bluuebunny/crossref_metadata_2025 huggingface dataset:
p53 mutation and deletion contribute to tumor immune evasion
Authors: Liu Siyang , Liu Tianyao , Jiang Jiaxuan , Guo Hongqian , Yang Rong
Published: February 2023

TP53 (or p53) is widely accepted to be a tumor suppressor. Upon various cellular stresses, p53 mediates cell cycle arrest and apoptosis to maintain genomic stability. p53 is also discovered to suppress tumor growth through regulating metabolism and ferroptosis. However, p53 is always lost or mutated in human and the loss or mutation of p53 is related to a high risk of tumors. Although the link between p53 and cancer has been well established, how the different p53 status of tumor cells help themselves evade immune response remains largely elusive. Understanding the molecular mechanisms of different status of p53 and tumor immune evasion can help optimize the currently used therapies. In this context, we discussed the how the antigen presentation and tumor antigen expression mode altered and described how the tumor cells shape a suppressive tumor immune microenvironment to facilitate its proliferation and metastasis.
Prevalence of sexual violence and associated factors among women attending antenatal care in Debre Markos at public health institutions in north-west Ethiopia, 2021
Authors: Abegaz Marta Yimam , Muche Haymanot Alem , Aynalem Getie Lake , Anteneh Tazeb Alemu , Tibebu Nebyu Solomon , Gedef Getachew Muluye , Mengstie Aregash Sitot
Published: February 2023

Background

Sexual violence refers to being forced to perform any unwanted sexual act. Due to the negative effects on both the mother and the fetus, sexual assault during pregnancy is a public health concern. Knowing the prevalence of sexual violence during pregnancy helps policymakers understand the extent of the problem and can be considered the first step toward implementing interventions for prevention and treatment. This study was done to determine the prevalence of sexual violence and its associated factors during pregnancy in public hospitals in Debre Markos.

Methods

An institution-based cross-sectional study was conducted among 306 pregnant women in Debre Markos, north west Ethiopia from May 1 to June 30, 2021, 2021. A systematic random sampling procedure was used to select study participants. Data were collected using a structured and interviewer-administered questionnaire, and a pre-test was done. Both bi-variable and multivariable logistic regression analyses were undertaken to identify significantly associated variables with sexual violence. The adjusted odds ratio (AOR) with its 95% confidence interval (CI) at a p-value of ≤ 0.05 was used to claim statistical association.

Results

There were 304 interviewed respondents with a response rate of 99.3%. In this study, the overall prevalence of sexual violence among pregnant mothers during the current pregnancy was 19.4%. A husband who had no formal education {AOR = 3.48; 95% CI: 1.06, 11.39}, pregnant mothers who had no formal education {AOR =  6.1; 95% CI: 1.50–18.11}, pregnant mothers who had secondary education {AOR = 2.80, 95% CI: 1.15, 6.81}, being a housewife {AOR = 3.87, 95 CI:1.21, 12.37}, and being a governmental employee {AOR = 4.49, 95% CI: 1.22, 16.40} were factors associated with sexual violence at the value of p ≤ 0.05.

Conclusions and recommendations

In this study, approximately one-fifth of the study participants experienced sexual violence during their current pregnancy. To reduce this, interventions should focus on the education of women as well as their partner about violence against women and on initiatives to economically empower women.
Crosstalk between microbiome, regulatory T cells and HCA2 orchestrates the inflammatory response in a murine psoriasis model
Authors: Schwarz Agatha , Philippsen Rebecca , Piticchio Serena G. , Hartmann Jan N. , Häsler Robert , Rose-John Stefan , Schwarz Thomas
Published: February 2023

The organ-specific microbiome plays a crucial role in tissue homeostasis, among other things by inducing regulatory T cells (Treg). This applies also to the skin and in this setting short chain fatty acids (SCFA) are relevant. It was demonstrated that topical application of SCFA controls the inflammatory response in the psoriasis-like imiquimod (IMQ)-induced murine skin inflammation model. Since SCFA signal via HCA2, a G-protein coupled receptor, and HCA2 expression is reduced in human lesional psoriatic skin, we studied the effect of HCA2 in this model. HCA2 knock-out (HCA2-KO) mice reacted to IMQ with stronger inflammation, presumably due to an impaired function of Treg. Surprisingly, injection of Treg from HCA2-KO mice even enhanced the IMQ reaction, suggesting that in the absence of HCA2 Treg switch from a suppressive into a proinflammatory type. HCA2-KO mice differed in the composition of the skin microbiome from wild type mice. Co-housing reversed the exaggerated response to IMQ and prevented the alteration of Treg, implying that the microbiome dictates the outcome of the inflammatory reaction. The switch of Treg into a proinflammatory type in HCA2-KO mice could be a downstream phenomenon. This opens the opportunity to reduce the inflammatory tendency in psoriasis by altering the skin microbiome.
SARS-COV-2 viroporins activate the NLRP3-inflammasome by the mitochondrial permeability transition pore
Authors: Guarnieri Joseph W. , Angelin Alessia , Murdock Deborah G. , Schaefer Patrick , Portluri Prasanth , Lie Timothy , Huang Jessica , Wallace Douglas C.
Published: February 2023

Background

Compared to healthy controls, severe COVID19 patients display increased levels of activated NLRP3-inflammasome (NLRP3-I) and interleukin (IL)-1β. SARS-CoV-2 encodes viroporin proteins E and Orf3a(2-E+2-3a) with homologs to SARS-CoV-1, 1-E+1-3a, which elevate NLRP3-I activation; by an unknown mechanism. Thus, we investigated how 2-E+2-3a activates the NLRP3-I to better understand the pathophysiology of severe COVID-19.

