bluuebunny/crossref_metadata_2025 huggingface dataset:
Common Variable Immunodeficiency and Neurodevelopmental Delay Due to a 13Mb Deletion on Chromosome 4 Including the NFKB1 Gene: A Case Report
Authors: Franco-Jarava Clara , Valenzuela Irene , Riviere Jacques G. , Garcia-Prat Marina , Martínez-Gallo Mónica , Dieli-Crimi Romina , Castells Neus , Batlle-Masó Laura , Soler-Palacin Pere , Colobran Roger
Published: June 2022

Syndromic immunodeficiencies are a heterogeneous group of inborn errors of immunity that can affect the development of non-immune organs and systems. The genetic basis of these immunodeficiencies is highly diverse, ranging from monogenic defects to large chromosomal aberrations. Antibody deficiency is the most prevalent immunological abnormality in patients with syndromic immunodeficiencies caused by chromosomal rearrangements, and usually manifests as a common variable immunodeficiency (CVID)-like phenotype. Here we describe a patient with a complex phenotype, including neurodevelopmental delay, dysmorphic features, malformations, and CVID (hypogammaglobulinemia, reduced pre-switch and switch memory B cells, and impaired vaccine response). Microarray-based comparative genomic hybridization (aCGH) revealed a 13-Mb deletion on chromosome 4q22.2-q24 involving 53 genes, some of which were related to the developmental manifestations in our patient. Although initially none of the affected genes could be linked to his CVID phenotype, subsequent reanalysis identified NFKB1 haploinsufficiency as the cause. This study underscores the value of periodic reanalysis of unsolved genetic studies performed with high-throughput technologies (eg, next-generation sequencing and aCGH). This is important because of the ongoing incorporation of new data establishing the relationship between genes and diseases. In the present case, NFKB1 had not been associated with human disease at the time aCGH was performed. Eight years later, reanalysis of the genes included in the chromosome 4 deletion enabled us to identify NFKB1 haploinsufficiency as the genetic cause of our patient’s CVID. In the future, other genes included in the deletion may be linked to human disease, allowing us to better define the molecular basis of our patient’s complex clinical phenotype.
Specific Antibody and the T-Cell Response Elicited by BNT162b2 Boosting After Two ChAdOx1 nCoV-19 in Common Variable Immunodeficiency
Authors: Goda Vera , Kriván Gergely , Kulcsár Andrea , Gönczi Márton , Tasnády Szabolcs , Matula Zsolt , Nagy Ginette , Bekő Gabriella , Horváth Máté , Uher Ferenc , Szekanecz Zoltán , Vályi-Nagy István
Published: June 2022

Common variable immunodeficiency (CVID) patients have markedly decreased immune response to vaccinations. In this study we evaluated humoral and T cell-mediated responses against severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) with additional flow cytometric changes in CVID patients receiving booster vaccination with BNT162b2 after two ChAdOx1 nCoV-19. The BNT162b2 vaccine raised the anti-spike protein S immunoglobulin G over the cut-off value from 70% to 83% in CVID, anti-neutralizing antibody had been raised over a cut-off value from 70% to 80% but levels after boosting were significantly less in both tests than in healthy controls (*p=0.02; **p=0.009 respectively). Anti-SARS-CoV-2 immunoglobulin A became less positive in CVID after boosting, but the difference was not significant. The cumulative interferon-γ positive T cell response by ELISpot was over the cut-off value in 53% of the tested individuals and raised to 83% after boosting. This and flow cytometric control of cumulative CD4+ and CD8+ virus-specific T cell absolute counts in CVID were also statistically not different from healthy individuals after boosting. Additional flow cytometric measures for CD45+ lymphocytes, CD3+, and CD19+ cells have not shown significant differences from controls except for lower CD4+T cell counts at both time points (**p=0.003; **p=0.002), in parallel CD4+ virus-specific T-cell ratio was significantly lower in CVID patients at the first time point (*p: 0.03). After boosting, in more than 33% of both CVID patients and also in their healthy controls we detected a decrease in absolute CD45+, CD3+, CD3+CD4+, and CD3+CD8+, CD19+, and CD16+56+ cell counts. CD16+CD56+ cell counts were significantly lower compared to controls before and after boosting (*p=0.02, *p=0.02). CVID patients receiving immunosuppressive therapy throughout the previous year or autologous stem cell transplantation two years before vaccination had worse responses in anti-spike, anti-neutralizing antibody, CD3+CD4+T, CD19+ B, and natural killer cell counts than the whole CVID group. Vaccinations had few side effects. Based on these data, CVID patients receiving booster vaccination with BNT162b2 after two ChadOx1 can effectively elevate the levels of protection against COVID-19 infection, but the duration of the immune response together with COVID-19 morbidity data needs further investigation among these patients.
FOXO3a Alleviates the Inflammation and Oxidative Stress via Regulating TGF-β and HO-1 in Ankylosing Spondylitis
Authors: Xu Shanshan , Zhang Xiaoyi , Ma Yubo , Chen Yuting , Xie Huimin , Yu Lingxiang , Wang Jinian , Xu Sheng–qian , Pan Faming
Published: June 2022

