bluuebunny/crossref_metadata_2025 huggingface dataset:
High-tech infrastructure and economic growth: The Materials Genome Initiative
Authors: Scott Troy , Walsh Amanda , Anderson Benjamin , O’Connor Alan , Tassey Gregory
Published: May 2021

This paper examines the economic impact potential of a major innovative effort by the US Government to systematically coordinate, implement, and manage a technical infrastructure to support innovation and subsequent market penetration of advanced material technologies. Called the Materials Genome Initiative (MGI), this high-tech infrastructure consists of a range of policy instruments that can be used to leverage the efficiency of both research and development and production. To determine and rank the potential economic impacts of various MGI infrastructure targets and thereby provide policy input for portfolio management, surveys were conducted to obtain industry estimates of materials infrastructure needs. From these surveys, the economic benefits of implementing the MGI were calculated. The analysis projects potential economic benefits from an improved materials innovation infrastructure of between $123 billion and $270 billion per year.
Alternariol exerts embryotoxic and immunotoxic effects on mouse blastocysts through ROS-mediated apoptotic processes
Authors: Huang Chien-Hsun , Wang Fu-Ting , Chan Wen-Hsiung
Published: May 2021

Alternariol (AOH), a mycotoxin belonging to the genus Alternaria, has been shown to induce cytotoxicity, including apoptosis and cell cycle arrest, in several mammalian cell types. However, its effects on early-stage embryonic development require further investigation. Here, we have shown that AOH exerts embryotoxic effects on mouse blastocyst-stage embryos and long-term adverse effects on immunity in one-day-old newborn mice of the next generation. Significant apoptosis and decrease in total cell number, predominantly through loss of inner cell mass (ICM), and to a minor extent, trophectoderm (TE) cells, were observed in AOH-treated blastocysts. Moreover, AOH exerted detrimental effects on pre- and post-implantation embryo development potential and induced a decrease in fetal weight in in vitro development and embryo transfer assays. Injection of pregnant mice with AOH (1, 3 and 5 mg/kg body weight/day) for 4 days resulted in apoptosis of blastocyst-stage embryos and injurious effects on embryonic development from the zygote to blastocyst stage or embryo degradation and a further decrease in fetal weight. Furthermore, AOH exerted a long-term impact on the next generation, triggering a significant increase in total oxidative stress content and expression of genes encoding antioxidant proteins. Lower expression of CXCL1, IL-1β and IL-8 related to innate immunity was detected in liver tissue extracts obtained from one-day-old newborns of AOH-injected pregnant mice (5 mg/kg body weight/day) relative to their non-treated counterparts. In addition, ROS served as an upstream regulator of AOH-triggered apoptotic processes and impairment of embryonic development. Our collective results highlight the potential of AOH as an embryotoxic and immunotoxic risk factor during embryo and infant development stages in mice.
Sequencing and Functional Annotation of mRNAs and lncRNAs from Tea (Camellia sinensis) Leaves During Infection by the Fungal Pathogen Lasiodiplodia theobromae
Authors: Li Dongxue , Jiang Silong , Wen Xiaodong , Song Xingchen , Yang Yuanyou , Wang Yu , Huang Honglin , Wang Delu , Chen Zhuo
Published: May 2021

Due to the absence of effective control measures, tea leaf spot, caused by Lasiodiplodia theobromae, can seriously reduce the production and quality of tea leaves. Analysis of the relationship between messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) of tea could help to prevent and control the disease. In this current study, high-performance sequencing of mRNA and lncRNA from tea leaves during infection by L. theobromae was conducted using the Illumina HiSeq 4000 platform. Of the differentially expressed mRNAs, 2,503 or 5,278 were significantly up- or down regulated, respectively, in challenged leaves relative to unchallenged leaves. Differentially expressed lncRNAs were also analyzed at the level of genes for the above two treatments. The numbers of significantly up- or downregulated lncRNAs were 3,403 or 1,477, respectively. Functional analysis of mRNA revealed that L. theobromae challenge can induce the upregulation of the genes of seven transmembrane MLO family protein -3, -6, -11, major allergen Pru ar 1, and so on. In total, 176 differentially expressed lncRNAs occurred in response to L. theobromae challenge as a result of cis regulation, with 146 differentially expressed mRNAs. At the biological process of defense response, the glycosyl hydrolase 9A1 gene was cis regulated by the differentially expressed lncRNA. The expression profiling and association studies of the tea host infected by L. theobromae will provide a resource for future research into host–pathogen interactions and disease resistance.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
A brand new era of cancer immunotherapy: breakthroughs and challenges
Authors: Bai Ri-Lan , Chen Nai-Fei , Li Ling-Yu , Cui Jiu-Wei
Published: May 2021