Methods

We generated a polycistronic expression-vector co-expressing 2-E+2-3a from a single transcript. To elucidate how 2-E+2-3a activates the NLRP3-I, we reconstituted the NLRP3-I in 293T cells and used THP1-derived macrophages to monitor the secretion of mature IL-1β. Mitochondrial physiology was assessed using fluorescent microscopy and plate reader assays, and the release of mitochondrial DNA (mtDNA) was detected from cytosolic-enriched fractions using Real-Time PCR.

Results

Expression of 2-E+2-3a in 293T cells increased cytosolic Ca++ and elevated mitochondrial Ca++, taken up through the MCUi11-sensitive mitochondrial calcium uniporter. Increased mitochondrial Ca++ stimulated NADH, mitochondrial reactive oxygen species (mROS) production and the release of mtDNA into the cytosol. Expression of 2-E+2-3a in NLRP3-I reconstituted 293T cells and THP1-derived macrophages displayed increased secretion of IL-1β. Increasing mitochondrial antioxidant defenses via treatment with MnTBAP or genetic expression of mCAT abolished 2-E+2-3a elevation of mROS, cytosolic mtDNA levels, and secretion of NLRP3-activated-IL-1β. The 2-E+2-3a-induced release of mtDNA and the secretion of NLRP3-activated-IL-1β were absent in cells lacking mtDNA and blocked in cells treated with the mitochondrial-permeability-pore(mtPTP)-specific inhibitor NIM811.

Conclusion

Our findings revealed that mROS activates the release of mitochondrial DNA via the NIM811-sensitive mitochondrial-permeability-pore(mtPTP), activating the inflammasome. Hence, interventions targeting mROS and the mtPTP may mitigate the severity of COVID-19 cytokine storms.
Cutaneous manifestations associated with immune checkpoint inhibitors
Authors: Watanabe Tomoya , Yamaguchi Yukie
Published: February 2023

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly and has extended to numerous cancers. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and T cell activation, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). However, ICI-driven alterations in the immune system can induce various immune-related adverse events (irAEs) that affect multiple organs. Among these, cutaneous irAEs are the most common and often the first to develop. Skin manifestations are characterized by a wide range of phenotypes, including maculopapular rash, psoriasiform eruption, lichen planus-like eruption, pruritus, vitiligo-like depigmentation, bullous diseases, alopecia, and Stevens-Johnson syndrome/toxic epidermal necrolysis. In terms of pathogenesis, the mechanism of cutaneous irAEs remains unclear. Still, several hypotheses have been proposed, including activation of T cells against common antigens in normal tissues and tumor cells, increased release of proinflammatory cytokines associated with immune-related effects in specific tissues/organs, association with specific human leukocyte antigen variants and organ-specific irAEs, and acceleration of concurrent medication-induced drug eruptions. Based on recent literature, this review provides an overview of each ICI-induced skin manifestation and epidemiology and focuses on the mechanisms underlying cutaneous irAEs.
CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies
Authors: Zhang Xiaomin , Zhang Hui , Lan Huixuan , Wu Jinming , Xiao Yang
Published: February 2023

Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export (SINEs), and T cell redirecting bispecific antibodies. However, MM remains an incurable neoplastic plasma cell disorder, and almost all MM patients inevitably relapse due to drug resistance. Encouragingly, B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in the treatment of relapsed/refractory (R/R) MM and brought new hopes for R/R MM patients in recent years. Due to antigen escape, the poor persistence of CAR-T cells, and the complicated tumor microenvironment, a significant population of MM patients still experience relapse after anti-BCMA CAR-T cell therapy. Additionally, the high manufacturing costs and time-consuming manufacturing processes caused by the personalized manufacturing procedures also limit the broad clinical application of CAR-T cell therapy. Therefore, in this review, we discuss current limitations of CAR-T cell therapy in MM, such as the resistance to CAR-T cell therapy and the limited accessibility of CAR-T cell therapy, and summarize some optimization strategies to overcome these challenges, including optimizing CAR structure, such as utilizing dual-targeted/multi-targeted CAR-T cells and armored CAR-T cells, optimizing manufacturing processes, combing CAR-T cell therapy with existing or emerging therapeutic approaches, and performing subsequent anti-myeloma therapy after CAR-T cell therapy as salvage therapy or maintenance/consolidation therapy.
The gut microbiota correlate with the disease characteristics and immune status of patients with untreated diffuse large B-cell lymphoma
Authors: Lin Zhouning , Mao Dan , Jin Changyu , Wang Jiaping , Lai Yanli , Zhang Yanli , Zhou Miao , Ge Qunfang , Zhang Ping , Sun Yongcheng , Xu Kaihong , Wang Yi , Zhu Huiling , Lai Binbin , Wu Hao , Mu Qitian , Ouyang Guifang , Sheng Lixia
Published: February 2023

Background

Gut microbiota characteristics in patients with diffuse large B-cell lymphoma (DLBCL) are reportedly different when compared with the healthy population and it remains unclear if the gut microbiota affects host immunity and clinical disease features. This research investigated the gut microbiota in patients with untreated DLBCL and analyzed its correlation with patient clinical characteristics, humoral, and cell immune status.

