bluuebunny/crossref_metadata_2025 huggingface dataset:
Observed Changes in Extreme Temperature and Precipitation Indices on the Qinghai-Tibet Plateau, 1960–2016
Authors: Gong Xiangwen , Wang Xuyang , Li Yuqiang , Ma Lei , Li Manyi , Si Hongtao
Published: June 2022

The Qinghai-Tibet Plateau (QTP), also known as the Earth’s “third pole,” is sensitive to climate change due to its extensive areas at high elevation, which are presently dominated by snow and ice. Based on daily observations from 1960 to 2016 at 94 meteorological stations, we quantified and compared changes in climate extremes on China’s QTP using 16 extreme temperature indices and 11 extreme precipitation indices, which calculated using colder (1961–1990) and warmer (1988–2016) base periods, respectively. The study showed that when a warmer base period is used, the trend magnitude of the cold temperature indices is amplified, while the trend magnitude of the warm temperature indices and the percentile-based precipitation indices are diminished. The regionally averaged temperature index trends were consistent with global warming, namely warmth indices such as the number of warm days, warm nights, summer days, and tropical nights all showed significant increases. However, the cold indices, such as the number of cool days, cool nights, ice days, and frost days, decreased significantly. The number of frost days and ice days decreased the fastest (3.9 and 2.9 days/decade, respectively), while the length of the growing season increased the fastest (2.9 days/decade). The warming trend strengthened with increasing latitude, and the occurrences of daytime extreme temperature events increased with increasing longitude. In addition, cold temperature events increased in frequency and intensity at high elevations, while warm temperature events decreased. We also found that average monthly maximum 1-day precipitation and maximum consecutive 5-day precipitation increased by 0.1 and 0.3 mm per decade, respectively. Extreme precipitation occurrences were more common in places with low latitudes and high longitudes. The strengthening Subtropical High Area (SHA) and Subtropical High Intensity (SHI), Westward movement of Subtropical High Western Ridge Point (SHW) have contributed to the changes in climate extremes on the Qinghai-Tibet Plateau. The study’s findings will provide a more comprehensive reference for predicting the occurrence of extreme events and improving the region’s disaster prevention capability.
Computational Structure Prediction for Antibody-Antigen Complexes From Hydrogen-Deuterium Exchange Mass Spectrometry: Challenges and Outlook
Authors: Tran Minh H. , Schoeder Clara T. , Schey Kevin L. , Meiler Jens
Published: June 2022

Although computational structure prediction has had great successes in recent years, it regularly fails to predict the interactions of large protein complexes with residue-level accuracy, or even the correct orientation of the protein partners. The performance of computational docking can be notably enhanced by incorporating experimental data from structural biology techniques. A rapid method to probe protein-protein interactions is hydrogen-deuterium exchange mass spectrometry (HDX-MS). HDX-MS has been increasingly used for epitope-mapping of antibodies (Abs) to their respective antigens (Ags) in the past few years. In this paper, we review the current state of HDX-MS in studying protein interactions, specifically Ab-Ag interactions, and how it has been used to inform computational structure prediction calculations. Particularly, we address the limitations of HDX-MS in epitope mapping and techniques and protocols applied to overcome these barriers. Furthermore, we explore computational methods that leverage HDX-MS to aid structure prediction, including the computational simulation of HDX-MS data and the combination of HDX-MS and protein docking. We point out challenges in interpreting and incorporating HDX-MS data into Ab-Ag complex docking and highlight the opportunities they provide to build towards a more optimized hybrid method, allowing for more reliable, high throughput epitope identification.
Chimeric Antigen Receptor (CAR) Regulatory T-Cells in Solid Organ Transplantation
Authors: Gille Ilse , Claas Frans H. J. , Haasnoot Geert W. , Heemskerk Mirjam H. M. , Heidt Sebastiaan
Published: June 2022

Solid organ transplantation is the treatment of choice for various end-stage diseases, but requires the continuous need for immunosuppression to prevent allograft rejection. This comes with serious side effects including increased infection rates and development of malignancies. Thus, there is a clinical need to promote transplantation tolerance to prevent organ rejection with minimal or no immunosuppressive treatment. Polyclonal regulatory T-cells (Tregs) are a potential tool to induce transplantation tolerance, but lack specificity and therefore require administration of high doses. Redirecting Tregs towards mismatched donor HLA molecules by modifying these cells with chimeric antigen receptors (CAR) would render Tregs far more effective at preventing allograft rejection. Several studies on HLA-A2 specific CAR Tregs have demonstrated that these cells are highly antigen-specific and show a superior homing capacity to HLA-A2+ allografts compared to polyclonal Tregs. HLA-A2 CAR Tregs have been shown to prolong survival of HLA-A2+ allografts in several pre-clinical humanized mouse models. Although promising, concerns about safety and stability need to be addressed. In this review the current research, obstacles of CAR Treg therapy, and its potential future in solid organ transplantation will be discussed.
DNA Damage Response Evaluation Provides Novel Insights for Personalized Immunotherapy in Glioma
Authors: Chen Mu , Huang Bingsong , Zhu Lei , Wang Qi , Pang Ying , Cheng Meng , Lian Hao , Liu Min , Zhao Kaijun , Xu Siyi , Zhang Jing , Zhong Chunlong
Published: June 2022

Background

DNA damage response (DDR) proficiency is the principal mechanism of temozolomide (TMZ) resistance in glioma. Accumulating evidence has also suggested the determining role of DDR in anticancer immunity. We propose that a comprehensive investigation of the DDR landscape can optimize glioma treatment.

