bluuebunny/crossref_metadata_2025 huggingface dataset:
Specific Anti-SARS-CoV-2 Humoral and Cellular Immune Responses After Booster Dose of BNT162b2 Pfizer-BioNTech mRNA-Based Vaccine: Integrated Study of Adaptive Immune System Components
Authors: Busà Rosalia , Sorrentino Maria Concetta , Russelli Giovanna , Amico Giandomenico , Miceli Vitale , Miele Monica , Di Bella Mariangela , Timoneri Francesca , Gallo Alessia , Zito Giovanni , Di Carlo Daniele , Conaldi Pier Giulio , Bulati Matteo
Published: March 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is modifying human activity all over the world with significant health and economic burden. The advent of the SARS-CoV-2 pandemic prompted the scientific community to learn the virus dynamics concerning transmissibility, epidemiology, and usefulness of vaccines in fighting emerging health hazards. Pieces of evidence suggest that the first and second doses of mRNA vaccines induce a significant antibody response in vaccinated subjects or patients who recovered from SARS-CoV-2 infection, demonstrating the importance of the previously formed memory. The aim of this work has been to investigate the effects of BNT162b2 Pfizer-BioNTech mRNA-based vaccine booster dose in a cohort of 11 uninfected immunocompetent (ICs), evaluating the humoral and cellular responses, with more carefulness on memory B and T cells. Our findings underscore the potential benefit of the third dose of mRNA vaccine on the lifespan of memory B and T cells, suggesting that booster doses could increase protection against SARS-CoV-2 infection.
TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model
Authors: Lima Carla , Maleski Adolfo Luis Almeida , Bernardo Jefferson Thiago Gonçalves , Zelli Vitor Cataldi , Komegae Evilin Naname , Lopes-Ferreira Monica
Published: March 2022

TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.
The Innate Cellular Immune Response in Xenotransplantation
Authors: Maeda Akira , Kogata Shuhei , Toyama Chiyoshi , Lo Pei-Chi , Okamatsu Chizu , Yamamoto Riho , Masahata Kazunori , Kamiyama Masafumi , Eguchi Hiroshi , Watanabe Masahito , Nagashima Hiroshi , Okuyama Hiroomi , Miyagawa Shuji
Published: March 2022

Xenotransplantation is very attractive strategy for addressing the shortage of donors. While hyper acute rejection (HAR) caused by natural antibodies and complement has been well defined, this is not the case for innate cellular xenogeneic rejection. An increasing body of evidence suggests that innate cellular immune responses contribute to xenogeneic rejection. Various molecular incompatibilities between receptors and their ligands across different species typically have an impact on graft outcome. NK cells are activated by direct interaction as well as by antigen dependent cellular cytotoxicity (ADCC) mechanisms. Macrophages are activated through various mechanisms in xenogeneic conditions. Macrophages recognize CD47 as a “marker of self” through binding to SIRPα. A number of studies have shown that incompatibility of porcine CD47 against human SIRPα contributes to the rejection of xenogeneic target cells by macrophages. Neutrophils are an early responder cell that infiltrates xenogeneic grafts. It has also been reported that neutrophil extracellular traps (NETs) activate macrophages as damage-associated pattern molecules (DAMPs). In this review, we summarize recent insights into innate cellular xenogeneic rejection.
Mice Dually Disrupted for Nod2 and Mincle Manifest Early Bacteriological Control but Late Susceptibility During Mycobacterium tuberculosis Infection
Authors: Dubé Jean-Yves , McIntosh Fiona , Behr Marcel A.
Published: March 2022

Pattern recognition receptors Mincle and NOD2 have been implicated in mycobacterial immunity. However, knockout (KO) animal infection studies with Mycobacterium tuberculosis (Mtb) have had mild/delayed phenotypes. Given that genetic susceptibility to infectious diseases can be polygenic, we hypothesized that murine double knockout (DKO) of Mincle and Nod2 would result in exacerbation of altered immunity to mycobacterial infection leading to a more extreme phenotype than either KO alone. To test this hypothesis, we monitored bacterial burden, immune responses and survival following in vivo infections with Mtb in DKO mice for comparison to wildtype (WT) and single KOs. Bacterial burden and immune responses were not significantly affected at 3 and 6 weeks after infection in all mutant mice. At later timepoints, Nod2-KO mice had reduced survival compared to wildtype mice, and Mincle-KO survival was intermediate. Unexpectedly, dual disruption had no further effect; rather, DKO mice phenocopied Nod2-KO mice. We observed that Mtb-related death, exclusively in mice with disrupted Nod2, was accompanied by greater pulmonary cell death and distinct large necrotic foci. Therefore, determining how these receptors contribute to mycobacterial resistance will require analysis of immunophenotypes and their consequences on host pathology.
SUMOylation Pattern Predicts Prognosis and Indicates Tumor Microenvironment Infiltration Characterization in Bladder Cancer
Authors: Xia Qi-Dong , Sun Jian-Xuan , Xun Yang , Xiao Jun , Liu Chen-Qian , Xu Jin-Zhou , An Ye , Xu Meng-Yao , Liu Zheng , Wang Shao-Gang , Hu Jia
Published: March 2022

Background

SUMOylation is an important component of post-translational protein modifications (PTMs), and bladder cancer (BCa) is the ninth most common cancer around the world. But the comprehensive role of SUMOylation in shaping tumor microenvironment (TME) and influencing tumor clinicopathological features and also the prognosis of patients remains unclear.