Methods

Thirty-five patients with untreated DLBCL and 20 healthy controls (HCs) were recruited to this study and microbiota differences in stool samples were analyzed by 16S rDNA sequencing. Absolute ratios of immune cell subset counts in peripheral blood were detected by flow cytometry and peripheral blood cytokine levels were detected by enzyme-linked immunosorbent assay. Relationships between changes in patient microbiomes and clinical characteristics, such as clinical stage, international prognostic index (IPI) risk stratification, cell origin, organ involved and treatment responses were investigated and correlations between differential microbiota and host immune indices were analyzed.

Results

The alpha-diversity index of intestinal microecology in DLBCL patients was not significantly different when compared with HCs (P>0.05), nonetheless beta-diversity was significantly decreased (P=0.001). p_Proteobacteria were dominant in DLBCL, while p_Bacteroidetes abundance was significantly decreased when compared with HCs (P<0.05). Gut microbiota characteristics were identified that were associated with clinical features, such as tumor load, risk stratification and cell origin, and correlation analyses were performed between differential flora abundance associated with these clinical features and host immune status. The p_Firmicutes was positively correlated with absolute lymphocyte values, g_Prevotella_2 and s_un_g_Prevotella_2 were negatively correlated with absolute lymphocyte values, T cell counts and CD4 cell counts, while g_Pyramidobacter, s_un_g_Pyramidobacter, and f_Peptostreptococcaceae were negatively correlated with IgA.

Conclusions

Dominant gut microbiota, abundance, diversity, and structure in DLBCL were influenced by the disease, correlated with patient immune status and this suggested that the microecology-immune axis may be involved in regulating lymphoma development. In the future, it may be possible to improve immune function in patients with DLBCL by regulating the gut microbiota, improve treatment response rates and increase patient survival rates.
Autoantibodies against complement factor B in rheumatoid arthritis
Authors: Matola Alexandra T. , Fülöp Angéla , Rojkovich Bernadette , Nagy György , Sármay Gabriella , Józsi Mihály , Uzonyi Barbara
Published: February 2023

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder affecting the joints. Many patients carry anti-citrullinated protein autoantibodies (ACPA). Overactivation of the complement system seems to be part of the pathogenesis of RA, and autoantibodies against the pathway initiators C1q and MBL, and the regulator of the complement alternative pathway, factor H (FH), were previously reported. Our aim was to analyze the presence and role of autoantibodies against complement proteins in a Hungarian RA cohort. To this end, serum samples of 97 ACPA-positive RA patients and 117 healthy controls were analyzed for autoantibodies against FH, factor B (FB), C3b, C3-convertase (C3bBbP), C1q, MBL and factor I. In this cohort, we did not detect any patient with FH autoantibodies but detected C1q autoantibodies in four patients, MBL autoantibodies in two patients and FB autoantibodies in five patients. Since the latter autoantibodies were previously reported in patients with kidney diseases but not in RA, we set out to further characterize such FB autoantibodies. The isotypes of the analyzed autoantibodies were IgG2, IgG3, IgGκ, IgGλ and their binding site was localized in the Bb part of FB. We detected in vivo formed FB–autoanti-FB complexes by Western blot. The effect of the autoantibodies on the formation, activity and FH-mediated decay of the C3 convertase in solid phase convertase assays was determined. In order to investigate the effect of the autoantibodies on complement functions, hemolysis assays and fluid phase complement activation assays were performed. The autoantibodies partially inhibited the complement-mediated hemolysis of rabbit red blood cells, inhibited the activity of the solid phase C3-convertase and C3 and C5b-9 deposition on complement activating surfaces. In summary, in ACPA-positive RA patients we identified FB autoantibodies. The characterized FB autoantibodies did not enhance complement activation, rather, they had inhibitory effect on complement. These results support the involvement of the complement system in the pathomechanism of RA and raise the possibility that protective autoantibodies may be generated in some patients against the alternative pathway C3 convertase. However, further analyses are needed to assess the exact role of such autoantibodies.
Interleukin-27-dependent transcriptome signatures during neonatal sepsis
Authors: Povroznik Jessica M. , Akhter Halima , Vance Jordan K. , Annamanedi Madhavi , Dziadowicz Sebastian A. , Wang Lei , Divens Ashley M. , Hu Gangqing , Robinson Cory M.
Published: February 2023

