Lu Xueqin , Wu Ruifeng , Ni Hanchen , Xu Lingli , Wu Wenjuan , Lu Cheng , Feng Jiayi , Jin Yongmei
Published: August 2023

Background

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death and disability both in U.S. and worldwide. Antioxidants have been proved critical in mitigating the development of atherosclerosis. This study aimed to investigate the associations between composite dietary antioxidant index (CDAI) and estimated 10-year ASCVD risk among U.S. adults.

Methods

Data extracted from the National Health and Nutrition Examination Survey were analyzed. A total of 10,984 adults aged 18 years and above were included in this study. CDAI was calculated based on the dietary intake reported in their 24-h recall interviews. The estimated 10-year ASCVD risk was calculated via Pooled Cohort Equations (PCE).

Results

After adjusting potential confounders, it was indicated that CDAI score was negatively correlated with 10-year ASCVD risk (OR 0.97, 95% CI 0.95–0.99). Stratify CDAI score by quartile, results showed that participants in the second, third, and fourth quartiles had lower ASCVD odds ratio (Q2: OR 0.87, 95% CI 0.69–1.09; Q3: OR 0.78, 95% CI 0.62–0.98; Q4: OR 0.74, 95% CI 0.59–0.94) than those in the first quartile (Q1, lowest CDAI score group), which was confirmed by the trend test as well (p < 0.05). Subgroup analyses stratified by sex, age, race/ethnicity, and smoking status did not show significant effect modification.

Conclusion

Higher dietary antioxidants intake is associated with lower ASCVD risk among U.S. adults, for which policymakers and healthcare professionals may consider increasing the consumption of antioxidant-rich foods as a preventive strategy for ASCVD.
Validation of the FACT-G7 in patients with hematologic malignancies
Authors: Du Xinwen , Mao Ling , Leng Yamei , Chen Fengjiao
Published: August 2023

Background

It is essential to evaluate the quality of life in patients with hematologic malignancies to reflect the therapeutic effect and prognosis, but lengthy assessments are often burdensome. The 7-Item Functional Assessment of Cancer Therapy-General (FACT-G7) is a brief, easy, and rapid index for evaluating quality of life. Nevertheless, there is no report about its application in Chinese patients with hematologic malignancies.

Objective

The purpose of this study was to validate the Chinese version of the FACT-G7 for patients with hematologic malignancies.

Methods

This study is a cross-sectional study. A total of 855 patients with hematologic malignancies completed the Functional Assessment of Cancer Therapy-General (FACT-G) and were scored the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) by nurses. Cronbach’s alpha, confirmatory factor analyses, Pearson’s correlation, and one-way analysis of variance were conducted to evaluate internal consistent reliability, structural validity and concurrent validity.

Results

The FACT-G7 showed acceptable internal consistency, as indicated by a Cronbach’s alpha of 0.73. The confirmatory factor analyses test for single-factor model fit for the FACT-G7 scale was almost adequate. The satisfactory correlations between the FACT-G7 and the FACT-G and its subscales, and ECOG-PS groups differed in FACT-G7 scores demonstrating concurrent validity.

Conclusion

This study suggested that the Chinese version of the FACT-G7 provides a useful and rapid measure for assessing quality of life in Chinese patients with hematologic malignancies, which providing a reference for further evaluation and care.
Identifying target organ location of Radix Achyranthis Bidentatae: a bioinformatics approach on active compounds and genes
Authors: Tran Minh Nhat , Baek Su-Jin , Jun Hyeong Joon , Lee Sanghun
Published: August 2023

Background: Herbal medicines traditionally target organs for treatment based on medicinal properties, and this theory is widely used for prescriptions. However, the scientific evidence explaining how herbs act on specific organs by biological methods has been still limited. This study used bioinformatic tools to identify the target organ locations of Radix Achyranthis Bidentatae (RAB), a blood-activating herb that nourishes the liver and kidney, strengthens bones, and directs prescription to the lower body.

Methods: RAB’s active compounds and targets were collected and predicted using databases such as TCMSP, HIT2.0, and BATMAN-TCM. Next, the RAB’s target list was analyzed based on two approaches to obtain target organ locations. DAVID and Gene ORGANizer enrichment-based approaches were used to enrich an entire gene list, and the BioGPS and HPA gene expression-based approaches were used to analyze the expression of core genes.

Results: RAB’s targets were found to be involved in whole blood, blood components, and lymphatic organs across all four tools. Each tool indicated a particular aspect of RAB’s target organ locations: DAVID-enriched genes showed a predominance in blood, liver, and kidneys; Gene ORGANizer showed the effect on low body parts as well as bones and joints; BioGPS and HPA showed high gene expression in bone marrow, lymphoid tissue, and smooth muscle.

Conclusion: Our bioinformatics-based target organ location prediction can serve as a modern interpretation tool for the target organ location theory of traditional medicine. Future studies should predict therapeutic target organ locations in complex prescriptions rather than single herbs and conduct experiments to verify predictions.
A randomized double-blinded study assessing the dose-response of ropivacaine with dexmedetomidine for maintenance of labor with epidural analgesia in nulliparous parturients
Authors: Shen Yao-Hua , Drzymalski Dan M. , Zhu Bin-Xiang , Lin Su-Feng , Tu Fang-Qin , Shen Bei , Xiao Fei
Published: August 2023

Background: The combination of ropivacaine and dexmedetomidine has been used as an epidural analgesic for inducing labor. However, there is limited data regarding the administration of epidural analgesia for labor maintenance, hence, this study aimed to determine the optimum concentration through dose-response curves of ropivacaine plus dexmedetomidine, which could be used along with the Programmed Intermittent Epidural Bolus (PIEB) technique.