This study aimed to investigate whether Forkhead box O3a (FOXO3a) modulates inflammation and oxidative stress in ankylosing spondylitis (AS). We applied bioinformatics analysis, quantitative real-time polymerase chain reaction, immunoblotting, enzyme linked immunosorbent assay, chromatin immunoprecipitation, and dual-luciferase reporter assay. Gene overexpression and knockdown of FOXO3a were conducted via lentivirus and small interfering RNA, respectively. Downregulated FOXO3a expression was first confirmed in AS patients. Interleukin-8 (IL-8) and IL-17A were highly expressed and negatively related with FOXO3a in AS. Total antioxidant capacity (T-AOC) were markedly decreased and positively associated with FOXO3a in AS. Overexpression of FOXO3a inhibited the secretion of inflammatory cytokines and promoted the production of antioxidant enzymes in Jurkat cells. Transforming growth factor-β (TGF-β) and heme oxygenase 1 (HO-1), which had binding sites to FOXO3a based on bioinformatics analysis, were abnormally expressed and positively related with FOXO3a. Accordingly, FOXO3a obviously elevated the protein and transcription levels of TGF-β and HO-1 in Jurkat cells. The above results were verified by silencing FOXO3a. Moreover, FOXO3a directly interacted with and promoted the transcription of TGF-β and HO-1. In summary, the modulation of cellular inflammation and oxidative stress via FOXO3a-mediated TGF-β and HO-1 activation is partly involved in the pathogenesis of AS.
Coupled Coccolith-Based Temperature and Productivity High-Resolution Reconstructions in the Eastern Equatorial Pacific During the Last Deglaciation and the Holocene
Authors: Saavedra-Pellitero Mariem , Hernández-Almeida Iván , Cabarcos Eloy , Baumann Karl-Heinz , Dunkley Jones Tom , Sierro Francisco Javier , Flores José-Abel
Published: June 2022

We present a new high-resolution reconstruction of annual sea-surface temperatures (SSTa) and net primary productivity (NPP) using novel coccolithophore-based models developed for the Eastern Equatorial Pacific (EEP). We combined published coccolithophore census counts from core-tops in the Eastern Pacific with 32 new samples from the Equatorial region, to derive a new statistical model to reconstruct SSTa. Results show that the addition of the new EEP samples improves existing coccolithophore-based SST-calibrations, and allow reconstructing SSTa in the EEP with higher confidence. We also merged the relative abundance of deep-photic species Florisphaera profunda in the same surface sediment samples with existing calibration datasets for tropical regions, to reconstruct annual NPP. Both temperature and productivity calibrations were successfully applied to fossil coccolith data from Ocean Drilling Project Site 1240, in the EEP. The coccolith-based SSTa estimates show a cooling during the Last Glacial Maximum (LGM) and the Younger Dryas, and warming at the start of the Holocene. This pattern differs in the timing and magnitude of the temperature changes from other available SST-reconstructions based on biogeochemical and faunal proxies. We discuss these discrepancies to be the result of different proxy sensitivities to insolation forcing, seasonal bias, and/or preservation artifacts. Reconstructed annual NPP shows a general decreasing trend from the late last glacial period to recent times, which we relate to the weakening of wind-driven equatorial upwelling towards the Holocene. We also calculated carbon export using our SSTa and NPP reconstructions, and compared to other geochemical-based reconstructions for the same location. Our coupled SSTa-NPP reconstruction provides key data to more fully assess the evolution of primary and export productivity as well as organic carbon burial in the EEP, with implications for its role in global biogeochemical cycles across glacial terminations.
Renal Expression of Annexin A1 Is Associated With the Severity of Renal Injury in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis
Authors: Wang Rui-Xue , Wu Liang , Chen Su-Fang , Li Zhi-Ying , Zhao Ming-Hui , Chen Min
Published: June 2022

Background

Increasing studies demonstrated the importance of activation of neutrophils in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Previous studies showed that annexin A1 (ANXA1) inhibited the recruitment, transendothelial migration and respiratory burst of neutrophils and induced apoptosis of neutrophils. The current study aimed to investigate the plasma and renal levels of ANXA1 as well as their association with the disease severity in AAV patients.

Methods

Thirty-one AAV patients in active stage and 35 AAV patients in remission stage were recruited. The expression of ANXA1 in renal specimens was assessed by immunohistochemistry. The co-localization of ANXA1 with renal intrinsic and infiltrating cells was detected by double immunofluorescence. The plasma levels of ANXA1 were determined by ELISA. The association of plasma and renal levels of ANXA1 with clinicopathological parameters was further analyzed.

Results

Plasma levels of ANXA1 were significantly higher in active AAV patients than those in AAV patients in remission as well as healthy controls. The renal expression of ANXA1 was significantly higher in active AAV patients than in healthy controls and disease controls. Double immunofluorescence assay showed that ANXA1 was expressed in glomerular endothelial cells, mesangial cells, podocytes, proximal tubular epithelial cells, neutrophils, monocytes/macrophages and T cells in AAV patients. The mean optical density of ANXA1 in glomeruli was correlated with serum creatinine levels (r = −0.491, P = 0.005) and eGFR (r = 0.492, P = 0.005) at renal biopsy and the proportion of crescents (r = −0.423, P = 0.018) in renal specimens of AAV patients. The expression of ANXA1 in glomeruli of AAV patients achieving complete renal recovery was significantly higher than those achieving partial renal recovery.

