bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: A PD-L1-Positive Patient With Pleomorphic Rhabdomyosarcoma Achieving an Impressive Response to Immunotherapy
Authors: Liu Jiayong , Liu Peijie , Gong Fuyu , Tian Youhui , Zhao Xiaochen
Published: March 2022

There is currently a lack of effective systemic treatment for patients with advanced pleomorphic rhabdomyosarcoma (PRMS). Although programmed death protein 1 (PD-1) inhibitors have shown efficacy in various solid tumors, their effects on PRMS have not been well established. Here, we present a case of a 12-year-old Chinese male adolescent with metastatic PRMS who benefited from the PD-1 inhibitor nivolumab. The patient initially underwent primary tumor resection but failed to respond to subsequent first-line chemotherapy and second-line pazopanib treatment. Pathological examination showed positive PD-L1 expression and tumor-infiltrating lymphocytes in the tumor tissue, and the patient was administered nivolumab as a posterior-line treatment. After attaining a clinically partial response (PR), surgical resection was performed, which was followed by adjuvant nivolumab. At the time of the submission of this manuscript, the patient achieved recurrence-free survival (RFS) lasting 45 months and counting. This is the first clinical evidence that a patient with refractory PRMS was controlled by anti-PD-1 antibody, with an RFS lasting more than 3 years. This case suggests that PD-L1 expression and T-cell infiltration could be used as potential biomarkers for PRMS immunotherapy.
Photobiomodulation Attenuates Neurotoxic Polarization of Macrophages by Inhibiting the Notch1-HIF-1α/NF-κB Signalling Pathway in Mice With Spinal Cord Injury
Authors: Ma Yangguang , Li Penghui , Ju Cheng , Zuo Xiaoshuang , Li Xin , Ding Tan , Liang Zhuowen , Zhang Jiawei , Li Kun , Wang Xuankang , Zhu Zhijie , Zhang Zhihao , Song Zhiwen , Quan Huilin , Hu Xueyu , Wang Zhe
Published: March 2022

Spinal cord injury (SCI) is a catastrophic disease with a complex pathogenesis that includes inflammation, oxidative stress, and glial scar formation. Macrophages are the main mediators of the inflammatory response and are distributed in the epicentre of the SCI. Macrophages have neurotoxic and neuroprotective phenotypes (also known as classically and alternatively activated macrophages or M1 and M2 macrophages) that are associated with pro- or anti- inflammatory gene expression. Our previous study demonstrated that photobiomodulation (PBM) alters the polarization state of macrophages in the SCI region towards the M2 phenotype and promotes the recovery of motor function in rats with SCI. However, the mechanism by which PBM promotes SCI repair remains largely undefined. This study is based on the replacement of conventional percutaneous irradiation with implantable biofibre optic in vivo irradiation. The aim was to further investigate the effects of PBM on SCI in mice under new irradiation patterns and its potential mechanisms of action. PBM was administered to male mice with clamped SCI for four consecutive weeks and significantly promoted the recovery of motor function in mice. Analysis of the macrophage phenotypes in the epicentre of the SCI in mice showed that PBM mainly inhibited the neurotoxic activation of macrophages in the SCI area and reduced the secretion of inflammatory factors such as IL-1α and IL-6; PBM had no effect on M2 macrophages. Immediately afterwards, we constructed in vitro models of the inflammatory polarization of macrophages and PBM intervention. We found that PBM attenuated the neurotoxicity of M1 macrophages on VSC 4.1 motor neurons and dorsal root ganglion (DRG) neurons. The effects of PBM on neurotoxic macrophages and the possible mechanisms of action were analysed using RNA sequencing (RNA-seq), which confirmed that the main role of PBM was to modulate the inflammatory response and immune system processes. Analysis of the differentially expressed genes (DEGs) associated with the inflammatory response showed that PBM had the most significant regulatory effects on genes such as interleukin (IL)-1α, IL-6, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and had obvious inhibitory effects on inflammation-related Notch1 and hypoxia-inducible factor-1α (HIF-1α) pathway genes. RNA-seq analysis of the effect of PBM on gene expression in resting-state macrophages and M2 macrophages did not show significant differences (data not shown). In conclusion, PBM promoted better motor recovery after SCI in mice by inhibiting the neurotoxic polarization of macrophages and the release of inflammatory mediators by acting on the Notch1-HIF-1α/NF-κB Signalling Pathway.
Effect of Infant RSV Infection on Memory T Cell Responses at Age 2-3 Years
Authors: Chirkova Tatiana , Rosas-Salazar Christian , Gebretsadik Tebeb , Jadhao Samadhan J. , Chappell James D. , Peebles R. Stokes , Dupont William D. , Newcomb Dawn C. , Berdnikovs Sergejs , Gergen Peter J. , Hartert Tina V. , Anderson Larry J.
Published: March 2022

Background

It is unknown whether RSV infection in infancy alters subsequent RSV immune responses.

Methods

In a nested cohort of healthy, term children, peripheral blood mononuclear cells (PBMCs) were collected at ages 2-3 years to examine RSV memory T cell responses among children previously RSV infected during infancy (first year of life) compared to those RSV-uninfected during infancy. The presence vs. absence of infant RSV infection was determined through a combination of RSV molecular and serologic testing. Memory responses were measured in RSV stimulated PBMCs.