Human newborns exhibit increased vulnerability and risk of mortality from infection that is consistent with key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the immune suppressive cytokine, IL-27, in neonatal cells and tissues from mice and humans. In a murine model of neonatal sepsis, mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of bacteria with reduced systemic inflammation. To explore a reprogramming of the host response in the absence of IL-27 signaling, we profiled the transcriptome of the neonatal spleen during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. We identified 634 genes that were differentially expressed, and those most upregulated in WT mice were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. These genes failed to increase in the IL-27Rα KO mice. We further isolated an innate myeloid population enriched in macrophages from the spleens of control and infected WT neonates and observed similar changes in gene expression aligned with changes in chromatin accessibility. This supports macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight the first report of improved pathogen clearance amidst a less inflammatory environment in IL-27Rα KO. This suggests a direct relationship between IL-27 signaling and bacterial killing. An improved response to infection that is not reliant upon heightened levels of inflammation offers new promise to the potential of antagonizing IL-27 as a host-directed therapy for neonates.
Bio-deposition approaches for sustainable execution of recycled aggregates in concretes
Authors: Ahmad Muhammad Arslan , Liu Bing , Li Qiuwei , Adeel Muhammad , Zhang Jinlong , Zhou Yingwu , Deng Xu
Published: February 2023

Our study offers a quantitative framework for microbial-induced calcium carbonate precipitation (MICP) to uplift the properties of recycled aggregate concrete (RAC). In this regard, a marine alkalophilic bacterium Bacillus sp. B6 was employed, and its growth and mineralization efficiency under seawater conditions was investigated. Optimization of MICP was achieved with different nutrient sources and bacterial introduction methods (dip and spray). The efficiency of treated recycled aggregates (RA) was determined by using scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) in combination with basic technologies of density improvement and water absorption. The results show that the optimal nutrient sources of carbon and nitrogen are glucose (7 g L−1) and tryptone (5 gL−1), respectively. Spray treated recycled aggregate (RA) is reported to be efficient with a reduction in water absorption (∼19%), and improvement in bulk (∼2.4%) and apparent density (∼1.7%). The effectiveness of the MICP treatment process is confirmed with SEM and EDX observations, indicating the filling of microcracks with calcium carbonates. As such, the mechanical properties of RAC with spray treated RA significantly increase by up to ∼24% in compressive strength as compared to the control treatment. Current findings will help revitalize the construction industry by utilizing the MICP-treated RA and minimizing the load on natural aggregates.
Access and reimbursement pathways for digital health solutions and in vitro diagnostic devices: Current scenario and challenges
Authors: Mantovani Andrea , Leopaldi Claudia , Nighswander Cassandra Maria , Di Bidino Rossella
Published: February 2023

Objectives

Digital therapeutics (DTx) are innovative solutions that use meaningful data to provide evidence-based decisions for the prevention, treatment, and management of diseases. Particular attention is paid to software-based in vitro diagnostics (IVDs). With this point of view, a strong connection between DTx and IVDs is observed.

Methods

We investigated the current regulatory scenarios and reimbursement approaches adopted for DTx and IVDs. The initial assumption was that countries apply different regulations for the access to the market and adopt different reimbursement systems for both DTx and IVDs. The analysis was limited to the US, European countries (Germany, France, and UK), and Australia due to maturity in digital health product adoption and regulatory processes, and recent regulations related to IVDs. The final aim was to provide a general comparative overview and identify those aspects that should be better addressed to support the adoption and commercialization of DTx and IVDs.

Results

Many countries regulate DTx as medical devices or software integrated with a medical device, and some have a more specific pathway than others. Australia has more specific regulations classifying software used in IVD. Some EU countries are adopting similar processes to the Digital Health Applications (DiGA) under Germany's Digitale-Versorgung Gesetz (DVG) law, which deems DTx eligible for reimbursement during the fast access pathway. France is working on a fast-track system to make DTx available to patients and reimbursable by the public system. The US retains some coverage through private insurance, federal and state programs like Medicaid and Veterans Affairs, and out-of-pocket spending. The updated Medical Devices Regulation (MDR) and In Vitro Diagnostic Regulation (IVDR) in the EU includes a classification system specifying how software integrated with medical devices, and IVDs specifically must be regulated.

Conclusion

The outlook for DTx and IVDs is changing as they are becoming more technologically advanced, and some countries are adapting their device classifications depending on specific features. Our analysis showed the complexity of the issue demonstrating how fragmented are regulatory systems for DTx and IVDs. Differences emerged in terms of definitions, terminology, requested evidence, payment approaches and the overall reimbursement landscape. The complexity is expected to have a direct impact on the commercialization of and access to DTx and IVDs. In this scenario, willingness to pay of different stakeholders is a key theme.
Quantitatively detecting Candida albicans enolase1 with a one-step double monoclonal antibody sandwich ELISA assay
Authors: Piao Jingzi , Li Ning , Zhang Lina , Meng Hanbing , Sun Qingqing , He Zhengxin
Published: February 2023

