bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Novel Compound Heterozygous Variants of the PNPLA6 Gene in Boucher–Neuhäuser Syndrome
Authors: He Junyu , Liu Xin , Liu Liyi , Zeng Shaohao , Shan Shuanghong , Liao Zhihong
Published: February 2022

Background: Boucher–Neuhäuser syndrome (BNS, MIM 215470) is a rare autosomal recessive syndrome caused by mutations in the PNPLA6 gene. Few BNS cases have been reported for functional validation at the RNA level. Herein, we report on the family of a 17-year-old girl with clinical characteristics of BNS, genetic validation, and a systematic review of PNPLA6 variants related to BNS.

Methods: Clinical data and blood samples were collected from the patient and their parents, and whole-exome sequencing was performed and confirmed by Sanger sequencing. RNA-sequencing (RNA-Seq) and quantitative RT-PCR (qRT-PCR) were performed, and the three-dimensional protein structures of the variants were predicted.

Results: We report a 17-year-old female with progressive night blindness since the age of four, primary amenorrhea, and non-development of secondary sexual characteristics. Her impaired vision was diagnosed as retinal pigmentary degeneration of the retina. She had congenital hypogonadotropic hypogonadism (CHH) but no cerebellar ataxia at present. Two novel compound heterozygous variants (c.2241del/p.Met748TrpfsTer65 and c.2986A>G/p.Thr996Ala) of the PNPLA6 gene (NM_006702.4) were identified by whole-exome sequencing. The former variant was carried from her healthy father and has not been reported previously. The latter was inherited from her healthy mother and was noted in a report without functional studies. The RT-PCR results showed that the mRNA expression of PNPLA6 was lower in this patient and her father than in the control group. She was diagnosed with BNS. Both variants (c.2241del and c.2986A>G) were likely pathogenic according to the ACMG criteria. The novel variants in the PNPLA6 gene related to Boucher–Neuhäuser syndrome were summarized in this article.

Conclusion: The possibility of Boucher–Neuhäuser syndrome should be considered when patients present with night blindness, impaired vision, and hypogonadotropic hypogonadism. Gene sequencing is currently the primary diagnostic method. Herein, novel compound heterozygous variants of PNPLA6 were identified in a BNS patient, and its function was verified at the RNA level. The PNPLA6 c.2241del variant is novel and potentially pathogenic, expanding the mutation spectrum in PNPLA6.
Development of an Immortalized Porcine Fibroblast Cell Panel With Different Swine Leukocyte Antigen Genotypes
Authors: Le Quy Van Chanh , Youk SeungYeon , Choi Munjeong , Jeon Hyoim , Kim Won-Il , Ho Chak-Sum , Park Chankyu
Published: February 2022

Immortalized cell lines are valuable resources to expand the molecular characterization of major histocompatibility complex genes and their presented antigens. We generated a panel of immortalized cell lines by transfecting human telomerase reverse transcriptase (hTERT) into primary fibroblast cells prepared from ear, fetal, and lung tissues of 10 pigs from five breeds and successfully cultured them for 30–45 passages. The cell growth characteristic of the immortalized fibroblasts was similar to that of primary fibroblast, which was unable to form colonies on soft agar. The genotypes of major swine leukocyte antigen (SLA) genes, including three classical class I (SLA-1, -2,and-3) and three class II genes (DQB1,DRB1, andDQA), were determined using high-resolution typing. A total of 58 alleles, including a novel allele forSLA-2, were identified. Each cell line was unique. A cell line derived from a National Institutes of Health miniature pig was homozygous across the six major SLA genes. The expression levels of SLA classical class I genes varied among the cell lines and were slightly upregulated in the immortalized compared to the primary cells based on semiquantitative reverse transcription polymerase chain reaction. The immortalized porcine fibroblast cell lines with diverse SLA haplotypes that were developed in this study have potential to be applied in studies regarding the molecular characteristics and genetic structure of SLA genes and epitope–major histocompatibility complex interactions in pigs.
Using Graph Attention Network and Graph Convolutional Network to Explore Human CircRNA–Disease Associations Based on Multi-Source Data
Authors: Li Guanghui , Wang Diancheng , Zhang Yuejin , Liang Cheng , Xiao Qiu , Luo Jiawei
Published: February 2022

Cumulative research studies have verified that multiple circRNAs are closely associated with the pathogenic mechanism and cellular level. Exploring human circRNA–disease relationships is significant to decipher pathogenic mechanisms and provide treatment plans. At present, several computational models are designed to infer potential relationships between diseases and circRNAs. However, the majority of existing approaches could not effectively utilize the multisource data and achieve poor performance in sparse networks. In this study, we develop an advanced method, GATGCN, using graph attention network (GAT) and graph convolutional network (GCN) to detect potential circRNA–disease relationships. First, several sources of biomedical information are fused via the centered kernel alignment model (CKA), which calculates the corresponding weight of different kernels. Second, we adopt the graph attention network to learn latent representation of diseases and circRNAs. Third, the graph convolutional network is deployed to effectively extract features of associations by aggregating feature vectors of neighbors. Meanwhile, GATGCN achieves the prominent AUC of 0.951 under leave-one-out cross-validation and AUC of 0.932 under 5-fold cross-validation. Furthermore, case studies on lung cancer, diabetes retinopathy, and prostate cancer verify the reliability of GATGCN for detecting latent circRNA–disease pairs.
Cytotoxic B Cells in Relapsing-Remitting Multiple Sclerosis Patients
Authors: Boldrini Vinícius O. , Marques Ana M. , Quintiliano Raphael P. S. , Moraes Adriel S. , Stella Carla R. A. V. , Longhini Ana Leda F. , Santos Irene , Andrade Marília , Ferrari Breno , Damasceno Alfredo , Carneiro Rafael P. D. , Brandão Carlos Otávio , Farias Alessandro S. , Santos Leonilda M. B.
Published: February 2022

Background

Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis.