Results

Compared to children not infected with RSV during the first year of life, children infected with RSV during infancy had lower memory T cell responses at ages 2-3 years to in vitro stimulation with RSV for most tested type-1 and type-17 markers for a number of memory T cell subsets.

Conclusions

RSV infection in infancy has long-term effects on memory T cell responses. This is the first study to show the potential for RSV infection in infancy to have long-term effects on the immune memory irrespective of the severity of the infection. Our results suggest a possible mechanism through which infant RSV infection may result in greater risk of subsequent childhood respiratory viral morbidity, findings also relevant to vaccine development.
Leveraging Antibody, B Cell and Fc Receptor Interactions to Understand Heterogeneous Immune Responses in Tuberculosis
Authors: Carpenter Stephen M. , Lu Lenette L.
Published: March 2022

Despite over a century of research,Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to kill 1.5 million people annually. Though less than 10% of infected individuals develop active disease, the specific host immune responses that lead toMtbtransmission and death, as well as those that are protective, are not yet fully defined. Recent immune correlative studies demonstrate that the spectrum of infection and disease is more heterogenous than has been classically defined. Moreover, emerging translational and animal model data attribute a diverse immune repertoire to TB outcomes. Thus, protective and detrimental immune responses toMtblikely encompass a framework that is broader than T helper type 1 (Th1) immunity. Antibodies, Fc receptor interactions and B cells are underexplored host responses toMtb. Poised at the interface of initial bacterial host interactions and in granulomatous lesions, antibodies and Fc receptors expressed on macrophages, neutrophils, dendritic cells, natural killer cells, T and B cells have the potential to influence local and systemic adaptive immune responses. Broadening the paradigm of protective immunity will offer new paths to improve diagnostics and vaccines to reduce the morbidity and mortality of TB.
Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma
Authors: Ding Lin , Yu Qian , Yang Shuo , Yang Wen-Jing , Liu Te , Xian Jing-Rong , Tian Tong-Tong , Li Tong , Chen Wei , Wang Bei-Li , Pan Bai-Shen , Zhou Jian , Fan Jia , Yang Xin-Rong , Guo Wei
Published: March 2022

Background

Inhibitory immune checkpoint proteins promote tumor immune escape and are associated with inferior patient outcome. However, the biological functions and regulatory roles of one of its members, HHLA2, in the tumor immune microenvironment have not been explored.

Methods

RandomForest analyses (371 cases), qRT-PCR (15 cases), and immunohistochemical staining (189 cases) were used to validate the prognostic value of HHLA2 in hepatocellular carcinoma (HCC) patients. Bioinformatic analyses were further performed to explore the biological functions and potential signaling pathways affected by HHLA2. Moreover, ESTIMATE, single sample gene set enrichment analysis, CIBERSORT, TIMER, and other deconvolution methods were used to analyze the composition and infiltration level of immune cells. Multiplex immunofluorescence assays were employed to validate the fractions of suppressive immune cells, and HHLA2-related molecular alterations were investigated. Finally, the clinical response to chemotherapy and immune checkpoint blockade was predicted by TIDE, Submap, and several other in silico analyses.

Results

RandomForest analysis revealed that HHLA2 was the most important inhibitory immune checkpoint associated with HCC patient prognosis (relative importance = 1). Our HCC cohorts further revealed that high HHLA2 expression was an independent prognostic biomarker of shorter overall survival (P<0.01) and time to recurrence (P<0.001) for HCC patients. Bioinformatics experiments revealed that HHLA2 may accelerate the cell cycle of cancer cells. Additionally, we found that high expression of HHLA2 was associated with immune infiltrates, including some immunosuppressive cells, cytokines, chemokines, and corresponding receptors, resulting in an immunosuppressive environment. Notably, HHLA2 expression was positively correlated with the infiltration of exhausted CD8+ T cells, which was validated by immunofluorescence. Genomic alteration analyses revealed that promoter hypermethylation of HHLA2 may be associated with its low expression. More importantly, patients with high HHLA2 expression may be more sensitive to chemotherapy and have better responses to immunotherapy.

Conclusions

High expression of HHLA2 is an independent prognostic biomarker for HCC patients. It can activate the cell cycle and foster an immunosuppressive tumor microenvironment by enriching exhausted CD8+ T cells. Promoter hypermethylation might lead to low expression of HHLA2 in HCC. Thus, targeting HHLA2 may be a practical therapeutic strategy for HCC patients in the future.
Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy
Authors: Gao Ran , Shi Guo-Ping , Wang Jing
Published: March 2022

Regulatory T cells (Tregs) are a subset of CD4+T cells with their immunosuppressive activities to block abnormal or excessive immune responses to self and non-autoantigens. Tregs express the transcription factor Foxp3, maintain the immune homeostasis, and prevent the initiation of anti-tumor immune effects in various ways as their mechanisms to modulate tumor development. Recognition of different phenotypes and functions of intratumoral Tregs has offered the possibilities to develop therapeutic strategies by selectively targeting Tregs in cancers with the aim of alleviating their immunosuppressive activities from anti-tumor immune responses. Several Treg-based immunotherapeutic approaches have emerged to target cytotoxic T lymphocyte antigen-4, glucocorticoid-induced tumor necrosis factor receptor, CD25, indoleamine-2, 3-dioxygenase-1, and cytokines. These immunotherapies have yielded encouraging outcomes from preclinical studies and early-phase clinical trials. Further, dual therapy or combined therapy has been approved to be better choices than single immunotherapy, radiotherapy, or chemotherapy. In this short review article, we discuss our current understanding of the immunologic characteristics of Tregs, including Treg differentiation, development, therapeutic efficacy, and future potential of Treg-related therapies among the general cancer therapy.
Novel Human FCGR1A Variants Affect CD64 Functions and Are Risk Factors for Sarcoidosis
Authors: Wu Jianming , Li Yunfang , Rendahl Aaron , Bhargava Maneesh
Published: March 2022

