bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19
Authors: Kuba Keiji , Yamaguchi Tomokazu , Penninger Josef M.
Published: December 2021

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.
Immune Response to Hepatitis B Virus Vaccine Among People Living With HIV: A Meta-Analysis
Authors: Tian Yakun , Hua Wei , Wu Yaxin , Zhang Tong , Wang Wen , Wu Hao , Guo Caiping , Huang Xiaojie
Published: December 2021

Background

There is conflicting evidence about whether a double dose of the hepatitis B virus (HBV) vaccine induces better immunity than the standard-dose vaccine for people living with HIV (PLWH). This study provides a meta-analysis that summarizes the efficacy of HBV vaccine regimens among HIV-infected patients, clarifying the role of particular factors such as dose and frequency of vaccination in vaccine responsiveness and highlighting the need for evidence-based practice to assess HBV vaccination among PLWH.

Methods

Randomized clinical trials (RCTs) and prospective studies reporting vaccination response rates among PLWH were found through a search of PubMed, Cochrane, and the Web of Science. The key outcome was vaccine response. A random-effects model was used to estimate the pooled response rate. Subgroup analysis was conducted to evaluate key factors and explore sources of heterogeneity. Possible biases were assessed using quality and publication bias assessment.

Results

Eligible studies included controlled trials that examined the effects of 17 interventional studies with 1,821 participants. Among PLWH who received the HBV vaccine, the pooled response rate of HBV vaccination was 71.5% (95% CI 64.0%–77.9%, p < 0.001). Compared with the standard dose (65.5%, 95% CI 53.1%–76.1%), the double dose (75.2%, 95% CI 66.2%–82.5%) was associated with a better response rate [Q(1) = 19.617, p < 0.001]. When stratified by schedule, the four-dose schedule (89.7%, 95% CI 83.1%–93.9%) had a higher response rate than the three-dose schedule (63.3%, 95% CI 56.6%–69.4%) and the difference was significant [Q(1) = 88.305, p < 0.001]. PLWH with higher CD4+ T-cell counts (>500 cells/mm3) at the time of vaccination had better response rates [Q(1) = 88.305, p < 0.001].

Conclusions

In this meta-analysis, the double dose of the HBV vaccine and multiple injections were associated with better immune responses than the standard HBV vaccine regimen in PLWH. Higher seroconversion rates were observed in PLWH with high CD4+ T-cell levels, indicating that individuals infected with HIV should receive the HBV vaccine as soon as possible after diagnosis.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/.
Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease
Authors: Martin-Rodriguez Omayra , Gauthier Thierry , Bonnefoy Francis , Couturier Mélanie , Daoui Anna , Chagué Cécile , Valmary-Degano Séverine , Gay Claire , Saas Philippe , Perruche Sylvain
Published: December 2021

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-β, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.
Dual UMIs and Dual Barcodes With Minimal PCR Amplification Removes Artifacts and Acquires Accurate Antibody Repertoire
Authors: Wang Qilong , Zeng Huikun , Zhu Yan , Wang Minhui , Zhang Yanfang , Yang Xiujia , Tang Haipei , Li Hongliang , Chen Yuan , Ma Cuiyu , Lan Chunhong , Liu Bin , Yang Wei , Yu Xueqing , Zhang Zhenhai
Published: December 2021

Antibody repertoire sequencing (Rep-seq) has been widely used to reveal repertoire dynamics and to interrogate antibodies of interest at single nucleotide-level resolution. However, polymerase chain reaction (PCR) amplification introduces extensive artifacts including chimeras and nucleotide errors, leading to false discovery of antibodies and incorrect assessment of somatic hypermutations (SHMs) which subsequently mislead downstream investigations. Here, a novel approach named DUMPArts, which improves the accuracy of antibody repertoires by labeling each sample with dual barcodes and each molecule with dual unique molecular identifiers (UMIs) via minimal PCR amplification to remove artifacts, is developed. Tested by ultra-deep Rep-seq data, DUMPArts removed inter-sample chimeras, which cause artifactual shared clones and constitute approximately 15% of reads in the library, as well as intra-sample chimeras with erroneous SHMs and constituting approximately 20% of the reads, and corrected base errors and amplification biases by consensus building. The removal of these artifacts will provide an accurate assessment of antibody repertoires and benefit related studies, especially mAb discovery and antibody-guided vaccine design.
Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles
Authors: Inaba Satoshi , Aizawa Yuta , Miwa Yuki , Imai Chihaya , Ohnishi Hidenori , Kanegane Hirokazu , Saitoh Akihiko
Published: December 2021