Conclusion

In AAV patients, the renal expression of ANXA1 was associated with the severity of renal injury.
Serum Level of 4-Hydroxynonenal in Community-Acquired Pneumonia: A Potential Biomarker for Severity and Prognosis
Authors: Jiang Ya-Lin , Liu Hong-Yan , Tang Min-Min , Cheng Jia-Yi , Zhao Hui , Fu Lin
Published: June 2022

Background

Four-hydroxynonenal (4-HNE) exerts a central role in the pathophysiological process of pulmonary diseases. The aim of this project was to evaluate the correlations between serum 4-HNE with severity and prognosis in patients with community-acquired pneumonia (CAP) by a prospective cohort study.

Materials and Methods

A total of 239 patients with CAP and healthy volunteers were recruited. Fasting blood was collected. Serum 4-HNE was measured with ELISA. Clinical characteristics and demographic information were obtained. The relationships between serum 4-HNE and clinical characteristics were evaluated through the Spearman or Pearson correlation coefficient. The associations of serum 4-HNE with severity and prognosis were estimated through logistic regression analysis.

Results

On admission, serum 4-HNE was upregulated in patients with CAP compared with healthy volunteers. Serum 4-HNE was gradually increased in line with CAP scores. Additionally, elderly patients with CAP were more prone to suffer from 4-HNE elevation. Moreover, serum 4-HNE was positively correlated with CAP severity scores. Meanwhile, the poor prognostic outcomes were tracked among patients with CAP. Higher serum 4-HNE on admission increased the risks of mechanical ventilation, vasoactive agent usage, and death in patients with CAP during hospitalization. The predictive powers for severity and death were increased in serum 4-HNE compared with CAP severity scores and inflammatory cytokines.

Conclusion

Serum 4-HNE on admission is positively correlated with the severity and poor prognosis among patients with CAP, indicating that 4-HNE participates in the pathophysiology of CAP. Serum 4-HNE may be used as an earlier biomarker for diagnosis and prognosis in patients with CAP.
Intrauterine Hematoma in the First Trimester and Pregnancy Complications: A Systematic Review and Meta-Analysis
Authors: Qin Zhao-juan , Xu Yu , Du Yi , Chen Ya-li , Sun Liang , Zheng Ai
Published: June 2022

Background

Studies evaluating the relationship between intrauterine hematoma in the first trimester and prenatal complications are conflicting.

Objectives

To evaluate whether intrauterine hematoma identified in the first trimester in women with singleton pregnancies is associated with adverse perinatal outcomes.

Search Strategy

A comprehensive literature search of three databases (Embase, PubMed, and Web of Science) was performed up to September 2021.

Selection Criteria

Cohort and case-control studies that have evaluated the relationship between intrauterine hematoma identified before 14 gestational weeks and the risk of prenatal complications, in women with a singleton pregnancy.

Data Collection and Analysis

Two members of our team independently assessed the studies for inclusion, collected the data of interest, and assessed the risk of bias, and calculated pooled odds ratios (ORs) using random-effects models.

Main Results

Nine studies, including 1,132 women with intrauterine hematoma and 11,179 controls met the inclusion criteria. Intrauterine hematoma increased the risk of spontaneous abortion [OR 2.15, 95% confidence interval (CI) 1.23–3.75], preterm birth (OR 1.83, 95% CI 1.37–2.43), fetal growth restriction (OR 2.33, 95% CI 1.13–4.83) and placental abruption (OR 3.16, 95% CI 1.23–8.13). No statistically significant association was found between intrauterine hematoma and preeclampsia (OR 1.30, 95% CI 0.87–1.94).

Conclusion

Intrauterine hematoma in the first trimester of pregnancy increases the risk of spontaneous abortion, preterm birth, placental abruption, and fetal growth restriction.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/.
Early Emergence and Dispersal of Delta SARS-CoV-2 Lineage AY.99.2 in Brazil
Authors: Romano Camila Malta , de Oliveira Cristina Mendes , da Silva Luciane Sussuchi , Levi José Eduardo
Published: June 2022

The year of 2021 was marked by the emergence and dispersal of a number of SARS-CoV-2 lineages, resulting in the “third wave” of COVID-19 in several countries despite the level of vaccine coverage. Soon after the first confirmed cases of COVID-19 by the Delta variant in Brazil, at least seven Delta sub-lineages emerged, including the globally spread AY.101 and AY.99.2. In this study we performed a detailed analysis of the COVID-19 scenario in Brazil from April to December 2021 by using data collected by the largest private medical diagnostic company in Latin America (Dasa), and SARS-CoV-2 genomic sequences generated by its SARS-CoV-2 genomic surveillance project (GENOV). For phylogenetic and Bayesian analysis, SARS-CoV-2 genomes available at GISAID public database were also retrieved. We confirmed that the Brazilian AY.99.2 and AY.101 were the most prevalent lineages during this period, overpassing the Gamma variant in July/August. We also estimated that AY.99.2 likely emerged a few weeks after the entry of the B.1.617.2 in the country, at some point between late April and May and rapidly spread to other countries. Despite no increased fitness described for the AY.99.2 lineage, a rapid shift in the composition of Delta SARS-CoV-2 lineages prevalence in Brazil took place. Understanding the reasons leading the AY.99.2 to become the dominant lineage in the country is important to understand the process of lineage competitions that may inform future control measures.
Mapping Lower-Limb Prosthesis Load Distributions Using a Low-Cost Pressure Measurement System
Authors: Hopkins Matthew O. , Turner Shruti , Vaidyanathan Ravi , McGregor Alison
Published: June 2022

Background

In the UK 55,000 people live with a major limb amputation. The prosthetic socket is problematic for users in relation to comfort and acceptance of the prosthesis; and is associated with the development of cysts and sores.