CD64 (or FcγRIA) is the sole functional high affinity IgG Fc receptor coded byFCGR1Agene in humans. TheFCGR1Agenetics has not been comprehensively investigated and effects of humanFCGR1Avariants on immune functions remain unknown. In the current study, we identified three novelFCGR1Avariants including the single nucleotide variant (SNV) rs1848781 (c.-131) in the proximalFCGR1Agene promoter region, the rs587598788 indel variant within theFCGR1Aintron 5, and the non-synonymous SNV rs1050204 (c.970G>A or FcγRIA-p.D324N) in theFCGR1Acoding region. Genotype-phenotype analyses revealed that SNV rs1848781 genotypes were significantly associated with CD64 expression levels. Promoter reporter assays show that rs1848781G allele had significantly higher promoter activity than the rs1848781C, confirming that the rs1848781 is a functionalFCGR1ASNV affecting promoter activity and gene expression. The rs587598788 indel genotypes were also significantly associated with levels of CD64 expression. Moreover, the non-synonymous SNV rs1050204 (FcγRIA-p.D324N) alleles significantly affected CD64-mediated phagocytosis, degranulation, and pro-inflammatory cytokine productions. Genetic analyses revealed thatFCGR1Agenotypes were significantly associated with sarcoidosis susceptibility and severity. Our data suggest thatFCGR1Agenetic variants may affect immune responses and play a role in sarcoidosis.
Revisiting Minocycline in Intracerebral Hemorrhage: Mechanisms and Clinical Translation
Authors: Zhang Ruiyi , Yong V. Wee , Xue Mengzhou
Published: March 2022

Intracerebral hemorrhage (ICH) is an important subtype of stroke with an unsatisfactory prognosis of high mortality and disability. Although many pre-clinical studies and clinical trials have been performed in the past decades, effective therapy that meaningfully improve prognosis and outcomes of ICH patients is still lacking. An active area of research is towards alleviating secondary brain injury after ICH through neuroprotective pharmaceuticals and in which minocycline is a promising candidate. Here, we will first discuss new insights into the protective mechanisms of minocycline for ICH including reducing iron-related toxicity, maintenance of blood-brain barrier, and alleviating different types of cell death from preclinical data, then consider its shortcomings. Finally, we will review clinical trial perspectives for minocycline in ICH. We hope that this summary and discussion about updated information on minocycline as a viable treatment for ICH can facilitate further investigations.
The Insider: Impact of the Gut Microbiota on Cancer Immunity and Response to Therapies in Multiple Myeloma
Authors: Brevi Arianna , Cogrossi Laura Lucia , Lorenzoni Marco , Mattorre Benedetta , Bellone Matteo
Published: March 2022

The human microbiota is a unique set of microorganisms colonizing the human body and evolving within it from the very beginning. Acting as an insider, the microbiota provides nutrients, and mutualistically interacts with the host’s immune system, thus contributing to the generation of barriers against pathogens. While a strong link has been documented between intestinal dysbiosis (i.e., disruption to the microbiota homeostasis) and diseases, the mechanisms by which commensal bacteria impact a wide spectrum of mucosal and extramucosal human disorders have only partially been deciphered. This is particularly puzzling for multiple myeloma (MM), a treatable but incurable neoplasia of plasma cells that accumulate in the bone marrow and lead to end-organ damage. Here we revise the most recent literature on data from both the bench and the bedside that show how the gut microbiota modulates cancer immunity, potentially impacting the progression of asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) to full blown MM. We also explore the effect of the gut microbiome on hematopoietic stem cell transplantation, chemotherapy, immunomodulating therapy and cancer immunotherapy in MM patients. Additionally, we identify the most cogent area of investigation that have the highest chance to delineate microbiota-related and pathobiology-based parameters for patient risk stratification. Lastly, we highlight microbiota-modulating strategies (i.e., diet, prebiotics, probiotics, fecal microbiota transplantation and postbiotics) that may reduce treatment-related toxicity in patients affected by MM as well as the rates of undertreatment of SMM patients.
Adenosinergic Pathway and Linked Suppression: Two Critical Suppressive Mechanisms of Human Donor Antigen Specific Regulatory T Cell Lines Expanded Post Transplant
Authors: Tripathi Sudipta , Martin-Moreno Paloma L. , Kavalam George , Schreiber Brittany L. , Waaga-Gasser Ana Maria , Chandraker Anil
Published: March 2022