Family history is one key in diagnosing inborn errors of immunity (IEI); however, disease status is difficult to determine in deceased relatives. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is one of the hyper IgM syndromes that is caused by a hypomorphic variant in the nuclear factor kappa beta essential modulator. We identified a novel IKBKG variant in a 7-month-old boy with pneumococcal rib osteomyelitis and later found that his mother has incontinentia pigmenti. Genetic analysis of preserved umbilical cords revealed the same variant in two of his deceased maternal uncles. Analysis of preserved umbilical cord tissue from deceased relatives can provide important information for diagnosing IEI in their descendants.
Extracellular ATP Limits Homeostatic T Cell Migration Within Lymph Nodes
Authors: Kobayashi Daichi , Sugiura Yuki , Umemoto Eiji , Takeda Akira , Ueta Hisashi , Hayasaka Haruko , Matsuzaki Shinsuke , Katakai Tomoya , Suematsu Makoto , Hamachi Itaru , Yegutkin Gennady G. , Salmi Marko , Jalkanen Sirpa , Miyasaka Masayuki
Published: December 2021

Whereas adenosine 5’-triphosphate (ATP) is the major energy source in cells, extracellular ATP (eATP) released from activated/damaged cells is widely thought to represent a potent damage-associated molecular pattern that promotes inflammatory responses. Here, we provide suggestive evidence that eATP is constitutively produced in the uninflamed lymph node (LN) paracortex by naïve T cells responding to C-C chemokine receptor type 7 (CCR7) ligand chemokines. Consistently, eATP was markedly reduced in naïve T cell-depleted LNs, including those of nude mice, CCR7-deficient mice, and mice subjected to the interruption of the afferent lymphatics in local LNs. Stimulation with a CCR7 ligand chemokine, CCL19, induced ATP release from LN cells, which inhibited CCR7-dependent lymphocyte migration in vitro by a mechanism dependent on the purinoreceptor P2X7 (P2X7R), and P2X7R inhibition enhanced T cell retention in LNs in vivo. These results collectively indicate that paracortical eATP is produced by naïve T cells in response to constitutively expressed chemokines, and that eATP negatively regulates CCR7-mediated lymphocyte migration within LNs via a specific subtype of ATP receptor, demonstrating its fine-tuning role in homeostatic cell migration within LNs.
Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease – A Systematic Review
Authors: Hryhorowicz Szymon , Kaczmarek-Ryś Marta , Zielińska Aleksandra , Scott Rodney J. , Słomski Ryszard , Pławski Andrzej
Published: December 2021

Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn’s disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.
Rotavirus Interactions With Host Intestinal Epithelial Cells
Authors: Amimo Joshua Oluoch , Raev Sergei Alekseevich , Chepngeno Juliet , Mainga Alfred Omwando , Guo Yusheng , Saif Linda , Vlasova Anastasia N.
Published: December 2021

Rotavirus (RV) is the foremost enteric pathogen associated with severe diarrheal illness in young children (<5years) and animals worldwide. RV primarily infects mature enterocytes in the intestinal epithelium causing villus atrophy, enhanced epithelial cell turnover and apoptosis. Intestinal epithelial cells (IECs) being the first physical barrier against RV infection employs a range of innate immune strategies to counteract RVs invasion, including mucus production, toll-like receptor signaling and cytokine/chemokine production. Conversely, RVs have evolved numerous mechanisms to escape/subvert host immunity, seizing translation machinery of the host for effective replication and transmission. RV cell entry process involve penetration through the outer mucus layer, interaction with cell surface molecules and intestinal microbiota before reaching the IECs. For successful cell attachment and entry, RVs use sialic acid, histo-blood group antigens, heat shock cognate protein 70 and cell-surface integrins as attachment factors and/or (co)-receptors. In this review, a comprehensive summary of the existing knowledge of mechanisms underlying RV-IECs interactions, including the role of gut microbiota, during RV infection is presented. Understanding these mechanisms is imperative for developing efficacious strategies to control RV infections, including development of antiviral therapies and vaccines that target specific immune system antagonists within IECs.
Marek’s Disease Virus Modulates T Cell Proliferation via Activation of Cyclooxygenase 2-Dependent Prostaglandin E2
Authors: Kamble Nitin , Gurung Angila , Kaufer Benedikt B. , Pathan Ansar Ahmed , Behboudi Shahriar
Published: December 2021

Marek’s disease virus (MDV), an avian alphaherpesvirus, infects chickens, transforms CD4+ T cells, and induces immunosuppression early during infection. However, the exact mechanisms involved in MDV-induced immunosuppression are yet to be identified. Here, our results demonstrate that MDV infectionin vitroandin vivoinduces activation of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). This exerts its inhibitory effects on T cell proliferation at day 21 post infectionviaPGE2 receptor 2 (EP2) and receptor 4 (EP4). Impairment of the MDV-induced T cell proliferation was associated with downregulation of IL-2 and transferrin uptake in a COX-2/PGE2 dependent mannerin vitro. Interestingly, oral administration of a COX-2 inhibitor, meloxicam, during MDV infection inhibited COX-2 activation and rescued T cell proliferation at day 21 post infection. Taken together, our results reveal a novel mechanism that contributes to immunosuppression in the MDV-infected chickens.
The Structure and Function of Gut Microbiomes of Two Species of Sea Urchins, Mesocentrotus nudus and Strongylocentrotus intermedius, in Japan
Authors: Haditomo Alfabetian Harjuno Condro , Yonezawa Masanori , Yu Juanwen , Mino Sayaka , Sakai Yuichi , Sawabe Tomoo
Published: December 2021