Invasive candidiasis (IC) is often a cause of severe concern for the hospitalized patients, particularly those who are critically sick. However management of this disease is challenging due to a lack of effective laboratory diagnostic techniques. Hence, we have developed a one-step double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) using a pair of specific monoclonal antibodies (mAbs) for the quantitative detection of Candida albicans enolase1 (CaEno1), which is considered as an important diagnostic biomarker for IC. The diagnostic efficiency of the DAS-ELISA was evaluated by using a rabbit model of systemic candidiasis and compared with other assays. The method validation results demonstrated that the developed method was sensitive, reliable, and feasible. The findings of the rabbit model plasma analysis indicated that the diagnostic efficiency of the CaEno1 detection assay was better in comparison to the (1,3)-β-D-glucan detection and blood culture. CaEno1 is present in the blood of infected rabbits for a brief period and at relatively low levels and thus the combination of CaEno1 antigen and IgG antibodies detection could aid to increase diagnostic efficiency. However, to improve the clinical application of CaEno1 detection in the future, efforts should be made to increase the detection limit of the test by promoting technical developments and by optimizing the protocol for the clinical serial determinations.
EMDS-7: Environmental microorganism image dataset seventh version for multiple object detection evaluation
Authors: Yang Hechen , Li Chen , Zhao Xin , Cai Bencheng , Zhang Jiawei , Ma Pingli , Zhao Peng , Chen Ao , Jiang Tao , Sun Hongzan , Teng Yueyang , Qi Shouliang , Huang Xinyu , Grzegorzek Marcin
Published: February 2023

Nowadays, the detection of environmental microorganism indicators is essential for us to assess the degree of pollution, but the traditional detection methods consume a lot of manpower and material resources. Therefore, it is necessary for us to make microbial data sets to be used in artificial intelligence. The Environmental Microorganism Image Dataset Seventh Version (EMDS-7) is a microscopic image data set that is applied in the field of multi-object detection of artificial intelligence. This method reduces the chemicals, manpower and equipment used in the process of detecting microorganisms. EMDS-7 including the original Environmental Microorganism (EM) images and the corresponding object labeling files in “.XML” format file. The EMDS-7 data set consists of 41 types of EMs, which has a total of 2,65 images and 13,216 labeled objects. The EMDS-7 database mainly focuses on the object detection. In order to prove the effectiveness of EMDS-7, we select the most commonly used deep learning methods (Faster-Region Convolutional Neural Network (Faster-RCNN), YOLOv3, YOLOv4, SSD, and RetinaNet) and evaluation indices for testing and evaluation. EMDS-7 is freely published for non-commercial purpose at: https://figshare.com/articles/dataset/EMDS-7_DataSet/16869571.
Ultrastructural study of the duck brain infected with duck Tembusu virus
Authors: Yang Sheng , Shi Yonghong , Wu Jingxian , Chen Qiusheng
Published: February 2023

Duck Tembusu virus (DTMUV) is an emerging avian flavivirus characterized by causing severe ovaritis and neurological symptoms in ducks. The pathology of the central nervous system (CNS) caused by DTMUV is rarely studied. This study aimed to systematically investigate the ultrastructural pathology of the CNS of ducklings and adult ducks infected with DTMUV via transmission electron microscopy technology at a cytopathological level. The results showed that DTMUV caused extensive lesions in the brain parenchyma of ducklings and slight damage in adult ducks. The neuron was the target cell of DTMUV, and virions were mainly observed in their cisternae of rough endoplasmic reticulum and the saccules of Golgi apparatus. The neuron perikaryon showed degenerative changes where the membranous organelles gradually decomposed and disappeared with DTMUV infection. Besides neurons, DTMUV infection induced marked swelling in astrocytic foot processes in ducklings and evident myelin lesions in ducklings and adult ducks. The activated microglia were observed phagocytizing injured neurons, neuroglia cells, nerve fibers, and capillaries after the DTMUV infection. Affected brain microvascular endothelial cells were surrounded by edema and had increased pinocytotic vesicles and cytoplasmic lesions. In conclusion, the above results systematically describe the subcellular morphological changes of the CNS after DTMUV infection, providing an ultrastructural pathological research basis for DTMUV-induced neuropathy.
A Klebsiella pneumoniae NDM-1+ bacteriophage: Adaptive polyvalence and disruption of heterogenous biofilms
Authors: Gilcrease Eddie B. , Casjens Sherwood R. , Bhattacharjee Ananda , Goel Ramesh
Published: February 2023

Bacteriophage KL-2146 is a lytic virus isolated to infect Klebsiella pneumoniae BAA2146, a pathogen carrying the broad range antibiotic resistance gene New Delhi metallo-betalactamase-1 (NDM-1). Upon complete characterization, the virus is shown to belong to the Drexlerviridae family and is a member of the Webervirus genus located within the (formerly) T1-like cluster of phages. Its double-stranded (dsDNA) genome is 47,844 bp long and is predicted to have 74 protein-coding sequences (CDS). After challenging a variety of K. pneumoniae strains with phage KL-2146, grown on the NDM-1 positive strain BAA-2146, polyvalence was shown for a single antibiotic-sensitive strain, K. pneumoniae 13,883, with a very low initial infection efficiency in liquid culture. However, after one or more cycles of infection in K. pneumoniae 13,883, nearly 100% infection efficiency was achieved, while infection efficiency toward its original host, K. pneumoniae BAA-2146, was decreased. This change in host specificity is reversible upon re-infection of the NDM-1 positive strain (BAA-2146) using phages grown on the NDM-1 negative strain (13883). In biofilm infectivity experiments, the polyvalent nature of KL-2146 was demonstrated with the killing of both the multidrug-resistant K. pneumoniae BAA-2146 and drug-sensitive 13,883 in a multi-strain biofilm. The ability to infect an alternate, antibiotic-sensitive strain makes KL-2146 a useful model for studying phages infecting the NDM-1+ strain, K. pneumoniae BAA-2146.
Thermostability modification of β-mannanase from Aspergillus niger via flexibility modification engineering
Authors: Tan Shundong , Tao Xiumei , Zheng Pu , Chen Pengcheng , Yu Xiaowei , Li Ning , Gao Tiecheng , Wu Dan
Published: February 2023

Introduction

β-Mannanases can hydrolyze mannans, which are widely available in nature. However, the optimum temperature of most β-mannanases is too low to be directly utilized in industry.