Objective

To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients.

Methods

In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses.

Results

RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-β (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients.

Conclusions

CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring “cytotoxic” subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.
CD137 Agonists Targeting CD137-Mediated Negative Regulation Show Enhanced Antitumor Efficacy in Lung Cancer
Authors: Yi Ling , Jin Xin , Wang Jinghui , Yan Zhuohong , Cheng Xu , Wen Tao , Yang Bin , Wang Xiaojue , Che Nanying , Liu Zhidong , Zhang Hongtao
Published: February 2022

Negative immune regulation plays a notable role in tumor immunity. This study aimed to confirm that CD137 mediates negative immunoregulation as well as agonist activity in tumor immunity. Soluble CD137 (sCD137), a prominent splice variant of membrane-bound CD137 (mCD137), was identified, and its concentration in the blood of lung cancer patients was increased. The baseline concentration of sCD137 in the blood was negatively correlated with the efficacy of neoadjuvant immunochemotherapy in a pilot study. The percentage of CD137+ regulatory T cells (Tregs) in the blood of lung cancer patients was also increased, and further enriched at the tumor site; Foxp3, CTLA-4, IL-10, IL-35-Ebi3, sCD137 and costimulatory molecules expression were also higher, indicating increased immunosuppressive activity. A high percentage of CD137+ Tregs in the tumor was associated with worse OS outcomes among patients with high CD137+CD8+ T cell infiltration levels. Notably, targeting CD137+ Tregs using an engineered CD137 agonist with wild-type mouse IgG2a Fc clearly decreased the total Treg numbers and eliminated the tumor in the CT26 model and prolonged the survival rate of a Lewis lung carcinoma (LLC) model. These results indicated it may be possible to empower CD137 agonist with ability to abolish CD137-mediated negative regulation to enhance its antitumor efficacy.
GlycoFibroTyper: A Novel Method for the Glycan Analysis of IgG and the Development of a Biomarker Signature of Liver Fibrosis
Authors: Scott Danielle A. , Wang Mengjun , Grauzam Stephane , Pippin Sarah , Black Alyson , Angel Peggi M. , Drake Richard R. , Castellino Stephen , Kono Yuko , Rockey Don C. , Mehta Anand S.
Published: February 2022

Our group has recently developed the GlycoTyper assay which is a streamlined antibody capture slide array approach to directly profile N-glycans of captured serum glycoproteins including immunoglobulin G (IgG). This method needs only a few microliters of serum and utilizes a simplified processing protocol that requires no purification or sugar modifications prior to analysis. In this method, antibody captured glycoproteins are treated with peptide N-glycosidase F (PNGase F) to release N-glycans for detection by MALDI imaging mass spectrometry (IMS). As alterations in N-linked glycans have been reported for IgG from large patient cohorts with fibrosis and cirrhosis, we utilized this novel method to examine the glycosylation of total IgG, as well as IgG1, IgG2, IgG3 and IgG4, which have never been examined before, in a cohort of 106 patients with biopsy confirmed liver fibrosis. Patients were classified as either having no evidence of fibrosis (41 patients with no liver disease or stage 0 fibrosis), early stage fibrosis (10 METAVIR stage 1 and 18 METAVIR stage 2) or late stage fibrosis (6 patients with METAVIR stage 3 fibrosis and 37 patients with METAVIR stage 4 fibrosis (cirrhosis)). Several major alterations in glycosylation were observed that classify patients as having no fibrosis (sensitivity of 92% and a specificity of 90%), early fibrosis (sensitivity of 84% with 90% specificity) or significant fibrosis (sensitivity of 94% with 90% specificity).
Haematopoietic Stem Cell Transplantation Results in Extensive Remodelling of the Clonal T Cell Repertoire in Multiple Sclerosis
Authors: Massey Jennifer , Jackson Katherine , Singh Mandeep , Hughes Brendan , Withers Barbara , Ford Carole , Khoo Melissa , Hendrawan Kevin , Zaunders John , Charmeteau-De Muylder Bénédicte , Cheynier Rémi , Luciani Fabio , Ma David , Moore John , Sutton Ian
Published: February 2022