Sea urchin is an indicator of coastal environmental changes in the global warming era, and is also a model organism in developmental biology and evolution. Due to the depletion of wild resources, new aquaculture techniques for improving stocks have been well studied. The gut microbiome shapes various aspects of a host’s physiology. However, these microbiome structures and functions on sea urchins, particularly Mesocentrotus nudus and Strongylocentrotus intermedius which are important marine bioresources commonly found in Japan, have not been fully investigated yet. Using metagenomic approaches including meta16S and shotgun metagenome sequencings, the structures, functions, and dynamics of the gut microbiome of M. nudus and S. intermedius, related to both habitat environment and host growth, were studied. Firstly, a broad meta16S analysis revealed that at the family level, Psychromonadaceae and Flavobacteriaceae reads (38–71%) dominated in these sea urchins, which is a unique feature observed in species in Japan. Flavobacteriaceae reads were more abundant in individuals after rearing in an aquarium with circulating compared to one with running water. Campylobacteraceae and Vibrionaceae abundances increased in both kinds of laboratory-reared sea urchins in both types of experiments. 2-weeks feeding experiments of M. nudus and S. intermedius transplanted from the farm to laboratory revealed that these gut microbial structures were affected by diet rather than rearing environments and host species. Secondly, further meta16S analysis of microbial reads related to M. nudus growth revealed that at least four Amplicon Sequence Variant (ASV) affiliated to Saccharicrinis fermentans, which is known to be a nitrogen (N2) fixing bacterium, showed a significant positive correlation to the body weight and test diameter. Interestingly, gut microbiome comparisons using shotgun metagenome sequencing of individuals showing higher and lower growth rates revealed a significant abundance of “Nitrate and nitrite ammonification” genes in the higher-grown individuals under the circulating water rearing. These findings provide new insights on the structure-function relationship of sea urchin gut microbiomes beyond previously reported nitrogen fixation function in sea urchin in 1950s; we discovered a nitrate reduction function into ammonium for the growth promotion of sea urchin.
Optical Coherence Tomography Findings of Underlying Choroidal Neovascularization in Punctate Inner Choroidopathy
Authors: Agarwal Aniruddha , Handa Sabia , Marchese Alessandro , Parrulli Salvatore , Invernizzi Alessandro , Erckens Roel J. , Berendschot Tos T. J. M. , Webers C. A. B. , Bansal Reema , Gupta Vishali
Published: December 2021

Purpose: To analyze findings on optical coherence tomography (OCT) suggestive of choroidal neovascularization (CNV) in lesions of punctate inner choroidopathy (PIC).

Methods: In this multi-center retrospective study, clinical data of patients with PIC were retrospectively analyzed. Quantitative data (height, width, and volume of PIC lesions), and qualitative data (disruption of ellipsoid zone (EZ)/Bruch's membrane (BM), outer retinal fuzziness, and choroidal back-shadowing) were compared between CNV+ and CNV– groups using Mann–Whitney U-test and Fischer's exact test.

Results: In total, 35 eyes (29 patients; 21 women; mean age: 33.3 ± 6.5 years) were selected for analysis. Of the 35 PIC lesions studied, 17 had underlying CNV. Lesions with CNV+ had larger height, width, and volume (p < 0.001) and several distinctive features, such as disruption of EZ and BM, outer retinal fuzziness, and hypo-reflective back-shadowing (p < 0.001) compared with CNV—lesions.

Conclusions: Quantitative and qualitative OCT analysis can aid in the prediction of an underlying CNV in the eyes with PIC.
Circulating Skeletal Troponin During Weaning From Mechanical Ventilation and Their Association to Diaphragmatic Function: A Pilot Study
Authors: Spadaro Savino , Dalla Corte Francesca , Scaramuzzo Gaetano , Grasso Salvatore , Cinnella Gilda , Rosta Valentina , Chiavieri Valentina , Alvisi Valentina , Di Mussi Rosa , Volta Carlo Alberto , Bellini Tiziana , Trentini Alessandro
Published: December 2021

Background: Patients with acute respiratory failure (ARF) may need mechanical ventilation (MV), which can lead to diaphragmatic dysfunction and muscle wasting, thus making difficult the weaning from the ventilator. Currently, there are no biomarkers specific for respiratory muscle and their function can only be assessed trough ultrasound or other invasive methods. Previously, the fast and slow isoform of the skeletal troponin I (fsTnI and ssTnI, respectively) have shown to be specific markers of muscle damage in healthy volunteers. We aimed therefore at describing the trend of skeletal troponin in mixed population of ICU patients undergoing weaning from mechanical ventilation and compared the value of fsTnI and ssTnI with diaphragmatic ultrasound derived parameters.

