bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis of the Immune Microenvironment in Checkpoint Inhibitor Pneumonitis
Authors: Lin Xinqing , Deng Jiaxi , Deng Haiyi , Yang Yilin , Sun Ni , Zhou Maolin , Qin Yinyin , Xie Xiaohong , Li Shiyue , Zhong Nanshan , Song Yong , Zhou Chengzhi
Published: January 2022

Background

While immune checkpoint inhibitors (ICIs) are a beacon of hope for non-small cell lung cancer (NSCLC) patients, they can also cause adverse events, including checkpoint inhibitor pneumonitis (CIP). Research shows that the inflammatory immune microenvironment plays a vital role in the development of CIP. However, the role of the immune microenvironment (IME) in CIP is still unclear.

Methods

We collected a cohort of NSCLC patients treated with ICIs that included eight individuals with CIP (CIP group) and 29 individuals without CIP (Control group). CIBERSORT and the xCell algorithm were used to evaluate the proportion of immune cells. Gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) were used to evaluate pathway activity. The ridge regression algorithm was used to analyze drug sensitivity.

Results

CIBERSORT showed significantly upregulated memory B cells, CD8+ T cells, and M1 Macrophages in the CIP group. The number of memory resting CD4+ T cells and resting NK cells in the CIP group was also significantly lower than in the Control group. The XCell analysis showed a higher proportion of Class-switched memory B-cells and M1 Macrophages in the CIP group. Pathway analysis showed that the CIP group had high activity in their immune and inflammatory response pathways and low activity in their immune exhaustion related pathway.

Conclusions

In this study, we researched CIP patients who after ICIs treatment developed an inflammatory IME, which is characterized by significantly increased activated immune cells and expression of inflammatory molecules, as well as downregulated immunosuppressive lymphocytes and signaling pathways. The goal was to develop theoretical guidance for clinical guidelines for the treatment of CIP in the future.
Do Oil and Gas Lease Stipulations in the Northwestern Gulf of Mexico Need Expansion to Better Protect Vulnerable Coral Communities? How Low Relief Habitats Support High Coral Biodiversity
Authors: Nuttall Marissa Faye , Hickerson Emma L. , Blakeway Raven D. , Schmahl George P. , Sammarco Paul W.
Published: January 2022

The continental shelf of the northwestern Gulf of Mexico harbors extensive reefs and banks that support diverse coral reefs and mesophotic communities. Mesophotic communities range in depth from 40 to 200 m and, in this region, foster some of the densest coral forests [aggregations of mesophotic octocoral, antipatharian, and branching stony coral communities] reported in published literature (10.23 ± 9.31 col/m2). The geologic features underlying the exposed substrates that harbor mesophotic communities are targeted for extensive hydrocarbon exploration and extraction, as they often contain oil and/or natural gas. The Bureau of Ocean Energy Management regulates offshore energy development in the United States and is tasked with protecting sensitive biological communities from impacts related to oil and gas activities. This study analyzed alpha and beta diversity of mesophotic coral forests on fourteen topographic banks in the northwestern Gulf of Mexico. The objective of the study was to examine differences in structure and community in relation to lease stipulations established by the Bureau of Ocean and Energy Management. It was determined that dense and diverse mesophotic coral forests and carbonate producers exist in present regulatory zones that prohibit oil and gas activities; however, the coral communities exist in higher densities, diversity, and richness in low relief substrates outside of these regulatory zones. Our findings suggest low relief hard substrates serve as important habitat for mesophotic coral forests; thus, we suggest the expansion of current stipulations should be considered to provide better protection to vulnerable coral communities on low relief features. Furthermore, additional studies to refine the relationship between low relief structures and biodiversity are needed to develop more meaningful habitat definitions to support resource management and improve resource protection in the future.
Historical Connectivity and Demography of the Ferocious Reef Crab, Eriphia ferox (Crustacea; Eriphiidae), Demonstrate That Taoyuan Algal Reef Is an Essential Population Source Along the East Taiwan Strait
Authors: Chen Mu-Han , Huang Ya-Yi , Huang Bi-Ying , Hsieh Hernyi Justin , Lee Jen Nie , Neo Mei Lin , Fukami Hironobu , Chen Chaolun Allen
Published: January 2022

The east Taiwan Strait is largely fringed by sandy and muddy habitats. However, a massive algal reef made of crustose coralline algae has been found along the coast off Taoyuan city in northwestern Taiwan. The porous structure of Taoyuan Algal Reef harbors high abundance and diversity in marine organisms, including the ferocious reef crab, Eriphia ferox. Such a pivotal geographic location and unique ecological features make Taoyuan Algal Reef a potential stepping stone connecting biotic reefs in the east Taiwan Strait, South China Sea to the south, and even the high latitude of Japan to the north. In this study, we examined the population connectivity and historical demography of E. ferox by analyzing mitochondrial cytochrome oxidase I (COI) fragments of 317 individuals sampled from 21 localities in the northwestern Pacific. Our analyses of haplotype network and pairwise FST comparisons revealed a lack of phylogeographical structure among E. ferox populations, implying the existence of a migration corridor connecting the South and East China Seas through the east Taiwan Strait. Multiple lines of evidence, including significant values in neutrality tests, unimodally shaped mismatch distributions, and Bayesian skyline plots elucidated the rapid population growth of E. ferox following the sea-level rise after Last Glacial Maximum (ca. 2–10 Ka). Such demographic expansion in E. ferox coincided with the time when Taoyuan Algal Reef started to build up around 7,500 years ago. Coalescent migration analyses further indicated that the large and continuous E. ferox population exclusively found in Datan Algal Reef, the heart of Taoyuan Algal Reef, was a source population exporting migrants both northward and southward to the adjacent populations. The bidirectional gene flow should be attributed to larval dispersal by ocean currents and secondary contact due to historical population expansion. Instead of serving as a stepping stone, our results support that Taoyuan Algal Reef is an essential population source for biotic reef-associated species along the east Taiwan Strait, and highlight the importance of conserving such a unique ecosystem currently threatened by anthropogenic development.
ImageMech: From Image to Particle Spring Network for Mechanical Characterization
Authors: Chiang Yuan , Chiu Ting-Wai , Chang Shu-Wei
Published: January 2022