Regulatory T cells are an important component of an immune response shaping the overall behavior to potential antigens including alloantigens. Multiple mechanisms have been shown to contribute towards developing and sustaining a immunological regulatory response. One of the described contact dependent suppressive mechanisms regulatory cells have been shown to utilize is through the production of adenosine from extracellular ATP mediated by CD39 and CD73. In this study we demonstrate that the adenosinergic pathway plays a major role in the suppressive/regulatory effects antigen specific regulatory T cell enriched lines (ASTRLs) that have been of expanded ex vivo from stable kidney transplant patients. We have previously shown that these ASTRL cells are capable of suppressing alloimmune responses in vitro and significantly prolonging allograft survival in an animal model of kidney transplantation. For this study nineteen ASTRLs were expanded from 17 kidney transplant patients by repeated stimulation of recipient peripheral blood mononuclear cells with donor specific HLA-DR peptides. All 19 ASTRLs showed upregulation of numerous markers associated with regulatory cells and were able to inhibit donor antigen specific T cell proliferation in a dose dependent fashion. ASTRLs suppressed indirect and direct alloimmune responses compatible with our previous animal study findings. Upregulation of both CD39 and CD73 was observed post expansion and ASTRLs demonstrated extracellular hydrolysis of ATP, indicating functionality of the upregulated proteins. We also showed that inhibition of the adenosinergic pathway using inhibitors of CD39 resulted in abrogation of suppression and increased antigen specific T cell proliferation. This demonstrates that the main mechanism of action of the suppressive activity donor peptide driven ASTRLs generated from kidney transplant patients is the adenosinergic pathway. Furthermore this suggests the possibility that combining infusion of Tregs with other treatments, such as adenosine receptor agonists or increasing CD39 expression in the grafts may further enhance a regulatory response to the allograft and possibly achieve transplantation tolerance.
Identification of the Predictive Models for the Treatment Response of Refractory/Relapsed B-Cell ALL Patients Receiving CAR-T Therapy
Authors: Gu Jingxian , Liu Sining , Cui Wei , Dai Haiping , Cui Qingya , Yin Jia , Li Zheng , Kang Liqing , Qiu Huiying , Han Yue , Miao Miao , Chen Suning , Xue Shengli , Wang Ying , Jin Zhengming , Zhu Xiaming , Yu Lei , Wu Depei , Tang Xiaowen
Published: March 2022

Background/Aims

Chimeric antigen receptor (CAR) T cells for refractory or relapsed (r/r) B-cell acute lymphoblastic leukemia (ALL) patients have shown promising clinical effectiveness. However, the factors impacting the clinical response of CAR-T therapy have not been fully elucidated. We here aimed to identify the independent factors of CAR-T treatment response and construct the models for predicting the complete remission (CR) and minimal residual disease (MRD)-negative CR in r/r B-ALL patients after CAR-T cell infusion.

Methods

Univariate and multivariate logistic regression analyses were conducted to identify the independent factors of CR and MRD-negative CR. The predictive models for the probability of remission were constructed based on the identified independent factors. Discrimination and calibration of the established models were assessed by receiver operating characteristic (ROC) curves and calibration plots, respectively. The predictive models were further integrated and validated in the internal series. Moreover, the prognostic value of the integration risk model was also confirmed.

Results

The predictive model for CR was formulated by the number of white blood cells (WBC), central neural system (CNS) leukemia, TP53 mutation, bone marrow blasts, and CAR-T cell generation while the model for MRD-negative CR was formulated by disease status, bone marrow blasts, and infusion strategy. The ROC curves and calibration plots of the two models displayed great discrimination and calibration ability. Patients and infusions were divided into different risk groups according to the integration model. High-risk groups showed significant lower CR and MRD-negative CR rates in both the training and validation sets (p < 0.01). Furthermore, low-risk patients exhibited improved overall survival (OS) (log-rank p < 0.01), higher 6-month event-free survival (EFS) rate (p < 0.01), and lower relapse rate after the allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T cell infusion (p = 0.06).

Conclusions

We have established predictive models for treatment response estimation of CAR-T therapy. Our models also provided new clinical insights for the accurate diagnosis and targeted treatment of r/r B-ALL.
Short-Term Instantaneous Prophylaxis and Efficient Treatment Against SARS-CoV-2 in hACE2 Mice Conferred by an Intranasal Nanobody (Nb22)
Authors: Wu Xilin , Wang Yaxing , Cheng Lin , Ni Fengfeng , Zhu Linjing , Ma Sen , Huang Bilian , Ji Mengmeng , Hu Huimin , Li Yuncheng , Xu Shijie , Shi Haixia , Zhang Doudou , Liu Linshuo , Nawaz Waqas , Hu Qinxue , Ye Sheng , Liu Yalan , Wu Zhiwei
Published: March 2022