Immunotherapy has opened a new era in cancer treatment. Drugs represented by immune checkpoint inhibitors have led to important breakthroughs in the treatment of various solid tumors, greatly improving the survival rate of cancer patients. Many types of immunotherapeutic drugs have become widely available; however, their efficacy is variable, and relatively few patients with advanced cancer experience life-altering durable survival, reflecting the complex and highly regulated nature of the immune system. The research field of cancer immunotherapy (CIT) still faces many challenges in pursuing the broader social goal of “curing cancer.” Increasing attention has been paid to strengthening the understanding of the molecular or cellular drivers of resistance to immunotherapy, actively exploring more effective therapeutic targets, and developing combination therapy strategies. Here, we review the key challenges that have emerged in the era of CIT and the possible solutions or development directions to overcome these difficulties, providing relevant references for basic research and the development of modified clinical treatment regimens.
Head-to-head comparison of the test performance of self-administered qualitative vs. laboratory-based quantitative fecal immunochemical tests in detecting colorectal neoplasm
Authors: Lu Ming , Zhang Yu-Han , Lu Bin , Cai Jie , Liu Cheng-Cheng , Chen Hong-Da , Dai Min
Published: May 2021

Background:

Fecal immunochemical tests (FITs) are the most widely used non-invasive tests in colorectal cancer (CRC) screening. However, evidence about the direct comparison of the test performance of the self-administered qualitative a laboratory-based quantitative FITs in a CRC screening setting is sparse.

Methods:

Based on a CRC screening trial (TARGET-C), we included 3144 pre-colonoscopy fecal samples, including 24 CRCs, 230 advanced adenomas, 622 non-advanced adenomas, and 2268 participants without significant findings at colonoscopy. Three self-administered qualitative FITs (Pupu tube) with positivity thresholds of 8.0, 14.4, or 20.8 μg hemoglobin (Hb)/g preset by the manufacturer and one laboratory-based quantitative FIT (OC-Sensor) with a positivity threshold of 20 μg Hb/g recommended by the manufacturer were tested by trained staff in the central laboratory. The diagnostic performance of the FITs for detecting colorectal neoplasms was compared in the different scenarios using the preset and adjusted thresholds (for the quantitative FIT).

Results:

At the thresholds preset by the manufacturers, apart from the qualitative FIT-3, significantly higher sensitivities for detecting advanced adenoma were observed for the qualitative FIT-1 (33.9% [95% CI: 28.7–39.4%]) and qualitative FIT-2 (22.2% [95% CI: 17.7–27.2%]) compared to the quantitative FIT (11.7% [95% CI: 8.4–15.8%]), while at a cost of significantly lower specificities. However, such difference was not observed for detecting CRC. For scenarios of adjusting the positivity thresholds of the quantitative FIT to yield comparable specificity or comparable positivity rate to the three qualitative FITs accordingly, there were no significant differences in terms of sensitivity, specificity, positive/negative predictive values and positive/negative likelihood ratios for detecting CRC or advanced adenoma between the two types of FITs, which was further evidenced in ROC analysis.

Conclusions:

Although the self-administered qualitative and the laboratory-based quantitative FITs had varied test performance at the positivity thresholds preset by the manufacturer, such heterogeneity could be overcome by adjusting thresholds to yield comparable specificities or positivity rates. Future CRC screening programs should select appropriate types of FITs and define the thresholds based on the targeted specificities and manageable positivity rates.
The role of regional chemotherapy for advanced limb melanoma in the era of potentially effective systemic therapies
Authors: Read Rebecca L. , Thompson John F.
Published: May 2021

To review the current role of regional chemotherapy in the management of advanced limb melanoma. Articles reporting the results of isolated limb infusion (ILI) were identified by performing a comprehensive literature search using the PubMed database. Keywords included isolated limb infusion, in-transit melanoma and melphalan. No publication date restrictions were applied. ILI data were compared with those from current systemic therapy clinical trials and the previously reviewed isolated limb perfusion (ILP) literature. Regional chemotherapy is today required in fewer patients because effective systemic therapies now provide an alternative treatment for those who develop extensive local melanoma recurrence or in-transit metastases (ITMs). However, regional chemotherapy may be a valuable treatment option when the side-effects of systemic therapies are of concern, or after systemic treatment failure. ILP achieves overall response rates (ORRs) of 64–100% and complete response rates (CRRs) of 25–89%. ILI achieves ORRs of 41–91% and CRRs of 6–39%. ILP and ILI can have a low risk of serious morbidity. Early results from treatment with ILP or ILI in conjunction with systemic immune therapies suggest that these modalities can be safely combined, which may be useful in patients with refractory limb disease. Regional chemotherapy remains important in the armamentarium of clinicians managing patients with unresectable limb melanoma and may be preferable in those who are frail, elderly or who are at high risk from complications of systemic therapies. The efficacy of combining regional chemotherapy with systemic immune therapy is currently being assessed.
Nivolumab for metastatic uveal melanoma: a multicenter, retrospective study
Authors: Tacar Seher Yildiz , Selcukbiricik Fatih , Yilmaz Mesut , Erturk Kayhan , Murat Sarici Ahmet , Gulturk Ilkay , Ayhan Murat , Tural Deniz
Published: May 2021