The emerging demand for advanced structural and biological materials calls for novel modeling tools that can rapidly yield high-fidelity estimation on materials properties in design cycles. Lattice spring model , a coarse-grained particle spring network, has gained attention in recent years for predicting the mechanical properties and giving insights into the fracture mechanism with high reproducibility and generalizability. However, to simulate the materials in sufficient detail for guaranteed numerical stability and convergence, most of the time a large number of particles are needed, greatly diminishing the potential for high-throughput computation and therewith data generation for machine learning frameworks. Here, we implement CuLSM, a GPU-accelerated compute unified device architecture C++ code realizing parallelism over the spring list instead of the commonly used spatial decomposition, which requires intermittent updates on the particle neighbor list. Along with the image-to-particle conversion tool Img2Particle, our toolkit offers a fast and flexible platform to characterize the elastic and fracture behaviors of materials, expediting the design process between additive manufacturing and computer-aided design. With the growing demand for new lightweight, adaptable, and multi-functional materials and structures, such tailored and optimized modeling platform has profound impacts, enabling faster exploration in design spaces, better quality control for 3D printing by digital twin techniques, and larger data generation pipelines for image-based generative machine learning models.
Effect of Aluminum Incorporation on the Reaction Process and Reaction Products of Hydrated Magnesium Silicate
Authors: Jia Yuan , Zou Yuxin , Zou Xinmei , Jiang Yaoting , Li Fangyuan , Ma Wangkun , Yan Hongli , Hua Rui
Published: January 2022

In this study, we investigated the impact of aluminium ion (Al3+) incorporation on the microstructure and the phase transformation of the magnesium silicate hydrate system. The magnesium silicate hydrate system with aluminium was prepared by mixing magnesium oxide and silica fume with different aluminium ion contents (the Al/Si molar ratios of 0.01, 0.02, 0.05, 0.1, 0.2) at room temperature. The high degree of polymerization of the magnesium silicate hydrate phases resulted in the limited incorporation of aluminium in the structure of magnesium silicate hydrate. The silicon-oxygen tetrahedra sites of magnesium silicate hydrate layers, however, were unable to substitute for silicon sites through inverted silicon-oxygen linkages. The increase in aluminium ion content raised the degree of polymerization of the magnesium silicate hydrate phases from 0.84 to 0.92. A solid solution was formed from residual aluminum-amorphous phases such as hydroxyl-aluminum and magnesium silicate hydrate phases. X-ray diffraction (XRD), field emission scanning electron microscope (F-SEM), and 29Si and 27Al MAS NMR data showed that the addition of Al3+ promotes the hydration process of MgO and has an obvious effect on the appearance of M-S-H gel. The gel with low aluminum content is fluffy, while the gel with high aluminum content has irregular flakes. The amount of Al3+ that enters the M-S-H gel increased with the increase of Al3+ content, but there was a threshold: the highest Al/Si molar ratio of M-S-H gel can be maintained at about 0.006.
Integrated Design in Load Carrying and Energy Absorption of Composite Tube
Authors: Hu Hanjie , Du Bing , Jiang Wenkai , Zheng Changqi , Zhu Ning , Liu Jingwei , Chen Liming
Published: January 2022

In this study, a type of tube with an open-hole AL alloy tube nested outside the CFRP tube is designed and fabricated, and the energy absorbing characteristics and failure mechanism under quasi-static axial compression are discussed. It is found that the summing tube composed of two single tubes has less energy absorption than the hybrid tube. Numerical simulation and theoretical models are used to evaluate the influence of the hybrid tube in terms of cost and weight, and it is found that under the same energy absorption, the hybrid tube has a weight reduction of 39.2% compared to the open-hole AL tube, which was 25.7% of the cost of the CFRP tube. This hybrid structure has potential as the load-carrying and energy absorption tube.
[18F] Sodium Fluoride Dose Reduction Enabled by Digital Photon Counting PET/CT for Evaluation of Osteoblastic Activity
Authors: Menendez Maria I. , Moore Richard R. , Abdel-Rasoul Mahmoud , Wright Chadwick L. , Fernandez Soledad , Jackson Rebecca D. , Knopp Michael V.
Published: January 2022