Methods

Using the data downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), we comprehensively evaluated the SUMOylation patterns of 570 bladder cancer samples, and systematically correlated these SUMOylation patterns with TME immune cell infiltrating characteristics. The SUMO score was constructed to quantify SUMOylation patterns of individuals using principal component analysis (PCA) algorithms.

Results

Two distinct SUMOylation patterns and gene clusters were finally determined. Significant differences in the prognosis of patients were found among two different SUMOylation patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system named SUMO score to quantify the SUMOylation pattern of individuals with BCa, which was discovered to be tightly connected with tumor clinicopathological characteristics and could predict the prognosis of patients with BCa. Moreover, SUMO score was a considerable predictive indicator for the survival outcome independent of tumor mutation burden (TMB) and low SUMO score was related to better response to immunotherapy using PD-1 blockade. We also found that there existed a significant relationship between sensitivity to commonly used chemotherapy drugs and SUMO score. Finally, a nomograph based on five features, namely, SUMO score, age, gender, T category, and M category was constructed to predict the survival probability of patients with BCa in 1, 3, and 5 years, respectively.

Conclusions

Our work demonstrated and overviewed the complicated regulation mechanisms of SUMOylation in bladder cancer, and better understanding and evaluating SUMOylation patterns could be helpful in guiding clinical therapeutic strategy and improving the prognosis of patients with BCa.
Bone Morphogenetic Proteins Shape Treg Cells
Authors: Kraj Piotr
Published: March 2022

The transforming growth factor-β (TGF-β) family includes cytokines controlling cell behavior, differentiation and homeostasis of various tissues including components of the immune system. Despite well recognized importance of TGF-β in controlling T cell functions, the immunomodulatory roles of many other members of the TGF-β cytokine family, especially bone morphogenetic proteins (BMPs), start to emerge. Bone Morphogenic Protein Receptor 1α (BMPR1α) is upregulated by activated effector and Foxp3+ regulatory CD4+ T cells (Treg cells) and modulates functions of both of these cell types. BMPR1α inhibits generation of proinflammatory Th17 cells and sustains peripheral Treg cells. This finding underscores the importance of the BMPs in controlling Treg cell plasticity and transition between Treg and Th cells. BMPR1α deficiency inin vitroinduced and peripheral Treg cells led to upregulation of Kdm6b (Jmjd3) demethylase, an antagonist of polycomb repressive complex 2 (PRC2), and cell cycle inhibitor Cdkn1a (p21Cip1) promoting cell senescence. This indicates that BMPs and BMPR1α may represent regulatory modules shaping epigenetic landscape and controlling proinflammatory reprogramming of Th and Treg cells. Revealing functions of other BMP receptors and their crosstalk with receptors for TGF-β will contribute to our understanding of peripheral immunoregulation.
Computed Tomography Imaging-Based Radiogenomics Analysis Reveals Hypoxia Patterns and Immunological Characteristics in Ovarian Cancer
Authors: Feng Songwei , Xia Tianyi , Ge Yu , Zhang Ke , Ji Xuan , Luo Shanhui , Shen Yang
Published: March 2022

Purpose

The hypoxic microenvironment is involved in the tumorigenesis of ovarian cancer (OC). Therefore, we aim to develop a non-invasive radiogenomics approach to identify a hypoxia pattern with potential application in patient prognostication.

Methods

Specific hypoxia-related genes (sHRGs) were identified based on RNA-seq of OC cell lines cultured with different oxygen conditions. Meanwhile, multiple hypoxia-related subtypes were identified by unsupervised consensus analysis and LASSO–Cox regression analysis. Subsequently, diversified bioinformatics algorithms were used to explore the immune microenvironment, prognosis, biological pathway alteration, and drug sensitivity among different subtypes. Finally, optimal radiogenomics biomarkers for predicting the risk status of patients were developed by machine learning algorithms.

Results

One hundred forty sHRGs and three types of hypoxia-related subtypes were identified. Among them, hypoxia-cluster-B, gene-cluster-B, and high-risk subtypes had poor survival outcomes. The subtypes were closely related to each other, and hypoxia-cluster-B and gene-cluster-B had higher hypoxia risk scores. Notably, the low-risk subtype had an active immune microenvironment and may benefit from immunotherapy. Finally, a four-feature radiogenomics model was constructed to reveal hypoxia risk status, and the model achieved area under the curve (AUC) values of 0.900 and 0.703 for the training and testing cohorts, respectively.