Methods: One hundred parturients were randomized into 4 groups who were administered four different doses of ropivacaine (dexmedetomidine at 0.4 μg mL−1): 0.04%, 0.06%, 0.08%, and 0.1%. The primary outcome that was determined included the proportion of patients experiencing breakthrough pain during their 1st stage of labor. Breakthrough pain was described as a visual analog scale [VAS] score of >30 mm, requiring supplemental epidural analgesia after the administration of at least one patient-controlled bolus. The effective concentration of analgesia that was used for labor maintenance in 50% (EC50) and 90% (EC90) of patients were calculated with the help of probit regression. Secondary outcomes included epidural block characteristics, side effects, neonatal outcomes, and patient satisfaction.

Results: The results indicated that the proportion of patients without breakthrough pain was 45% (10/22), 55% (12/22), 67% (16/24), and 87% (20/23) for 0.04%, 0.06%, 0.08%, and 0.10% doses of the analgesic that were administered, respectively. The EC50 value was 0.051% (95% confidence interval [CI], 0.011%–0.065%) while the EC90 value was recorded to be 0.117% (95% CI, 0.094%–0.212%). Side effects were similar among groups.

Conclusion: A ropivacaine dose of 0.117% can be used as epidural analgesia for maintaining the 1st stage of labor when it was combined with dexmedetomidine (0.4 μg mL−1) and the PIEB technique.

Clinical Trial Register:https://www.chictr.org.cn/index.aspx, identifier ChiCTR2200059557
The First-year Integration Test: a validation study
Authors: Willems Jonas , Vanoverberghe Veerle , Coertjens Liesje , Donche Vincent
Published: August 2023

To date, there has been little agreement on what important facets should be incorporated in quantitative measures of the academic and social first-year experience. Moreover, such scales are typically developed in academic higher education (HE) contexts (i.e., universities providing more theoretical and scientific education), and are disconnected from the experiences of students in professional HE contexts (i.e., university colleges, offering more vocational education that prepares students for practicing a specific occupation, such as social work). The First-year Integration Test (FIT) is a newly developed instrument that aims to map out students’ perceptions of how they are dealing with their academic and social transition in the first semester of HE, and was based on thorough qualitative research in professional HE. In the present study, the psychometric value of FIT is explored. Results show that FIT has good construct validity, and all scales are internally consistent. Also, evidence was found for the convergent, discriminant and criterion-related validity of the instrument. We argue that FIT holds potential as a tool for generating student feedback, as a monitoring tool within an institution’s quality assurance system, and as a valuable research instrument.
Individual- and institution-level predictors of the turnover intention of medical staff among rural primary medical institutions in Xinjiang Production and Construction Corps, China: a cross-sectional multi-level analysis
Authors: Lin Taoyu , Li Ye , Li Yuanyuan , Guo Wei , Guo Xiaoying , Tang Changmin
Published: August 2023

Background

Primary medical staff (PMS) are the guardians of population health. However, their loss further worsens the shortage and uneven distribution of human health resources, which should be addressed immediately. This study aimed to investigate the current status of turnover intention of rural PMS in Xinjiang Production and Construction Corps (XPCC) in China and its influencing factors atthe individual and institutional levels to provide reliable baseline data for intervention strategies to protect valuable rural PMS.

Methods

Participants were recruited from rural public health institutions of the XPCC using a cross-sectional multistage sampling process. Data on participants’ turnover intention and individual- and institution-level indicators were obtained through standardized electronic questionnaires and statistical reports of regional health administrative departments. The key factors influencing PMS turnover intention were identified us ingunivariateandmulti-level logistic regression analysis.

Findings

Overall, 20.5% (447/2182) of participants reported turnover intention. Univariate analysis showed that the occurrence of turnover intention was significantly influenced by marriage, education, age, year of working, monthly income, human resource management practices (HRMP), job satisfaction, per capita served population (PCSP) and number of beds (p < 0.05). Multi-level logistic regression analysis showed that bachelor’s degree or above and intermediate professional title were closely related to the occurrence of turnover intention (p < 0.05), age 41–50 years old and above, high human resource management practice, and high job satisfaction effectively reduced the odds (p < 0.05). The odds of turnover intention increased by 37% (p < 0.10) for PMS in institutions with PCSP more than 250 people. In contrast, the odds of turnover intention decreased to 68% (p < 0.05) for PMS in institutions with more than 50 beds.

Conclusion

Government-run primary medical institutions face the risk of PMS turnover intention. From a personal perspective, the high-risk population fortheturnover intention was mainly the PMS with bachelor’s degrees or above and intermediate professional titles. The low-risk population was the PMS with aged over 40 years, a higher evaluation of human resource management practice, and job satisfaction. From the perspective of primary medical institutions, larger institutions can reduce the turnover intention of individuals, whereas the size of the service population has the opposite effect.