The aim of the study was to assess the quality and reproducibility of reducing the injected [18F] sodium fluoride ([18F]NaF) dose while maintaining diagnostic imaging quality in bone imaging in a preclinical skeletal model using digital photon counting PET (dPET) detector technology. Beagles (n = 9) were administered three different [18F]NaF doses: 111 MBq (n = 5), 20 MBq (n = 5), and 1.9 MBq (n = 9). Imaging started ≃45 min post-injection for ≃30 min total acquisition time. Images were reconstructed using Time-of-Flight, ultra-high definition (voxel size of 1 × 1 × 1 mm3), with 3 iterations and 3 subsets. Point spread function was modeled and Gaussian filtering was applied. Skeleton qualitative and quantitative molecular image assessment was performed. The overall diagnostic quality of all images scored excellent (61%) and acceptable (39%) by all the reviewers. [18F]NaF SUVmean showed no statistically significant differences among the three doses in any of the region of interest assessed. This study demonstrated that a 60-fold [18F]NaF dose reduction was not significantly different from the highest dose, and it had not significant effect on overall image quality and quantitative accuracy. In the future, ultra-low dose [18F]NaF dPET/CT imaging may significantly decrease PET radiation exposure to preclinical subjects and personnel.
Correlation Study Between Abnormal Morphology of Meibomian Glands and Meibum in Patients With Dry Eye Disease Under in vivo Confocal Microscopy
Authors: Zheng Qian , Xue Yuanyuan , Zhong Xiaowei , Li Guangwei , Shi Weiyun , Wang Ting
Published: January 2022

Objective: To observe differences in meibomian gland morphology among patients with meibomian gland dysfunction (MGD) with liquid meibum, with solid meibum, and a non-MGD group by laser scanning in vivo confocal microscopy (IVCM), and then analyze the correlation between meibomian gland abnormalities and dry eye disease.

Methods: Twenty-one patients with MGD (42 eyes) with liquid meibum, 21 patients with MGD (38 eyes) with solid meibum, and 24 non-MGD patients (39 eyes) were enrolled in the study. IVCM examination and Schirmer II test were performed, and non-invasive tear-film breakup time (NIBUT) was measured.

Results: Data obtained from all the patients were normally distributed; therefore, one-way analysis of variance was performed. The meibomian gland opening diameter and gland opening area of the patients with MGD were greater than those of the non-MGD patients, and values of the liquid meibum group were greater than those of the solid meibum group (F = 17.96, p < 0.001; F = 8.84, p < 0.001, respectively). Due to changes in meibomian gland opening diameter and dilation of meibomian gland acini, the acinar longest diameter and unit area of the patients with MGD were also greater than those of the non-MGD patients, and the values of the solid meibum group were greater than those of the liquid meibum group (F = 36.52, p < 0.001; F = 27.81, p < 0.001, respectively). In the aspect of acinar shortest diameter, there was no difference among the three groups (F = 0.24, P > 0.05). Highest inflammatory cell density was observed in the solid meibum group, followed by the liquid meibum group, and the non-MGD group (F = 111.54, p < 0.001). Similarly, the results of the Schirmer II test and NIBUT showed that the condition of the patients with MGD in the solid meibum group was worst, followed by that of the liquid meibum group and the non-MGD group (F = 99.57, p < 0.001; F = 11.87, p < 0.001, respectively).

Conclusions: The different meibum in the patients with MGD is accompanied by different meibomian gland morphologies. Compared with the patients with liquid meibum, those with solid meibum have more obvious dilatation of meibomian glands under confocal microscopy and in these patients, the density of inflammatory cells among glands is higher, and the quality of tears is worse.
Role of a Pyroptosis-Related lncRNA Signature in Risk Stratification and Immunotherapy of Ovarian Cancer
Authors: Zhang Zeyu , Xu Zhijie , Yan Yuanliang
Published: January 2022

Background: Pyroptosis is a newly recognized form of cell death. Emerging evidence has suggested the crucial role of long non-coding RNAs (lncRNAs) in the tumorigenesis and progression of ovarian cancer (OC). However, there is still poor understanding of pyroptosis-related lncRNAs in OC.

Methods: The TCGA database was accessed for gene expression and clinical data of 377 patients with OC. Two cohorts for training and validation were established by random allocation. Correlation analysis and Cox regression analysis were performed to identify pyroptosis-related lncRNAs and construct a risk model.

Results: Six pyroptosis-related lncRNAs were included in the final signature with unfavorable survival data. Subsequent ROC curves showed promising predictive value of patient prognosis. Further multivariate regression analyses confirmed the signature as an independent risk factor in the training (HR: 2.242, 95% CI: 1.598–3.145) and validation (HR: 1.884, 95% CI: 1.204–2.95) cohorts. A signature-based nomogram was also established with a C-index of.684 (95% CI: 0.662–0.705). Involvement of the identified signature in multiple immune-related pathways was revealed by functional analysis. Moreover, the signature was also associated with higher expression of three immune checkpoints (PD-1, B7-H3, and VSIR), suggesting the potential of the signature as an indicator for OC immunotherapies.

Conclusion: This study suggests that the identified pyroptosis-related lncRNA signature and signature-based nomogram may serve as methods for risk stratification of OC. The signature is also associated with the tumor immune microenvironment, potentially providing an indicator for patient selection of immunotherapy in OC.
Adalimumab in Vogt-Koyanagi-Harada Disease Refractory to Conventional Therapy
Authors: Yang Shizhao , Tao Tianyu , Huang Zhaohao , Liu Xiuxing , Li He , Xie Lihui , Wen Feng , Chi Wei , Su Wenru
Published: January 2022

Background: No study explores the effectiveness of adalimumab in sight-threatening Vogt-Koyanagi-Harada (VKH) patients in China.

Objective: To evaluate the short-term effectiveness and safety of adalimumab (ADA) in patients with sight-threatening Vogt-Koyanagi-Harada (VKH) disease refractory to conventional therapy.