Objectives

We have developed a prototype low-cost system combining low-profile pressure sensitive sensors with an inertial measurement unit to assess loading distribution within prosthetic sockets. The objective of this study was to determine the ability of this prototype to assess in-socket loading profiles of a person with an amputation during walking, with a view to understanding socket design and fit.

Methods

The device was evaluated on four transtibial participants of various age and activity levels. The pressure sensors were embedded in the subject's sockets and an inertial measurement unit was attached to the posterior side of the socket. Measurements were taken during level walking in a gait lab.

Results

The sensors were able to dynamically collect data, informing loading profiles within the socket which were in line with expected distributions for patellar-tendon-bearing and total-surface-bearing sockets. The patellar tendon bearing subject displayed loading predominately at the patellar tendon, tibial and lateral gastrocnemius regions. The total-surface bearing subjects indicated even load distribution throughout the socket except in one participant who presented with a large socket-foot misalignment.

Conclusions

The sensors provided objective data showing the pressure distributions inside the prosthetic socket. The sensors were able to measure the pressure in the socket with sufficient accuracy to distinguish pressure regions that matched expected loading patterns. The information may be useful to aid fitting of complex residual limbs and for those with reduced sensation in their residual limb, alongside the subjective feedback from prosthesis users.
A General Map of Transcriptional Expression of Virulence, Metabolism, and Biofilm Formation Adaptive Changes of Staphylococcus aureus When Exposed to Different Antimicrobials
Authors: Ren Zun , Yu Jinlong , Du Jiafei , Zhang Yubo , Hamushan Musha , Jiang Feng , Zhang Feiyang , Wang Boyong , Tang Jin , Shen Hao , Han Pei
Published: June 2022

Biofilm formation of Staphylococcus aureus is the major cause of implant-associated infections (IAIs). Antimicrobial treatment is one of the most effective therapeutic options for S. aureus infections. However, it can also lead to adaptive transcriptomic changes due to extreme selective pressure, which may increase the risk of antimicrobial resistance. To study the transcriptional changes in S. aureus upon exposure to antimicrobial agents, we obtained expression profiles of S. aureus treated with six antimicrobials (flucloxacillin, vancomycin, ciprofloxacin, clindamycin, erythromycin, and linezolid, n = 6 for each group). We also included an untreated control group (n = 8) downloaded from the Gene Expression Omnibus (GEO) database (GSE70043, GSE56100) for integrated bioinformatic analyses. We identified 82 (44 up, 38 down) and 53 (17 up, 36 down) differentially expressed genes (DEGs) in logarithmic and stationary phases, respectively. When exposed to different antimicrobial agents, we found that manganese import system genes and immune response gene sbi (immunoglobulin G-binding protein Sbi) were upregulated in S. aureus at all stages. During the logarithmic phase, we observed adaptive transcriptomic changes in S. aureus mainly in the stability of protein synthesis, adhesion, and biofilm formation. In the stationary phase, we observed a downregulation in genes related to amino biosynthesis, ATP synthesis, and DNA replication. We verified these results by qPCR. Importantly, these results could help our understanding of the molecular mechanisms underlying the proliferation and antimicrobial resistance of S. aureus.
Clustered Regularly Interspaced Short Palindromic Repeats Genotyping of Multidrug-Resistant Salmonella Heidelberg Strains Isolated From the Poultry Production Chain Across Brazil
Authors: Monte Daniel F. M. , Nethery Matthew A. , Berman Hanna , Keelara Shivaramu , Lincopan Nilton , Fedorka-Cray Paula J. , Barrangou Rodolphe , Landgraf Mariza
Published: June 2022

Salmonella enterica subsp. enterica serovar Heidelberg has been associated with a broad host range, such as poultry, dairy calves, swine, wild birds, environment, and humans. The continuous evolution of S. Heidelberg raises a public health concern since there is a global dispersal of lineages harboring a wide resistome and virulome on a global scale. Here, we characterized the resistome, phylogenetic structure and clustered regularly interspaced short palindromic repeats (CRISPR) array composition of 81 S. Heidelberg strains isolated from broiler farms (n = 16), transport and lairage (n = 5), slaughterhouse (n = 22), and retail market (n = 38) of the poultry production chain in Brazil, between 2015 and 2016 using high-resolution approaches including whole-genome sequencing (WGS) and WGS-derived CRISPR genotyping. More than 91% of the S. Heidelberg strains were multidrug-resistant. The total antimicrobial resistance (AMR) gene abundances did not vary significantly across regions and sources suggesting the widespread distribution of antibiotic-resistant strains from farm to market. The highest AMR gene abundance was observed for fosA7, aac(6′)-Iaa, sul2, tet(A), gyrA, and parC for 100% of the isolates, followed by 88.8% for blaCMY–2. The β-lactam resistance was essentially driven by the presence of the plasmid-mediated AmpC (pAmpC) blaCMY–2 gene, given the isolates which did not carry this gene were susceptible to cefoxitin (FOX). Most S. Heidelberg strains were classified within international lineages, which were phylogenetically nested with Salmonella strains from European countries; while CRISPR genotyping analysis revealed that the spacer content was overall highly conserved, but distributed into 13 distinct groups. In summary, our findings underscore the potential role of S. Heidelberg as a key pathogen disseminated from farm to fork in Brazil and reinforce the importance of CRISPR-based genotyping for salmonellae. Hence, we emphasized the need for continuous mitigation programs to monitor the dissemination of this high-priority pathogen.
Characterization of the Protective Efficacy Against QX Strain of a Recombinant Infectious Bronchitis Virus With H120 Backbone and QX Spike Gene
Authors: Weng Wenlian , Liu Qingyan , Xue Wenxiang , Wang Huan , Fang Shouguo , Sun Yingjie , Tan Lei , Song Cuiping , Qiu Xusheng , Liu Weiwei , Ding Chan , Liao Ying
Published: June 2022