Autologous haematopoietic stem cell transplantation (AHSCT) is a vital therapeutic option for patients with highly active multiple sclerosis (MS). Rates of remission suggest AHSCT is the most effective form of immunotherapy in controlling the disease. Despite an evolving understanding of the biology of immune reconstitution following AHSCT, the mechanism by which AHSCT enables sustained disease remission beyond the period of lymphopenia remains to be elucidated. Auto-reactive T cells are considered central to MS pathogenesis. Here, we analyse T cell reconstitution for 36 months following AHSCT in a cohort of highly active MS patients. Through longitudinal analysis of sorted naïve and memory T cell clones, we establish that AHSCT induces profound changes in the dominant T cell landscape of both CD4+ and CD8+ memory T cell clones. Lymphopenia induced homeostatic proliferation is followed by clonal attrition; with only 19% of dominant CD4 (p <0.025) and 13% of dominant CD8 (p <0.005) clones from the pre-transplant repertoire detected at 36 months. Recovery of a thymically-derived CD4 naïve T cell repertoire occurs at 12 months and is ongoing at 36 months, however diversity of the naïve populations is not increased from baseline suggesting the principal mechanism of durable remission from MS after AHSCT relates to depletion of putative auto-reactive clones. In a cohort of MS patients expressing the MS risk allele HLA DRB1*15:01, public clones are probed as potential biomarkers of disease. AHSCT appears to induce sustained periods of disease remission with dynamic changes in the clonal T cell repertoire out to 36 months post-transplant.
The Influence of Temperature on the Antiviral Response of mIgM+ B Lymphocytes Against Hirame Novirhabdovirus in Flounder (Paralichthys olivaceus)
Authors: Tang Xiaoqian , Ma Xinbiao , Cao Jing , Sheng Xiuzhen , Xing Jing , Chi Heng , Zhan Wenbin
Published: February 2022

Hirame novirhabdovirus (HIRRV) is an ongoing threat to the aquaculture industry. The water temperature for the onset of HIRRV is below 15°C, the peak is about 10°C, but no mortality is observed over 20°C. Previous studies found the positive signal of matrix protein of HIRRV (HIRRV-M) was detected in the peripheral blood leukocytes of viral-infected flounder. Flow cytometry and indirect immunofluorescence assay showed that HIRRV-M was detected in mIgM+ B lymphocytes in viral-infected flounder maintained at 10°C and 20°C, and 22% mIgM+ B lymphocytes are infected at 10°C while 13% are infected at 20°C, indicating that HIRRV could invade into mIgM+ B lymphocytes. Absolute quantitative RT-PCR showed that the viral copies in mIgM+ B lymphocytes were significantly increased at 24 h post infection (hpi) both at 10°C and 20°C, but the viral copies in 10°C infection group were significantly higher than that in 20°C infection group at 72 hpi and 96 hpi. Furthermore, the B lymphocytes were sorted from HIRRV-infected flounder maintained at 10°C and 20°C for RNA-seq. The results showed that the differentially expression genes in mIgM+ B lymphocyte of healthy flounder at 10°C and 20°C were mainly enriched in metabolic pathways. Lipid metabolism and Amino acid metabolism were enhanced at 10°C, while Glucose metabolism was enhanced at 20°C. In contrast, HIRRV infection at 10°C induced the up-regulation of the Complement and coagulation cascades, FcγR-mediated phagocytosis, Platelets activation, Leukocyte transendothelial migration and Natural killer cell mediated cytotoxicity pathways at 72 hpi. HIRRV infection at 20°C induced the up-regulation of the Antigen processing and presentation pathway at 72 hpi. Subsequently, the temporal expression patterns of 16 genes involved in Antigen processing and presentation pathway were investigated by qRT-PCR, and results showed that the pathway was significantly activated by HIRRV infection at 20°C but inhibited at 10°C. In conclusion, HIRRV could invade into mIgM+ B lymphocytes and elicit differential immune response under 10°C and 20°C, which provide a deep insight into the antiviral response in mIgM+ B lymphocytes.
Trends in Geographic Sensitivity of Marine Fishes Over Decades in the North Sea
Authors: Tu Chih-Wei , Lai Yin-Zheng , Chen Hsiao Chien , Kuo Chi-Yun , Lee Pei-Fen , Ko Chia-Ying
Published: February 2022

Accounting for biotic interactions is important for predicting species and ecosystem variation under changing climate but difficult to achieve in practice. The proportion of geographical overlap between species, called species geographical sensitivity (SGS), could be used to gauge the potential for species interactions. Species with increasingly high SGS could have the potential to experience more interactions with other species and vice versa, which might have important implications in ecological assessment, particularly at a community level, in the face of climate change. We compiled fish occurrences in the North Sea from 1983 to 2020 and calculated annual mean SGS (mSGS) to systematically evaluate their temporal changes and to estimate influences of species traits on the relative temporal changes in mSGS. The results showed that 36.3% of species significantly changed their mSGS over time, with high correlations between changes in species range size and overlap with other species. The species’ averaged mSGS before warming was highly correlated with the relative change in mSGS. Depth range, body length, and age at maturity together explained most variation in mSGS among these species. Contemporary climate change is expected to reorganize species distributions and interactions and substantially alter marine ecosystem functioning. Our assessment opens a new avenue for evaluating climate change impacts on species geographical interactions, and such geographical changes may be contingent on species traits.
Facilitating Salt Marsh Restoration: The Importance of Event-Based Bed Level Dynamics and Seasonal Trends in Bed Level Change
Authors: Willemsen Pim W. J. M. , Horstman Erik M. , Bouma Tjeerd J. , Baptist Martin J. , van Puijenbroek Marinka E. B. , Borsje Bas W.
Published: February 2022