Methods: In this prospective observational study we enrolled consecutive patients recovering from acute hypoxemic respiratory failure (AHRF) within 24 h from the start of weaning. Every day an arterial blood sample was collected to measure fsTnI, ssTnI, and global markers of muscle damage, such as ALT, AST, and CPK. Moreover, thickening fraction (TF) and diaphragmatic displacement (DE) were assessed by diaphragmatic ultrasound. The trend of fsTnI and ssTnI was evaluated during the first 3 days of weaning.

Results: We enrolled 62 consecutive patients in the study, with a mean age of 67 ± 13 years and 43 of them (69%) were male. We did not find significant variations in the ssTnI trend (p = 0.623), but fsTnI significantly decreased over time by 30% from Day 1 to Day 2 and by 20% from Day 2 to Day 3 (p < 0.05). There was a significant interaction effect between baseline ssTnI and DE [F(2) = 4.396, p = 0.015], with high basal levels of ssTnI being associated to a higher decrease in DE. On the contrary, the high basal levels of fsTnI at day 1 were characterized by significant higher DE at each time point.

Conclusions: Skeletal muscle proteins have a distinctive pattern of variation during weaning from mechanical ventilation. At day 1, a high basal value of ssTnI were associated to a higher decrease over time of diaphragmatic function while high values of fsTnI were associated to a higher displacement at each time point.
Persistence of Antibodies Against Spike Glycoprotein of SARS-CoV-2 in Healthcare Workers Post Double Dose of BBV-152 and AZD1222 Vaccines
Authors: Choudhary Hari Ram , Parai Debaprasad , Chandra Dash Girish , Kshatri Jaya Singh , Mishra Narayan , Choudhary Prasanta Kumar , Pattnaik Dipti , Panigrahi Kumudini , Behera Susmita , Ranjan Sahoo Nihar , Podder Sreeparna , Mishra Adyasha , Raghav Sunil Kumar , Mishra Sanjeeb Kumar , Pradhan Subrat Kumar , Sahoo Subrat Kumar , Pattnaik Matrujyoti , Rout Usha Kiran , Nanda Rashmi Ranjan , Mondal Nityananda , Kanungo Srikanta , Palo Subrata Kumar , Bhattacharya Debdutta , Pati Sanghamitra
Published: December 2021

Purpose: We investigated the persistence of the vaccine-induced immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among healthcare workers (HCWs) in Odisha who received a complete dose of either Covaxin or Covishield vaccine.

Methods: This 24-week longitudinal cohort study was conducted from January to July 2021 with participants from 6 healthcare and research facilities of Odisha to understand the dynamicity of the vaccine-induced IgG antibodies against SARS-CoV-2 after the complete dose of vaccines.

Results: Serum samples were collected from 614 participants during each follow-up and were tested in two chemiluminescent microparticle immunoassay (CLIA)-based platforms to detect SARS-CoV-2 antibodies both qualitatively and quantitatively. Among these participants, 308 (50.2%) participants were Covishield recipients and the rest 306 (49.8%) participants took Covaxin. A total of 81 breakthrough cases were recorded and the rest 533 HCWs without any history of postvaccination infection showed significant antibody waning either from T3 (Covaxin recipient) or T4 (Covishield recipient). The production of vaccine-induced IgG antibodies is significantly higher (p < 0.001) in Covishield compared with Covaxin. Covishield recipients produced higher median anti-S IgG titer than Covaxin. No statistically significant differences in antibody titers were observed based on age, gender, comorbidities, and blood groups.

Conclusion: This 6-month follow-up study documents a 2-fold and 4-fold decrease in spike antibody titer among Covishield and Covaxin recipients, respectively. The clinical implications of antibody waning after vaccination are not well understood. It also highlights the need for further data to understand the long-term persistence of vaccine-induced antibody and threshold antibody titer required for protection against reinfection.
Case Series: Video-Assisted Minimally Invasive Cardiac Surgery During Pregnancy
Authors: Lu Anyi , Ye Yingxian , Hu Jiaqi , Wei Ning , Wei Jinfeng , Lin Bimei , Wang Sheng
Published: December 2021

Surgical intervention is expected to improve maternal outcomes in pregnant patients with heart disease once the conservative treatment fails. For pregnant patients with heart disease, the risk of cardiac surgery under cardiopulmonary bypass (CPB) must be balanced due to the high fetal loss. The video-assisted minimally invasive cardiac surgery (MICS) has been progressively applied and shows advantages in non-pregnant patients over the years. We present five cases of pregnant women who underwent a video-assisted minimally invasive surgical approach for cardiac surgery and the management strategies. In conclusion, the video-assisted MICS is feasible and safe to pregnant patients, with good maternal and fetal outcomes under the multidisciplinary assessment and management.
MLL-SEPT5 Fusion Transcript in Myelodysplastic Syndrome Patient With t(11;22)(q23;q11)
Authors: Zou Duobing , Chen Ying , Wu Ningning , Zhang Yi , Ouyang Guifang , Mu Qitian
Published: December 2021

Objectives: This study aimed to identify unknown mixed lineage leukemia (MLL) translocation partner genes in a de novo patient with myelodysplastic syndrome (MDS) with t(11;22)(q23;q11) and investigate the clinical and molecular features of this patient.