Methods

To further improve the thermostability of Anman (mannanase from Aspergillus niger CBS513.88), B-factor and Gibbs unfolding free energy change were used to modify the flexible of Anman, and then combined with multiple sequence alignment and consensus mutation to generate an excellent mutant. At last, we analyzed the intermolecular forces between Anman and the mutant by molecular dynamics simulation.

Results

The thermostability of combined mutant mut5 (E15C/S65P/A84P/A195P/T298P) was increased by 70% than the wild-type Amman at 70°C, and the melting temperature (Tm) and half-life (t1/2) values were increased by 2°C and 7.8-folds, respectively. Molecular dynamics simulation showed reduced flexibility and additional chemical bonds in the region near the mutation site.

Discussion

These results indicate that we obtained a Anman mutant that is more suitable for industrial application, and they also confirm that a combination of rational and semi-rational techniques is helpful for screening mutant sites.
Mechanisms of gut microbiota-immune-host interaction on glucose regulation in type 2 diabetes
Authors: Zhou Yu-Dian , Liang Feng-Xia , Tian Hao-Ran , Luo Dan , Wang Ya-Yuan , Yang Shu-Rui
Published: February 2023

Intestinal absorption of food is one of the sources of glucose. Insulin resistance and impaired glucose tolerance caused by lifestyle and diet are the precursors of type 2 diabetes. Patients with type 2 diabetes have trouble controlling their blood sugar levels. For long-term health, strict glycemic management is necessary. Although it is thought to be well correlated with metabolic diseases like obesity, insulin resistance, and diabetes, its molecular mechanism is still not completely understood. Disturbed microbiota triggers the gut immune response to reshape the gut homeostasis. This interaction not only maintains the dynamic changes of intestinal flora, but also preserves the integrity of the intestinal barrier. Meanwhile, the microbiota establishes a systemic multiorgan dialog on the gut-brain and gut-liver axes, intestinal absorption of a high-fat diet affects the host’s feeding preference and systemic metabolism. Intervention in the gut microbiota can combat the decreased glucose tolerance and insulin sensitivity linked to metabolic diseases both centrally and peripherally. Moreover, the pharmacokinetics of oral hypoglycemic medications are also influenced by gut microbiota. The accumulation of drugs in the gut microbiota not only affects the drug efficacy, but also changes the composition and function of them, thus may help to explain individual therapeutic variances in pharmacological efficacy. Regulating gut microbiota through healthy dietary patterns or supplementing pro/prebiotics can provide guidance for lifestyle interventions in people with poor glycemic control. Traditional Chinese medicine can also be used as complementary medicine to effectively regulate intestinal homeostasis. Intestinal microbiota is becoming a new target against metabolic diseases, so more evidence is needed to elucidate the intricate microbiota-immune-host relationship, and explore the therapeutic potential of targeting intestinal microbiota.
Effects of Aspergillus niger on cyanogenic glycosides removal and fermentation qualities of ratooning sorghum
Authors: Zhai Jianrong , Wang Bo , Sun Yingpeng , Yang Jianfeng , Zhou Junfeng , Wang Tianyu , Zhang Wenlan , Qi Cai , Guo Yanjun
Published: February 2023

Introduction

Cyanogenic glycosides (CNglcs) are bioactive plant products involving in plant defense against herbivores by virtue of their abilities to release toxic hydrogen cyanide (HCN). Aspergillus niger has been shown to be effective in producing β-glucosidase, which could degrade CNglcs. However, whether A. niger could remove CNglcs under ensiling conditions is still unknown.

Methods

In this study, we first investigated the HCN contents in ratooning sorghums for two years, then the sorghums were ensiled with or without the addition of A. niger.

Results

Two years’ investigation indicated that the contents of HCN in fresh ratooning sorghum were larger than 801 mg/kg FW (fresh weight), which could not be reduced by silage fermentation under safety threshold (200 mg/kg FW). A. niger could produce β-glucosidase over a range of pH and temperature, which degraded the CNglcs and removed the hydrogen cyanide (HCN) at early days of ratooning sorghum fermentation. The addition of A. niger (2.56 × 107 CFU/ml) altered the microbial community, increased bacterial diversity, improved the nutritive qualities, and reduced the HCN contents in ensiled ratooning sorghum lower than 100 mg/kg FW after 60 days of fermentation. Overall, the addition of 150 ml A. niger + 50 ml sterile water per 3 kg silage could efficiently remove CNglcs from ratooning sorghum silage.