Methods

We identified the pronounced enrichment of DDR in TMZ-resistant glioma cells by RNA sequencing. Nine differentially expressed genes between TMZ-sensitive/resistant glioma cells were selected to construct the DDR score through lasso regression analysis. Two glioma cohorts from TCGA and CGGA were interrogated to evaluate the predictive ability of DDR score. Multiple algorithms were applied to estimate the immunotherapeutic responses of two DDR phenotypes. Immunohistochemistry was used to determine the protein levels of PD-L1 and TGFβ in glioma specimens. The oncoPredict package was employed to predict the candidate chemotherapy agents.

Results

DDR score exhibited a robust prognostic capability in TCGA and CGGA cohorts and served as an independent predictive biomarker in glioma patients. Functional enrichment analyses revealed that high and low DDR score groups were characterized by distinct immune activity and metabolic processes. Elevated levels of infiltrating immune cells (including CD8+ T cells, CD4+ T cells, and dendritic cells) were observed in the high DDR score glioma. Further, high DDR scores correlated with increased mutation burden, up-regulated immune checkpoints, and tumor immunity activation, indicating a profound interplay between DDR score and glioma immunogenicity. In addition, PD-L1 and TGFβ were overexpressed in recurrent glioma specimens compared with primary ones. Finally, we estimated that PI3K inhibitors may serve as latent regimens for high DDR score patients.

Conclusion

Our study highlighted the promising prognostic role of DDR score in glioma. Individual assessment of DDR status for patients with glioma may provide new clues for developing immunotherapeutic strategies.
Estrogen May Enhance Toll-Like Receptor 4-Induced Inflammatory Pathways in People With HIV: Implications for Transgender Women on Hormone Therapy
Authors: Kettelhut Aaren , Bowman Emily , Gabriel Janelle , Hand Brittany , Liyanage Namal P. M. , Kulkarni Manjusha , Avila-Soto Frances , Lake Jordan E. , Funderburg Nicholas T.
Published: June 2022

Background

Transgender women (TW) are at increased risk for both human immunodeficiency virus (HIV) and cardiovascular disease (CVD). Antiretroviral therapy-treated HIV has been associated with a two-fold increased risk of CVD, potentially due to dysregulated Toll-like receptor (TLR)-induced immune activation. Use of estrogens in feminizing hormone therapy (FHT) may enhance inflammatory responses and the risk of cardiovascular mortality in TW. Despite this, the immunomodulatory effects of estrogen use in TW with HIV have been inadequately explored.

Methods

As an in vitro model for FHT, cryopreserved PBMCs (cryoPBMCs) from HIV negative (HIV-), HIV+ ART-suppressed (HIV+SP), and HIV+ ART-unsuppressed (HIV+USP) cisgender men were cultured overnight in the presence of 17-β estradiol or 17-α ethinylestradiol with and without the TLR4 agonist LPS or the TLR8 agonist ssPolyU. Monocyte activation (CD69, HLA-DR, CD38) was assessed by flow cytometry. Cytokine levels (IL-6, TNF-α, IL-1β, and IL-10) were measured in cell culture supernatants by Legendplex. Levels of phosphorylated TLR signaling molecules (JNK, MAPK p38) were assessed by Phosflow. Plasma levels of immune activation biomarkers (LPS-binding protein, monocyte activation markers sCD14 and sCD163, and inflammatory molecules IL-6 and TNF-α receptor I) were measured by ELISA.

Results

PBMCs from people with HIV (PWH) produced greater levels of inflammatory cytokines following exposure to LPS or ssPolyU compared to levels from cells of HIV- individuals. While estrogen exposure alone induced mild changes in immune activation, LPS-induced TLR4 activation was elevated with estrogen in cisgender men (CM) with HIV, increasing monocyte activation and inflammatory cytokine production (IL-6, TNF-α). Interestingly, testosterone inhibited LPS-induced cytokine production in CM regardless of HIV status. Plasma markers of immune activation and microbial translocation (e.g., sCD14, sCD163, LPS-binding protein) were generally higher in PWH compared to HIV- CM, and these markers were positively associated with in vitro responsiveness to estrogen and LPS in CM with HIV.

Conclusions

Our in vitro data suggest that estrogen exposure may enhance innate immune activation in PWH. Further examination is needed to fully understand the complex interactions of FHT, HIV, and CVD in TW, and determine optimal FHT regimens or supplementary treatments aimed at reducing excess immune activation.
Fasciola hepatica Fatty Acid Binding Protein 1 Modulates T cell Polarization by Promoting Dendritic Cell Thrombospondin-1 Secretion Without Affecting Metabolic Homeostasis in Obese Mice
Authors: Zawistowska-Deniziak Anna , Lambooij Joost M. , Kalinowska Alicja , Patente Thiago A. , Łapiński Maciej , van der Zande Hendrik J. P. , Basałaj Katarzyna , de Korne Clarize M. , Chayé Mathilde A. M. , Gasan Thomas A. , Norbury Luke J. , Giera Martin , Zaldumbide Arnaud , Smits Hermelijn H. , Guigas Bruno
Published: June 2022

Background

The parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets.