Conclusion

As a non-invasive approach, computed tomography-based radiogenomics biomarkers may enable the pretreatment prediction of the hypoxia pattern, prognosis, therapeutic effect, and immune microenvironment in patients with OC.
Cannabidiol and SARS-CoV-2 Infection
Authors: Vallée Alexandre
Published: March 2022

Cannabidiol (CBD) can prevent the inflammatory response of SARS-CoV-2 spike protein in Caco-2-cells. This action is coupled with the inhibition of IL-1beta, IL-6, IL-18, and TNF-alpha, responsible for the inflammatory process during SARS-CoV-2 infection. CBD can act on the different proteins encoded by SARS-CoV-2 and as an antiviral agent to prevent the viral infection. Furthermore, recent studies have shown the possible action of CBD as an antagonist of cytokine release syndromes. In the SARS-CoV-2 pathophysiology, the angiotensin-converting enzyme 2 (ACE2) seems to be the key cell receptor for SARS-CoV-2 infection. The WNT/β-catenin pathway and PPARγ interact in an opposite manner in many diseases, including SARS-CoV-2 infection. CBD exerts its activity through the interaction with PPARγ in SARS-CoV-2 infection. Thus, we can hypothesize that CBD may counteract the inflammatory process of SARS-CoV-2 by its interactions with both ACE2 and the interplay between the WNT/β-catenin pathway and PPARγ. Vaccines are the only way to prevent COVID-19, but it appears important to find therapeutic complements to treat patients already affected by SARS-CoV-2 infection. The possible role of CBD should be investigated by clinical trials to show its effectiveness.
Distribution of Harmful Algae (Karenia spp.) in October 2021 Off Southeast Hokkaido, Japan
Authors: Kuroda Hiroshi , Taniuchi Yukiko , Watanabe Tsuyoshi , Azumaya Tomonori , Hasegawa Natsuki
Published: March 2022

An unprecedented large-scale outbreak of harmful algae, including Karenia selliformis and Karenia mikimotoi, was reported in mid-September 2021 in the northwest Pacific Ocean off southeastern Hokkaido, Japan. It inflicted catastrophic damage on coastal fisheries in the ensuing months. To understand the spatiotemporal distribution of Karenia spp. abundance, we conducted extensive ship-based surveys across several water masses during 4–14 October, 2021 and analyzed in-situ data in combination with Sentinel-3-derived ocean color imagery with a horizontal resolution of 300 m. High chlorophyll-a concentrations (exceeding 10 mg m–3) were identified mainly in coastal shelf–slope waters of <1,000-m water depth occupied by Surface Coastal Oyashio Water or Modified Soya Warm Current Water. Karenia spp. abundance was strongly correlated with chlorophyll-a concentration, which typically had a shallow vertical maximum within the surface mixed layer. Large- and small-scale distributions of Karenia spp. abundance at the ocean surface were estimated from two satellite-imagery products: maximum line height and red-band difference. Maps generated of Karenia spp. abundance revealed snapshots of dynamic Karenia bloom distributions. Specifically, the cores of Karenia blooms were located on continental shelves, sometimes locally exceeded 104 cells mL–1, and seemed to be connected intermittently to very nearshore waters. Relatively high-abundance areas (>103 cells mL–1) of Karenia spp. on the shelf were characterized by submesoscale (i.e., 1–10 km) patch- or streak-like distributions, or both. Within a roughly 24-h period from 12 to 13 October, Karenia-spp. abundances averaged over the shelf abruptly increased more than doubled; these abundance spikes were associated with the combined effects of physical advection and algal growth. The obtained maps and features of Karenia spp. abundance will provide basic estimates needed to understand the processes and mechanisms by which algal blooms can inflict damage on regional fisheries.
Micro-/Meso-Scale Distinction and Horizontal Migration of Tintinnid (Ciliophora: Tintinnida) Assemblages in Three Regions Around the North Pacific Ocean
Authors: Feng Meiping , Lin Shiquan , Zhang Wuchang , Wang Chunsheng , Liu Hongbin , Cheung Shunyan , Li Haibo , Stukel Michael R. , Irving John Paul , Li Na
Published: March 2022

We explored the relationships among different tintinnid populations on micro-, meso-, and basin-scales from three regions across the Pacific Ocean, including the Costa Rica Dome (CRD) in the Eastern Pacific Ocean, the Celebes Sea (CS), and the Tokara Strait (TS) in the Western Pacific Ocean. We quantified the species occurrence, vertical and biogeographic distribution patterns, and morphological parameters of tintinnid assemblages. A total of 46 tintinnid species were observed, with more than half (63.0%) in common among the three areas, accounting for 97.1% of the total abundances. The numerically abundant forms remained more or less the same set of species in the three areas. However, community structure analyses, in terms of species, lorica oral diameter (LOD) size classes, and genera, revealed clear distinctions among different regions, as well as among different water depths. A Lagrangian simulation of passive dispersal in ocean currents across the Pacific Ocean, supported the hypothesis that greater similarity between tintinnid populations in the CS and TS (relative to CRD), was related to ocean circulation linkages between the populations. A latitudinal decline of tintinnid species richness was observed, mainly as a result of a decline of redundant species and warm-water species in colder areas. These data provide information unique insight into population variability of microzooplankton communities on micro- to meso- and even large scales in the world oceans.
Impaired Antibody Response Following the Second Dose of the BNT162b2 Vaccine in Patients With Myeloproliferative Neoplasms Receiving Ruxolitinib
Authors: Ikeda Daisuke , Terao Toshiki , Miura Daisuke , Narita Kentaro , Fukumoto Ami , Kuzume Ayumi , Kamura Yuya , Tabata Rikako , Tsushima Takafumi , Takeuchi Masami , Hosoki Takaaki , Matsue Kosei
Published: March 2022