Infectious bronchitis virus (IBV) has been prevalent in chicken farms for many years, and its control relies on extensive vaccine administration. The continuous emergence of new variants and the low cross-protection efficiency prompt the development of new vaccines. In this study, we develop a reverse genetics technique based on the classical vaccine strain H120 genome, via in vitro ligation method. Using the H120 genome as the backbone, we constructed the recombinant virus rH120-QX(S) by replacing the H120 S gene with the QX S gene, a prevalent strain in China. Biological characteristics of the rH120-QX(S) virus, such as 50% egg lethal dose (ELD50), 50% egg infectious dose (EID50), dwarf embryo, growth curve, and genetic stability, are measured, which are comparable to the parental virus H120. There are no clinical symptoms and tissue lesions in the trachea and kidney in the rH120-QX(S)-infected specific-pathogen-free (SPF) chickens, demonstrating that this recombinant virus does not confer pathogenicity. Furthermore, protection studies show that there is 100% homologous protection of rH120-QX(S) to the virulent QX strain, as shown by the absence of clinical signs and no lethality. Taken together, our results demonstrate that swapping the S gene onto the H120 genetic backbone is a precise and effective way to produce genetically defined IBV vaccine candidates.
Comparison of Gut Microbiota Diversity Between Captive and Wild Tokay Gecko (Gekko gecko)
Authors: Tang Sanqi , Li Yuhui , Huang Chengming , Yan Shufa , Li Yongtai , Chen Zening , Wu Zhengjun
Published: June 2022

Captive animals and wild animals may exhibit different characteristics due to the heterogeneity of their living environments. The gut microbiota play an important role in the digestion and absorption, energy metabolism, immune regulation, and physiological health of the host. However, information about the gut microbiota of captive and wild Gekko gecko is currently limited. To determine the difference in gut microbiota community composition, diversity, and structure between captive and wild geckos, we used the Illumina miseq platform to conduct high-throughput sequencing and bioinformatics analysis of the v3–v4 hypervariable region of 16S rRNA in 54 gecko samples. Our results showed that Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria were the dominant gut microbiota phyla of the gecko. The dominant genera comprised mainly Pseudomonas, Burkholderia-caballeronia-paraburkholderia, Ralstonia, Romboutsia, and Bacteroides. Captive geckos had significantly higher alpha diversity and potential pathogenic bacteria than wild populations. Moreover, significant differences in beta diversity of gut microbiota were observed between two populations. Functional prediction analysis showed that the relative abundance of functional pathways of wild geckos was more higher in metabolism, genetic information processing and organismal system function than those in captive geckos. Total length significantly affected gut microbial community (R2 = 0.4527, p = 0.001) and explained 10.45% of the total variation for gut microbial community variance between two groups. These results may be related to differences in diet and living environment between two populations, suggesting that the management of captive populations should mimic wild environments to the greatest extent possible to reduce the impact on their gut microbiota.
Thiamine Is Required for Virulence and Survival of Pseudomonas syringae pv. tomato DC3000 on Tomatoes
Authors: Liu Jun , Zhang Xuejiang , Deng Siyi , Wang Hua , Zhao Youfu
Published: June 2022