Methods: Medical records of VKH patients who had been treated with systemic glucocorticoids and immunosuppressants but whose condition was poorly controlled were collected and analyzed. Primary outcomes comprised of best-corrected visual acuity (BCVA), intraocular inflammation, relapses, and glucocorticoid-sparing effects. Other outcomes included central macular thickness (CMT), intraocular manifestations and adverse events (AEs).

Results: Nine refractory VKH patients with a median age of 30 (16, 43) years old were enrolled in this study and received treatment for a median of 10 (7, 11) months. Mean BCVA improved from LogMar 0.63 ± 0.50 (20/72 or 0.36 ± 0.26 in Snellen chart) at baseline to LogMar 0.50 ± 0.37 (20/82 or 0.41 ± 0.28 in Snellen chart) at final visit (P = 0.090). The anterior chamber cell grade decreased from 2 (1.75, 3)+ at baseline to 0.5 (0, 1.25)+ cell at final visit (P < 0.001). The vitritis grade decreased from 1 (1, 1) + cell at baseline to 0 (0, 1)+ cell at final visit (P < 0.001). Patients suffered a median of 1 (0, 2) relapse during treatment. CMT remained stable from 238.50 ± 144.94 μm at baseline to 219.28 ± 77.20 μm at final visit (P = 0.553). The mean prednisone dosage decreased from 21.91 ± 18.39 mg/d to 2.73 ± 4.10 mg/d (P = 0.005). No severe AEs were found during treatment.

Conclusions: The outcomes indicated that ADA was an effective and safe option for VKH patients refractory to conventional therapy by controlling inflammation, preserving visual function and reducing the daily glucocorticoid dose.
ERANET JTC 2011: Submission and Activation of an International Academic Translational Project in Advanced Breast Cancer. Experience From the ET-FES Study
Authors: Monti Manuela , Degenhardt Tom , Brain Etienne , Wuerstlein Rachel , Argusti Alessandra , Puntoni Matteo , Rollandi Gian Andrea , Corradengo Davide , Boni Luca , Ilhan Harun , Nanni Oriana , Cortes Javier , Piris-Gimenez Alejandro , Piccardo Arnoldo , Iacozzi Massimiliano , Matteucci Federica , Di Iorio Valentina , Alberini Jean Louis , Schröder Carolien , Harbeck Nadia , Gennari Alessandra
Published: January 2022

Background: Academic research is important to face unmet medical needs. The Oncological community encounters many hurdles in setting up multicenter investigator-driven trials mainly due to administrative complexity. The purpose of a network organization at a multinational level is to facilitate clinical trials through standardization, coordination, and education for drug development and regulatory approval.

Methods: The application of an European grant foresees the creation of a consortium which aims at facilitating multi-center academic clinical trials.

Results: The ERA-NET TRANSCAN Call 2011 on “Validation of biomarkers for personalized cancer medicine” was released on December 2011. This project included Italian, Spanish, French and German centers. The approval process included Consortium constitution, project submission, Clinical Trial Submission, and activation on a national level. The different timescales for submitting study documents in each Country and the misalignment of objections by each Competent Authority CA, generated several requests for changes to the study documents which meant amendments had to be made; as requested by the 2001/20/EC Directive, the alignment of core documents is mandatory. This procedure impacted significantly on study activation timelines. Time to first patient in was 14, 10, 28, and 31 months from the date of submission in Italy, France, Spain, and Germany, respectively. Accrual was stopped on 22nd January 2021 due to an 18F FES shortage as the primary reason but also for having exceeded the project deadlines with consequent exhaustion of the funds allocated for the project.

Conclusions: Pharmaceutical companies might be reluctant to fund research projects aimed at treatment individualization if the approval for a wider indication has already been achieved. Academic trials therefore become fundamental for promoting trials which are not attractive to big pharma. It was very difficult and time consuming to activate an academic clinical trial, for this reason, a study may become “old” as new drugs entered into the market. National institutions should promote the development of clinical research infrastructures and network with competence in regulatory, ethical, and legal skills to speed up academic research.
Molecular Characterization and Clinical Relevance of ALDH2 in Human Cancers
Authors: Ma Bo , Liu Zaoqu , Xu Hui , Liu Long , Huang Tao , Meng Lingfang , Wang Libo , Zhang Yuyuan , Li Lifeng , Han Xinwei
Published: January 2022

Background: Aldehyde dehydrogenase 2 (ALDH2) is well-known to be a key enzyme in alcohol metabolism. However, a comprehensive understanding of ALDH2 across human cancers is lacking.

Methods: A systematic and comprehensive analysis of the molecular alterations and clinical relevance for ALDH2 in more than 10,000 samples from 33 cancer types was performed. qRT-PCR was performed on 60 cancer and 60 paired nontumor tissues.

Results: It was observed that ALDH2 was generally downregulated in most cancers, which was mainly driven by DNA hypermethylation rather than mutations or copy number variations. Besides, ALDH2 was closely related to the inhibition and activation of tumor pathways and a variety of potential targeted agents had been discovered in our research. Last but not least, ALDH2 had the best prediction efficacy in assessing immunotherapeutic response compared with PD-L1, PD-1, CTLA4, CD8, and tumor mutation burden (TMB) in cutaneous melanoma. According to the analysis of large-scale public data and 60 pairs of clinical cancer samples, we found the downregulation of ALDH2 expression tends to suggest the malignant phenotypes and adverse prognosis, which might enhance the precise diagnosis and timely intervention of cancer patients.