Systemic treatment options with proven efficacy for the treatment of metastatic uveal melanoma are limited. In this study, we aimed to evaluate the efficacy of nivolumab in metastatic uveal melanoma patients. In our multi-center study, the files of patients who received nivolumab treatment with a diagnosis of metastatic uveal melanoma were retrospectively reviewed and their information was recorded. Seventeen patients were enrolledand 16 patients were evaluable for efficacy. The objective response rate (ORR) was 18% including one confirmed complete response and two confirmed partial responses. The median progression-free survival (PFS) was 5.8 months (95% CI, 0.03–11.57 months), and the median overall survival (OS) was 10.5 months (95% CI, 3.87–14.14 months). Significant longer OS and PFS were observed in patients with the performance status of the Eastern Cooperative Oncology Group (ECOG-PS) 0. Although significant longer OS was detected in patients with low median lactate dehydrogenase (LDH) levels, no significant difference was found in PFS. Grade 1 and 2 fatigue and decreased appetite were the most common side effects associated with treatment (17%); grade 3 and 4 side effects were not observed. Immunotherapy is also emerging as a treatment option among the limited number of treatment options in metastatic uveal melanoma (mUM), but its efficacy needs to be demonstrated with prospective studies involving a larger number of patients.
“Go”, “No Go,” or “Where to Go”; does microbiota dictate T cell exhaustion, programming, and HIV persistence?
Authors: Shukla Sudhanshu , Kumari Sangeeta , Bal Saswat K. , Monaco Daniela C. , Ribeiro Susan Pereira , Sekaly Rafick-Pierre , Sharma Ashish Arunkumar
Published: May 2021

Purpose of review

People living with HIV who fail to fully reconstitute CD4+T cells after combination antiretroviral therapy therapy (i.e. immune nonresponders or INRs) have higher frequencies of exhausted T cells are enriched in a small pool of memory T cells where HIV persists and have an abundance of plasma metabolites of bacterial and host origins. Here, we review the current understanding of critical features of T cell exhaustion associated with HIV persistence; we propose to develop novel strategies to reinvigorate the effector function of exhausted T cells with the aim of purging the HIV reservoir.

Recent findings

We and others have recently reported the role of microbiota and metabolites in regulating T cell homeostasis, effector function, and senescence. We have observed that bacteria of the Firmicute phyla (specifically members of the genus Lactobacilli), associated metabolites (β-hydroxybutyrate family), and bile acids can promote regulatory T cell differentiation in INRs with a senescent peripheral blood gene expression profile.

The cross-talk between immune cells and gut microbes at the intestinal mucosa (a major effector site of the mucosal immune response), regulates the priming, proliferation, and differentiation of local and distant immune responses. This cross-talk via the production of major metabolite families (like serum amyloid A, polysaccharide A, and aryl hydrocarbon receptor ligands) plays a key role in maintaining immune homeostasis. HIV infection/persistence leads to gut dysbiosis/microbial translocation, resulting in the local and systemic dissemination of microbes. The ensuing increase in immune cell-microbiome (including pathogens) interaction promotes heightened inflammatory responses and is implicated in regulating innate/adaptive immune effector differentiation cascades that drive HIV persistence. The exact role of the microbiota and associated metabolites in regulating T cell- mediated effector functions that can restrict HIV persistence continue to be the subject of on-going studies and are reviewed here.
Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies for Hematological Cancers: Present and Future
Authors: Heine Renaud , Thielen Frederick W. , Koopmanschap Marc , Kersten Marie José , Einsele Hermann , Jaeger Ulrich , Sonneveld Pieter , Sierra Jorge , Smand Carin , Uyl-de Groot Carin A.
Published: May 2021

Since 2018, 2 chimeric antigen receptor (CAR) T-cell therapies received approval from the European Medicine Agency, with list prices around 320 000 Euro (€) (EUR) per treatment. These high prices raise concerns for patient access and the sustainability of healthcare systems. We aimed to estimate the costs and budget impact associated with CAR T-cell therapies for current and future indications in hematological cancers from 2019 to 2029. We focused on the former France, Germany, Spain, Italy and the United Kingdom (EU-5) and the Netherlands. We conducted a review of list prices, health technology assessment reports, budget impact analysis dossiers, and published cost-effectiveness analyses. We forecasted the 10-year health expenditures on CAR T-cells for several hematological cancers in selected European Union countries. Nine cost-effectiveness studies were identified and list prices for CAR T-cell therapies ranged between 307 200 EUR and 350 000 EUR. Estimated additional costs for pre- and post-treatment were 50 359 EUR per patient, whereas the incremental costs of CAR T-cell therapy (when compared with care as usual) ranged between 276 086 EUR and 328 727 EUR. We estimated market entry of CAR T-cell therapies for chronic mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia in 2021, 2022, 2022, 2022, and 2025, respectively. Cumulative expenditure estimates for existing and future indications from 2019 to 2029 were on average 28.5 billion EUR, 32.8 billion EUR, and 28.9 billion EUR when considering CAR T-cell therapy costs only, CAR T-cell therapy costs including pre- and post-treatment, and incremental CAR T-cell therapy costs, respectively. CAR T-cell therapies seem to be promising treatment options for hematological cancers but the financial burden on healthcare systems in the former EU-5 and the Netherlands will contribute to a substantial rise in healthcare expenditure in the field of hematology.
Cleaning Neonatal Units in Low-resource Settings: A Hot-topic in Waiting?
Authors: Graham Wendy J. , Okomo Uduak , Gon Giorgia , Aiken Alexander M.
Published: May 2021