Pseudomonas syringae pv. tomato DC3000 (PstDC3000) is an important plant pathogen that infects tomatoes and Arabidopsis. Thiamine and its derivative thiamine pyrophosphate (TPP) are cofactors that play an important role in the growth and survival of many bacterial microorganisms. However, the role of thiamine-related genes has not been determined in PstDC3000. Hence, to investigate the role of TPP in growth, resistance to stresses, and virulence of PstDC3000, double and quadruple mutants of thiamine biosynthesis-related genes (thiD/E, thiS/G, and thiD/E/S/G deletion mutants) as well as a single mutant of a lipoprotein-related gene (apbE) were constructed. Our results showed that growth of the thiD/E, thiS/G, and thiD/E/S/G mutants in the mannitol-glutamate (MG) medium was significantly lower than that of the wild type (WT) and their growth could be restored to the WT level with the addition of exogenous thiamine, whereas mutation of the apbE gene did not affect its growth in vitro. While tolerance to acid, osmotic, and oxidative stresses for the double mutants was similar to the WT, tolerance to stresses for the apbE mutant was reduced as compared to the WT. In addition, all four mutants exhibited reduced virulence and growth in tomatoes. However, when the double and quadruple mutants were inoculated with exogenous thiamine, the virulence and growth rate of these mutants were restored to the WT level. These results indicated that the thiD/E, thiS/G, and thiD/E/S/G mutants exhibiting growth deficiency in planta are probably due to a lack of thiamine biosynthesis, thus reducing colonization in tomatoes. On the other hand, it is possible that the apbE mutant exhibited reduced stress tolerances, thus resulting in reduced colonization. Overall, our findings suggest that the thiamine biosynthetic (TBS) pathway plays an important role in the colonization and infection of PstDC3000. Therefore, the thiamine biosynthetic pathway could be used as the target to develop new control measures for a bacterial spot in tomatoes.
Intestinal Microbes in Patients With Schizophrenia Undergoing Short-Term Treatment: Core Species Identification Based on Co-Occurrence Networks and Regression Analysis
Authors: Xiang Min , Zheng Liqin , Pu Daoshen , Lin Feng , Ma Xiaodong , Ye Huiqian , Pu Daoqiong , Zhang Ying , Wang Dong , Wang Xiaoli , Zou Kaiqing , Chen Linqi , Zhang Yong , Sun Zhanjiang , Zhang Tao , Wu Guolin
Published: June 2022

Schizophrenia, a common mental disorder, has a tremendous impact on the health and economy of people worldwide. Evidence suggests that the microbial-gut-brain axis is an important pathway for the interaction between the gut microbiome and the development of schizophrenia. What is not clear is how changes in the gut microbiota composition and structure during antipsychotic treatment improve the symptoms of schizophrenia. In this study, 25 patients with schizophrenia were recruited. Their fecal samples were collected before and after hospital treatment for 14–19 days. The composition and structure of the intestinal microbiota were evaluated by 16S rRNA sequencing analysis, and the results showed significant differences in fecal microbiota before and after treatment. Firmicutes (relative abundances of 82.60 and 86.64%) and Gemminger (relative abundances of 14.17 and 13.57%) were the first dominant species at the phylum and genus levels, respectively. The random forest algorithm and co-occurrence network analysis demonstrated that intestinal flora (especially the core species ASV57) could be used as biomarkers to distinguish different clinical states and match treatment regimens accordingly. In addition, after fecal microbiota transplantation, antibiotic-treated recipient mice showed multiple behavioral improvements. These included decreased psychomotor hyperactivity, increased social interaction, and memory. In conclusion, this study suggests that differences in the composition and structure of gut microbiota after treatment are associated with the development and severity of schizophrenia. Results may provide a potential target for the treatment of this disorder.
Systematic Approach to Address Early Pandemic's Diagnostic Unmet Needs
Authors: Cabrera Catherine , Pilobello Kanoelani , Dalvin Steven , Bobrow Johanna , Shah Darshi , Garg Lori Freed , Chalise Sujata , Doyle Patrick , Miller Glenn A. , Walt David R. , Suliman Sara , Jolly Pawan
Published: June 2022

During the first few months of the global Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, the medical research community had to expeditiously develop, select, and deploy novel diagnostic methods and tools to address the numerous testing challenges presented by the novel virus. Integrating a systematic approach to diagnostic selection with a rapid validation protocol in a clinical setting can shorten the timeline to bring new technologies to practice. In response to the urgent need to provide tools for identifying SARS-CoV-2-positive individuals, we developed a framework for assessing technologies against a set of prioritized performance metrics to guide device selection. We also developed and proposed clinical validation frameworks for the rapid screening of new technologies. The rubric described here represents a versatile approach that can be extended to future technology assessments and can be implemented in preparation for future emerging pathogens.
Effects of Inoculation With Acinetobacter on Fermentation of Cigar Tobacco Leaves
Authors: Zheng Tianfei , Zhang Qianying , Wu Qiaoyin , Li Dongliang , Wu Xinying , Li Pinhe , Zhou Quanwei , Cai Wen , Zhang Juan , Du Guocheng
Published: June 2022

Metabolic activity of the microbial community greatly affects the quality of cigar tobacco leaves (CTLs). To improve the quality of CTLs, two extrinsic microbes (Acinetobacter sp. 1H8 and Acinetobacter indicus 3B2) were inoculated into CTLs. The quality of CTLs were significantly improved after fermentation. The content of solanone, 6-methyl-5-hepten-2-one, benzeneacetic acid, ethyl ester, cyclohexanone, octanal, acetophenone, and 3,5,5-trimethyl-2-cyclohexen-1-one were significantly increased after inoculated Acinetobacter sp. 1H8. The inoculation of Acinetobacter sp. 1H8 enhanced the normal evolutionary trend of bacterial community. The content of trimethyl-pyrazine, 2,6-dimethyl-pyrazine, and megastigmatrienone were significantly increased after inoculated Acinetobacter indicus 3B2. The inoculation of Acinetobacter indicus 3B2 completely changed the original bacterial community. Network analysis revealed that Acinetobacter was negatively correlated with Aquabacterium, positively correlated with Bacillus, and had significant correlations with many volatile flavor compounds. This work may be helpful for improving fermentation product quality by regulating microbial community, and gain insight into the microbial ecosystem.
Changes in the Distribution Preference of Soil Microbial Communities During Secondary Succession in a Temperate Mountain Forest
Authors: Li Peikun , Zhang Jian , Wang Senlin , Zhang Panpan , Chen Wenju , Ding Shengyan , Xi Jingjing
Published: June 2022