Conclusion: This study advanced the understanding of ALDH2 across cancers, and provided important insight into chemotherapy, immunotherapy and prognosis of patients with cancer.
Genomic Characterization of a Novel Freshwater Cyanophage Reveals a New Lineage of Cyanopodovirus
Authors: Zhang Dong , He Yiliang , Gin Karina Yew-Hoong
Published: January 2022

Cyanobacteria are one of the dominant autotrophs in tropical freshwater communities, yet phages infecting them remain poorly characterized. Here we present the characterization of cyanophage S-SRP02, isolated from a tropical freshwater lake in Singapore, which infects Synechococcus sp. Strain SR-C1 isolated from the same lake. S-SRP02 represents a new evolutionary lineage of cyanophage. Out of 47 open reading frames (ORFs), only 20 ORFs share homology with genes encoding proteins of known function. There is lack of auxiliary metabolic genes which was commonly found as core genes in marine cyanopodoviruses. S-SRP02 also harbors unique structural genes highly divergent from other cultured phages. Phylogenetic analysis and viral proteomic tree further demonstrate the divergence of S-SRP02 from other sequenced phage isolates. Nonetheless, S-SRP02 shares synteny with phage genes of uncultured phages obtained from the Mediterranean Sea deep chlorophyll maximum fosmids, indicating the ecological importance of S-SRP02 and its related viruses. This is further supported by metagenomic mapping of environmental viral metagenomic reads onto the S-SRP02 genome.
SGP-C: A Broad Host Range Temperate Bacteriophage; Against Salmonella gallinarum
Authors: Ilyas Syeda Zainab , Tariq Hafsa , Basit Abdul , Tahir Hamza , Haider Zulquernain , Rehman Shafiq ur
Published: January 2022

Salmonella gallinarum is a poultry restricted-pathogen causing fowl-typhoid disease in adult birds with mortality rates up-to 80% and exhibit resistance against commonly used antibiotics. In this current study, a temperate broad host range bacteriophage SGP-C was isolated against S. gallinarum from poultry digesta. It showed infection ability in all the 15 tested field strains of S. gallinarum. The SGP-C phage produced circular, turbid plaques with alternate rings. Its optimum activity was observed at pH 7.0 and 37–42°C, with a latent period of 45 min and burst size of 187 virions/bacterial cell. The SGP-C lysogens, SGPC-L5 and SGPC-L6 exhibited super-infection immunity against the same phage, an already reported feature of lysogens. A virulence index of 0.5 and 0.001 as MV50 of SGP-C suggests its moderate virulence. The genome of SGP-C found circular double stranded DNA of 42 Kbp with 50.04% GC content, which encodes 63 ORFs. The presence of repressor gene at ORF49, and absence of tRNA sequence in SGP-C genome indicates its lysogenic nature. Furthermore, from NGS analysis of lysogens we propose that SGP-C genome might exist either as an episome, or both as integrated and temporary episome in the host cell and warrants further studies. Phylogenetic analysis revealed its similarity with Salmonella temperate phages belonging to family Siphoviridae. The encoded proteins by SGP-C genome have not showed homology with any known toxin and virulence factor. Although plenty of lytic bacteriophages against this pathogen are already reported, to our knowledge SGP-C is the first lysogenic phage against S. gallinarum reported so far.
Serotype Distribution, Antimicrobial Susceptibility, Multilocus Sequencing Type and Virulence of Invasive Streptococcus pneumoniae in China: A Six-Year Multicenter Study
Authors: Zhou Menglan , Wang Ziran , Zhang Li , Kudinha Timothy , An Haoran , Qian Chenyun , Jiang Bin , Wang Yao , Xu Yingchun , Liu Zhengyin , Zhang Hong , Zhang Jingren
Published: January 2022

Background:Streptococcus pneumoniae is an important human pathogen that can cause severe invasive pneumococcal diseases (IPDs). The aim of this multicenter study was to investigate the serotype and sequence type (ST) distribution, antimicrobial susceptibility, and virulence of S. pneumoniae strains causing IPD in China.

Methods: A total of 300 invasive S. pneumoniae isolates were included in this study. The serotype, ST, and antimicrobial susceptibility of the strains, were determined by the Quellung reaction, multi-locus sequence typing (MLST) and broth microdilution method, respectively. The virulence level of the strains in the most prevalent serotypes was evaluated by a mouse sepsis model, and the expression level of well-known virulence genes was measured by RT-PCR.

Results: The most common serotypes in this study were 23F, 19A, 19F, 3, and 14. The serotype coverages of PCV7, PCV10, PCV13, and PPV23 vaccines on the strain collection were 42.3, 45.3, 73.3 and 79.3%, respectively. The most common STs were ST320, ST81, ST271, ST876, and ST3173. All strains were susceptible to ertapenem, levofloxacin, moxifloxacin, linezolid, and vancomycin, but a very high proportion (>95%) was resistant to macrolides and clindamycin. Based on the oral, meningitis and non-meningitis breakpoints, penicillin non-susceptible Streptococcus pneumoniae (PNSP) accounted for 67.7, 67.7 and 4.3% of the isolates, respectively. Serotype 3 strains were characterized by high virulence levels and low antimicrobial-resistance rates, while strains of serotypes 23F, 19F, 19A, and 14, exhibited low virulence and high resistance rates to antibiotics. Capsular polysaccharide and non-capsular virulence factors were collectively responsible for the virulence diversity of S. pneumoniae strains.