Globally, about 3-quarters of births now occur in healthcare facilities, with the proportion being 50% for sub-Saharan Africa, where healthcare-associated infections among newborns are typically 3–20 times higher than in facilities in high-income countries. As this upward trend in institutional deliveries continues, the demand for specialized neonatal care also rises, with dedicated units often only available in tertiary referral hospitals in the case of low- and middle-income countries. Preventing nosocomial infections among vulnerable newborns requires effective and feasible control strategies and interventions. The role of cleaning and cleaners in reducing risks and maintaining a clean safe environment has until very recently been neglected at policy, program, practice, and research levels. There is now an opportunity to reposition cleaning within global and national initiatives related to Water, Sanitation and Hygiene, Infection Prevention and Control, and Antimicrobial Resistance. The evidence base should also be strengthened on cost-effective bundles of cleaning interventions, particularly in the context of low-resource settings. Here increasing overcrowding and shortages of staff and supplies present major threats to neonatal survival and well-being and heighten the case for optimizing the use of low-cost, back-to-basics interventions like cleaning.
Guided Self-rehabilitation Contracts Combined With AbobotulinumtoxinA in Adults With Spastic Paresis
Authors: Gracies Jean-Michel , Francisco Gerard E. , Jech Robert , Khatkova Svetlana , Rios Carl D. , Maisonobe Pascal
Published: May 2021

Background and Purpose:

Guided self-rehabilitation contracts (GSCs) are a diary-based rehabilitation strategy, wherein specific muscles are identified for prescription of high-load, home self-stretching techniques. We assessed the effect of GSCs combined with simultaneous upper limb (UL) and lower limb (LL) abobotulinumtoxinA injections on composite active range of motion (CXA) in adults with chronic spastic paresis.

Methods:

This was an international, prospective, single-arm, open-label study (ENGAGE, NCT02969356). Personalized GSCs were monitored by phone every other week, alongside 2 consecutive abobotulinumtoxinA injections (1500 U) across UL and LL, over 6 to 9 months. Primary outcomes were responder rates (CXA improvement ≥35° [UL] or ≥5° [LL]) at week 6 cycle 2. Secondary outcomes were active function (UL: Modified Frenchay Scale [MFS]; LL: 10-m barefoot maximal walking speed [WS]) and quality of life (12-item Short Form Health Survey, SF-12).

Results:

Of the 153 treated participants, 136 had primary endpoint data; 72.1% (95% confidence interval [CI], 64.0-78.9) were responders. Mean (SD) CXA changes from baseline to last study visit were +49.3° (63.4) for UL and +20.1° (27.6) for LL. Mean (95% CI) changes from baseline to week 12 cycle 2 were +0.55 (0.43-0.66) in MFS, +0.12 m/s (0.09-0.15) for WS, and +4.0 (2.8-5.2) for SF-12 physical scores. In the safety population (n = 157), 49.7% of participants reported treatment-emergent adverse events (AEs); 12.1% reported 25 serious AEs.

Discussion and Conclusions:

GSC combined with simultaneous UL and LL abobotulinumtoxinA injections led to improvements in CXA and function in both limbs, and quality-of-life physical scores. These results suggest the beneficial effect of combined GSC and abobotulinumtoxinA therapy in the management of spastic paresis.

Video Abstract available for more insight from the authors (see the Supplementary Video, available at: http://links.lww.com/JNPT/A346).
Systematic Review of Self-Management Assessment Tools for Children With Inflammatory Bowel Disease
Authors: Vernon-Roberts Angharad , Rouse Emma , Gearry Richard B. , Day Andrew S.
Published: May 2021

The relapsing pattern of illness and diverse management strategies for children with inflammatory bowel disease (IBD) may inhibit their opportunities to develop self-management skills. Interventions focused on the development of these skills require population-specific outcome measures. We provide a comprehensive overview of self-management skills assessment tools that are available for children with IBD that target processes and behaviors outlined as beneficial for the development of these skills. Seven health literature databases were searched using terms related to self-management, transition, IBD, Crohn’s disease, ulcerative colitis, and children. Identified studies underwent a process of title and then full text review. Included studies underwent data extraction using a priori quality assessment criteria related to self-management skills, health literacy, suitability for the target population, validity and reliability testing. The searches identified 523 papers, 123 of which underwent full-text review and 10 included in the final analysis. The assessment tools identified showed great diversity in their development approach, content, methodological rigor, and health literacy considerations. The most frequently included self-management skills were related to adherence, communication, attending clinic, and disease/treatment knowledge. None of the tools satisfied the criteria of selection for use in the target population. While many chronic diseases of childhood follow a predictable disease course with established treatment pathways, IBD presents a unique set of challenges. The development of self-management skills is vital for successful disease management, but these skills should be assessed by a tool appropriate for the population and their diverse needs.
Predisposition of COVID-19 patients to secondary infections: set in stone or subject to change?
Authors: Sopirala Madhuri M.
Published: May 2021

Purpose of review

There likely are several predisposing factors to secondary infections in patients with Coronavirus disease 2019 (COVID-19), some of which may be preventable. The aim of this review is to explore the literature, summarize potential predisposing factors to secondary infections and their incidence. It also summarizes a variety of healthcare scenarios in which different kinds of secondary infections occur.