Soil microbes play a crucial role in a forest ecosystem. However, whether the distribution of bacteria and fungi in different forest succession stages is random or following ecological specialization remains to be further studied. In the present study, we characterized soil bacterial and fungal communities to determine their distribution preference, with different succession communities in a temperate mountain forest. The Kruskal–Wallis method was used to analyze structural differences between bacterial and fungal communities in different succession processes. The specificity of soil microbial distribution in a secondary forest was studied by network analysis. The torus-translation test was used to analyze the species distribution preference of soil microbes in different succession stages. Results showed that the species composition of soil bacteria and fungi differed significantly in different succession processes. The modularity index of fungi (0.227) was higher than that of bacteria (0.080). Fungi (54.47%) had specific preferences than bacteria (49.95%) with regard to forests in different succession stages. Our work suggests that the distribution pattern of most soil microbes in a temperate mountain forest was not random but specialized in temperate mountain forests. Different microbes showed different distribution preferences. Fungi were more sensitive than bacteria during secondary succession in a temperate mountain forest. In addition, microbe–environment relations varied during secondary succession. Our results provided new insight into the mechanism through which complex soil microbial communities responded to changes in forest community succession.
Combined Functional Assessment for Predicting Clinical Outcomes in Stroke Patients After Post-acute Care: A Retrospective Multi-Center Cohort in Central Taiwan
Authors: Weng Shuo-Chun , Hsu Chiann-Yi , Shen Chiung-Chyi , Huang Jin-An , Chen Po-Lin , Lin Shih-Yi
Published: June 2022

Background and Objective

In 2014, Taiwan’s National Health Insurance administration launched a post-acute care (PAC) program for patients to improve their functions after acute stroke. The present study was aimed to determine PAC assessment parameters, either alone or in combination, for predicting clinical outcomes.

Methods

We retrospectively enrolled stroke adult patients through one PAC network in central Taiwan between January 2014 and December 2020. We collected data on post-stroke patients’ functional ability at baseline and after PAC stay. The comprehensive assessment included the following: Modified Rankin Scale (MRS), Functional Oral Intake Scale (FOIS), Mini-Nutritional Assessment (MNA), Berg Balance Scale (BBS), Fugl-Meyer Assessment (FMA), Mini-Mental State Examination (MMSE), aphasia test, and quality of life. The above items were assessed first at baseline and again at discharge from PAC. Logistic regression was used to determine factors that were associated with PAC length of stay (LOS), 14-day hospital readmission, and 1-year mortality.

Results

A total of 267 adults (mean age 67.2 ± 14.7 years) with completed data were analyzed. MRS, activities of daily living (ADLs), instrumental activities of daily living (IADLs), BBS, and MMSE all had improved between disease onset and PAC discharge. Higher baseline and greater improvement of physical and cognitive functions between initial and final PAC assessments were significantly associated with less readmission, and lower mortality. Furthermore, the improved ADLs, FOIS, MNA, FMA-motor, and MMSE scores were related to LOS during PAC. Using logistic regression, we found that functional improvements ≥5 items [adjusted odds ratio (aOR) = 0.16; 95% confidence interval (CI) = 0.05–0.45] and improved MMSE (aOR = 0.19; 95% CI = 0.05–0.68) were significantly associated with reduced post-PAC mortality or readmission. Whereas, functional improvements ≥7 items, improved FOIS, and MNA significantly prolonged LOS during PAC.

Conclusion

Physical performance parameters of patients with acute stroke improved after PAC. PAC assessment with multiple parameters better predicted clinical outcomes. These parameters could provide information on rehabilitation therapy for acute stroke patients receiving PAC.
Studies on the Regulation and Molecular Mechanism of Panax Ginseng Saponins on Senescence and Related Behaviors of Drosophila melanogaster
Authors: Zhao Qiushi , Liu Ying , Zhang Siyu , Zhao Yuchu , Wang Chenxi , Li Keqiang , Jin Zecheng , Qiao Juhui , Liu Meichen
Published: June 2022

In an increasingly aged global population, achieving healthy life expectancy through natural and safe drug interventions is highly desirable. Here we show that total ginsenosides (TGGR), the main active components in the traditional Chinese medicine, ginseng, promote longevity across species. In Drosophila, an intriguing effect of TGGR on lifespan was the relatively narrow treatment window to elicit long-term benefits. TGGR administration during early adulthood, and especially during midlife, was sufficient to extend lifespan in both sexes. TGGR did not increase lifespan by reducing food intake or reproductive capacity; rather, TGGR increased the fertility of male Drosophila. TGGR augmented healthspan readouts associated with youth and with healthy aging, such as motility, intestinal barrier integrity, and biorhythm homeostasis. TGGR treatment also improved some types of stress resistance in both sexes, including increased tolerance to starvation and oxidation, and shifting “aged” gene expression patterns toward “healthy” patterns seen in the young. Gene expression, pharmacological and genetic epistatic analyses demonstrated that TGGR effects require normal expression of genes involved in insulin, TOR and MAPK signaling. The positive effects of TGGR on both healthspan and lifespan, coupled with its mechanism of action via evolutionarily conserved signaling pathways, demonstrate it to be a promising anti-aging drug.
Increased Levels of Serum IL-15 and TNF-β Indicate the Progression of Human Intracranial Aneurysm
Authors: Yang Shuzhe , Liu Qingyuan , Yang Junhua , Wu Jun , Wang Shuo
Published: June 2022

Objective

Existing evidence suggests that chronic inflammation promotes the progression of human intracranial aneurysm (IA) and many cytokines have been detected to participate in the process of inflammation. However, rare cytokines in plasma have been used as proxies for progression of IA. This study aimed to identify novel cytokines as biomarkers to predict the development of IA.