Methodology/Principal Findings

The immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis.

Conclusions/Significance

We show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.
Comparative Immunogenicity of Bacterially Expressed Soluble Trimers and Nanoparticle Displayed Influenza Hemagglutinin Stem Immunogens
Authors: Kar Uddipan , Khaleeq Sara , Garg Priyanka , Bhat Madhuraj , Reddy Poorvi , Vignesh Venkada Subramanian , Upadhyaya Aditya , Das Mili , Chakshusmathi Ghadiyaram , Pandey Suman , Dutta Somnath , Varadarajan Raghavan
Published: June 2022

Current influenza vaccines need to be updated annually due to mutations in the globular head of the viral surface protein, hemagglutinin (HA). To address this, vaccine candidates have been designed based on the relatively conserved HA stem domain and have shown protective efficacy in animal models. Oligomerization of the antigens either by fusion to oligomerization motifs or display on self-assembling nanoparticle scaffolds, can induce more potent immune responses compared to the corresponding monomeric antigen due to multivalent engagement of B-cells. Since nanoparticle display can increase manufacturing complexity, and often involves one or more mammalian cell expressed components, it is important to characterize and compare various display and oligomerization scaffolds. Using a structure guided approach, we successfully displayed multiple copies of a previously designed soluble, trimeric influenza stem domain immunogen, pH1HA10, on the ferritin like protein, MsDps2 (12 copies), Ferritin (24 copies) and Encapsulin (180 copies). All proteins were expressed in Escherichia coli. The nanoparticle fusion immunogens were found to be well folded and bound to the influenza stem directed broadly neutralizing antibodies with high affinity. An 8.5 Å Cryo-EM map of Msdps2-pH1HA10 confirmed the successful design of the nanoparticle fusion immunogen. Mice immunization studies with the soluble trimeric stem and nanoparticle fusion constructs revealed that all of them were immunogenic, and protected mice against homologous (A/Belgium/145-MA/2009) and heterologous (A/Puerto Rico/8/1934) challenge with 10MLD50 mouse adapted virus. Although nanoparticle display conferred a small but statistically significant improvement in protection relative to the soluble trimer in a homologous challenge, heterologous protection was similar in both nanoparticle-stem immunized and trimeric stem immunized groups. Such rapidly producible, bacterially expressed antigens and nanoparticle scaffolds are useful modalities to tackle future influenza pandemics.
Hearing Loss as the Main Clinical Presentation in NLRP3-Associated Autoinflammatory Disease
Authors: Oziębło Dominika , Leja Marcin L. , Jeznach Aldona , Orzechowska Magdalena , Skirecki Tomasz , Więsik-Szewczyk Ewa , Furmanek Mariusz , Bałdyga Natalia , Skarżyński Henryk , Ołdak Monika
Published: June 2022

The NLRP3 gene mutations are the cause of autosomal dominant autoinflammatory disorders (NLRP3-AID). Recently, hearing loss (HL) has been found to be the sole or major manifestation of NLRP3-AID. Here, we tested 110 autosomal dominant HL families with a custom panel of 237 HL genes and found one family carrying the NLRP3 c.1872C>G, p.Ser624Arg mutation. Functional studies revealed that this novel variant is a gain of function mutation, leading to increased activity of caspase-1 and subsequent oversecretion of proinflammatory interleukin-1β. Clinical reanalysis of the affected individuals, together with serological evidence of inflammation and pathological cochlear enhancement on FLAIR-MRI images, guided our diagnosis to atypical NLRP3-AID. The study highlights the role of genetic analysis in patients with progressive postlingual HL. This can help to identify individuals with hereditary HL as a consequence of NLRP3-AID and allow timely and effective treatment with interleukin-1-receptor antagonist.
Vaccine Protection Through Placenta and Breastfeeding: The Unmet Topic in COVID-19 Pandemic
Authors: Laguila Altoé Ariane , Marques Mambriz Anna Paula , Cardozo Daniela Maira , Valentini Zacarias Joana Maira , Laguila Visentainer Jeane Eliete , Bahls-Pinto Larissa Danielle
Published: June 2022