Data on the effect of ruxolitinib on antibody response to severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccination in patients with myeloproliferative neoplasms (MPN) is lacking. We prospectively evaluated anti-spike-receptor binding domain antibody (anti-S Ab) levels after the second dose of the BNT162b2 (Pfizer-BioNTech) vaccine in MPN patients. A total of 74 patients with MPN and 81 healthy controls who were vaccinated were enrolled in the study. Of the MPN patients, 27% received ruxolitinib at the time of vaccination. Notably, MPN patients receiving ruxolitinib had a 30-fold lower median anti-S Ab level than those not receiving ruxolitinib (p < 0.001). Further, the anti-S Ab levels in MPN patients not receiving ruxolitinib were significantly lower than those in healthy controls (p < 0.001). Regarding a clinical protective titre that has been shown to correlate with preventing symptomatic infection, only 10% of the MPN patients receiving ruxolitinib had the protective value. Univariate analysis revealed that ruxolitinib, myelofibrosis, and longer time from diagnosis to vaccination had a significantly negative impact on achieving the protective value (p = 0.001, 0.021, and 0.019, respectively). In subgroup analysis, lower numbers of CD3+ and CD4+ lymphocytes were significantly correlated with a lower probability of obtaining the protective value (p = 0.011 and 0.001, respectively). In conclusion, our results highlight ruxolitinib-induced impaired vaccine response and the necessity of booster immunisation in MPN patients. Moreover, T-cell mediated immunity may have an important role in the SARS-CoV-2 vaccine response in patients with MPN, though further studies are warranted.
Correlation Analysis of Plasma Myeloperoxidase Level With Global Registry of Acute Coronary Events Score and Prognosis in Patients With Acute Non-ST-Segment Elevation Myocardial Infarction
Authors: Zhang Nan , Wang Jing-Xian , Wu Xiao-Yuan , Cui Yan , Zou Zhong-He , Liu Yin , Gao Jing
Published: March 2022

Background

Myeloperoxidase (MPO) and global registry of acute coronary events (GRACE) risk scores were independently used to predict adverse outcomes in patients with acute coronary syndrome (ACS). However, the relationship between MPO level and GRACE score, and whether the combination of MPO and GRACE can better predict major adverse cardiovascular events (MACEs) in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI), have not been previously investigated.

Methods

A prospective cohort of 271 consecutive patients with NSTEMI were enrolled in this study. Plasma MPO levels were measured by ELISA. Baseline demographic and clinical information was collected, and GRACE scores were calculated at admission. The correlation between MPO and MACEs was evaluated with the GRACE score during a 1-year follow-up.

Results

The results showed that plasma MPO level was correlated with inflammatory indices (including high-sensitivity C-reactive protein (hs-CRP), leukocyte count, neutrophil count, and fibrinogen), N-terminal pro-B type natriuretic peptide (NT-proBNP), and hypersensitive troponin T (hsTNT) levels (All p-values < 0.05), and there was a statistically significant correlation between plasma MPO level and GRACE score (r = 0.22, p < 0.001). The Kaplan-Meier curves showed that patients with higher MPO levels had lower event-free survival (Log-rank P < 0.001). The multivariate Cox model showed MPO was an independent risk factor for 1-year MACEs in patients with NSTEMI (HR: 3.85, 95% CI: 1.4–10.6, p = 0.009). Subgroup analysis showed that MPO was a strong prognostic biomarker, and its prognostic value was more significant in patients with age >65 years and N-terminal pro-B type natriuretic peptide (NT-proBNP) level >1,000 pg/ml. For high-risk patients with GRACE scores, a higher level of MPO has a higher prognostic value.

Conclusion

Elevated plasma MPO levels are associated with high inflammatory status and GRACE scores in patients with NSTEMI. For high-risk patients with GRACE scores, higher MPO levels were more predictive of future MACEs.
Medication Errors and Type 2 Diabetes Management: A Qualitative Exploration of Physicians' Perceptions, Experiences and Expectations From Quetta City, Pakistan
Authors: Habib Muhammad Kashif , Khan Muhammad Naeem , Sadiq Abdul , Iqbal Qaiser , Raziq Abdul , Ahmad Nafees , Iqbal Zaffar , Haider Sajjad , Anwar Muhammad , Khilji Fazal ur Rehman , Saleem Fahad , Khan Amer Hayat
Published: March 2022

Background

Type 2 Diabetes-related medication errors are frequently reported from the hospitals and consequently are of major concern. However, such reports are insufficient when developing healthcare settings are pursued in literature. Keeping this inadequacy in mind, we therefore aimed to explore physicians' perceptions, experiences and expectations of medication errors when managing patients with Type 2 Diabetes Mellitus.

Methods

A qualitative design was adopted. By using a semi-structured interview guide through the phenomenology-based approach, in-depth, face-to-face interviews were conducted. Physicians practicing at the medicine ward of Sandeman Provincial Hospital, Quetta, were purposively approached for the study. All interviews were audio-taped, transcribed verbatim, and were then analyzed for thematic contents by the standard content analysis framework.

Results

Although the saturation was reached at the 13th interview, we conducted additional two interviews to ensure the saturation. Fifteen physicians were interviewed, and thematic content analysis revealed six themes and nine subthemes. Mixed conceptualization and characterization of medication errors were identified. Medication errors were encountered by all physicians however poor understanding of the system, deficiency of logistics and materials were rated as barriers in reporting medication errors. Among contributors of medication errors, physicians themselves as well as dispensing and patient-related factors were identified. Physicians suggested targeted training sessions on medication error-related guidelines and reporting system. Parallel, establishment of an independent unit, involving the pharmacists, and strict supervision of paramedics to minimize medication errors was also acknowledged during data analysis.