Recent findings

Apart from immune dysregulation, severe resource limitations in healthcare settings have made COVID-19 units conducive to a variety of secondary infections. Long-term effect of excess antibiotic use in COVID-19 patients is yet to be studied. Very few studies have assessed secondary infections as the primary outcome measure making it difficult to know the true incidence. Mortality attributable to secondary infections in COVID-19 patients is also unclear.

Incidence of secondary infections in COVID-19 patients is likely higher than what is reported in the literature. Well designed studies are needed to understand the incidence and impact of secondary infections in this patient population. Many of these may be preventable especially now, as personal protective equipment and other healthcare resources are recovering. Infection prevention and control (IPC) and antimicrobial stewardship programmes (ASP) must reassess current situation to correct any breaches that could potentially cause more harm in these already vulnerable patients as we brace for a future surge with another pandemic wave.
Risk Factors for Intraoperative Seizures in Glioma Surgery: Electrocorticography Matters
Authors: Lettieri Christian , Ius Tamara , Verriello Lorenzo , Budai Riccardo , Isola Miriam , Valente Mariarosaria , Skrap Miran , Gigli Gian Luigi , Pauletto Giada
Published: May 2021

Purpose:

Few and contradictory data are available regarding intraoperative seizures during surgery for low-grade gliomas. Aim of this study was to evaluate possible risk factors for the occurrence of IOS.

Methods:

The authors performed a retrospective analysis of 155 patients affected by low-grade gliomas and tumor-related epilepsy, who underwent surgery in our Department, between 2007 and 2018. A statistical analysis was performed by means of univariate and multivariate regression to evaluate any possible correlation between seizure occurrence and several demographic, clinical, neurophysiological, and histopathological features.

Results:

Intraoperative seizure occurred in 39 patients (25.16%) with a total of 62 seizure events recorded. Focal seizures were the prevalent seizure type: among them, 39 seizures did not show motor signs, being those with only electrographic and/or with cognitive features the most represented subtypes. Twenty-six seizures occurring during surgery were not spontaneous: direct cortical stimulation with Penfield paradigm was the most prevalent evoking factor. The univariate analysis showed that the following prognostic factors were statistically associated with the occurrence of intraoperative seizure: the awake technique (P = 0.01) and the interictal epileptiform discharges detected on the baseline electrocorticography (ECoG) (P < 0.001). After controlling for confounding factors with multivariate analysis, the awake surgery and the epileptic ECoG pattern kept statistical significance.

Conclusions:

The awake surgery procedure and the epileptic ECoG pattern are risk factors for intraoperative seizure. ECoG is mandatory to detect electrographic seizures or seizures without motor signs.
Experimental investigation to verify if excessive plastic sheeting shielding produce micro clusters of SARS-CoV-2
Authors: Ishigaki Yo , Kawauchi Yuto , Yokogawa Shinji , Saito Akira , Kitamura Hiroko , Moritake Takashi
Published: May 2021

We experimentally investigated indoor air ventilation using the CO2 tracer technique to verify the infection cluster of SARS-CoV-2 that erupted at an office space. Multi-placed observations revealed extremely low air change rates (0.1/h) at the site. The local infection clusters were observed several meters away from a door that is the only ventilation in the office, which suggests a negative effect of plastic sheeting shielding. The thermo-fluid simulation showed that the plastic sheet blocked the airflow and trapped the exhaled air in each partition cell. As risk suppression methods, improving air ventilation by opening windows and using fans were verified, and significant improvements (10–28/h) were observed for each partition cells.
Feasibility of an Innovative Absorbable Ventilation Tube Designed to Provide Intermediate-Term Middle Ear Ventilation
Authors: Skovlund Sandra , Cofer Shelagh , Weinreich Heather
Published: May 2021

Myringotomy with ventilation tube placement is a common surgical procedure performed in children and adults to remove fluid build-up behind the tympanic membrane. However, retention of tubes beyond achievement of therapeutic response increases risk for complications and additional intervention. This small feasibility study was conducted to demonstrate proof-of-concept of a novel bioabsorbable ventilation tube that provides the necessary duration of ventilation with absorption shortly thereafter in humans. Tubes were placed in 15 ears of 14 patients meeting indications for short or intermediate-duration of middle ear ventilation. Two independent examiners documented tube patency and tube absorption status at 3, 6 and 12 weeks or until absorption was complete. Results indicate that average ventilation time was 12 weeks (range 3 weeks to 18 months). There was no observation of blockage. These findings support the feasibility of a novel bioabsorbable ventilation tube.
Antigen-experienced CXCR5-CD19lowB cells are plasmablast precursors expanded in SLE
Authors: Szelinski Franziska , Stefanski Ana Luisa , Wiedemann Annika , Schrezenmeier Eva , Rincon-Arevalo Hector , Reiter Karin , Lettau Marie , Dang Van Duc , Fuchs Sebastian , Frei Andreas P. , Alexander Tobias , Lino Andreia C. , Dörner Thomas
Published: May 2021

B cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). We analysed two independent cohorts of healthy donors and SLE patients using a combined approach of flow and mass cytometry. We have found that IgD-CD27+switched and atypical IgD-CD27-memory B cells, which are increased in SLE, represent heterogeneous populations composed each of three different subsets, such as CXCR5+CD19int, CXCR5-CD19highand CXCR5-CD19low. Here, we characterize a hitherto unknown antigen-experienced CXCR5-CD19lowB cell subsets enhanced in SLE and carrying a plasmablast (PB) phenotype enriched for switched immunoglobulins, and expressing CD38, CD95, CD71,PRDM1, XBP-1, andIRF4. CXCR5-CD19lowresemble activated B cells with a characteristically diminished B cell receptor responsiveness. CXCR5-CD19lowB cells increased with PB frequencies in SLE and upon BNT162b2 vaccination suggesting their interrelationship. Our data suggest that CXCR5-CD19lowB cells are precursors of plasmablasts, thus co-targeting this subset may have therapeutic value in SLE.
Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries
Authors: Qu Hui-Qi , Snyder James , Connolly John , Glessner Joseph , Kao Charlly , Sleiman Patrick , Hakonarson Hakon
Published: May 2021

The novel therapeutic target cytokine LIGHT (TNFSF14) was recently shown to play a major role in COVID19-induced acute respiratory distress syndrome (ARDS). This study aims to investigate the associations of plasma LIGHT and another potentially targetable cytokine, Interleukin-18 (IL-18), with ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), caused by non-COVID19 viral or bacterial sepsis. A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this cohort study. Day 0 plasma LIGHT and IL-18, as well as 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured by sensitive bead immunoassay and associated with symptom severity. We observed significantly increased LIGHT level in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level was associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis. There was no correlation between LIGHT and IL-18. For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. The association of plasma LIGHT with AHRF suggests that targeting the pathway warrants exploration, and ongoing trials may soon elucidate whether this is beneficial. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway requires a precision application.
Effective interferon (IFN)-λ treatment regimen to control lethal MERS-CoV infection in mice
Authors: Dijkman Ronald , Selvaraj Muneeswaran , Gad Hans Hendrik , Hartmann Rune , More Sunil , Perlman Stanley , Thiel Volker , Channappanavar Rudragouda
Published: May 2021

Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made towards identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and interferon-stimulated gene (ISG) response is another antiviral strategy known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the pro-inflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, is shown to be less pro-inflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-α) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to IFN-a treated cells. Similarly, mice treated with two dose IFN-λ were better protected compared to mice receiving a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from lethal MERS-CoV-infection. A two dose IFN-λ regimen significantly reduced lung viral RNA and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identify an ideal regimen for IFN-λ use and demonstrate the protective efficacy of IFN-λ in MERS-CoV infected mice.
The P5-ATPase ATP13A1 modulates MR1-mediated antigen presentation
Authors: Kulicke Corinna A. , Zan Erica De , Hein Zeynep , Gonzalez-Lopez Claudia , Ghanwat Swapnil , Veerapen Natacha , Besra Gurdyal S. , Klenerman Paul , Christianson John C. , Springer Sebastian , Nijman Sebastian , Cerundolo Vincenzo , Salio Mariolina
Published: May 2021

The monomorphic antigen presenting molecule MHC-I-related protein 1 (MR1) presents small molecule metabolites to mucosal-associated invariant T (MAIT) cells. The MR1-MAIT cell axis has been implicated in a variety of infectious and non-communicable diseases and recent studies have begun to develop an understanding of the molecular mechanisms underlying this specialised antigen presentation pathway. Yet, the proteins regulating MR1 folding, loading, stability, and surface expression remain to be identified. Here, we performed a gene trap screen to discover novel modulators of MR1 surface expression through insertional mutagenesis of an MR1-overexpressing clone derived from the near-haploid human cell line HAP1 (HAP1.MR1). The most significant positive regulators identified included β2-microglobulin, a known regulator of MR1 surface expression, and ATP13A1, a P5-ATPase in the endoplasmic reticulum (ER) with putative transporter function not previously associated with MR1-mediated antigen presentation. CRISPR/Cas9-mediated knock-out of ATP13A1 in both HAP1.MR1 and THP-1 cell lines revealed a profound reduction in MR1 protein levels and a concomitant functional defect specific to MR1-mediated antigen presentation. Collectively, these data are consistent with the ER-resident ATP13A1 as a key post-transcriptional determinant of MR1 surface expression.
APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice
Authors: Bonnar Orla , Shaw Kira , Grijseels Dori M. , Clarke Devin , Bell Laura , Anderle Silvia , King Sarah L. , Hall Catherine N.
Published: May 2021

Young mice possessing the e4 allele of the Apolipoprotein (APOE) gene (a risk factor for Alzheimer’s disease (AD)) have previously been shown to have dramatic decreases in vascular function, suggesting APOE4 may confer its risk via the vasculature. However, in human carriers, vascular and cognitive function decrease later in life. Mouse data may be confounded by an increased impact of anaesthesia and surgery in APOE4 animals, and has also focused on sensory cortices, ignoring medial lobe structures more sensitive to AD.