The coronavirus disease 2019 (COVID-19) pandemic has turned pregnant women’s healthcare into a worldwide public health challenge. Although initial data did not demonstrate pregnancy as a more susceptible period to severe outcomes of acute severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection, there are an increasing number of reports showing that not only pregnant women might be at significantly higher risk than non-pregnant women by COVID-19 but also the fetus. These findings may be related to adaptive changes that occur during pregnancy, such as the reduction in the residual respiratory capacity, the decrease in viral immune responses, and the increased risk for thromboembolic events. Additionally, despite the SARS-CoV-2 vertical transmission evidence being uncommon, maternal illness severity might reflect serious perinatal and neonatal outcomes. Thus, protecting the maternal–fetal dyad against COVID-19 is critical. Even though pregnant women initially were excluded from vaccine trials, several studies have provided safety and efficacy of the overall vaccine COVID-19 platforms. Vaccination during pregnancy becomes a priority and can generate benefits for both the mother and newborn: maternal neutralizing antibodies are transmitted through the placenta and breastfeeding. Moreover, regarding passive immunization, human milk contains other bioactive molecules and cells able to modulate the newborn’s immune response, which can be amplified after the vaccine. Nonetheless, many issues remain to be elucidated, considering the magnitude of the protective immunity transferred, the duration of the induced immunity, and the optimal interval for pregnant immunization. In this review, we assessed these unmet topics supported by literature evidence regarding the vaccine’s immunogenicity, pregnancy immune heterogeneity, and the unique human milk antiviral features.
Ferroptosis and Autoimmune Diseases
Authors: Lai Benjamin , Wu Chien-Hsiang , Wu Chao-Yi , Luo Shue-Fen , Lai Jenn-Haung
Published: June 2022

Adequate control of autoimmune diseases with an unclear etiology resulting from autoreactivation of the immune system remains a major challenge. One of the factors that trigger autoimmunity is the abnormal induction of cell death and the inadequate clearance of dead cells that leads to the exposure or release of intracellular contents that activate the immune system. Different from other cell death subtypes, such as apoptosis, necroptosis, autophagy, and pyroptosis, ferroptosis has a unique association with the cellular iron load (but not the loads of other metals) and preserves its distinguishable morphological, biological, and genetic features. This review addresses how ferroptosis is initiated and how it contributes to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases. The mechanisms responsible for ferroptosis-associated events are discussed. We also cover the perspective of targeting ferroptosis as a potential therapeutic for patients with autoimmune diseases. Collectively, this review provides up-to-date knowledge regarding how ferroptosis occurs and its significance in autoimmune diseases.
Survival Strategies of Mangrove (Ceriops tagal (perr.) C. B. Rob) and the Inspired Corrosion Inhibitor
Authors: Cui Miaomiao , Wang Zuankai , Wang Bin
Published: June 2022

Corrosion is ubiquitous, inevitable, and very common in our daily lives; it has been one of the most significant challenges and needs to be addressed for the development of modern society. Corrosion-resisting strategies found in nature have been promising for many halophytes surviving in marine tidal zones facing high salinity and humidity. Among the halophytes, mangroves have developed a lot of functions to deal with such extreme conditions that could provide novel inspirations for the fabrication of engineering materials, especially for materials resisting corrosion. In this study, we first investigated two survival strategies of mangroves, namely, functional salt-secreting and mangrove tannin composite. Salt-secreting realized by mangrove salt glands could make mangroves excrete excessive salt and avoid harmful effects. On the other hand, mangrove tannins existing in large quantities in mangrove bark could help the mangroves survive some marine bacteria. Inspired by the functional mangrove tannins, we developed a corrosion inhibitor to protect Q235 carbon steel in acid 3.5 wt% NaCl solution. Furthermore, we found that the mangrove-inspired corrosion inhibitor could be adsorbed at the metal–solution interface, functioning as a cathodic inhibitor with 60.51% anti-corrosion efficiency.
Phase-Field Model of Hydride Blister Growth Kinetics on Zirconium Surface
Authors: Wu Shuai , Sheng Jie , Yang Chao , Shi Xiaoming , Huang Houbing , Liu Yu , Song Haifeng
Published: June 2022

The precipitation of zirconium hydride blisters on the surface of zirconium alloy cladding destroys the integrity of the material and leads to material failure, which has serious potential safety hazards. To study the corrosion kinetics of zirconium hydride blisters, we established a phase-field model coupled with anisotropic elastic, which can reflect the microstructure evolution process of zirconium hydride blisters. The model studies the natural growth of hydride blister and the structural evolution process after applying radial stress and discusses the corrosion characteristics, stress distribution, and displacement changes. Zirconium hydride blisters tend to be semi-ellipsoidal in natural growth. Applying radial outward stress will promote the growth of blisters and aggravate the harm of corrosion. The stress state changes with applying stress, which affects the elastic driving force, resulting in the change of blister morphology. This work is helpful to understand the corrosion kinetic mechanism of hydride blisters.
Case Report: Extensive Tumor Profiling in Primary Neuroendocrine Breast Cancer Cases as a Role Model for Personalized Treatment in Rare and Aggressive Cancer Types
Authors: Schaffrin-Nabe Dörthe , Schuster Stefan , Tannapfel Andrea , Voigtmann Rudolf
Published: June 2022

Neuroendocrine breast cancer (NEBC) is a rare entity accounting for <0.1% of all breast carcinomas and <0.1% of all neuroendocrine carcinomas. In most cases treatment strategies in NEBC are empirical in absence of prospective trial data on NEBC cohorts. Herein, we present two case reports diagnosed with anaplastic and small cell NEBC. After initial therapies failed, comprehensive tumor profiling was applied, leading to individualized treatment options for both patients. In both patients, targetable alterations of the PI3K/AKT/mTOR pathway were found, including a PIK3CA mutation itself and an STK11 mutation that negatively regulates the mTOR complex. The epicrisis of the two patients exemplifies how to manage rare and difficult to treat cancers and how new diagnostic tools contribute to medical management.
Using the Health Belief Model to Predict Vaccination Intention Among COVID-19 Unvaccinated People in Thai Communities
Authors: Seangpraw Katekaew , Pothisa Tharadon , Boonyathee Sorawit , Ong-Artborirak Parichat , Tonchoy Prakasit , Kantow Supakan , Auttama Nisarat , Choowanthanapakorn Monchanok
Published: June 2022