Conclusion

With a longer life expectancy and a trend of growing population, the incidences of medication errors are also expected to increase. Our study highlighted prescribing, dispensing and administration phases as contributing factors of medication errors. Although, physicians had poor understanding of medication errors and reporting system, they believed getting insights on guidelines and reporting system is essential. A review of admission and discharge reconciliation must be prioritized and a culture of teamwork, communication and learning from mistakes is needed.
Contrast Sensitivity Is Associated With Chorioretinal Thickness and Vascular Density of Eyes in Simple Early-Stage High Myopia
Authors: Liu Xinting , Wang Yanli , Ying Xiaoxiao , Zhang Fen , Huang Jing , Yu Hang , Wang Qian , Zheng Miaoran , Hou Fang , Lesmes Luis , Lu Zhong-Lin , Lu Fan , Mao Xinjie
Published: March 2022

Objective

To evaluate the contrast sensitivity function (CSF), chorioretinal thickness and vascular density as well as their relationships in subjects with simple early-stage high myopia.

Methods

Eighty-one young subjects were enrolled in this study. They were categorized into the simple high myopia group (sHM, n = 51) and the low-moderate myopia group (control group, n = 30). Monocular CSF under best correction was measured with the qCSF method. Retinal superficial and deep vascular density, inner and outer retinal thickness and choroidal thickness were measured using optical coherence tomography angiography.

Results

The area under log CSF (AULCSF) and cutoff spatial frequency (Cutoff SF) of the sHM group were significantly reduced compared to those of the control group (P = 0.003 and P < 0.001, respectively). The parafoveal and perifoveal retinal thickness, deep vascular density and choroidal thickness were also significantly reduced in the sHM group (all P < 0.05). Multiple regression analysis revealed that AULCSF was significantly correlated with retinal deep vascular density, outer retinal thickness in the parafoveal and perifoveal areas (all P < 0.05).

Conclusion

Compared to low to moderate myopic eyes, patients with simple high myopia have thinner retinal and choroidal thickness, lower retinal vascular density, and reduced contrast sensitivity. Moreover, the CSF was correlated with the measures of chorioretinal structure and vasculature. The results suggest that the CSF is a sensitive functional endpoint in simple early-stage high myopia.
Optimal Treatment for Patients With Cavernous Transformation of the Portal Vein
Authors: Wei Bo , Huang Zhiyin , Tang Chengwei
Published: March 2022

Cavernous transformation of the portal vein (CTPV) is a sequela of extrahepatic and/or intrahepatic portal vein obstruction caused by a combination of local and risk factors. It was ever taken as a relatively rare disease due to its scant literature, which was mainly based on clinical series and case reports. CTPV often manifests as gastroesophageal variceal bleeding, splenomegaly, and portal biliopathy after the long-term insidious presentation. It is unable for CTPV to be recanalized with anticoagulation because it is a complete obstruction of the mesentericoportal axis. Endoscopic therapy is mainly used for temporary hemostasis in acute variceal bleeding. Meso-Rex shunting characterized by portal-flow-preserving shunts has been widely performed in children with CTPV. The multitude of complications associated with CTPV in adults can be effectively addressed by various interventional vascular therapies. With the ubiquity of radiological examinations, optimal treatment for patients with CTPV becomes important. Multivisceral transplantation, such as liver-small intestinal transplantation, may be lifesaving and should be considered for patients with diffuse mesenteric venous thrombosis.
Pyoderma Gangrenosum, Acne, and Hidradenitis Suppurativa Syndrome: A Case Report and Literature Review
Authors: Huang Jundong , Tsang Lemuel Shui-Lun , Shi Wei , Li Ji
Published: March 2022

Pyoderma gangrenosum, acne, and hidradenitis suppurativa syndrome is a rare inflammatory disease characterized by pyoderma gangrenosum (PG), mild to severe facial acne, and hidradenitis suppurativa (HS). It only affects the skin and represents cutaneous characteristics of a spectrum of autoinflammation. Lack of pyogenic sterile arthritis (PA) distinguishes the pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome from pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PA-PASH), pyoderma gangrenosum, acne, hidradenitis suppurtiva, and ankylosing spondylitis (PASS), and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndromes. The exact etiology and pathogenesis of PASH syndrome remain unknown. Both PG and HS are contained in the spectrum of neutrophilic dermatitis, which is considered as an autoinflammatory syndrome. From a pathophysiological point of view, they show similar mechanisms, including neutrophil-rich cutaneous infiltration and overexpression of the interleukin-1 (IL-1) family. These findings provide guidance for these intractable diseases. In this review, we described a case of PASH syndrome in a patient who initially failed to respond to immunosuppressive treatment but responded to a combination of colchicine and thalidomide. We reviewed the relevant literature that focuses on PASH syndrome management.
Identification of 27 Novel Variants in Genes COL4A3, COL4A4, and COL4A5 in Lithuanian Families With Alport Syndrome
Authors: Cerkauskaite Agne , Savige Judy , Janonyte Karolina , Jeremiciute Ieva , Miglinas Marius , Kazenaite Edita , Laurinavicius Arvydas , Strupaite-Sileikiene Rasa , Vainutiene Vija , Burnyte Birute , Jankauskiene Augustina , Rolfs Arndt , Bauer Peter , Schröder Sabine , Cerkauskiene Rimante
Published: March 2022