Intertidal salt marshes provide a range of valuable ecosystem services which typically increase with marsh width. Understanding the drivers for salt marsh expansion versus retreat is thus key to managers. Previous research highlights the influence of short-term (daily/event) bed level dynamics on germination and establishment and subsequent vegetation presence. However, more recent literature suggests the importance of medium-term seasonal bed level dynamics on viable seed availability and subsequent vegetation presence. This study aims to assess event-based and seasonal bed level dynamics for vegetation presence in natural and semi-natural salt marshes and to provide generic thresholds for vegetation presence. To gain insight into bed level dynamics, data was used from autonomous Optical and Acoustic Surface Elevation Dynamics sensors (O-SED and A-SED) around the edge of natural and semi-natural salt marshes. Sensors were installed at vegetated and unvegetated measurement station Field observations from 22 O-SEDs deployed at 4 well-established natural salt marshes in the Western Scheldt estuary and 4 O-SEDs at a well-established semi-natural salt marsh in the Wadden Sea were reanalyzed. Six novel A-SEDs were deployed at a pioneer semi-natural salt marsh in the Ems-Dollard Estuary. The measurement duration at all salt marshes was at least 1 year. The A-SED sensor was successfully validated against manual measurements. Furthermore, vegetation data and water level data were obtained. No significant difference was observed between natural and semi-natural salt marshes. However, a significant difference between vegetated and unvegetated measurement stations for short-term bed level dynamics was observed. Vegetation was found to be present at locations restricted by short-term bed level variability smaller than or equal to 12 mm, emphasizing the presence of a short-term threshold. Although trends in the non-growing season were significantly different between vegetated and unvegetated stations, seasonal thresholds for vegetation presence were not found. The findings imply that knowledge of bed level-dynamics in well-established natural marshes can be used to predict vegetation presence in constructed semi-natural marshes. The importance of local short-term dynamics for vegetation presence instead of longer-term dynamics highlights possibilities for developing favorable conditions for vegetation presence in marsh restoration projects and the construction of new salt marsh ecosystems.
Full-Length Transcriptome of the Whale Shark (Rhincodon typus) Facilitates the Genome Information
Authors: Lou Fangrui , Wang Li , Wang Zhiyang , Wang Lei , Zhao Linlin , Zhou Qingjie , Lu Zhichuang , Tang Yongzheng
Published: February 2022

Rhincodon typus is a keystone and indicator species in marine ecosystems. Meanwhile, R. typus has been listed on the IUCN red list of vulnerable species. Here we used ONT platform to determine the full-length (FL) transcriptome of R. typus and obtained 14,930 FL transcripts. Among all FL transcripts, 14,915 transcripts were covered 11,892 genetic loci and 1,642 novel genetic loci were further found. Meanwhile, we identified 714 novel transcripts by compared FL transcripts with the R. typus genome. Based on FL transcripts, we also predicted the distribution patterns of ASs, LncRNAs, polyAs, CDSs and methylation sites on FL transcriptome of R. typus. Furthermore, a total of 31,021 (97.86%) CDSs can obtained annotation information. Overall, our work firstly provided the FL transcriptome and these sequences complete the annotated R. typus genome information. Furthermore, these information are a potential resource to study biological processes of R. typus.
Influence of Physical-Chemical Soil Parameters on Microbiota Composition and Diversity in a Deep Hyperarid Core of the Atacama Desert
Authors: Fuentes Bárbara , Choque Alessandra , Gómez Francisco , Alarcón Jaime , Castro-Nallar Eduardo , Arenas Franko , Contreras Daniel , Mörchen Ramona , Amelung Wulf , Knief Claudia , Moradi Ghazal , Klumpp Erwin , Saavedra Claudia P. , Prietzel Jörg , Klysubun Wantana , Remonsellez Francisco , Bol Roland
Published: February 2022

The extreme environmental conditions and lack of water on the soil surface in hyperarid deserts hamper microbial life, allowing only highly specialized microbial communities to the establish colonies and survive. Until now, the microbial communities that inhabit or have inhabited soils of hyperarid environments at greater depths have been poorly studied. We analyzed for the first time the variation in microbial communities down to a depth of 3.4 m in one of the driest places of the world, the hyperarid Yungay region in the Atacama Desert, and we related it to changes in soil physico-chemical characteristics. We found that the moisture content changed from 2 to 11% with depth and enabled the differentiation of three depth intervals: (i) surface zone A (0–60 cm), (ii) intermediate zone B (60–220 cm), and (iii) deep zone C (220–340 cm). Each zone showed further specific physicochemical and mineralogical features. Likewise, some bacterial phyla were unique in each zone, i.e., members of the taxa Deinococcota, Halobacterota, and Latescibacterota in zone A; Crenarchaeota, Fusobacteriota, and Deltaproteobacterium Sva0485 in zone B; and Fervidibacteria and Campilobacterota in zone C, which indicates taxon-specific preferences in deep soil habitats. Differences in the microbiota between the zones were rather abrupt, which is concomitant with abrupt changes in the physical-chemical parameters. Overall, moisture content, total carbon (TC), pH, and electric conductivity (EC) were most predictive of microbial richness and diversity, while total sulfur (TS) and total phosphorous (TP) contents were additionally predictive of community composition. We also found statistically significant associations between taxa and soil properties, most of which involved moisture and TC contents. Our findings show that under-explored habitats for microbial survival and existence may prevail at greater soil depths near water or within water-bearing layers, a valuable substantiation also for the ongoing search for biosignatures on other planets, such as Mars.
Genome Analysis and Description of Three Novel Diazotrophs Geomonas Species Isolated From Paddy Soils
Authors: Liu Guo-Hong , Yang Shang , Tang Rong , Xie Cheng-Jie , Zhou Shun-Gui
Published: February 2022