To clarify how APOE4 expression alters neurovascular function, we studied the visual cortex and hippocampus of awake APOE3 and APOE4 targeted replacement mice, using 2-photon microscopy of neurons and blood vessels.

We found milder vascular deficits than studies using anaesthetised preparations: functional hyperaemia was unaffected in APOE4 mice and neuronal or vascular function did not decrease with age. Instead, vascular responsiveness was lower at all ages, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, independently, APOE4 expression is not catastrophic but alters neurovascular physiology towards a state more sensitive to insults such as surgery or beta amyloid accumulation. Understanding how APOE4 expression interacts with these insults will be critical for understanding the emergence of AD in APOE4 carriers.
How many replicates to accurately estimate fish biodiversity using environmental DNA on coral reefs?
Authors: Stauffer Salomé , Jucker Meret , Keggin Thomas , Marques Virginie , Andrello Marco , Bessudo Sandra , Cheutin Marie-Charlotte , Borrero-Pérez Giomar Helena , Richards Eilísh , Dejean Tony , Hocdé Régis , Juhel Jean-Baptiste , Ladino Felipe , Letessier Tom B. , Loiseau Nicolas , Maire Eva , Mouillot David , Martinezguerra Maria Mutis , Manel Stéphanie , Fernández Andrea Polanco , Valentini Alice , Velez Laure , Albouy Camille , Pellissier Loïc , Waldock Conor
Published: May 2021

Quantifying the diversity of species in rich tropical marine environments remains challenging. Environmental DNA (eDNA) metabarcoding is a promising tool to face this challenge through the filtering, amplification, and sequencing of DNA traces from water samples. However, the reliability of biodiversity detection from eDNA samples can be low in marine environments because eDNA density is low and certainly patchy in this vast, heterogenous and dynamic environment. So, the number of sampling replicates and filtered volume necessary to obtain accurate estimates of biodiversity in rich tropical marine environments using eDNA metabarcoding is still unknown. Here, we used a paired sampling design of 30L per replicate on 68 reef transects from 8 sites in three tropical regions and identified fish Molecular Taxonomic Units (MOTUs) using a 12S marker. We quantified local biodiversity variation as MOTU richness, compositional turnover and compositional nestedness between replicated pairs of seawater samples. We report strong turnover of MOTUs between replicated pairs of samples undertaken in the same location, time, and conditions. Paired samples contained non-overlapping assemblages rather than subsets of one-another. As a result, localised diversity accumulation curves showed that even 6 replicates (180L) in the same location underestimated local diversity (for an area <1km). However, sampling of regional diversity using ∼25 replicates in variable locations (often covering 10s of km) achieved saturation of biodiversity accumulation curves. Our results demonstrate high variability of diversity estimates perhaps arising from heterogeneous and local distribution of eDNA distribution in seawater or highly skewed frequencies of eDNA traces. This high compositional variability has consequences for using eDNA to monitor temporal and spatial biodiversity changes of local assemblages. Future biomonitoring efforts could be strongly undermined by a high level of false-negative detections under low replication protocols. We reveal the need to increase replicates or increase sampled water volume to better inform management of marine biodiversity using eDNA.
Decomposing age effects in EEG alpha power
Authors: Tröndle Marius , Popov Tzvetan , Pedroni Andreas , Pfeiffer Christian , Barańczuk-Turska Zofia , Langer Nicolas
Published: May 2021

Increasing life expectancy is prompting the need to understand how the brain changes during healthy aging. Research utilizing Electroencephalography (EEG) has found that the power of alpha oscillations decrease from adulthood on. However, non-oscillatory (aperiodic) components in the data may confound results and thus require re-investigation of these findings. The present report aims at analyzing a pilot and two additional independent samples (total N = 533) of resting-state EEG from healthy young and elderly individuals. A newly developed algorithm will be utilized that allows the decomposition of the measured signal into aperiodic and aperiodic-adjusted signal components. By using multivariate sequential Bayesian updating of the age effect in each signal component, evidence across the datasets will be accumulated. It is hypothesized that previously reported age-related alpha power differences will disappear when absolute power is adjusted for the aperiodic signal component. Consequently, age-related differences in the intercept and slope of the aperiodic signal component are expected. Importantly, using a battery of neuropsychological tests, we will assess how the previously reported relationship between cognitive functions and alpha oscillations changes when taking the aperiodic signal into account; this will be done on data of the young and aged individuals separately. The aperiodic signal components and adjusted alpha parameters could potentially offer a promising biomarker for cognitive decline, thus finally the test–retest reliability of the aperiodic and aperiodic-adjusted signal components will be assessed.
A robust method for performing 1H-NMR lipidomics in embryonic zebrafish
Authors: Morgan Rhiannon S. , Walmsley Gemma , Peffers Mandy J. , Barrett-Jolley Richard , Phelan Marie M.
Published: May 2021