Background

The coronavirus disease 2019 (COVID-19) pandemic has become one of the biggest challenges to individual health and the public health system worldwide. COVID-19 morbidity and mortality are increasing, impacting almost every country including Thailand. This study used the Health Belief Model (HBM) as a framework to examine the intention of unvaccinated people living in northern Thailand to receive COVID-19 vaccines.

Methods

This cross-sectional study was conducted during October and November 2021. A total of 1,024 participants who are currently living in four northern provinces of Thailand, Chiang Mai, Chiang Rai, Lamphun, and Phayao, were recruited to participate in the study. The questionnaire was developed using an HBM structure to obtain information about the perceived severity, perceived susceptibility, self-efficacy, perceived benefits and barriers, cues to action, and preventive behaviors relating to COVID-19 vaccination and the decision to become vaccinated. Multiple linear regression was used to analyze the data.

Results

The unvaccinated participants were an average of 44.45 ± 16.63 years of age and more than half were women (54.5%). The COVID-19 preventive behavior score used perceived severity (B = 0.26), self-efficacy (B = 0.51), perceived benefits and barriers (B = 0.11), and cues to action (B = 0.18) after adjusting for age, underlying disease, and body mass index (R2 = 42.5%). The COVID-19 vaccination decision score was positively correlated with perceived severity (B = 0.13), perceived susceptibility (B = 0.25), perceived benefits and barriers (B = 0.21), and cues to action (B = 0.27) after adjusting for underlying disease (R2 = 38.7%).

Discussion

The results demonstrated the usefulness of using the HBM structure to understand individual intention to receive a COVID-19 vaccine. Communities should consider a COVID-19 health campaign and programs that use the HBM model as a framework for altering perceptions and beliefs about the COVID-19 vaccine and improving vaccination rates among unvaccinated people in rural northern Thailand.
Spread of Human T-Lymphotropic Virus 1 and 2 Among Relatives of People Who Use Illicit Drugs in Northern Brazil
Authors: Oliveira-Filho Aldemir Branco , Frade Paula Cristina Rodrigues , Fonseca Ricardo Roberto de Souza , Sawada Leila , Martins Luísa Caricio , Machado Luiz Fernando Almeida , Vallinoto Antonio Carlos Rosário , Ishak Ricardo , Lemos José Alexandre Rodrigues de , Fischer Benedikt , Kupek Emil
Published: June 2022

The human T-lymphotropic virus 1 (HTLV-1) and 2 (HTLV-2) can be transmitted between humans by mechanisms associated with horizontal and vertical routes. Recently, high prevalence rates and levels of genetic diversity for HTLV-1 and HTLV-2 were detected among people who use illicit drugs (PWUDs) in the Brazilian state of Pará. None of the PWUDs with HTLV-1 or HTLV-2 were aware of their carrier condition of the retrovirus, and they ability to spread it to their family group, sexual partners, and other contacts. Thus, this study evaluated the presence of HTLV-1 and HTLV-2 in families of PWUDs in the state of Pará, in Northern Brazil. This descriptive study used convenience sampling and accessed 37 PWUDs and their respective families (n = 97) in 18 municipalities in the state of Pará, northern Brazil. All participants provided personal data and were tested for the presence of HTLV-1 and HTLV-2 using enzyme-linked immunosorbent assay and western blotting. HTLV positive samples were selected for Nested-PCR, and viral genotyping by nucleotide sequencing and phylogenetic analysis. HTLV-1 or HTLV-2 infections were detected in 15 families of PWUDs: 27 family members of PWUDs were infected with HTLV-1 (27.8%) and another 20 of them with HTLV-2 (20.6%). Subtypes 1a [subgroup A (54.5%)], 2b (20.5%), and 2c (25.0%) were detected. High horizontal (76.9%) and vertical (61.4%) transmission rates of HTLV were ascertained. Factors that facilitate the acquisition and transmission of HTLV-1 and HTLV-2 were reported by the participants, such as long-term relationships, unprotected sex, breastfeeding, and lack of knowledge about the condition of being a carrier of the retrovirus. Evidence indicates intrafamilial transmission of HTLV from PWUDs to members of their respective families. Key interventions should urgently be employed for the control and prevention of HTLV-1 and HTLV-2 to reduce the spread of this retrovirus in PWUDs and the general population in Northern Brazil and elsewhere.
Comparison of the Immunogenic Properties of Lactiplantibacillus plantarum Carrying the Mycobacterial Ag85B-ESAT-6 Antigen at Various Cellular Localizations
Authors: Wiull Kamilla , Boysen Preben , Kuczkowska Katarzyna , Moen Lars Fredrik , Carlsen Harald , Eijsink Vincent G. H. , Mathiesen Geir
Published: June 2022