Methods: Bone marrow cells were assessed by karyotype analysis to reveal chromosomal abnormalities. Fluorescence in situ hybridization (FISH) was performed to detect MLL gene rearrangement using an MLL-specific break-apart probe. LDI-PCR and RT-PCR were performed, and the PCR products were sequenced using an Illumina MiSeq sequencer (Illumina, San Diego, CA, USA). The sequence data of the PCR products were analyzed using bioinformatics tools. Meanwhile, clinical data were collected to evaluate the prognosis of the patient.

Results: Chromosomal karyotype analysis showed that the karyotype of the patient was 46, XX, t(11;22)(q23;q11)[10]/46, XX[1]. Subsequently, FISH data confirmed MLL gene rearrangement in the patient. LDI-PCR precisely showed that SEPT5 was the MLL translocation partner gene. RT-PCR and sequencing analysis disclosed the presence of MLL-SEPT5 fusion transcript and confirmed the fusion between MLL exon 8 and SEPT5 exon 3. Moreover, the patient had a recurrence shortly after allogeneic hematopoietic stem cell transplantation.

Conclusion: Although the MLL-SEPT5 fusion transcript was occasionally described in acute myeloid leukemia, it was first identified in MDS. Patients with MLL-SEPT5 fusion gene exhibited a poor prognosis even with an aggressive treatment.
Potential Associations Between Microbiome and COVID-19
Authors: Wang Huifen , Wang Haiyu , Sun Ying , Ren Zhigang , Zhu Weiwei , Li Ang , Cui Guangying
Published: December 2021

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has plunged the world into a major crisis. The disease is characterized by strong infectivity, high morbidity, and high mortality. It is still spreading in some countries. Microbiota and their metabolites affect human physiological health and diseases by participating in host digestion and nutrition, promoting metabolic function, and regulating the immune system. Studies have shown that human microecology is associated with many diseases, including COVID-19. In this research, we first reviewed the microbial characteristics of COVID-19 from the aspects of gut microbiome, lung microbime, and oral microbiome. We found that significant changes take place in both the gut microbiome and airway microbiome in patients with COVID-19 and are characterized by an increase in conditional pathogenic bacteria and a decrease in beneficial bacteria. Then, we summarized the possible microecological mechanisms involved in the progression of COVID-19. Intestinal microecological disorders in individuals may be involved in the occurrence and development of COVID-19 in the host through interaction with ACE2, mitochondria, and the lung-gut axis. In addition, fecal bacteria transplantation (FMT), prebiotics, and probiotics may play a positive role in the treatment of COVID-19 and reduce the fatal consequences of the disease.
The Mevalonate Pathway Is Important for Growth, Spore Production, and the Virulence of Phytophthora sojae
Authors: Yang Xinyu , Jiang Xue , Yan Weiqi , Huang Qifeng , Sun Huiying , Zhang Xin , Zhang Zhichao , Ye Wenwu , Wu Yuanhua , Govers Francine , Liang Yue
Published: December 2021

The mevalonate (MVA) pathway in eukaryotic organisms produces isoprenoids, sterols, ubiquinone, and dolichols. These molecules are vital for diverse cellular functions, ranging from signaling to membrane integrity, and from post-translational modification to energy homeostasis. However, information on the MVA pathway in Phytophthora species is limited. In this study, we identified the MVA pathway genes and reconstructed the complete pathway in Phytophthora sojae in silico. We characterized the function of the MVA pathway of P. sojae by treatment with enzyme inhibitor lovastatin, deletion of the geranylgeranyl diphosphate synthase gene (PsBTS1), and transcriptome profiling analysis. The MVA pathway is ubiquitously conserved in Phytophthora species. Under lovastatin treatment, mycelial growth, spore production, and virulence of P. sojae were inhibited but the zoospore encystment rate increased. Heterozygous mutants of PsBTS1 showed slow growth, abnormal colony characteristics, and mycelial morphology. Mutants showed decreased numbers of sporangia and oospores as well as reduced virulence. RNA sequencing analysis identified the essential genes in sporangia formation were influenced by the enzyme inhibitor lovastatin. Our findings elucidate the role of the MVA pathway in P. sojae and provide new insights into the molecular mechanisms underlying the development, reproduction, and virulence of P. sojae and possibly other oomycetes. Our results also provide potential chemical targets for management of plant Phytophthora diseases.
Meclizine Inhibits Pseudorabies Virus Replication by Interfering With Virus Entry and Release
Authors: Liu Panrao , Hu Danhe , Yuan Lili , Lian Zhengmin , Yao Xiaohui , Zhu Zhenbang , Nowotny Norbert , Shi Yi , Li Xiangdong
Published: December 2021