Conclusion

In conclusion, A. niger could produce β-glucosidase which degraded the CNglcs during the early days of fermentation, benefiting the ensiling process and improving the utilization of ratooning sorghum.
Opto-APC: Engineering of cells that display phytochrome B on their surface for optogenetic studies of cell-cell interactions
Authors: Russ Marissa , Ehret Anna K. , Hörner Maximilian , Peschkov Daniel , Bohnert Rebecca , Idstein Vincent , Minguet Susana , Weber Wilfried , Lillemeier Björn F. , Yousefi O. Sascha , Schamel Wolfgang W.
Published: February 2023

The kinetics of a ligand-receptor interaction determine the responses of the receptor-expressing cell. One approach to experimentally and reversibly change this kinetics on demand is optogenetics. We have previously developed a system in which the interaction of a modified receptor with an engineered ligand can be controlled by light. In this system the ligand is a soluble Phytochrome B (PhyB) tetramer and the receptor is fused to a mutated PhyB-interacting factor (PIFS). However, often the natural ligand is not soluble, but expressed as a membrane protein on another cell. This allows ligand-receptor interactions in two dimensions. Here, we developed a strategy to generate cells that display PhyB as a membrane-bound protein by expressing the SpyCatcher fused to a transmembrane domain in HEK-293T cells and covalently coupling purified PhyB-SpyTag to these cells. As proof-of-principle, we use Jurkat T cells that express a GFP-PIFS-T cell receptor and show that these cells can be stimulated by the PhyB-coupled HEK-293T cells in a light dependent manner. Thus, we call the PhyB-coupled cells opto-antigen presenting cells (opto-APCs). Our work expands the toolbox of optogenetic technologies, allowing two-dimensional ligand-receptor interactions to be controlled by light.
Metabolome combined with gut microbiome revealed the lipid-lowering mechanism of Xuezhiping capsule on hyperlipidemic hamster induced by high fat diet
Authors: Wang Li , Zhang Zhixin , Luo Gan , Wang Ying , Du Ke , Gao Xiaoyan
Published: February 2023

Introduction: Hyperlipidemia is a common metabolic disorder with presence of excess fat or lipids in the blood, may induce liver injury, oxidative stress and inflammatory. Xuezhiping capsule (XZP) is a famous Chinese patent medicine clinically used for anti-hyperlipidemia. However, the regulation mechanism of XZP on hyperlipidemia has not been elucidated so far.

Methods: This study aimed to explore the effects of XZP on hypolipidemic, antioxidant and anti-inflammatory effects, and the potential mechanism by a combination of untargeted metabolomics and 16S rRNA sequencing.

Results: The results indicated that XZP reduced the level of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), increased the level of high density liptein cholesterol (HDL-C), alleviated excessive accumulation of lipid droplets in liver. Biochemical indexes of liver function including gamma glutamyl transferase (GGT) and glutamic oxaloacetic transaminase (GOT) in liver were remarkably decreased. Meanwhile, XZP increased the level of oxidative stress biochemical indexes including superoxide dismutase (SOD) and glutathione (GSH). In addition, XZP increased the level of peroxisome proliferators-activated receptors α (PPARα), acetyl CoA carboxylase 1 (ACOX1) and cholesterol 7-alpha hydroxylase (CYP7A1) in liver, and improved lipid metabolism in serum, liver and fecal lipid metabolism. XZP increased diversity index and the ratio of Firmicutes and Bacteroidetes, regulated seventeen genera, and illustrated strong correlations with liver lipid metabolism and phenotypic indicators.

Discussion: These findings suggest that XZP reduced blood lipid and liver lipid, protected liver function, anti inflammation and anti-oxidation, ameliorate lipid metabolic disorders by modulating alpha linolenic acid and linoleic acid metabolism, bile acid metabolism, arachidonic acid metabolism, and regulated gut microbiota composition of high-fat diet (HFD) hamsters.
Predictors of cognitive and physical decline: Results from the Health Aging and Body Composition Study
Authors: Handing Elizabeth P. , Hayden Kathleen M. , Leng Xiaoyan Iris , Kritchevsky Stephen B.
Published: February 2023

Background

Risk factors for cognitive decline and physical decline have been studied independently, however older adults might experience decline in both areas i.e., dual decline. Risk factors associated with dual decline are largely unknown and have significant implications on health outcomes. The aim of this study is to explore risk factors associated with dual decline.

Methods

Using data from the Health, Aging and Body Composition (Health ABC) study, a longitudinal prospective cohort study, we examined trajectories of decline based on repeated measures of the Modified Mini-Mental State Exam (3MSE) and the Short Physical Performance Battery (SPPB) across 6 years (n=1,552). We calculated four mutually exclusive trajectories of decline and explored predictors of decline: cognitive decline (n = 306) = lowest quartile of slope on the 3MSE or 1.5 SD below mean at baseline, physical decline (n = 231) = lowest quartile of slope on the SPPB or 1.5 SD below mean at baseline, dual decline (n = 110) = lowest quartile in both measures or 1.5 SD below mean in both measures at baseline. Individuals who did not meet criteria for one of the decline groups were classified as the reference group. (n= 905).