Conclusion: Our study provides a comprehensive insight into the epidemiology and virulence diversity of S. pneumoniae strains causing IPD in China.
Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1–Nup98 Complex to Compete With mRNA Nuclear Export
Authors: Li Tinghan , Wen Yibo , Guo Hangtian , Yang Tingting , Yang Haitao , Ji Xiaoyun
Published: January 2022

The accessory protein Orf6 is uniquely expressed in sarbecoviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an ongoing pandemic. SARS-CoV-2 Orf6 antagonizes host interferon signaling by inhibition of mRNA nuclear export through its interactions with the ribonucleic acid export 1 (Rae1)–nucleoporin 98 (Nup98) complex. Here, we confirmed the direct tight binding of Orf6 to the Rae1-Nup98 complex, which competitively inhibits RNA binding. We determined the crystal structures of both SARS-CoV-2 and SARS-CoV-1 Orf6 C-termini in complex with the Rae1–Nup98 heterodimer. In each structure, SARS-CoV Orf6 occupies the same potential mRNA-binding groove of the Rae1–Nup98 complex, comparable to the previously reported structures of other viral proteins complexed with Rae1-Nup98, indicating that the Rae1–Nup98 complex is a common target for different viruses to impair the nuclear export pathway. Structural analysis and biochemical studies highlight the critical role of the highly conserved methionine (M58) of SARS-CoVs Orf6. Altogether our data unravel a mechanistic understanding of SARS-CoVs Orf6 targeting the mRNA-binding site of the Rae1–Nup98 complex to compete with the nuclear export of host mRNA, which further emphasizes that Orf6 is a critical virulence factor of SARS-CoVs.
Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults
Authors: Badji Atef , Pereira Joana B. , Shams Sara , Skoog Johan , Marseglia Anna , Poulakis Konstantinos , Rydén Lina , Blennow Kaj , Zetterberg Henrik , Kern Silke , Zettergren Anna , Wahlund Lars-Olof , Girouard Hélène , Skoog Ingmar , Westman Eric
Published: January 2022

Background:Hypertension is an important risk factor for Alzheimer’s disease (AD). The pathophysiological mechanisms underlying the relationship between AD and hypertension are not fully understood, but they most likely involve microvascular dysfunction and cerebrovascular pathology. Although previous studies have assessed the impact of hypertension on different markers of brain integrity, no study has yet provided a comprehensive comparison of cerebrospinal fluid (CSF) biomarkers and structural brain differences between normotensive and hypertensive groups in a single and large cohort of older adults in relationship to cognitive performances.

Objective:The aim of the present work was to investigate the differences in cognitive performances, CSF biomarkers and magnetic resonance imaging (MRI) of brain structure between normotensive, controlled hypertensive, uncontrolled hypertensive, and untreated hypertensive older adults from the Gothenburg H70 Birth Cohort Studies.

Methods:As an indicator of vascular brain pathology, we measured white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, enlarged perivascular space (epvs), and fractional anisotropy (FA). To assess markers of AD pathology/neurodegeneration, we measured hippocampal volume, temporal cortical thickness on MRI, and amyloid-β42, phosphorylated tau, and neurofilament light protein (NfL) in cerebrospinal fluid. Various neuropsychological tests were used to assess performances in memory, attention/processing speed, executive function, verbal fluency, and visuospatial abilities.

Results:We found more white matter pathology in hypertensive compared to normotensive participants, with the highest vascular burden in uncontrolled participants (e.g., lower FA, more WMHs, and epvs). No significant difference was found in any MRI or CSF markers of AD pathology/neurodegeneration when comparing normotensive and hypertensive participants, nor among hypertensive groups. No significant difference was found in most cognitive functions between groups.

Conclusion:Our results suggest that good blood pressure control may help prevent cerebrovascular pathology. In addition, hypertension may contribute to cognitive decline through its effect on cerebrovascular pathology rather than AD-related pathology. These findings suggest that hypertension is associated with MRI markers of vascular pathology in the absence of a significant decline in cognitive functions.
Progressive Multi-Scale Vision Transformer for Facial Action Unit Detection
Authors: Wang Chongwen , Wang Zicheng
Published: January 2022

Facial action unit (AU) detection is an important task in affective computing and has attracted extensive attention in the field of computer vision and artificial intelligence. Previous studies for AU detection usually encode complex regional feature representations with manually defined facial landmarks and learn to model the relationships among AUs via graph neural network. Albeit some progress has been achieved, it is still tedious for existing methods to capture the exclusive and concurrent relationships among different combinations of the facial AUs. To circumvent this issue, we proposed a new progressive multi-scale vision transformer (PMVT) to capture the complex relationships among different AUs for the wide range of expressions in a data-driven fashion. PMVT is based on the multi-scale self-attention mechanism that can flexibly attend to a sequence of image patches to encode the critical cues for AUs. Compared with previous AU detection methods, the benefits of PMVT are 2-fold: (i) PMVT does not rely on manually defined facial landmarks to extract the regional representations, and (ii) PMVT is capable of encoding facial regions with adaptive receptive fields, thus facilitating representation of different AU flexibly. Experimental results show that PMVT improves the AU detection accuracy on the popular BP4D and DISFA datasets. Compared with other state-of-the-art AU detection methods, PMVT obtains consistent improvements. Visualization results show PMVT automatically perceives the discriminative facial regions for robust AU detection.
Coronary Artery Disease in Patients Presenting With Acute Ischemic Stroke or Transient Ischemic Attack and Elevated Troponin Levels
Authors: Kruska Mathieu , Kolb Anna , Fastner Christian , Mildenberger Iris , Hetjens Svetlana , Kittel Maximilian , Bail Kathrin , Behnes Michael , Akin Ibrahim , Borggrefe Martin , Szabo Kristina , Baumann Stefan
Published: January 2022

Background: There is little information concerning the invasive coronary angiography (ICA) findings of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) with elevated troponin levels and suspected myocardial infarction (MI). This study analyzed patient characteristics associated with ICA outcomes.