The bacille Calmette-Guèrin (BCG) vaccine has been used for a century; nonetheless, tuberculosis (TB) remains one of the deadliest diseases in the world. Thus, new approaches to developing a new, more efficient vaccine are desirable. Mucosal vaccines are of particular interest, considering that Mycobacterium tuberculosis first enters the body through the mucosal membranes. We have previously demonstrated the immunogenicity of a recombinant Lactiplantibacillus plantarum delivery vector with TB hybrid antigen Ag85B-ESAT-6 anchored to the cell membrane. The goal of the present study was to analyze the impact of antigen localization in the immune response. Thus, we assessed two novel vaccine candidates, with the TB antigen either non-covalently anchored to the cell wall (LysMAgE6) or located intracellularly (CytAgE6). In addition, we compared two expression systems, using an inducible (LipoAgE6) or a constitutive promoter (cLipoAgE6) for expression of covalently anchored antigen to the cell membrane. Following administration to mice, antigen-specific CD4+ T-cell proliferation and IFN-γ and IL-17A secretion were analyzed for lung cell and splenocyte populations. Generally, the immune response in lung cells was stronger compared to splenocytes. The analyses showed that the type of expression system did not significantly affect the immunogenicity, while various antigen localizations resulted in markedly different responses. The immune response was considerably stronger for the surface-displaying candidate strains compared to the candidate with an intracellular antigen. These findings emphasize the significance of antigen exposure and further support the potential of L. plantarum as a mucosal vaccine delivery vehicle in the fight against TB.
Engineering of Src Homology 2 Domain Leading to Sulfotyrosine Recognition With a High Affinity by Integrating a Distinctive Selection Theme and Next-Generation Sequencing
Authors: Zhao Dongping , Li Chan , Jiang Haoqiang , Yin Yuqing , Zhou Changjing , Huang Haiming , Qi Yunkun , Li Lei
Published: June 2022

Tyrosine sulfation plays a vital role in various biochemical reactions. Although sulfated tyrosine (sTyr) has a similar structure to phosphotyrosine (pTyr), the number of available sTyr sites is significantly less than that of pTyr sites, mainly because of the lack of effective sTyr probes. A few sTyr binders were identified on the basis of structural similarity by engineering the pTyr-binding pocket of an Src Homology 2 (SH2) domain through phage selections against sTyr peptides. Nevertheless, they still interact with pTyr peptides with comparable affinity. This study aims to identify sTyr superbinders using the SH2 domain as a template. We created a distinctive phage selection scheme that separately covered selections against sTyr and pTyr peptides, followed by next-generation sequencing (NGS). After selections, phage pools showed strong enzyme-linked immunosorbent assay (ELISA) signal intensities for both modified peptides, indicating that the variants evolved with a high affinity for these peptides, which causes difficulty in identifying sTyr-specific binders. In contrast, NGS data from selected pools showed significant differences, suggesting the enrichment of sTyr-specific variants during selections. Accordingly, we obtained the sTyr features based on NGS data analysis and prioritized a few potential sTyr binders. The variant SH2-4 showed a stronger affinity for sTyr than pTyr and was superior to previous sTyr binders as measured by the Biolayer Interferometry assay. In summary, we described the strategy of integrating NGS data mining with a novel selection scheme to identify sTyr superbinders.
Rapid and Ultrasensitive Detection of Methicillin-Resistant Staphylococcus aureus Based on CRISPR-Cas12a Combined With Recombinase-Aided Amplification
Authors: Wang Ying , Liang Xuan , Xu Jie , Nan Lan , Liu Fang , Duan Guangcai , Yang Haiyan
Published: June 2022

Staphylococcus aureus is one of the main pathogens causing hospital and community-acquired infections, in particular, infections caused by methicillin-resistant Staphylococcus aureus (MRSA) cause a higher mortality rate than those caused by methicillin-sensitive strains, which poses a serious global public health problem. Therefore, rapid and ultrasensitive detection of patients with clinical MRSA infection and timely control of infection are essential. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) based on nucleic acid detection methods are well-known for its high specificity and sensitivity and programmability. Here, we successfully proposed a method based on CRISPR-Cas12a combined with recombinase-aided amplification (RAA) through fluorescent readout to achieve accurate identification and highly sensitive detection of MRSA in clinical samples. Results showed that the limit of detection (LoD) of the RAA-Cas12a method could reach 10 copies/μl at 60 min of reaction. Specificity tests showed that the method could distinguish MRSA from clinically common bacteria. The results of RAA-Cas12a were consistent with that of antimicrobial susceptibility tests (AST) and polymerase chain reaction (PCR) in 83 clinical samples. These results indicated that the detection method based on RAA-Cas12a has high sensitivity and specificity, and provides important value for rapid detection of MRSA.
Delineating the Role of the msaABCR Operon in Staphylococcal Overflow Metabolism
Authors: G C Bibek , Sahukhal Gyan S. , Elasri Mohamed O.
Published: June 2022