Current COVID-19 vaccines need to take at least one month to complete inoculation and then become effective. Around 51% of the global population is still not fully vaccinated. Instantaneous protection is an unmet need among those who are not fully vaccinated. In addition, breakthrough infections caused by SARS-CoV-2 are widely reported. All these highlight the unmet needing for short-term instantaneous prophylaxis (STIP) in the communities where SARS-CoV-2 is circulating. Previously, we reported nanobodies isolated from an alpaca immunized with the spike protein, exhibiting ultrahigh potency against SARS-CoV-2 and its variants. Herein, we found that Nb22, among our previously reported nanobodies, exhibited ultrapotent neutralization against Delta variant with an IC50 value of 0.41 ng/ml (5.13 pM). Furthermore, the crystal structural analysis revealed that the binding of Nb22 to WH01 and Delta RBDs both effectively blocked the binding of RBD to hACE2. Additionally, intranasal Nb22 exhibited protection against SARS-CoV-2 Delta variant in the post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). Of note, intranasal Nb22 also demonstrated high efficacy against SARS-CoV-2 Delta variant in STIP for seven days administered by single dose and exhibited long-lasting retention in the respiratory system for at least one month administered by four doses, providing a strategy of instantaneous short-term prophylaxis against SARS-CoV-2. Thus, ultrahigh potency, long-lasting retention in the respiratory system and stability at room-temperature make the intranasal or inhaled Nb22 to be a potential therapeutic or STIP agent against SARS-CoV-2.
Wide-Geographic and Long-Term Analysis of the Role of Pathogens in the Decline of Pinna nobilis to Critically Endangered Species
Authors: Grau Amalia , Villalba Antonio , Navas José I. , Hansjosten Beatriz , Valencia José M. , García-March José R. , Prado Patricia , Follana-Berná Guillermo , Morage Titouan , Vázquez-Luis Maite , Álvarez Elvira , Katharios Pantelis , Pavloudi Christina , Nebot-Colomer Elisabet , Tena-Medialdea José , Lopez-Sanmartín Monserrat , Peyran Claire , Čižmek Hrvoje , Sarafidou Georgia , Issaris Yiannis , Tüney-Kizilkaya Inci , Deudero Salud , Planes Serge , Catanese Gaetano
Published: March 2022

A mass mortality event (MME) affecting the fan mussel Pinna nobilis was first detected in Spain in autumn 2016 and spread north- and eastward through the Mediterranean Sea. Various pathogens have been blamed for contributing to the MME, with emphasis in Haplosporidium pinnae, Mycobacterium sp. and Vibrio spp. In this study, samples from 762 fan mussels (necropsies from 263 individuals, mantle biopsies from 499) of various health conditions, with wide geographic and age range, taken before and during the MME spread from various environments along Mediterranean Sea, were used to assess the role of pathogens in the MME. The number of samples processed by both histological and molecular methods was 83. The most important factor playing a main role on the onset of the mass mortality of P. nobilis throughout the Mediterranean Sea was the infection by H. pinnae. It was the only non-detected pathogen before the MME while, during MME spreading, its prevalence was higher in sick and dead individuals than in asymptomatic ones, in MME-affected areas than in non-affected sites, and it was not associated with host size, infecting both juveniles and adults. Conversely, infection with mycobacteria was independent from the period (before or during MME), from the affection of the area by MME and from the host health condition, and it was associated with host size. Gram (-) bacteria neither appeared associated with MME.
TROPOMI-Retrieved Underwater Light Attenuation in Three Spectral Regions in the Ultraviolet and Blue
Authors: Oelker Julia , Losa Svetlana N. , Richter Andreas , Bracher Astrid
Published: March 2022

Ultraviolet (UV) radiation plays an important role in the ocean for the biogeochemical cycling through photooxidation of colored dissolved organic matter and metals. It also influences the release of trace gases into the atmosphere. Understanding interaction and climate feedback mechanisms of these processes requires global long-term monitoring of UV radiation in the ocean. Ocean color sensors provide the diffuse attenuation coefficient for downwelling solar irradiance (Kd) as an estimate for the mean light penetration depth in the surface ocean. However, Kd products for the UV spectral range are currently only indirectly inferred from measurements in the visible spectral region. We exploit the UV and visible wavelengths of the TROPOMI sensor onboard Sentinel-5P to directly infer diffuse attenuation coefficients in the UV and blue spectral range. Our approach is based on Differential Optical Absorption Spectroscopy in combination with radiative transfer modeling which has been used in earlier studies to successfully derive Kd in the blue from the vibrational Raman scattering (VRS) signal. VRS was detected in the backscattered radiances of TROPOMI-like sensors at a spectral resolution around 0.5 nm. We adapt this method for the TROPOMI sensor and more spectral regions to obtain two novel Kd products in the UV range (312.5–338.5 nm and 356.5–390 nm), additionally to the blue Kd (390–423 nm). One month of TROPOMI data show high sensitivity to retrieve VRS (fit errors <15%). The resulting Kd values in the UV and blue agree reasonably (RMSD <0.31 m−1) with in-situ data measured during a transatlantic cruise. Kd-blue compared to wavelength-converted Kd(490) products from OLCI and OC-CCI shows that the differences between the three data sets are within uncertainties given for the OC-CCI product. TROPOMI Kd-blue results have higher quality and much higher spatial coverage and resolution than previous ones from SCIAMACHY, GOME-2, and OMI. Perspectively, global TROPOMI Kd products, once thoroughly validated, can be used as input for modeling, e.g., photochemical reaction rates of climatically important compounds and inhibition of primary productivity.
The Status of Marine Megafauna Research in Macaronesia: A Systematic Review
Authors: McIvor Ashlie J. , Williams Collin T. , Alves Filipe , Dinis Ana , Pais Miguel P. , Canning-Clode João
Published: March 2022