Methods

Patients with unruptured intracranial aneurysms (UIAs) undergoing microsurgical clipping were prospectively recruited from January 2017 to June 2020 and were separated into two groups based on their ELAPSS score (low risk group < 10, intermediate-high risk group ≥ 10). Propensity score matching (PSM) was used to reduce imbalances in the baseline characteristics between groups. All blood samples were collected before surgery. A human serum 48-cytokines examination was performed to analyze the concentrations of serological cytokines. Clinical data and cytokines were compared between groups.

Results

A total of 184 patients were enrolled in this study. The low risk group contained 77 patients and 107 patients were included in the intermediate-high risk group. Finally, there were 69 patients in each group after PSM with a matching rate of 1:1. The concentrations of 3 serum cytokines were significantly increased in intermediate-high risk patients, namely, interleukin-15 (IL-15), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-β (TNF-β) (P< 0.05, |log2fold change| > 2). The result of receiver operator characteristic (ROC)curve revealed that TNF-β had the highest predictive accuracy, with an area under the curve (AUC) value of 0.725 [95% confidence interval (CI) 0.639–0.811,P< 0.001] followed by IL-15 (AUC = 0.691, 95% CI 0.602–0.781,P< 0.001) and MCP-1 (AUC = 0.661, 95% CI 0.569–0.753,P= 0.001). Multivariate logistic analysis demonstrated high IL-15 [odds ratio (OR), 3.23; 95% CI, 1.47–7.12;P= 0.004] and high TNF-β (OR, 8.30; 95% CI, 3.25–21.25;P< 0.001) as the risk factors that correlated with intermediate-high risk of IA progression.

Conclusion

UIA patients with intermediate-high growth risk exhibited increased serum levels of IL-15, MCP-1, and TNF-β. Serum IL-15, and TNF-β could serve as biomarkers to predict the progression of UIAs.
Vestibular Hair Cells Require CAMSAP3, a Microtubule Minus-End Regulator, for Formation of Normal Kinocilia
Authors: O’Donnell Josephine , Zheng Jing
Published: June 2022

Kinocilia are exceptionally long primary sensory cilia located on vestibular hair cells, which are essential for transmitting key signals that contribute to mammalian balance and overall vestibular system function. Kinocilia have a “9+2” microtubule (MT) configuration with nine doublet MTs surrounding two central singlet MTs. This is uncommon as most mammalian primary sensory cilia have a “9+0” configuration, in which the central MT pair is absent. It has yet to be determined what the function of the central MT pair is in kinocilia. Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3) regulates the minus end of MTs and is essential for forming the central MT pair in motile cilia, which have the “9+2” configuration. To explore the role of the central MT pair in kinocilia, we created a conditional knockout model (cKO), Camsap3-cKO, which intended to eliminate CAMSAP3 in limited organs including the inner ear, olfactory bulb, and kidneys. Immunofluorescent staining of vestibular organs demonstrated that CAMSAP3 proteins were significantly reduced in Camsap3-cKO mice and that aged Camsap3-cKO mice had significantly shorter kinocilia than their wildtype littermates. Transmission electron microscopy showed that aged Camsap3-cKO mice were in fact missing that the central MT pair in kinocilia more often than their wildtype counterparts. In the examination of behavior, wildtype and Camsap3-cKO mice performed equally well on a swim assessment, right-reflex test, and evaluation of balance on a rotarod. However, Camsap3-cKO mice showed slightly altered gaits including reduced maximal rate of change of paw area and a smaller paw area in contact with the surface. Although Camsap3-cKO mice had no differences in olfaction from their wildtype counterparts, Camsap3-cKO mice did have kidney dysfunction that deteriorated their health. Thus, CAMSAP3 is important for establishing and/or maintaining the normal structure of kinocilia and kidney function but is not essential for normal olfaction. Our data supports our hypothesis that CAMSAP3 is critical for construction of the central MT pair in kinocilia, and that the central MT pair may be important for building long and stable axonemes in these kinocilia. Whether shorter kinocilia might lead to abnormal vestibular function and altered gaits in older Camsap3-cKO mice requires further investigation.
Absolute Winding Number Differentiates Mouse Spatial Navigation Strategies With Genetic Risk for Alzheimer’s Disease
Authors: Badea Alexandra , Li Didong , Niculescu Andrei R. , Anderson Robert J. , Stout Jacques A. , Williams Christina L. , Colton Carol A. , Maeda Nobuyo , Dunson David B.
Published: June 2022

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer’s disease, and even in cognitively normal individuals at risk for Alzheimer’s disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer’s disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer’s disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer’s disease.