Staphylococcus aureus is an important human pathogen that can infect almost every organ system, resulting in a high incidence of morbidity and mortality. The msaABCR operon is an important regulator of several staphylococcal phenotypes, including biofilm development, cell wall crosslinking, antibiotic resistance, oxidative stress, and acute and chronic implant-associated osteomyelitis. Our previous study showed that, by modulating murein hydrolase activity, the msaABCR operon negatively regulates the proteases that govern cell death. Here, we report further elucidation of the mechanism of cell death, which is regulated by the msaABCR operon at the molecular level in the USA300 LAC strain. We showed that deletion of msaABCR enhances weak-acid-dependent cell death, because, in the biofilm microenvironment, this mutant strain consumes glucose and produces acetate and acetoin at higher rates than wild-type USA300 LAC strain. We proposed the increased intracellular acidification leads to increased cell death. MsaB, a dual-function transcription factor and RNA chaperone, is a negative regulator of the cidR regulon, which has been shown to play an important role in overflow metabolism and programmed cell death during biofilm development in S. aureus. We found that MsaB binds directly to the cidR promoter, which represses expression of the cidR regulon and prevents transcription of the cidABC and alsSD operons. In addition, we observed that pyruvate induced expression of the msaABCR operon (MsaB). The results reported here have enabled us to decipher the role of the msaABCR operon in staphylococcal metabolic adaption during biofilm development.
Tract-Based Spatial Statistics Analysis of Diffusion Tensor Imaging in Older Adults After the PICMOR Intervention Program: A Pilot Study
Authors: Sugimoto Hikaru , Otake-Matsuura Mihoko
Published: June 2022

Diffusion tensor imaging (DTI) enables the investigation of white matter properties in vivo by applying a tensor model to the diffusion of water molecules in the brain. Using DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), an attempt has been made to detect age-related alterations in the white matter microstructure in aging research. However, the use of comprehensive DTI measures to examine the effects of cognitive intervention/training on white matter fiber health in older adults remains limited. Recently, we developed a cognitive intervention program called Photo-Integrated Conversation Moderated by Robots (PICMOR), which utilizes one of the most intellectual activities of daily life, conversations. To examine the effects of PICMOR on cognitive function in older adults, we conducted a randomized controlled trial and found that verbal fluency task scores were improved by this intervention. Based on these behavioral findings, we collected in this pilot study diffusion-weighted images from the participants to identify candidate structures for white matter microstructural changes induced by this intervention. The results from tract-based spatial statistics analyses showed that the intervention group, who participated in PICMOR-based conversations, had significantly higher FA values or lower MD, AD, or RD values across various fiber tracts, including the left anterior corona radiata, external capsule, and anterior limb of the internal capsule, compared to the control group, who participated in unstructured free conversations. Furthermore, a larger improvement in verbal fluency task scores throughout the intervention was associated with smaller AD values in clusters, including the left side of these frontal regions. The present findings suggest that left frontal white matter structures are candidates for the neural underpinnings responsible for the enhancement of verbal fluency. Although our findings are limited by the lack of comparable data at baseline, we successfully confirmed the hypothesized pattern of group differences in DTI indices after the intervention, which fits well with the results of other cognitive intervention studies. To confirm whether this pattern reflects intervention-induced white matter alterations, longitudinal data acquisition is needed in future research.
Age-Related Midbrain Inflammation and Senescence in Parkinson’s Disease
Authors: Russo Taylor , Riessland Markus
Published: June 2022

Immune responses are arising as a common feature of several neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS), but their role as either causative or consequential remains debated. It is evident that there is local inflammation in the midbrain in PD patients even before symptom onset, but the underlying mechanisms remain elusive. In this mini-review, we discuss this midbrain inflammation in the context of PD and argue that cellular senescence may be the cause for this immune response. We postulate that to unravel the relationship between inflammation and senescence in PD, it is crucial to first understand the potential causative roles of various cell types of the midbrain and determine how the possible paracrine spreading of senescence between them may lead to observed local immune responses. We hypothesize that secretion of pro-inflammatory factors by senescent cells in the midbrain triggers neuroinflammation resulting in immune cell-mediated killing of midbrain dopaminergic (DA) neurons in PD.
Acute and Protracted Prenatal Stress Produce Mood Disorder-Like and Ethanol Drinking Behaviors in Male and Female Adult Offspring
Authors: Dong Erbo , Zhang Huaibo , Chu Alison , Pandey Subhash C.
Published: June 2022

Background

Alcohol use disorder (AUD) is a complex and chronic relapsing brain disease, which is often co-morbid with psychiatric disorders such as anxiety and depression. AUD phenotypes differ in men and women. Although genetic factors play an important role in its pathophysiology, epidemiologic evidence suggests that during prenatal development, individuals are more vulnerable to the negative effects of environmental factors that may predispose them to AUD later in life. We explored the effects of prenatal stress on the development of AUD phenotypes as well as anxiety- and depression-like behaviors using rat model.

Methods

In this study, timed-pregnant Sprague Dawley dams were used. Dams in the control group were left undisturbed throughout gestation, whereas dams in stress groups were either subjected to protracted or acute restraint stress under bright light. At adulthood, the anxiety-like, ethanol drinking, and sucrose drinking behaviors were measured using the Light/Dark Box test and two-bottle free-choice procedure.