Results

Multinomial logistic regression tested the association of 17 baseline risk factors with decline. Odds of dual decline where significantly higher for individuals at baseline with depressive symptoms (CES-D >16) (Odds Ratio (OR)=2.49, 95% Confidence Interval (CI): 1.05-6.29), ApoE-ε4 carrier (OR= 2.09, 95% CI: 1.06-1.95), or if individuals had lost 5+lbs in past year (OR=1.79, 95% CI: 1.13-2.84). Odds were significantly lower for individuals with a higher score on the Digit Symbol Substitution Test per standard deviation (OR per SD: 0.47, 95% CI 0.36-0.62) and faster 400-meter gait (OR per SD= 0.49, 95% CI: 0.37-0.64).

Conclusion

Among predictors, depressive symptoms at baseline significantly increased the odds of developing dual decline but was not associated with decline in the exclusively cognitive or physical decline groups. APOE-ε4 status increased the odds for cognitive decline and dual decline but not physical decline. More research on dual decline is needed because this group represents a high risk, vulnerable subset of older adults.
A neural active inference model of perceptual-motor learning
Authors: Yang Zhizhuo , Diaz Gabriel J. , Fajen Brett R. , Bailey Reynold , Ororbia Alexander G.
Published: February 2023

The active inference framework (AIF) is a promising new computational framework grounded in contemporary neuroscience that can produce human-like behavior through reward-based learning. In this study, we test the ability for the AIF to capture the role of anticipation in the visual guidance of action in humans through the systematic investigation of a visual-motor task that has been well-explored—that of intercepting a target moving over a ground plane. Previous research demonstrated that humans performing this task resorted to anticipatory changes in speed intended to compensate for semi-predictable changes in target speed later in the approach. To capture this behavior, our proposed “neural” AIF agent uses artificial neural networks to select actions on the basis of a very short term prediction of the information about the task environment that these actions would reveal along with a long-term estimate of the resulting cumulative expected free energy. Systematic variation revealed that anticipatory behavior emerged only when required by limitations on the agent's movement capabilities, and only when the agent was able to estimate accumulated free energy over sufficiently long durations into the future. In addition, we present a novel formulation of the prior mapping function that maps a multi-dimensional world-state to a uni-dimensional distribution of free-energy/reward. Together, these results demonstrate the use of AIF as a plausible model of anticipatory visually guided behavior in humans.
Selection of patients with acute vertebrobasilar artery occlusion for endovascular treatment by magnetic resonance imaging
Authors: Chen Jun , Zhang Jiwei , Zhu Xianjin , Zhang Xuebin , Jiang Bin , Liu Qi , Wei Zheng Z.
Published: February 2023

Background and purpose

The best method for selecting patients with acute vertebrobasilar artery occlusion (VBAO) who would benefit from endovascular treatment (EVT) is still the key question. This study aimed to assess the efficacy of magnetic resonance imaging (MRI) for selecting patients with acute VBAO for EVT.

Materials and methods

A total of 14 patients with suspected acute VBAO on MR angiography (MRA) in the EVT database (from April 2016 to August 2019) were enrolled. Acute Stroke Prognosis Early Computed Tomography Score (ASPECTS) and pons–midbrain index were assessed on diffusion-weighted imaging (DWI). EVT included a stent retriever and a rescue treatment (angioplasty and/or stenting). The proportion of successful reperfusion and favorable functional outcomes (modified Rankin Scale ≤ 3) at 90 days was documented.

Results

A total of 11 patients were included in the final analysis. The median DWI-ASPECTS and pons–midbrain index were 7 and 2, respectively. Underlying stenosis was detected in 10 of 11 (90.9%) patients. Balloon angioplasty and/or stenting were used as rescue therapy for five patients and two patients, respectively. A total of nine patients (81.8%) achieved successful reperfusion (mTICI, 2b, or 3). The 90-day mRS score of 0–3 was achieved in six (54.5%) patients. The mortality rate within 90 days was 18.2% (two of 11 patients).

Conclusion

DWI plus MRA could help select the patients with acute VBAO for EVT by assessing ASPECTS and the pons–midbrain index. Patients could achieve good reperfusion and favorable functional outcomes.
A homozygous PRKN-associated juvenile Parkinson's disease with pregnancy in China
Authors: Li Hong-xing , Dong Mei , Peng Xiao-xiao , Liu Yi-zhe , Wang Han , Li Chao , Du Yi-yi , Zhang Kai , Zong Qiang
Published: February 2023

Background

Although Parkinson's disease (PD) is the second most common neurodegenerative disorder, pregnancy in patients with PD is a relatively rare occurrence because the most common age of onset of PD is beyond the childbearing age, except in patients with Young-Onset PD (YOPD) caused by parkin RBR E3 ubiquitin protein ligase (PRKN) mutations.

Case

In this study, we report the case of a 30-year-old Chinese woman who was affected by PRKN-associated YOPD and was treated with levodopa/benserazide during pregnancy. She gave birth to a healthy baby boy with an Apgar score of 9 through an uncomplicated vaginal delivery.

Conclusion

This case further suggests that levodopa/benserazide during pregnancy is safe in the treatment of PRKN-associated YOPD.