The embryonic zebrafish is an ideal system for lipid analyses with relevance to many areas of bioscience research, including biomarkers and therapeutics. Research in this area has been hampered by difficulties in extracting, identifying and quantifying lipids. We employed 1H-NMR at 700MHz to profile lipids in developing zebrafish embryos. The optimal method for lipidomics in embryonic zebrafish incorporated rapid lipid extraction using chloroform and an environment without oxygen depletion. Pools of 10 embryos gave the most acceptable signal-to-noise ratio, and the inclusion of chorions in the sample had no significant effect on lipid abundances. Embryos, bisected into cranial (head and yolk sac) and caudal (tail) regions, were compared by principal component analysis and analysis of variance. The lipid spectra (including lipid annotation) are available in the public repository MetaboLights (MTBLS2396).
Structural basis for the inhibition of the Bacillus subtilis c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM
Authors: Pathania Monisha , Tosi Tommaso , Millership Charlotte , Hoshiga Fumiya , Morgan Rhodri M. L. , Freemont Paul S. , Gründling Angelika
Published: May 2021

Cyclic-di-adenosine monophosphate (c-di-AMP) is an important nucleotide signalling molecule, which plays a key role in osmotic regulation in bacteria. Cellular c-di-AMP levels are tightly regulated, as both high and low levels have a negative impact on bacterial growth. Here, we investigated how the activity of the main Bacillus subtilis c-di-AMP cyclase CdaA is regulated by the phosphoglucomutase GlmM. c-di-AMP is produced from two molecules of ATP by proteins containing a deadenylate cyclase (DAC) domain. CdaA is a membrane-linked cyclase with an N-terminal transmembrane domain followed by the cytoplasmic DAC domain. Here we show, using the soluble catalytic B. subtilis CdaACD domain and purified full-length GlmM or the GlmMF369 variant lacking the C-terminal flexible domain 4, that the cyclase and phosphoglucomutase form a stable complex in vitro and that GlmM is a potent cyclase inhibitor. We determined the crystal structure of the individual B. subtilis CdaACD and GlmM proteins, both of which form dimers in the structures, and of the CdaACD:GlmMF369 complex. In the complex structure, a CdaACD dimer is bound to a GlmMF369 dimer in such a manner that GlmM blocks the oligomerization of CdaACD and formation of active head-to-head cyclase oligomers, thus providing molecular details on how GlmM acts as cyclase inhibitor. The function of a key amino acid residue in CdaACD in complex formation was confirmed by mutagenesis analysis. As the amino acids at the CdaACD:GlmM interphase are conserved, we propose that the observed inhibition mechanism of CdaA by GlmM is conserved among Firmicutes.
TatA and TatB generate a hydrophobic mismatch that is important for function and assembly of the Tat translocon in Escherichia coli
Authors: Mehner-Breitfeld Denise , Ringel Michael T. , Tichy Daniel Alexander , Endter Laura J. , Stroh Kai Steffen , Lünsdorf Heinrich , Risselada Herre Jelger , Brüser Thomas
Published: May 2021

The Tat system has the unique purpose to translocate folded proteins across energy-transducing membranes. It occurs in bacteria and archaea, as well as in eukaryotic organelles of bacterial origin. In the bacterial model system Escherichia coli, the three components TatA, TatB, and TatC assemble to functional translocons. TatA and TatB both possess an N-terminal transmembrane helix (TMH) that is followed by an amphipathic helix (APH). The TMHs of TatA and TatB generate a hydrophobic mismatch with only 12 consecutive hydrophobic residues that span the membrane. We shortened or extended this stretch of hydrophobic residues in either TatA, TatB, or both, and analyzed effects on transport functionality and translocon assembly. The wild type length functioned best but was not an absolute requirement, as some variation was clearly tolerated. Defects of shortenings or extensions were enhanced by simultaneous mutations in TatA and TatB, indicating partial compensations of mutations in TatA by wild type TatB or vice versa. Length variation in TatB destabilized TatBC-containing complexes, revealing that the 12-residues-length is important for Tat component interactions and translocon assembly. To also address potential effects on TatA associations, we characterized these by metal tagging transmission electron microscopy and carried out molecular dynamics simulations. In these simulations, interacting short TMHs of larger TatA assemblies were thinning the membrane together with laterally aligned tilted APHs that generated a deep V-shaped groove. The conserved length of 12 hydrophobic residues may thus not only be important for translocon interactions, but also for a membrane destabilization during Tat transport. If this is the case, the specific short length could be a compromise between functionality and proton leakage minimization.