Five strictly anaerobic strains, designated RG2T, RG3, RG10T, RF4T, and RG29, were isolated from paddy soils in China. Strains RG2T, RF4T, RG10T, RG3, and RG29 grew at temperatures ranging 5–42°C and pH ranging 5.5–8.5. Strains RG2T, RF4T, RG3, and RG29 could tolerate NaCl up to 0–0.7% (w/v) while strain RG10T could tolerate NaCl up to 0–0.8% (w/v). The isolated strains showed the highest 16S rRNA gene sequence similarities to the type strains of Geomonas terrae Red111T and Geomonas paludis Red736T. In phylogenetic (based on 16S rRNA gene sequence) and phylogenomic trees, strains clustered with the members of the genus Geomonas. Menaquinone-8 was the predominant quinone present in all strains. The major fatty acid profiles of all strains were C15:1 ω6c, C16:0, iso-C15:0, and Summed Feature 3. The digital DNA–DNA hybridization (dDDH) and average nucleotide identity (ANI) values between the isolated strains and the closely related Geomonas species were lower than the cutoff value (ANI 95–96% and dDDH 70%) for prokaryotic species delineation. Based on physiological, biochemical, and chemotaxonomic properties, strains RG2T, RG10T, and RF4T could easily be differentiated with the members of the genus Geomonas. Additionally, all the isolated strains possessed nifHDK clusters and catalytic compartments of nitrogenase. Based on the above results, the isolated five strains represent three novel species of the genus Geomonas, for which the names Geomonas oryzisoli sp. nov., Geomonas subterranea sp. nov., and Geomonas nitrogeniifigens sp. nov. are proposed. The type strains are RG10T (= GDMCC1.2537T = KCTC 26318T), RG2T (= GDMCC1.2536T = KCTC 25317T), and RF4T (= GDMCC 1.2547T = KCTC 25316T).
Crystalline Sponge Method by Three-Dimensional Electron Diffraction
Authors: Chen Pohua , Liu Yang , Zhang Chaochao , Huang Fei , Liu Leifeng , Sun Junliang
Published: February 2022

The crystalline sponge method has shown to be a novel strategy for the structure determination of noncrystalline, oily, or trace amount of a compound. A target compound was absorbed and oriented orderly in the pregrown porous crystal for x-ray diffraction analysis. However, the diffusion in the micron-sized crystals is rather difficult. Lots of trial-and-error experiments are needed to optimize the guest-soaking process and to improve data quality. Nanocrystals are better in diffusion, yet it could not conduct a single crystal x-ray diffraction (SCXRD) analysis. Three-dimensional electron diffraction (3D-ED) is a powerful diffraction tool for the structure determination of small crystals. In this work, we successfully carried out the crystalline sponge method by 3D-ED technique using {(ZnI2)3-[2,4,6-tris(4-pyridyl)-1,3,5-triazine]2·x(guest)}n (1-Guest) porous complex nanocrystals. On account of the better diffuse ability of nanocrystals, the time needed for solvent exchange and guest soaking protocols are shortened 50-fold faster versus the original protocol. The crystal structure of the crystalline sponge incorporated with three different guests was fully resolved using a merged dataset. The structure model was identical to previously reported ones using x-ray, showing that the accuracy of the 3D-ED was comparable with SCXRD. The refinement results can also give the precise occupancy of the guest molecule soaked in the porous crystal. This work not only provides a new data collection strategy for crystalline sponge method but also demonstrates the potential of 3D-ED techniques to study host-guest interaction by solving the fine structure of porous material.
Intermittent Theta Burst Stimulation Increases Natural Oscillatory Frequency in Ipsilesional Motor Cortex Post-Stroke: A Transcranial Magnetic Stimulation and Electroencephalography Study
Authors: Ding Qian , Chen Songbin , Chen Jixiang , Zhang Shunxi , Peng Yuan , Chen Yujie , Chen Junhui , Li Xiaotong , Chen Kang , Cai Guiyuan , Xu Guangqing , Lan Yue
Published: February 2022

Objective

Intermittent theta burst stimulation (iTBS) has been widely used as a neural modulation approach in stroke rehabilitation. Concurrent use of transcranial magnetic stimulation and electroencephalography (TMS-EEG) offers a chance to directly measure cortical reactivity and oscillatory dynamics and allows for investigating neural effects induced by iTBS in all stroke survivors including individuals without recordable MEPs. Here, we used TMS-EEG to investigate aftereffects of iTBS following stroke.