Pseudorabies virus (PRV) is a pathogen that causes substantial economic losses to the swine industry. With the emergence and widespread of PRV variants since 2011 in China, current commercial vaccines cannot provide complete protection against PRV infection. Therefore, antiviral drugs may work as an alternative way to control and prevent PRV. In this study, the inhibitory effects and underlying molecular mechanisms of meclizine against PRV were studied. Meclizine displayed a significant inhibitory effect against PRV when it was added before, simultaneously with, or after virus infection. The inhibitory effect of meclizine occurred during viral entry and cell-to-cell spreading but not at viral attachment into PK-15 cells. Meclizine also inhibited viral particle release at the late stage of infection. The antiviral effect of meclizine was tested in mice, and the results showed that meclizine reduced the severity of clinical symptoms and the viral loads in tissues, and delayed the death, after PRV challenge. The above results indicated that meclizine had an inhibitory effect on PRV. Our findings will contribute to the development of potential therapeutic drugs against PRV infection.
Absence of Cardiolipin From the Outer Leaflet of a Mitochondrial Inner Membrane Mimic Restricts Opa1-Mediated Fusion
Authors: Ge Yifan , Boopathy Sivakumar , Nguyen Tran H. , Lugo Camila Makhlouta , Chao Luke H.
Published: December 2021

Cardiolipin is a tetra-acylated di-phosphatidylglycerol lipid enriched in the matrix-facing (inner) leaflet of the mitochondrial inner membrane. Cardiolipin plays an important role in regulating mitochondria function and dynamics. Yet, the mechanisms connecting cardiolipin distribution and mitochondrial protein function remain indirect. In our previous work, we established an in vitro system reconstituting mitochondrial inner membrane fusion mediated by Opa1. We found that the long form of Opa1 (l-Opa1) works together with the proteolytically processed short form (s-Opa1) to mediate fast and efficient membrane fusion. Here, we extend our reconstitution system to generate supported lipid bilayers with asymmetric cardiolipin distribution. Using this system, we find the presence of cardiolipin on the inter-membrane space-facing (outer) leaflet is important for membrane tethering and fusion. We discuss how the presence of cardiolipin in this leaflet may influence protein and membrane properties, and future applications for this approach.
Neuromorphic Dynamics at the Nanoscale in Silicon Suboxide RRAM
Authors: Buckwell Mark , Ng Wing H. , Mannion Daniel J. , Cox Horatio R. J. , Hudziak Stephen , Mehonic Adnan , Kenyon Anthony J.
Published: December 2021

Resistive random-access memories, also known as memristors, whose resistance can be modulated by the electrically driven formation and disruption of conductive filaments within an insulator, are promising candidates for neuromorphic applications due to their scalability, low-power operation and diverse functional behaviors. However, understanding the dynamics of individual filaments, and the surrounding material, is challenging, owing to the typically very large cross-sectional areas of test devices relative to the nanometer scale of individual filaments. In the present work, conductive atomic force microscopy is used to study the evolution of conductivity at the nanoscale in a fully CMOS-compatible silicon suboxide thin film. Distinct filamentary plasticity and background conductivity enhancement are reported, suggesting that device behavior might be best described by composite core (filament) and shell (background conductivity) dynamics. Furthermore, constant current measurements demonstrate an interplay between filament formation and rupture, resulting in current-controlled voltage spiking in nanoscale regions, with an estimated optimal energy consumption of 25 attojoules per spike. This is very promising for extremely low-power neuromorphic computation and suggests that the dynamic behavior observed in larger devices should persist and improve as dimensions are scaled down.
Sedation-Induced Burst Suppression Predicts Positive Outcome Following Traumatic Brain Injury
Authors: Frohlich Joel , Johnson Micah A. , McArthur David L. , Lutkenhoff Evan S. , Dell'Italia John , Real Courtney , Shrestha Vikesh , Spivak Norman M. , Ruiz Tejeda Jesús E. , Vespa Paul M. , Monti Martin M.
Published: December 2021

While electroencephalogram (EEG) burst-suppression is often induced therapeutically using sedatives in the intensive care unit (ICU), there is hitherto no evidence with respect to its association to outcome in moderate-to-severe neurological patients. We examined the relationship between sedation-induced burst-suppression (SIBS) and outcome at hospital discharge and at 6-month follow up in patients surviving moderate-to-severe traumatic brain injury (TBI). For each of 32 patients recovering from coma after moderate-to-severe TBI, we measured the EEG burst suppression ratio (BSR) during periods of low responsiveness as assessed with the Glasgow Coma Scale (GCS). The maximum BSR was then used to predict the Glasgow Outcome Scale extended (GOSe) at discharge and at 6 months post-injury. A multi-model inference approach was used to assess the combination of predictors that best fit the outcome data. We found that BSR was positively associated with outcomes at 6 months (P = 0.022) but did not predict outcomes at discharge. A mediation analysis found no evidence that BSR mediates the effects of barbiturates or propofol on outcomes. Our results provide initial observational evidence that burst suppression may be neuroprotective in acute patients with TBI etiologies. SIBS may thus be useful in the ICU as a prognostic biomarker.
Safety and Effectiveness of Oral Methylprednisolone Therapy in Comparison With Intramuscular Adrenocorticotropic Hormone and Oral Prednisolone in Children With Infantile Spasms
Authors: Zhu Hong-Min , Yuan Chun-Hui , Luo Meng-Qing , Deng Xiao-Long , Huang Sheng , Wu Ge-Fei , Hu Jia-Sheng , Yao Cong , Liu Zhi-Sheng
Published: December 2021

Background and Purpose: To assess the safety and effectiveness of oral methylprednisolone (oMP) in comparison with intramuscular adrenocorticotropic hormone (imACTH) and oral prednisolone (oP) therapies in children with infantile spasms (IS).