Marine megafauna serve valuable ecological and economical roles globally, yet, many species have experienced precipitous population declines. The significance of marine megafauna is particularly evident in Macaronesia, a complex of oceanic archipelagos in the Northeast Atlantic Ocean. Macaronesian islands provide important habitats for marine megafauna species, in turn supporting considerable regional economic activity (e.g., ecotourism and fisheries). Despite this, concerted efforts to manage marine megafauna throughout Macaronesia have been limited. This systematic review provides the first description of the trends in marine megafauna research in this unique insular ecosystem, to provide a better understanding of taxa-specific research needs and future directions for conservation. We identified and validated 408 peer-reviewed publications until 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Literature was dominated by marine mammal research conducted in the northern archipelagos (Azores, Madeira, and Canary Islands) and marine turtle research conducted in Cabo Verde. Much less research focused on large-bodied fish, especially in Madeira and Canary Islands, leaving some of the most vulnerable species regionally data deficient. Research across scientific disciplines focused more on biological studies than management and policy, and anthropogenic impacts were quantified more frequently on mammals or turtles and less on fishes. By identifying gaps in our knowledge of megafauna in relation to threats faced by these organisms, we offer taxa-specific recommendations for future research direction. Although, overall our results indicate that determining population level connectivity should be a major research priority among many marine megafauna species as this information is vital to numerous management strategies, including marine protected areas. In this review, we present a basis of understanding of the current work in Macaronesia, highlighting critical data gaps that are urgently needed to guide the next steps toward establishing conservation priorities for marine megafauna in the region.
The Efficacy and Safety of Transurethral 2 μm Laser Bladder Lesion Mucosal En Bloc Resection in the Treatment of Cystitis Glandularis
Authors: Zhao Changyuan , Wang Kexin , Men Chao , Xin Yue , Xia Haibo
Published: March 2022

Objective

To study the safety and feasibility of transurethral bladder lesion mucosal en bloc resection with 2 μm laser for cystitis glandularis.

Methods

From July 2018 to July 2019, 58 patients with cystitis glandularis received surgical treatment were selected. All patients in this study were randomly divided into experimental group (transurethral 2 μm laser bladder lesion mucosal en bloc resection) and control group (traditional transurethral resection of bladder lesion mucosal). By analyzing the perioperative and follow-up clinical data of these two operation procedures, we discuss the efficacy and safety of transurethral 2 μm laser bladder lesion mucosal en bloc resection in the treatment of cystitis glandularis.

Results

Patients of two groups received operation successfully without serious complications such as bladder perforation. Compared with the experimental group, the laser treated group hadless bleeding in operation, shorter post-operative catheter indwelling time. These differences were statistically significant. No significant difference existed between two groups in terms of operative time, Bladder flushing time, irritation symptoms of bladder.

Conclusion

Transurethral 2 μm laser bladder lesion mucosal en bloc resection is safe and effective for the treatment of cystitis glandularis, and it is worthy of further clinical application.
Groundnut Bud Necrosis Virus Modulates the Expression of Innate Immune, Endocytosis, and Cuticle Development-Associated Genes to Circulate and Propagate in Its Vector, Thrips palmi
Authors: Mahanta Deepak Kumar , Jangra Sumit , Priti  , Ghosh Amalendu , Sharma Parva Kumar , Iquebal Mir Asif , Jaiswal Sarika , Baranwal Virendra Kumar , Kalia Vinay Kumari , Chander Subhas
Published: March 2022

Thrips palmi (Thysanoptera: Thripidae) is the predominant tospovirus vector in Asia-Pacific region. It transmits economically damaging groundnut bud necrosis virus (GBNV, family Tospoviridae) in a persistent propagative manner. Thrips serve as the alternate host, and virus reservoirs making tospovirus management very challenging. Insecticides and host plant resistance remain ineffective in managing thrips–tospoviruses. Recent genomic approaches have led to understanding the molecular interactions of thrips–tospoviruses and identifying novel genetic targets. However, most of the studies are limited to Frankliniella species and tomato spotted wilt virus (TSWV). Amidst the limited information available on T. palmi–tospovirus relationships, the present study is the first report of the transcriptome-wide response of T. palmi associated with GBNV infection. The differential expression analyses of the triplicate transcriptome of viruliferous vs. nonviruliferous adult T. palmi identified a total of 2,363 (1,383 upregulated and 980 downregulated) significant transcripts. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed the abundance of differentially expressed genes (DEGs) involved in innate immune response, endocytosis, cuticle development, and receptor binding and signaling that mediate the virus invasion and multiplication in the vector system. Also, the gene regulatory network (GRN) of most significant DEGs showed the genes like ABC transporter, cytochrome P450, endocuticle structural glycoprotein, gamma-aminobutyric acid (GABA) receptor, heat shock protein 70, larval and pupal cuticle proteins, nephrin, proline-rich protein, sperm-associated antigen, UHRF1-binding protein, serpin, tyrosine–protein kinase receptor, etc., were enriched with higher degrees of interactions. Further, the expression of the candidate genes in response to GBNV infection was validated in reverse transcriptase-quantitative real-time PCR (RT-qPCR). This study leads to an understanding of molecular interactions between T. palmi and GBNV and suggests potential genetic targets for generic pest control.
Metabolic Alternations During Gestation in Dezhou Donkeys and the Link to the Gut Microbiota
Authors: Li Yan , Ma Qingshan , Liu Guiqin , Zhang Zhenwei , Zhan Yandong , Zhu Mingxia , Wang Changfa
Published: March 2022