Introduction:

Alport syndrome (AS) is an inherited disorder characterized by hematuria, proteinuria, and kidney function impairment, and frequently associated with extrarenal manifestations. Pathogenic variants in COL4A5 usually cause X-linked Alport syndrome (XLAS), whereas those in the COL4A3 or COL4A4 genes are associated with autosomal dominant (AD) or recessive (AR) inheritance. To date, more than 3000 different disease-causing variants in COL4A5, COL4A3, and COL4A4 have been identified. The aim of this study was to evaluate the clinical and genetic spectrum of individuals with novel, pathogenic or likely pathogenic variants in the COL4A3-A5 genes in a previously unstudied cohort.

Methods

In this study molecular analysis by next generation sequencing (NGS) was performed on individuals from a Lithuanian cohort, with suspected AS. The presence of AS was assessed by reviewing clinical evidence of hematuria, proteinuria, chronic kidney disease (CKD), kidney failure (KF), a family history of AS or persistent hematuria, and specific histological lesions in the kidney biopsy such as thinning or lamellation of the glomerular basement membrane (GBM). Clinical, genetic, laboratory, and pathology data were reviewed. The novelty of the COL4A3-A5 variants was confirmed in the genetic variant databases (Centogene, Franklin, ClinVar, Varsome, InterVar). Only undescribed variants were included in this study.

Results

Molecular testing of 171 suspected individuals led to the detection of 99 individuals with 44 disease causing variants including 27, previously undescribed changes, with the frequency of 9/27 (33,3%) in genes COL4A5, COL4A3 and COL4A4 equally. Three individuals were determined as having digenic AS causing variants: one in COL4A3 and COL4A4, two in COL4A4 and COL4A5. The most prevalent alterations in genes COL4A3-5 were missense variants (n = 19), while splice site, frameshift, unknown variant and stop codon changes were detected more in genes COL4A4 and COL4A5 and accounted for 3, 3, 1 and 1 of all novel variants, respectively.

Conclusion

Genotype-phenotype correlation analysis suggested that some variants demonstrated intra-familial phenotypic variability. These novel variants represented more than half of all the variants found in a cohort of 171 individuals from 109 unrelated families who underwent testing. Our study expands the knowledge of the genetic and phenotypic spectrum for AS.
Production of Epoxyketone Peptide-Based Proteasome Inhibitors by Streptomyces sp. BRA-346: Regulation and Biosynthesis
Authors: Domingues Vieira Bruna , Niero Henrique , de Felício Rafael , Giolo Alves Luiz Fernando , Freitas Bazzano Cristina , Sigrist Renata , Costa Furtado Luciana , Felix Persinoti Gabriela , Veras Costa-Lotufo Leticia , Barretto Barbosa Trivella Daniela
Published: March 2022

Streptomyces sp. BRA-346 is an Actinobacteria isolated from the Brazilian endemic tunicate Euherdmania sp. We have reported that this strain produces epoxyketone peptides, as dihydroeponemycin (DHE) and structurally related analogs. This cocktail of epoxyketone peptides inhibits the proteasome chymotrypsin-like activity and shows high cytotoxicity to glioma cells. However, low yields and poor reproducibility of epoxyketone peptides production by BRA-346 under laboratory cultivation have limited the isolation of epoxyketone peptides for additional studies. Here, we evaluated several cultivation methods using different culture media and chemical elicitors to increase the repertoire of peptide epoxyketone production by this bacterium. Furthermore, BRA-346 genome was sequenced, revealing its broad genetic potential, which is mostly hidden under laboratory conditions. By using specific growth conditions, we were able to evidence different classes of secondary metabolites produced by BRA-346. In addition, by combining genome mining with untargeted metabolomics, we could link the metabolites produced by BRA-346 to its genetic capacity and potential regulators. A single biosynthetic gene cluster (BGC) was related to the production of the target epoxyketone peptides by BRA-346. The candidate BGC displays conserved biosynthetic enzymes with the reported eponemycin (EPN) and TMC-86A (TMC) BGCs. The core of the putative epoxyketone peptide BGC (ORFs A-L), in which ORF A is a LuxR-like transcription factor, was cloned into a heterologous host. The recombinant organism was capable to produce TMC and EPN natural products, along with the biosynthetic intermediates DH-TMC and DHE, and additional congeners. A phylogenetic analysis of the epn/tmc BGC revealed related BGCs in public databases. Most of them carry a proteasome beta-subunit, however, lacking an assigned specialized metabolite. The retrieved BGCs also display a diversity of regulatory genes and TTA codons, indicating tight regulation of this BGC at the transcription and translational levels. These results demonstrate the plasticity of the epn/tmc BGC of BRA-346 in producing epoxyketone peptides and the feasibility of their production in a heterologous host. This work also highlights the capacity of BRA-346 to tightly regulate its secondary metabolism and shed light on how to awake silent gene clusters of Streptomyces sp. BRA-346 to allow the production of pharmacologically important biosynthetic products.
Diatoms and Their Microbiomes in Complex and Changing Polar Oceans
Authors: Gilbertson Reuben , Langan Emma , Mock Thomas
Published: March 2022