Methods: In this prospective, open-label, non-blinded, uncontrolled observational study, children (aged 2–24 months) with newly diagnosed IS presenting with hypsarrhythmia or its variants on electroencephalogram (EEG) were included. It was followed by imACTH, oP, or oMP (32–48 mg/day for 2 weeks followed by tapering) treatments. Electroclinical remission/spasm control, relapse, and adverse effects were evaluated in the short-term (days 14 and 42) and intermediary-term (3, 6, and 12 months) intervals.

Results: A total of 320 pediatric patients were enrolled: 108, 107, and 105 in the imACTH, oMP, and oP groups, respectively. The proportion of children achieving electroclinical remission on days 14 and 42 was similar among the three groups (day 14: 53.70 vs. 60.75 vs. 51.43%, p = 0.362; day 42: 57.55 vs. 63.46 vs. 55.34%, p = 0.470). The time to response was significantly faster in the oMP group (6.5 [3.00, 10.00] days vs. 8.00 [5.00, 11.00] days for imACTH and 8.00 [5.00, 13.00] days for oP, p = 0.025). Spasm control at 3, 6, and 12 months was also similar in the three groups (P = 0.775, 0.667, and 0.779). The relapse rate in the imACTH group (24.10%) was lower than oMP (30.77%) and oP groups (33.33%), and the time taken for relapse in the imACTH group (79.00 [56.50, 152.00] days) was longer than oMP (62.50 [38.00, 121.75] days) and oP groups (71.50 [40.00, 99.75] days), but the differences were not statistically significant (p = 0.539 and 0.530, respectively). The occurrence of adverse effects was similar among the three groups.

Conclusions: The short and intermediary-term efficacy and recurrence rates of oMP are not inferior to those of imACTH and oP for the treatment of IS. Significantly, the time to achieve electroclinical remission with oMP was quicker than that with imACTH and oP. Considering its convenience, affordability, and the absence of irreversible side effects, oMP can serve as a form of first-line treatment for newly diagnosed IS.
Measurement of Lead Localization Accuracy Based on Magnetic Resonance Imaging
Authors: He Changgeng , Zhang Feng , Li Linze , Jiang Changqing , Li Luming
Published: December 2021

Post-implantation localization of deep brain stimulation (DBS) lead based on a magnetic resonance (MR) image is widely used. Existing localization methods use artifact center method or template registration method, which may lead to a considerable deviation of > 2 mm, and result in severe side effects or even surgical failure. Accurate measurement of lead position can instantly inform surgeons of the imprecise implantation. This study aimed to identify the influencing factors in DBS lead post-implantation localization approach, analyze their influence, and describe a localization approach that uses the individual template method to reduce the deviation. We verified that reconstructing direction should be parallel or perpendicular to lead direction, instead of the magnetic field. Besides, we used simplified relationship between magnetic field angle and deviation error to correct the localization results. The mean localization error can be reduced after correction and favors the feasibility of direct localization of DBS lead using MR images. We also discussed influence of in vivo noise on localization frequency and the possibility of using only MR images to localize the contacts.
Alteration of Effective Connectivity in the Default Mode Network of Autism After an Intervention
Authors: Yu Han , Qu Hang , Chen Aiguo , Du Yifan , Liu Zhimei , Wang Wei
Published: December 2021

Neuroimaging has revealed numerous atypical functional connectivity of default mode network (DMN) dedicated to social communications (SC) in autism spectrum disorder (ASD), yet their nature and directionality remain unclear. Here, preschoolers with autism received physical intervention from a 12-week mini-basketball training program (12W-MBTP). Therefore, the directionality and nature of regional interactions within the DMN after the intervention are evaluated while assessing the impact of an intervention on SC. Based on the results of independent component analysis (ICA), we applied spectral dynamic causal modeling (DCM) for participants aged 3–6 years (experimental group, N = 17, control group, N = 14) to characterize the longitudinal changes following intervention in intrinsic and extrinsic effective connectivity (EC) between core regions of the DMN. Then, we analyzed the correlation between the changes in EC and SRS-2 scores to establish symptom-based validation. We found that after the 12W-MBTP intervention, the SRS-2 score of preschoolers with ASD in the experimental group was decreased. Concurrently, the inhibitory directional connections were observed between the core regions of the DMN, including increased self-inhibition in the medial prefrontal cortex (mPFC), and the changes of EC in mPFC were significantly correlated with change in the social responsiveness scale-2 (SRS-2) score. These new findings shed light on DMN as a potential intervention target, as the inhibitory information transmission between its core regions may play a positive role in improving SC behavior in preschoolers with ASD, which may be a reliable neuroimaging biomarker for future studies.