Methods

We studied 22 stroke survivors (age: 65.2 ± 11.4 years; chronicity: 4.1 ± 3.5 months) with upper limb motor deficits. Upper-extremity component of Fugl-Meyer motor function assessment and action research arm test were used to measure motor function of stroke survivors. Stroke survivors were randomly divided into two groups receiving either Active or Sham iTBS applied over the ipsilesional primary motor cortex. TMS-EEG recordings were performed at baseline and immediately after Active or Sham iTBS. Time and time-frequency domain analyses were performed for quantifying TMS-evoked EEG responses.

Results

At baseline, natural frequency was slower in the ipsilesional compared with the contralesional hemisphere (P= 0.006). Baseline natural frequency in the ipsilesional hemisphere was positively correlated with upper limb motor function following stroke (P= 0.007). After iTBS, natural frequency in the ipsilesional hemisphere was significantly increased (P< 0.001).

Conclusions

This is the first study to investigate the acute neural adaptations after iTBS in stroke survivors using TMS-EEG. Our results revealed that natural frequency is altered following stroke which is related to motor impairments. iTBS increases natural frequency in the ipsilesional motor cortex in stroke survivors. Our findings implicate that iTBS holds the potential to normalize natural frequency in stroke survivors, which can be utilized in stroke rehabilitation.
Distinctive Temporal Trajectories of Alzheimer’s Disease Biomarkers According to Sex and APOE Genotype: Importance of Striatal Amyloid
Authors: Kim Jun Pyo , Chun Min Young , Kim Soo-Jong , Jang Hyemin , Kim Hee Jin , Jeong Jee Hyang , Na Duk L. , Seo Sang Won
Published: February 2022

Purpose

Previously, sex and apolipoprotein E (APOE) genotype had distinct effects on the cognitive trajectory across the Alzheimer’s disease (AD) continuum. We therefore aimed to investigate whether these trajectory curves including β-amyloid (Aβ) accumulation in the cortex and striatum, and tau accumulation would differ according to sex and APOE genotype.

Methods

We obtained 534 subjects for 18F-florbetapir (AV45) PET analysis and 163 subjects for 18F-flortaucipir (AV1451) PET analysis from the Alzheimer’s Disease Neuroimaging Initiative database. For cortical Aβ, striatal Aβ, and tau SUVR, we fitted penalized splines to model the slopes of SUVR value as a non-linear function of baseline SUVR value. By integrating the fitted splines, we obtained the predicted SUVR curves as a function of time.

Results

The time from initial SUVR to the cutoff values were 14.9 years for cortical Aβ, 18.2 years for striatal Aβ, and 22.7 years for tau. Although there was no difference in cortical Aβ accumulation rate between women and men, striatal Aβ accumulation was found to be faster in women than in men, and this temporal difference according to sex was more pronounced in tau accumulation. However, APOE ε4 carriers showed faster progression than non-carriers regardless of kinds of AD biomarkers’ trajectories.

Conclusion

Our temporal trajectory models illustrate that there is a distinct progression pattern of AD biomarkers depending on sex and APOE genotype. In this regard, our models will be able to contribute to designing personalized treatment and prevention strategies for AD in clinical practice.
Neurofilament Light Chain as a Biomarker for Monitoring the Efficacy of Transcranial Magnetic Stimulation on Alcohol Use Disorder
Authors: Zhang Tian , Song Bin , Li Yanfei , Duan Ranran , Gong Zhe , Jing Lijun , Wang Kaixin , Ma Bingquan , Jia Yanjie
Published: February 2022

Objective

This study assessed the effects of repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) on serum neurofilament light chain (NfL) levels, alcohol consumption, craving, and psychological impairment in participants with alcohol use disorder (AUD).

Methods

Participants with AUD were randomly assigned to receive one of two treatments (active or sham rTMS). All participants received 10 daily active or sham rTMS sessions over the left DLPFC for 2 weeks, with follow-up visits at baseline and immediately after the completion of the treatments. Serum samples were obtained before and after the intervention. Days of heavy drinking, visual analog scale (VAS) scores, and mental health component scores (MCSs) of the Medical Outcomes Study 36-Item Short Form Health Survey were used to assess the effects of rTMS.

Results

Active rTMS had a significant effect on reducing days of heavy drinking, alcohol craving, and serum NfL levels, and improved social functioning and mental health. The improvement with active rTMS was significantly greater than that with sham rTMS. Correlation analysis revealed that the reduction in the baseline drinking level was positively correlated with declines in the VAS and NfL levels but not with psychological scores.

Conclusion

Repetitive transcranial magnetic stimulation of the left DLPFC was associated with reducing alcohol consumption and craving in patients with AUD and positively impacted neuropsychological and social function. Serum NfL levels may be useful as an early serological indicator of alcohol-induced brain injury.
Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology
Authors: Gage Meghan , Rao Nikhil S. , Samidurai Manikandan , Putra Marson , Vasanthi Suraj S. , Meyer Christina , Wang Chong , Thippeswamy Thimmasettappa
Published: February 2022