Diatoms, a key group of polar marine microbes, support highly productive ocean ecosystems. Like all life on earth, diatoms do not live in isolation, and they are therefore under constant biotic and abiotic pressures which directly influence their evolution through natural selection. Despite their importance in polar ecosystems, polar diatoms are understudied compared to temperate species. The observed rapid change in the polar climate, especially warming, has created increased research interest to discover the underlying causes and potential consequences on single species to entire ecosystems. Next-Generation Sequencing (NGS) technologies have greatly expanded our knowledge by revealing the molecular underpinnings of physiological adaptations to polar environmental conditions. Their genomes, transcriptomes, and proteomes together with the first eukaryotic meta-omics data of surface ocean polar microbiomes reflect the environmental pressures through adaptive responses such as the expansion of protein families over time as a consequence of selection. Polar regions and their microbiomes are inherently connected to climate cycles and their feedback loops. An integrated understanding built on “omics” resources centered around diatoms as key primary producers will enable us to reveal unifying concepts of microbial co-evolution and adaptation in polar oceans. This knowledge, which aims to relate past environmental changes to specific adaptations, will be required to improve climate prediction models for polar ecosystems because it provides a unifying framework of how interacting and co-evolving biological communities might respond to future environmental change.
Identification of Glycoside Transporters From the Human Gut Microbiome
Authors: Wang Zhi , Tauzin Alexandra S. , Laville Elisabeth , Potocki-Veronese Gabrielle
Published: March 2022

Transport is a crucial step in the metabolism of glycosides by bacteria, which is itself key for microbiota function and equilibrium. However, most transport proteins are function-unknown or only predicted, limiting our understanding of how bacteria utilize glycosides. Here, we present an activity-based screening method to identify functional glycoside transporters from microbiomes. The method is based on the co-expression in Escherichia coli of genes encoding transporters and carbohydrate-active enzymes (CAZymes) from metagenomic polysaccharide utilization loci (PULs) cloned in fosmids. To establish the proof of concept of the methodology, we used two different metagenomic libraries derived from human gut microbiota to select 18 E. coli clones whose metagenomic sequence contained at least one putative glycoside transporter and one functional CAZyme, identified by screening for various glycoside-hydrolase activities. Growth tests were performed on plant-derived glycosides, which are the target substrates of the CAZymes identified in each PUL. This led to the identification of 10 clones that are able to utilize oligosaccharides as sole carbon sources, thanks to the production of transporters from the PTS, ABC, MFS, and SusCD families. Six of the 10 hit clones contain only one transporter, providing direct experimental evidence that these transporters are functional. In the six cases where two transporters are present in the sequence of a clone, the transporters’ function can be predicted from the flanking CAZymes or from similarity with transporters characterized previously, which facilitates further functional characterization. The results expand the understanding of how glycosides are selectively metabolized by bacteria and offers a new approach to screening for glycoside-transporter specificity toward oligosaccharides with defined structures.
A Novel Cross-Priming Amplification-Based Assay for Tuberculosis Diagnosis in Children Using Gastric Aspirate
Authors: Quan Shuting , Jiang Tingting , Jiao Weiwei , Zhu Yu , Liao Qiong , Liu Yang , Fang Min , Shi Yan , Duan Li , Shi Xiaomei , Wang Yacui , Tian Xue , Wan Chaomin , Sun Lin , Shen Adong
Published: March 2022

Low detection rates of Mycobacterium tuberculosis (MTB) by culture and smear microscopy prevent early diagnosis of tuberculosis (TB) in children. Therefore, developing rapid and accurate diagnostic techniques are critical to achieving the global aim of minimizing childhood TB. The present study was performed to evaluate the diagnostic effectiveness of the novel cross-priming amplification-based EasyNAT MTB complex assay (EasyNAT) in childhood TB. Five hundred and six children with suspected TB were enrolled from January 2018 to October 2021. Gastric aspirate (GA) samples were tested by bacterial culture, acid-fast bacillus microscopy, EasyNAT, Xpert MTB/RIF (Xpert), or Xpert MTB/RIF Ultra (Xpert Ultra). Among 239 children simultaneously tested by EasyNAT and Xpert methods, both assays showed similar sensitivities in total active TB cases [22.6% (31/137) vs. 26.3% (36/137), p = 0.441] and in bacteriologically confirmed TB cases [both 60.0% (9/15)]. The two assays presented similar specificities of 98.0% (100/102) and 99.0% (101/102), respectively (p = 1.000). Among 267 children who were simultaneously tested with EasyNAT and Xpert Ultra, Xpert Ultra demonstrated higher sensitivity than EasyNAT in total active TB cases [50.9% (89/175) vs. 30.3% (53/175), p < 0.001]. EasyNAT and Xpert Ultra yielded similar specificities, at 97.8% (90/92) and 100.0% (92/92), respectively (p = 0.155). These findings indicated that Xpert Ultra was superior to EasyNAT despite its higher cost and EasyNAT was not inferior to Xpert in the diagnosis of childhood TB using GA samples. EasyNAT may therefore be a suitable alternative diagnostic method for childhood TB based on its cost-effectiveness, speed, and accuracy.
Comparison of Microbial Community and Metabolites in Four Stomach Compartments of Myostatin-Gene-Edited and Non-edited Cattle
Authors: Zhou Xinyu , Gu Mingjuan , Zhu Lin , Wu Di , Yang Miaomiao , Gao Yajie , Wang Xueqiao , Bai Chunling , Wei Zhuying , Yang Lei , Li Guangpeng
Published: March 2022