The maternal intestinal microbial community changes dramatically during pregnancy and plays an important role in animal growth, metabolism, immunity and reproduction. However, our understanding of microbiota compositional dynamics during the whole pregnancy period in donkey is incomplete. This study was carried out to evaluate gut microbiota alterations as well as the correlation with serum biochemical indices, comparing pregnant donkeys to non-pregnant donkeys. A total of 18 pregnant (including EP, early-stage pregnancy; MP, middle-stage pregnancy and LP, late-stage pregnancy) and six non-pregnant (C as a control) donkey blood samples and rectum contents were collected. The results showed that pregnant donkeys had higher microbial richness than non-pregnant donkeys and that the lowest microbial diversity occurred at the EP period. Moreover, the relative abundances of the families Clostridiaceae and Streptococcaceae were significantly higher in the EP group (p < 0.05) than that in the C and MP groups, while the relative abundances of the families Lachnospiraceae and Rikenellaceae were significantly lower in the EP group (p < 0.05) than that in the C group. The predicted microbial gene functions related to the inflammatory response and apoptosis, such as Staphylococcus aureus infection, the RIG-1-like receptor signaling pathway and apoptosis, were mainly enriched in EP. Furthermore, pregnant donkeys had higher glucose levels than non-pregnant donkeys, especially at EP period. EP donkeys had lower triglyceride, total protein and albumin levels but higher malondialdehyde, interleukin 1β, interleukin 6 and tumor necrosis factor-α levels than those in the C and MP groups. Additionally, there were strong correlations between inflammatory cytokine levels and the relative abundances of genera belonging to the Clostridiaceae and Streptococcaceae families. This is the first comparative study performed in donkeys that indicates that pregnancy status (especially in the early pregnancy period) alters the gut microbiota composition, which was correlated with serum biochemical parameters. These results could provide useful information for improving the reproductive management in Dezhou donkeys.
Hyperaccumulation of Gadolinium by Methylorubrum extorquens AM1 Reveals Impacts of Lanthanides on Cellular Processes Beyond Methylotrophy
Authors: Good Nathan M. , Lee Harvey D. , Hawker Emily R. , Su Morgan Z. , Gilad Assaf A. , Martinez-Gomez N. Cecilia
Published: March 2022

Lanthanides (Ln) are a new group of life metals, and many questions remain regarding how they are acquired and used in biology. Methylotrophic bacteria can acquire, transport, biomineralize, and use Ln as part of a cofactor complex with pyrroloquinoline quinone (PQQ) in alcohol dehydrogenases. For most methylotrophic bacteria use is restricted to the light Ln, which range from lanthanum to samarium (atomic numbers 57–62). Understanding how the cell differentiates between light and heavy Ln, and the impacts of these metals on the metabolic network, will advance the field of Ln biochemistry and give insights into enzyme catalysis, stress homeostasis, and metal biomineralization and compartmentalization. We report robust methanol growth with the heavy Ln gadolinium by a genetic variant of the model methylotrophic bacterium Methylorubrum extorquens AM1, named evo-HLn, for “evolved for Heavy Lanthanides.” A non-synonymous single nucleotide polymorphism in a cytosolic hybrid histidine kinase/response regulator allowed for sweeping transcriptional alterations to heavy metal stress response, methanol oxidation, and central metabolism. Increased expression of genes for Ln acquisition and uptake, production of the Ln-chelating lanthanophore, PQQ biosynthesis, and phosphate transport and metabolism resulted in gadolinium hyperaccumulation of 36-fold with a trade-off for light Ln accumulation. Gadolinium was hyperaccumulated in an enlarged acidocalcisome-like compartment. This is the first evidence of a bacterial intracellular Ln-containing compartment that we name the “lanthasome.” Carotenoid and toblerol biosynthesis were also upregulated. Due to its unique capabilities, evo-HLn can be used to further magnetic resonance imaging (MRI) and bioremediation technologies. In this regard, we show that gadolinium hyperaccumulation was sufficient to produce MRI contrast in whole cells, and that evo-HLn was able to readily acquire the metal from the MRI contrast agent gadopentetic acid. Finally, hyperaccumulation of gadolinium, differential uptake of light and heavy Ln, increased PQQ levels, and phosphate transport provide new insights into strategies for Ln recovery.
A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice
Authors: Yeo Huimin , Chong Connie Wan Hui , Chen Elijah Weihua , Lim Ze Qin , Ng Qing Yong , Yan Benedict , Chu Justin Jang Hann , Chow Vincent T. K. , Alonso Sylvie
Published: March 2022

Enterovirus 71 (EV-A71) causes hand, foot, and mouth disease (HFMD) in children and has been associated with neurological complications. With no specific treatment and a monovalent vaccine limited to the Chinese market, HFMD remains a serious public health concern and an economic burden to affected societies. The molecular mechanisms underpinning EV-A71 neurovirulence have yet to be fully elucidated. In this work, we provide experimental evidence that a single amino acid substitution (I to K) at position 149 in structural protein VP2 of a non-mouse-adapted EV-A71 strain completely and specifically abrogated its infectivity in murine motor neuron-like NSC-34 cells. We showed that VP2 I149K mutant was impaired in murine SCARB2-mediated entry step but retained the ability to attach at the cell surface. In vivo, VP2 I149K mutant was fully attenuated in a symptomatic mouse model of progressive limb paralysis. While viral titers in limb muscles were comparable to mice infected with parental wild-type strain, significantly lower viral titers were measured in the spinal cord and brain, with minimal tissue damage, therefore indicating that VP2 I149K mutant is specifically impaired in its ability to invade the central nervous system (CNS). This study highlights the key role of amino acid at position 149 in VP2 in EV-A71 neurovirulence, and lends further support that the EF loop of VP2 represents a potential therapeutic target.
Computed Tomography Density and β-Amyloid Deposition of Intraorbital Optic Nerve May Assist in Diagnosing Mild Cognitive Impairment and Alzheimer’s Disease: A 18F-Flutemetamol Positron Emission Tomography/Computed Tomography Study
Authors: Wu Han , Lei Zhe , Ou Yinghui , Shi Xin , Xu Qian , Shi Keqing , Ding Jing , Zhao Qianhua , Wang Xiuzhe , Cai Xiaolong , Liu Xueyuan , Lou Jingjing , Liu Xingdang
Published: March 2022