Results

Compared to the control group, both the male and female offspring in the stress groups exhibited anxiety-like behavior and consumed significantly higher amounts of ethanol in which the acute stress group demonstrated the higher ethanol preference. Moreover, male but not female offspring from the stress groups had decreased sucrose preferences.

Conclusion

These findings suggest that protracted and acute prenatal stress in late pregnancy can induce in anxiety-, depressive-like behaviors, and excessive ethanol intake in adult offspring.
Noradrenergic Modulation of the Piriform Cortex: A Possible Avenue for Understanding Pre-Clinical Alzheimer’s Disease Pathogenesis
Authors: Rajani Vishaal , Yuan Qi
Published: June 2022

Olfactory dysfunction is one of the biomarkers for Alzheimer’s disease (AD) diagnosis and progression. Deficits with odor identification and discrimination are common symptoms of pre-clinical AD, preceding severe memory disorder observed in advanced stages. As a result, understanding mechanisms of olfactory impairment is a major focus in both human studies and animal models of AD. Pretangle tau, a precursor to tau tangles, is first observed in the locus coeruleus (LC). In a recent animal model, LC pretangle tau leads to LC fiber degeneration in the piriform cortex (PC), a cortical area associated with olfactory dysfunction in both human AD and rodent models. Here, we review the role of LC-sourced NE in modulation of PC activity and suggest mechanisms by which pretangle tau-mediated LC dysfunction may impact olfactory processing in preclinical stage of AD. Understanding mechanisms of early olfactory impairment in AD may provide a critical window for detection and intervention of disease progression.
Utility of the SERPINC1 Gene Test in Ischemic Stroke Patients With Antithrombin Deficiency
Authors: Kim Seondeuk , Lee Woo-Jin , Moon Jangsup , Jung Keun-Hwa
Published: June 2022

Objective

Antithrombin (AT) plays a critical role in the coagulation system, and its deficiency induces hypercoagulability. AT deficiency is caused not only by inherited variants in the SERPINC1 gene but also by acquired conditions. Therefore, AT deficiency alone could not ensure the presence of the SERPINC1 mutation. We evaluated the utility of the SERPINC1 gene test in ischemic stroke, an important clinical type of arterial thrombosis.

Methods

This retrospective, observational study investigated symptomatic patients who underwent the SERPINC1 gene test because of decreased AT activity (<80%) during 2009-2021 at a tertiary hospital. For the detection of sequence variants in the SERPINC1 gene, direct Sanger sequencing and multiplex ligation-dependent probe amplification were performed. The phenotypes of patients with SERPINC1 gene mutations were examined, and the conditions associated with the pathogenic variants were analyzed.

Results

In our cohort (n = 19), 13 of 19 patients (68.4%) had the pathogenic variant of the SERPINC1 gene. Ischemic stroke (n = 7) was significantly associated with the pathogenic variants (p = 0.044), and the pathogenicity detection rate was 100%. For any kind of arterial thrombosis (n = 8), the detection rate of the pathogenic variant was 87.5%, but was not statistically significant (p = 0.177). The detection rates of the pathogenic variant in ischemic stroke or arterial thrombosis groups were both higher than those in the venous thrombosis-only group (54.5%).

Conclusion

The SERPINC1 gene test was useful in determining the cause of AT deficiency-related arterial thrombosis, especially ischemic stroke. We propose the diagnostic flow of SERPINC1-related ischemic stroke.
Positive Relationship Between Paroxysmal Vertigo and Right-to-Left Shunt: A Large Observational Study
Authors: Liu Kaiming , Tian Xiulin , Hong Wenwu , Xiao Yujin , Chen Juanyan , Jin Haidi , Wang Faming , Xu Xiaopei , Zang Tao , Zhang Liang , Pan Mengxiong , Zou Xiaodong
Published: June 2022

Background

The association between paroxysmal vertigo and right-to-left shunt (RLS) is rarely reported. This study investigates the prevalence and correlation of RLS in patients with different paroxysmal vertigo diseases.

Methods

Patients with paroxysmal vertigo from seven hospitals in China were included in this observational study between 2017 and 2021. Migraine patients within the same period were included for comparison. Demographic data and medical history were collected; contrast transthoracic echocardiography was performed; and the clinical features, Dizziness Handicap Inventory, and incidence of RLS in each group were recorded.

Results

A total of 2,751 patients were enrolled. This study's results demonstrated that the proportion of RLS in patients with benign recurrent vertigo (BRV) and vestibular migraine (VM) was significantly higher than that in patients with benign paroxysmal positional vertigo, Meniere's disease, and vestibular paroxysmia (P < 0.05). No statistical difference was shown between the frequency of RLS in patients with BRV and those with migraine and VM. A positive correlation was shown between the RLS grade and Dizziness Handicap Inventory scores of patients with VM and BRV (P < 0.01) after effectively controlleding the effect of confounding variables.

Conclusions

RLS was significantly associated with BRV and VM. RLS may be involved in the pathogeneses of BRV and VM and may serve as a differential reference index for the paroxysmal vertigo.

Trial Registration

CHRS, NCT04939922, registered 14 June 2021- retrospectively registered, https://register.clinicaltrials.gov.