Methods: A total of 8,322 patients with AIS or TIA, treated between March 2010 and May 2020, were retrospectively screened for elevated serum troponin I at hospital admission. Patients in whom ICA was performed, due to suspected type 1 MI based on symptoms, echocardiography, and ECG, were categorized according to ICA results (non-obstructive coronary artery disease (CAD): ≥1 stenosis ≥50% but no stenosis ≥80%; obstructive CAD: any stenosis ≥80% or hemodynamically relevant stenosis assessed by FFR/iwFR).

Results: Elevated troponin levels were detected in 2,205 (22.5%) patients, of whom 123 (5.6%) underwent ICA (mean age 71 ± 12 years; 67% male). CAD was present in 98 (80%) patients, of whom 51 (41%) were diagnosed with obstructive CAD. Thus, ICA findings of obstructive CAD accounted for 2.3% of patients with troponin elevation and 0.6% of all stroke patients. The clinical hallmarks of myocardial ischemia, including angina pectoris (31 vs. 15%, p < 0.05) and regional wall motion abnormalities (49 vs. 32%, p = 0.07), and increased cardiovascular risk indicated obstructive CAD. While there was no association between lesion site or stroke severity and ICA findings, causal large-artery atherosclerosis was significantly more common in patients with obstructive coronary disease (p < 0.05).

Conclusion: The rate of obstructive CAD in patients with stroke or TIA and elevated troponin levels with suspected concomitant type I MI is low. The cumulation of several cardiovascular risk factors and clinical signs of MI were predictive. AIS patients with large-artery atherosclerosis and elevated troponin may represent an especially vulnerable subgroup of stroke patients with risk for obstructive CAD.
Co-sparse Non-negative Matrix Factorization
Authors: Wu Fan , Cai Jiahui , Wen Canhong , Tan Haizhu
Published: January 2022

Non-negative matrix factorization, which decomposes the input non-negative matrix into product of two non-negative matrices, has been widely used in the neuroimaging field due to its flexible interpretability with non-negativity property. Nowadays, especially in the neuroimaging field, it is common to have at least thousands of voxels while the sample size is only hundreds. The non-negative matrix factorization encounters both computational and theoretical challenge with such high-dimensional data, i.e., there is no guarantee for a sparse and part-based representation of data. To this end, we introduce a co-sparse non-negative matrix factorization method to high-dimensional data by simultaneously imposing sparsity in both two decomposed matrices. Instead of adding some sparsity induced penalty such as l1 norm, the proposed method directly controls the number of non-zero elements, which can avoid the bias issues and thus yield more accurate results. We developed an alternative primal-dual active set algorithm to derive the co-sparse estimator in a computationally efficient way. The simulation studies showed that our method achieved better performance than the state-of-art methods in detecting the basis matrix and recovering signals, especially under the high-dimensional scenario. In empirical experiments with two neuroimaging data, the proposed method successfully detected difference between Alzheimer's patients and normal person in several brain regions, which suggests that our method may be a valuable toolbox for neuroimaging studies.
Oral Bacteriotherapy Reduces the Occurrence of Chronic Fatigue in COVID-19 Patients
Authors: Santinelli Letizia , Laghi Luca , Innocenti Giuseppe Pietro , Pinacchio Claudia , Vassalini Paolo , Celani Luigi , Lazzaro Alessandro , Borrazzo Cristian , Marazzato Massimiliano , Tarsitani Lorenzo , Koukopoulos Alexia E. , Mastroianni Claudio M. , d'Ettorre Gabriella , Ceccarelli Giancarlo
Published: January 2022

Long COVID refers to patients with symptoms as fatigue, “brain fog,” pain, suggesting the chronic involvement of the central nervous system (CNS) in COVID-19. The supplementation with probiotic (OB) would have a positive effect on metabolic homeostasis, negatively impacting the occurrence of symptoms related to the CNS after hospital discharge. On a total of 58 patients hospitalized for COVID-19, 24 (41.4%) received OB during hospitalization (OB+) while 34 (58.6%) taken only the standard treatment (OB–). Serum metabolomic profiling of patients has been performed at both hospital acceptance (T0) and discharge (T1). Six months after discharge, fatigue perceived by participants was assessed by administrating the Fatigue Assessment Scale. 70.7% of participants reported fatigue while 29.3% were negative for such condition. The OB+ group showed a significantly lower proportion of subjects reporting fatigue than the OB– one (p < 0.01). Furthermore, OB+ subjects were characterized by significantly increased concentrations of serum Arginine, Asparagine, Lactate opposite to lower levels of 3-Hydroxyisobutirate than those not treated with probiotics. Our results strongly suggest that in COVID-19, the administration of probiotics during hospitalization may prevent the development of chronic fatigue by impacting key metabolites involved in the utilization of glucose as well as in energy pathways.
Altered Taste Function in Young Individuals With Type 1 Diabetes
Authors: Catamo Eulalia , Robino Antonietta , Tinti Davide , Dovc Klemen , Franceschi Roberto , Giangreco Manuela , Gasparini Paolo , Barbi Egidio , Cauvin Vittoria , Rabbone Ivana , Battelino Tadej , Tornese Gianluca
Published: January 2022