Objective

The aim was to study whether the computed tomography (CT) density and β-amyloid (Aβ) level of intraorbital optic nerve could assist in diagnosing mild cognitive impairment (MCI) and Alzheimer’s disease (AD).

Methods

A total of sixty subjects were recruited in our study, including nine normal control (NC) subjects (i.e., 4 men and 5 women), twenty four MCI subjects (i.e., 11 men and 13 women), and twenty seven AD subjects (i.e., 14 men and 13 women). All subjects conducted 18F-flutemetamol amyloid positron emission tomography (PET)/CT imaging. Blinded to the clinical information of the subjects, two physicians independently measured and calculated the standardized uptake value ratio (SUVR) of the bilateral occipital cortex, SUVR of the bilateral intraorbital optic nerve, and CT density of the bilateral intraorbital optic nerve by using GE AW 4.5 Workstation.

Results

Between AD and NC groups, the differences of the bilateral intraorbital optic nerve SUVR were statistically significant; between AD and MCI groups, the differences of the left intraorbital optic nerve SUVR were statistically significant. Between any two of the three groups, the differences in the bilateral intraorbital optic nerve density were statistically significant. The bilateral occipital SUVR was positively correlated with the bilateral intraorbital optic nerve SUVR and negatively correlated with the bilateral intraorbital optic nerve density. Bilateral intraorbital optic nerve SUVR was negatively correlated with the bilateral intraorbital optic nerve density. The area under the receiver operating characteristic (ROC) curve of multiple logistic regression was 0.9167 (for MCI vs. NC) and 0.8951 (for AD vs. MCI). The Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores were positively associated with the intraorbital optic nerve density and were negatively associated with the intraorbital optic nerve SUVR. The regression equation of MoCA was y = 16.37-0.9734 × x1 + 0.5642 × x2-3.127 × x3 + 0.0275 × x4; the R2 was 0.848. The regression equation of MMSE was y = 19.57-1.633 × x1 + 0.4397 × x2-1.713 × x3 + 0.0424 × x4; the R2 was 0.827.

Conclusion

The CT density and Aβ deposition of the intraorbital optic nerve were associated with Aβ deposition of the occipital cortex and the severity of cognitive impairment. The intraorbital optic nerve CT density and intraorbital optic nerve Aβ deposition could assist in diagnosing MCI and AD.
Retrospective Comparative Analysis of Clinical and Imaging Features of Craniocervical Artery Dissection: Spontaneous CAD vs. Minor Traumatic CAD
Authors: Xu Dan , Wu Yongjun , Li Jingjing , Xing Shihui , Chen Hongbing , Chen Xinran , Tan Yan , Zhou Kun , Zhang Guofen , Zhang Jian
Published: March 2022

Background and Objectives

Craniocervical artery dissection (CAD) is the most common cause of ischemic stroke in young adults. The etiologies of CAD can be classified into three types, such as spontaneous (sCAD), minor traumatic (mtCAD), and genetic origin. Recent studies indicated that clinical presentations and imaging features could guide management and inform prognosis. This retrospective analysis sought to compare the clinical and imaging features of sCAD vs. mtCAD in providing evidence-based advice on medical treatment, functional rehabilitation, secondary stroke prevention, and prognosis, ultimately formulating clinical guidelines in managing CAD.

Methods

In total, 148 patients with CAD were identified from the medical records database and subdivided into sCAD and mtCAD based on the clinical presentations and imaging features. A retrospective comparative analysis was performed according to their clinical presentations and imaging features.

Results

Patients with mtCAD are significantly younger than sCAD with 120 cases of sCAD average aged 43.61 ± 12.75, while 28 cases of mtCAD average aged 35.68 ± 14.54. Patients with mtCAD had more cases of neck pain compared to sCAD. Patients with mtCAD had more cases of CAD at extracranial locations compared to sCAD. Patients with mtCAD had more cases of multiple site dissection compared to sCAD. Double lumen and intramural haematoma are the most common imaging findings with mtCAD patients having statistical significantly more cases of intramural haematoma and long tapering stenosis.

Conclusion

Patients with mtCAD were presented at a much younger age with symptoms of neck pain compared to sCAD. Patients with mtCAD predominantly presented at extracranial sites with more prominent features of multiple site dissection, intramural haematoma, and long tapering stenosis. These clinical and imaging features can translate into clinical practice guidelines for patients with CAD to improve the optimal functional outcome and reduce both morbidity and mortality.