Modeling a real-world scenario of organophosphate nerve agent (OPNA) exposure is challenging. Military personnel are premedicated with pyridostigmine, which led to the development of OPNA models with pyridostigmine/oxime pretreatment to investigate novel therapeutics for acute and chronic effects. However, civilians are not premedicated with pyridostigmine/oxime. Therefore, experimental models without pyridostigmine were developed by other laboratories though often only in males. Following OPNA exposure, prolonged convulsive seizures (CS) or status epilepticus (SE) are concerning. The duration and severity of CS/SE determine the extent of brain injury in survivors even after treating with medical countermeasures (MCM)/antidotes such as atropine, an oxime, and an anticonvulsant such as diazepam/midazolam. In this study, using a large mixed sex cohort of adult male and female rats, without pretreatment, we demonstrate severe SE lasting for >20 min in 82% of the animals in response to soman (GD,132 μg/kg, s.c.). Atropine sulfate (2 mg/kg, i.m.) and HI-6 (125 mg/kg, i.m.) were administered immediately following soman, and midazolam (3 mg/kg, i.m.) 1 h post-exposure. Immediate MCM treatment is impractical in civilian exposure to civilians, but this approach reduces mortality in experimental models. Interestingly, female rats, irrespective of estrous stages, had an average of 44 min CS (stage ≥ 3), while males had an average of 32 min CS during SE, starting from soman exposure to midazolam treatment. However, in telemetry device implanted groups, there were no significant sex differences in SE severity; males had 40 min and females 43 min of continuous CS until midazolam was administered. No animals died prior to midazolam administration and less than 5% died in the first week after soman intoxication. In telemetered animals, there was a direct correlation between EEG changes and behavioral seizures in real-time. In the long-term, convulsive spontaneously recurring seizures (SRS) were observed in 85% of randomly chosen animals. At 4-months post-soman, the brain histology confirmed reactive gliosis and neurodegeneration. The novel findings of this study are that, in non-telemetered animals, the SE severity following soman intoxication was significantly greater in females compared to males and that the estrous cycle did not influence the response.
Transcorneal Electrical Stimulation Induces Long-Lasting Enhancement of Brain Functional and Directional Connectivity in Retinal Degeneration Mice
Authors: Agadagba Stephen K. , Eldaly Abdelrahman B. M. , Chan Leanne Lai Hang
Published: February 2022

To investigate neuromodulation of functional and directional connectivity features in both visual and non-visual brain cortices after short-term and long-term retinal electrical stimulation in retinal degeneration mice. We performed spontaneous electrocorticography (ECoG) in retinal degeneration (rd) mice following prolonged transcorneal electrical stimulation (pTES) at varying currents (400, 500 and 600 μA) and different time points (transient or day 1 post-stimulation, 1-week post-stimulation and 2-weeks post-stimulation). We also set up a sham control group of rd mice which did not receive any electrical stimulation. Subsequently we analyzed alterations in cross-frequency coupling (CFC), coherence and directional connectivity of the primary visual cortex and the prefrontal cortex. It was observed that the sham control group did not display any significant changes in brain connectivity across all stages of electrical stimulation. For the stimulated groups, we observed that transient electrical stimulation of the retina did not significantly alter brain coherence and connectivity. However, for 1-week post-stimulation, we identified enhanced increase in theta-gamma CFC. Meanwhile, enhanced coherence and directional connectivity appeared predominantly in theta, alpha and beta oscillations. These alterations occurred in both visual and non-visual brain regions and were dependent on the current amplitude of stimulation. Interestingly, 2-weeks post-stimulation demonstrated long-lasting enhancement in network coherence and connectivity patterns at the level of cross-oscillatory interaction, functional connectivity and directional inter-regional communication between the primary visual cortex and prefrontal cortex. Application of electrical stimulation to the retina evidently neuromodulates brain coherence and connectivity of visual and non-visual cortices in retinal degeneration mice and the observed alterations are largely maintained. pTES holds strong possibility of modulating higher cortical functions including pathways of cognition, awareness, emotion and memory.
Cancer Related Subarachnoid Hemorrhage: A Multicenter Retrospective Study Using Propensity Score Matching Analysis
Authors: Chen Shijian , Zhang Jian , Lu Xianfu , Cen Gengyu , Song Yiting , Deng Xuhui , Xie Yiju , Liu Liuyu , Liu Qianqian , Huang Junling , Li Jing , Yang Hong , Shi Shengliang , Pan Liya , Liang Zhijian
Published: February 2022

Objective

To investigate the clinical features, risk factors and underlying pathogenesis of cancer related subarachnoid hemorrhage (SAH).

Methods

Clinical data of SAH in patients with active cancer from January 2010 to December 2020 at four centers were retrospectively reviewed. Patients with active cancer without SAH were matched to SAH patients with active cancer group. Logistic regression was applied to investigate the independent risk factors of SAH in patients with active cancer, after a 1:1 propensity score matching (PSM). A receiver operator characteristic curve was configured to calculate the optimal cut-off value of the joint predictive factor for cancer related SAH.

Results

A total of 82 SAH patients with active cancer and 309 patients with active cancer alone were included. Most SAH patients with cancer had poor outcomes, with 30-day mortality of 41.5%, and with 90-day mortality of 52.0%. The PSM yielded 75 pairs of study participants. Logistic regression revealed that a decrease in platelet and prolonged prothrombin time were the independent risk factors of cancer related SAH. In addition, receiver operator characteristic curve of the joint predictive factor showed the largest AUC of 0.8131, with cut-off value equaling to 11.719, with a sensitivity of 65.3% and specificity of 89.3%.