Clinical Trial Registration: This study registered with the Chinese Clinical Trial Registry (ChiCTR1900024973) on August 05, 2019.
Exploring the Two Coupled Conformational Changes That Activate the Munc18-1/Syntaxin-1 Complex
Authors: Gong Jihong , Wang Xianping , Cui Chaoyang , Qin Yuyang , Jin Ziqi , Ma Cong , Yang Xiaofei
Published: December 2021

Calcium-dependent synaptic vesicle exocytosis is mediated by SNARE complex formation. The transition from the Munc18-1/syntaxin-1 complex to the SNARE complex is catalyzed by the Munc13-1 MUN domain and involves at least two conformational changes: opening of the syntaxin-1 linker region and extension of Munc18-1 domain 3a. However, the relationship and the action order of the two conformational changes remain not fully understood. Here, our data show that an open conformation in the syntaxin-1 linker region can bypass the requirement of the MUN NF sequence. In addition, an extended state of Munc18-1 domain 3a can compensate the role of the syntaxin-1 RI sequence. Altogether, the current data strongly support our previous notion that opening of the syntaxin-1 linker region by Munc13-1 is a key step to initiate SNARE complex assembly, and consequently, Munc18-1 domain 3a can extend its conformation to serve as a template for association of synaptobrevin-2 and syntaxin-1.
Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
Authors: Deng Pan-Yue , Avraham Oshri , Cavalli Valeria , Klyachko Vitaly A.
Published: December 2021

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in Fmr1 KO mice, manifested by markedly increased action potential (AP) firing rate and decreased threshold. Unlike excitability changes found in many central neurons, no significant changes were observed in AP rising and falling time, peak potential, amplitude, or duration. Sensory neuron hyperexcitability was caused primarily by increased input resistance, without changes in cell capacitance or resting membrane potential. Analyses of the underlying mechanisms revealed reduced activity of HCN channels and reduced expression of HCN1 and HCN4 in Fmr1 KO compared to WT. A selective HCN channel blocker abolished differences in all measures of sensory neuron excitability between WT and Fmr1 KO neurons. These results reveal a hyperexcitable state of peripheral sensory neurons in Fmr1 KO mice caused by dysfunction of HCN channels. In addition to the intrinsic neuronal dysfunction, the accompanying paper examines deficits in sensory neuron association/communication with their enveloping satellite glial cells, suggesting contributions from both neuronal intrinsic and extrinsic mechanisms to sensory dysfunction in the FXS mouse model.
Circulating Vitamin D Levels and Risk of Vitiligo: Evidence From Meta-Analysis and Two-Sample Mendelian Randomization
Authors: Song Jie , Liu Ke , Chen Weiwei , Liu Bin , Yang Hong , Lv Linshuoshuo , Sun Xiaohui , Mao Yingying , Ye Ding
Published: December 2021

Background: The association between circulating vitamin D levels and risk of vitiligo was inconsistent among observational studies, and whether these observed associations were causal remained unclear. Therefore, we aimed to evaluate the effect of vitamin D on the risk of vitiigo using meta-analysis and Mendelian randomization (MR).

Methods: At the meta-analysis stage, literature search was performed in PubMed and Web of Science to identify eligible observational studies examining the association of circulating 25-hydroxyvitamin D [25(OH)D] or 25-hydroxyvitamin D3 [25(OH)D3] levels with risk of vitiligo up to April 30, 2021. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) of 25(OH)D and 25(OH)D3 in patients with vitiligo relative to controls were pooled. Then at the MR stage, genetic instruments for circulating 25(OH)D (N = 120,618) and 25(OH)D3 (N = 40,562) levels were selected from a meta-analysis of genome-wide association studies (GWAS) of European descent, and summary statistics of vitiligo were obtained from a meta-analysis of three GWASs including 4,680 cases and 39,586 controls. We used inverse-variance weighted (IVW) as main method, followed by weighted-median and likelihood-based methods. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.

Results: In the meta-analysis, patients with vitiligo had a lower level of circulating 25(OH)D compared with controls [SMD = −1.40; 95% confidence interval (CI): −1.91, −0.89; P < 0.001], while no statistically significant difference of 25(OH)D3 between vitiligo cases and controls was found (SMD = −0.63; 95% CI: −1.29, 0.04; P = 0.064). However, in the MR analyses, genetically predicted 25(OH)D [odds ratio (OR) = 0.93, 95% CI = 0.66–1.31, P = 0.66] and 25(OH)D3 levels (OR = 0.95, 95% CI = 0.80–1.14, P = 0.60) had null associations with risk of vitiligo using the IVW method. Sensitivity analyses using alternative MR methods and instrumental variables (IV) sets obtained consistent results, and no evidence of pleiotropy or outliers was observed.

Conclusion: Our study provided no convincing evidence for a causal effect of 25(OH)D or 25(OH)D3 levels on the risk of vitiligo. Further longitudinal and experimental studies, as well as functional studies are warranted to elucidate the role of vitamin D in the development of vitiligo.