Myostatin (MSTN), a major negative regulator of skeletal muscle mass and an endocrine factor, can regulate the metabolism of various organisms. Inhibition of the MSTN gene can improve meat production from livestock. Rumen microorganisms are associated with production and health traits of cattle, but changes in the microbial composition and metabolome in the four stomach compartments of MSTN gene–edited cattle have not previously been studied. Our results indicated that microbial diversity and dominant bacteria in the four stomach compartments were very similar between MSTN gene–edited and wild-type (WT) cattle. The microbiota composition was significantly different between MSTN gene–edited and WT cattle. Our results show that the relative abundance of the phylum Proteobacteria in the reticulum of MSTN gene–edited cattle was lower than that of WT cattle, whereas the relative abundance of the genus Prevotella in the omasum of MSTN gene–edited cattle was significantly higher than that of WT cattle. Metabolomics analysis revealed that the intensity of L-proline and acetic acid was significantly different in the rumen, reticulum, and abomasum between the two types of cattle. Meanwhile, pathway topology analysis indicated that the differential metabolites were predominantly involved in arginine biosynthesis and glutamate metabolism in the rumen, reticulum, and omasum but were mainly involved in pyruvate metabolism and glycolysis/gluconeogenesis in the abomasum. Spearman correlation network analysis further demonstrated that there was a significant correlation between microflora composition and metabolic pathways. These findings provide clues for studying nutrient digestion and absorption ability of MSTN gene–edited cattle.
Mutations in PpAGO3 Lead to Enhanced Virulence of Phytophthora parasitica by Activation of 25–26 nt sRNA-Associated Effector Genes
Authors: Xu Junjie , Li Yilin , Jia Jinbu , Xiong Wenjing , Zhong Chengcheng , Huang Guiyan , Gou Xiuhong , Meng Yuling , Shan Weixing
Published: March 2022

Oomycetes represent a unique group of plant pathogens that are destructive to a wide range of crops and natural ecosystems. Phytophthora species possess active small RNA (sRNA) silencing pathways, but little is known about the biological roles of sRNAs and associated factors in pathogenicity. Here we show that an AGO gene, PpAGO3, plays a major role in the regulation of effector genes hence the pathogenicity of Phytophthora parasitica. PpAGO3 was unique among five predicted AGO genes in P. parasitica, showing strong mycelium stage-specific expression. Using the CRISPR-Cas9 technology, we generated PpAGO3ΔRGG1-3 mutants that carried a deletion of 1, 2, or 3 copies of the N-terminal RGG motif (QRGGYD) but failed to obtain complete knockout mutants, which suggests its vital role in P. parasitica. These mutants showed increased pathogenicity on both Nicotiana benthamiana and Arabidopsis thaliana plants. Transcriptome and sRNA sequencing of PpAGO3ΔRGG1 and PpAGO3ΔRGG3 showed that these mutants were differentially accumulated with 25–26 nt sRNAs associated with 70 predicted cytoplasmic effector genes compared to the wild-type, of which 13 exhibited inverse correlation between gene expression and 25–26 nt sRNA accumulation. Transient overexpression of the upregulated RXLR effector genes, PPTG_01869 and PPTG_15425 identified in the mutants PpAGO3ΔRGG1 and PpAGO3ΔRGG3, strongly enhanced N. benthamiana susceptibility to P. parasitica. Our results suggest that PpAGO3 functions together with 25–26 nt sRNAs to confer dynamic expression regulation of effector genes in P. parasitica, thereby contributing to infection and pathogenicity of the pathogen.
Analysis of the Formation of Sauce-Flavored Daqu Using Non-targeted Metabolomics
Authors: Luo Shuai , Zhang Qiaoling , Yang Fan , Lu Jianjun , Peng Zheng , Pu Xiuxin , Zhang Juan , Wang Li
Published: March 2022

Sauce-flavored Daqu exhibits different colors after being stacked and fermented at high temperatures. Heiqu (black Daqu, BQ) with outstanding functions is difficult to obtain because its formation mechanism is unclear. In this study, we compared the metabolites in different types of Daqu using ultra-high-performance liquid chromatography triple quadrupole mass spectrometry to explore the formation process of BQ. We found that 251 differential metabolites were upregulated in BQ. Metabolic pathway analysis showed that “tyrosine metabolism” was enriched, and most metabolites in this pathway were differential metabolites upregulated in BQ. The tyrosine metabolic pathway is related to enzymatic browning and melanin production. In addition, the high-temperature and high-humidity fermentation environment of sauce-flavored Daqu promoted an increase in the melanoidin content via a typical Maillard reaction; thus, the melanoidin content in BQ was much higher than that in Huangqu and Baiqu. By strengthening the Maillard reaction precursor substances, amino acids, and reducing sugars, the content of Daqu melanoidin increased significantly after simulated fermentation. Therefore, the enzymatic browning product melanin and Maillard reaction product melanoidin are responsible for BQ formation. This study revealed the difference between BQ and other types of Daqu and provides theoretical guidance for controlling the formation of BQ and improving the quality of liquor.