Past studies on altered taste function in individuals with type 1 diabetes have yielded inconsistent results. We therefore evaluated taste recognition and possible association with personal and diseases characteristics in young individuals with type 1 diabetes and healthy controls. Taste recognition and intensity for 6-n-propylthiouracil (PROP), quinine, citric acid, sucrose, and sodium chloride were assessed using a filter paper method in 276 participants with type 1 diabetes and 147 healthy controls. Personal and clinical data were recorded for all participants during a baseline visit. Regression analysis was adjusted for sex, age, and standardized BMI. Overall, 47% of participants with type 1 diabetes vs. 63.5% of healthy controls recognized all tastes (p = 0.006). Moreover, a lower capacity for recognizing the bitter taste of PROP and the sour taste of citric acid was found in participants with type 1 diabetes compared to healthy controls (p = 0.014 and p = 0.003, respectively). While no significant effect of glycemic control on taste recognition was found, an association with lower age at onset emerged. Our findings suggest an impaired taste perception in individuals with type 1 diabetes, possibly linked to age at onset.
Superiority of Microencapsulated Essential Oils Compared With Common Essential Oils and Antibiotics: Effects on the Intestinal Health and Gut Microbiota of Weaning Piglet
Authors: Mo Kaibin , Li Jing , Liu Fenfen , Xu Ying , Huang Xianhui , Ni Hengjia
Published: January 2022

Essential oils (EOs) have long been considered an alternative to antibiotics in the breeding industry. However, they are unstable and often present unpleasant odors, which hampers their application. Microencapsulation can protect the active gradients from oxidation and allow them to diffuse slowly in the gastrointestinal tract. The purpose of this study was to investigate the effect of microencapsulation technology on the biological function of EOs and the possibility of using microencapsulate EOs (MEEOs) as an alternative to antibiotics in weaning piglets. First, we prepared MEEOs and common EOs both containing 2% thymol, 5% carvacrol and 3% cinnamaldehyde (w/w/w). Then, a total of 48 weaning piglets were randomly allotted to six dietary treatments: (1) basal diet; (2) 75 mg/kg chlortetracycline; (3) 100 mg/kg common EOs; (4) 500 mg/kg common EOs; (5) 100 mg/kg MEEOs; and (6) 500 mg/kg MEEO. The trial lasted 28 days. The results showed that piglets in the 100 mg/kg MEEOs group had the lowest diarrhea index during days 15–28 (P < 0.05). In addition, 100 mg/kg MEEOs significantly alleviated intestinal oxidative stress and inflammation (P < 0.05), whereas 500 mg/kg common EOs caused intestinal oxidative stress (P < 0.05) and may lead to intestinal damage through activation of inflammatory cytokine response. MEEOs (100 mg/kg) significantly reduced the ratio of the relative abundance of potential pathogenic and beneficial bacteria in the cecum and colon (P < 0.05), thus contributing to the maintenance of intestinal health. On the other hand, chlortetracycline caused an increase in the ratio of the relative abundance of potential pathogenic and beneficial bacteria in the colon (P < 0.05), which could potentially have adverse effects on the intestine. The addition of a high dose of MEEOs may have adverse effects on the intestine and may lead to diarrhea by increasing the level of colonic acetic acid (P < 0.05). Collectively, the results suggest that microencapsulation technology significantly promotes the positive effect of EOs on the intestinal health of weaning piglets and reduces the adverse effect of EOs, and 100 mg/kg MEEOs are recommended as a health promoter in piglets during the weaning period.
Lycium barbarum Extracts Extend Lifespan and Alleviate Proteotoxicity in Caenorhabditis elegans
Authors: Zhou Haitao , Ding Shanshan , Sun Chuanxin , Fu Jiahui , Yang Dong , Wang Xi'e , Wang Chih-chen , Wang Lei
Published: January 2022

Lycium barbarum berry (Ningxia Gouqi, Fructus lycii, goji berry, or wolfberry), as a traditional Chinese herb, was recorded beneficial for longevity in traditional Chinese medical scriptures and currently is a natural dietary supplement worldwide. However, under modern experimental conditions, the longevity effect of L. barbarum berry and the underlying mechanisms have been less studied. Here, we reported that total water extracts of L. barbarum berry (LBE), which contains 22% polysaccharides and other components, such as anthocyanins, extended the lifespan of Caenorhabditis elegans without side effects on worm fertility and pharyngeal pumping. Interestingly, we found that the lifespan extension effect was more prominent in worms with shorter mean lifespan as compared to those with longer mean lifespan. Furthermore, we showed that the lifespan extension effect of LBE depended on deacetylase sir-2.1. Remarkably, LBE rescued heat shock transcription factor-1 (hsf-1) deficiency in wild-type worms with different mean lifespans, and this effect also depended on sir-2.1. In addition, we found that LBE extended lifespan and alleviated toxic protein aggregation in neurodegenerative worms with hsf-1 deficiency. Our study suggested that LBE may be a potential antiaging natural dietary supplement especially to individuals with malnutrition or chronic diseases and a potential therapeutic agent for neurodegenerative diseases characterized by hsf-1 deficiency.