Conclusion

Patients with cancer related SAH often have poor outcomes. The decrease in platelet and prolonged prothrombin time are the independent risk factors of cancer related SAH, and the joint predictive factor with cutoff value equal to 11.719 should hence serve as a novel biomarker of cancer related SAH.
Predicting Spike Features of Hodgkin-Huxley-Type Neurons With Simple Artificial Neural Network
Authors: Wang Tian , Wang Ye , Shen Jiamin , Wang Lei , Cao Lihong
Published: February 2022

Hodgkin-Huxley (HH)-type model is the most famous computational model for simulating neural activity. It shows the highest accuracy in capturing neuronal spikes, and its model parameters have definite physiological meanings. However, HH-type models are computationally expensive. To address this problem, a previous study proposed a spike prediction module (SPM) to predict whether a spike will take place 1 ms later based on three voltage values with intervals of 1 ms. Although SPM does well, it fails to evaluate the informative features of the spike. In this study, the feature prediction module (FPM) based on simple artificial neural network (ANN) was proposed to predict spike features including maximum voltage, minimum voltage, and dropping interval. Nine different HH-type models were adopted whose firing patterns cover most of the firing behaviors observed in the brain. Voltage and spike feature samples under constant external input current were collected for training and testing. Experiment results illustrated that the combination of SPM and FPM can accurately predict the spiking part of different HH-type models and can generalize to unseen types of input current. The combination of SPM and FPM may offer a possible way to simulate the action potentials of biological neurons with high accuracy and efficiency.
Ultrasound-Guided Nerve Hydrodissection With 5% Dextrose 4 Weeks After Steroid Injection in Treatment of Carpal Tunnel Syndrome: A Retrospective Study
Authors: He Juan-juan , Wei Xiao-mei , Dou Zu-lin , Zhang Jiang-shan , Wei Zhen-hai , Zhang Wei-xi , Jiang Li
Published: February 2022

Objective

To investigate the efficacy and safety of ultrasound-guided nerve hydrodissection (HD) with 5% dextrose (D5W) as add-on therapy after corticosteroid injection in carpal tunnel syndrome (CTS), and provide a novel strategy.

Methods

In this retrospective study, patients with CTS who received ultrasound-guided nerve HD with D5W as add-on therapy after corticosteroid injection (combination group) were enrolled. Patients who received corticosteroid injection without add-on therapy (steroid group) were recruited as the control group. Ultrasound-guided nerve HD with D5W was performed 4 weeks after corticosteroid injection. Treatment effectiveness were assessed by visual analog scale (VAS) and Boston Carpal Tunnel Syndrome Questionnaire (BCTQ). The assessment was performed at baseline and 4, 8, and 12 weeks after corticosteroid injection. In addition, adverse events were recorded in this study.

Results

A total of 49 patients and 62 wrists meeting the criteria were included, with 24 patients and 31 wrists in the steroid group and 25 patients and 31 wrists in the combination group. Compared with baseline data, both groups showed greater improvement in VAS, BCTQs (BCTQ severity), and BCTQf (BCTQ function) at 4, 8, and 12 weeks follow-up. VAS, BCTQs, and BCTQf scores at baseline and week 4 were comparable between steroid group and combination group. Compared with steroid group, combination group exhibited a significant reduction in VAS, BCTQs, and BCTQf at 8- and 12-week follow-up (P ≤ 0.01). No adverse event occurred in any group.

Conclusions

Our results showed that ultrasound-guided nerve HD with D5W as add-on therapy after corticosteroid injection was efficacious and safe in CTS, and combination therapy is more beneficial than corticosteroid monotherapy in the improvement of symptoms and function at 8- and 12-week follow-up.
Cortical Thickness and Clinical Findings in Prescholar Children With Autism Spectrum Disorder
Authors: Lucibello Simona , Bertè Giovanna , Verdolotti Tommaso , Lucignani Martina , Napolitano Antonio , D’Abronzo Rosa , Cicala Maria G. , Pede Elisa , Chieffo Daniela , Mariotti Paolo , Colosimo Cesare , Mercuri Eugenio , Battini Roberta
Published: February 2022

The term autism spectrum disorder (ASD) includes a wide variability of clinical presentation, and this clinical heterogeneity seems to reflect a still unclear multifactorial etiopathogenesis, encompassing different genetic risk factors and susceptibility to environmental factors. Several studies and many theories recognize as mechanisms of autism a disruption of brain development and maturation time course, suggesting the existence of common neurobiological substrates, such as defective synaptic structure and aberrant brain connectivity. Magnetic resonance imaging (MRI) plays an important role in both assessment of region-specific structural changes and quantification of specific alterations in gray or white matter, which could lead to the identification of an MRI biomarker. In this study, we performed measurement of cortical thickness in a selected well-known group of preschool ASD subjects with the aim of finding correlation between cortical metrics and clinical scores to understand the underlying mechanism of symptoms and to support early clinical diagnosis. Our results confirm that recent brain MRI techniques combined with clinical data can provide some useful information in defining the cerebral regions involved in ASD although large sample studies with homogeneous analytical and multisite approaches are needed.