bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining the Risk of Developing Rheumatic Heart Disease Following a Negative Screening Echocardiogram
Authors: Zimmerman Meghan , Scheel Amy , DeWyer Alyssa , Nambogo Jane-Liz , Otim Isaac Omara , Tompsett Alison , Rwebembera Joselyn , Okello Emmy , Sable Craig , Beaton Andrea
Published: February 2021

Background: Screening echocardiograms can detect early-stage rheumatic heart disease (RHD), offering a chance to limit progression. Implementation of screening programs is challenging and requires further research. This is the first large-scale study assessing the risk of RHD among previous screen-negative children.

Methods: This retrospective cohort study, conducted in Gulu, Uganda, performed school-based echo screening on children ages 5–18 years. Surveys were used to determine which children underwent initial screening 3–5 years prior. Age, gender, and disease severity were compared between cohorts. Relative risk (RR) of RHD was calculated for those with a prior screen-negative echo (exposed cohort) compared to those undergoing first screening (unexposed cohort).

Results: Echo screening was completed in 75,708 children; 226 were excluded, leaving 1,582 in the exposed cohort and 73,900 in the unexposed cohort. Prevalence of new RHD was 0.6% (10/1,582) and 1% (737/73,900), in the exposed and unexposed cohorts, respectively. The RR of RHD was 0.64 (95% CI 0.3–1.2, p = 0.15), a nearly 40% reduced risk of RHD in those with a prior negative echo. There was no difference in age or gender between RHD cohorts. All cases in the exposed cohort were borderline/mild; 2.6% of cases in the unexposed cohort had moderate/severe disease.

Conclusion: There was no statistical difference in RHD prevalence between previous screen-negative children and children with no prior echocardiogram, however, there was a trend toward decreased risk and severity. This information has important implications for the design of screening programs and the use of screening echocardiograms in endemic RHD regions.
Stratigraphic Architecture of the Karoo River Channels at the End-Capitanian
Authors: Bordy Emese M. , Paiva Francisco
Published: February 2021

The main Karoo Basin of southern Africa contains the continental record of the end-Triassic, end-Permian, and end-Capitanian mass extinction events. Of these, the environmental drivers of the end-Capitanian are least known. Integrating quantitative stratigraphic architecture analysis from abundant outcrop profiles, paleocurrent measurements, and petrography, this study investigates the stratigraphic interval that records the end-Capitanian extinction event in the southwestern and southern main Karoo Basin and demonstrates that this biotic change coincided with a subtle variation in the stratigraphic architectural style ∼260 Ma ago. Our multi-proxy sedimentological work not only defines the depositional setting of the succession as a megafan system that drained the foothills of the Cape Fold Belt, but also attempts to differentiate the tectonic and climatic controls on the fluvial architecture of this paleontologically important Permian succession. Our results reveal limited changes in sediment sources, paleocurrents, sandstone body geometries, and possibly a constant hot, semi-arid paleoclimate during the deposition of the studied interval; however, the stratigraphic trends show upward increase in 1) laterally accreted, sandy architectural elements and 2) architectural elements that build a portion of the floodplain deposits. We consider this to reflect a long-term retrogradational stacking pattern of facies composition that can be linked to changes on the medial parts of southward draining megafans, where channel sinuosity increased, and depositional energy decreased at the end-Capitanian. The shift in the fluvial architecture was likely triggered by basin-wide allogenic controls rather than local autogenic processes because this trend is observed in the coeval stratigraphic intervals from geographically disparate areas in the southwestern and southern main Karoo Basin. Consequently, we propose that this regional backstepping most likely resulted from tectonic events in the adjacent Cape Fold Belt.
Strong-Motions From Damaging Moderate Magnitude (5.9 ≥ Mw) Earthquakes in Japan Recorded by K-NET and KiK-net
Authors: Dhakal Yadab P.
Published: February 2021

Strong-motions from 79 moderate magnitude (5.9 ≥ Mw) earthquakes that caused various degrees of impact on humans and built-environment in Japan between 1996 and 2019, after the start of K-NET and KiK-net, are presented. As such, most of the earthquakes occurred beneath the land, and agencies had reported damages from events as small as Mw 4.1. Together, large peak ground accelerations exceeding 500 cm/s2were recorded during 15 earthquakes, reaching approximately 1128 cm/s2during one event. Similarly, large peak ground velocities exceeding 30 cm/s were recorded during ten earthquakes, reaching about 76 cm/s to the maximum. Most of the large values aforementioned were recorded within a hypocentral distance of approximately 30 km and on soil site conditions. Intermediate to long-period ground motions are of growing concerns in urban areas located on sedimentary basins with mid-rise and high-rise buildings. The threshold magnitude for the large ground motions at the periods of about 2–5 s is not well understood. In March 2013, the Japan Meteorological Agency introduced four levels of long-period ground motion intensity (LPGMI) based on absolute velocity response spectra (AVRS) between 1.6 and 7.8 s. In the present data set, LPGMI of level 3 (AVRS 50–100 cm/s) and level 4 (AVRS >100 cm/s) were observed each at a single site from shallow-focus earthquakes of Mw 5.8 and 5.9 at distances of approximately 12 and 15 km, respectively. However, the peak response periods were relatively short (1.6–1.8 s). The data showed that LPGM from moderate earthquakes is of lower concern regarding earthquake early warning at distances beyond 200 km. The 2018 Mw 5.5 North Osaka earthquake, despite the moderate magnitude, caused the loss of six human lives and brought significant damage to buildings and lifelines. Comparing the data with the ground motion prediction equations (GMPEs) and other events suggested that the North Osaka earthquake was probably a higher stress drop event. These moderate earthquakes’ observations hinted that the commonly used GMPEs in Japan may not sufficiently grasp these earthquakes' hazards.
Keep Calm in Heated Debates: How People Perceive Different Styles of Discourse in a Scientific Debate
Authors: Tkotz Juliane , Kienhues Dorothe , Jucks Regina , Bromme Rainer
Published: February 2021

Scientific debates are, in an epistemological sense, argumentative approaches aimed at coming to the most appropriate conclusion. However, as these debates sometimes involve interpersonal rather than content-driven attacks (e.g., an argument between scientific experts might involve personal dislike), the following question arises: How do such communication behaviors affect people’s perception of the argument? In an empirical study, we presented prospective teachers (N = 222) with a newspaper article about two scientific experts controversially discussing the pros and cons of a fictional vocabulary training program. Using a 1 × 2 between-subject design, the article contained either a neutral or an incivil discourse style. The dependent measures evaluated how participants perceived the experts’ trustworthiness and how they viewed the practical relevance of the scientific topic at hand. Results revealed that participants who read the neutral-style discourse perceived the two experts as having more expertise, higher integrity, and higher benevolence than participants who read the incivil-style discourse. However, the groups did not differ in their ratings of how beneficial the scientific findings might be in the classroom. Overall, this study shows that discourse style indeed influences the perceived trustworthiness of experts, in that it might be damaged in heated debates. The study therefore suggests that the scientific community’s methodological and social conventions should be addressed in higher education, in this case teacher education, as understanding these conventions is important for substantially evaluating heated scientific debates.
Leadership in the Time of COVID: Connecting Community Resources to Meet the Needs of North Carolina Students
Authors: Price Douglas C. , Mansfield Katherine Cumings
Published: February 2021

The purpose of this brief research report is to share what we learned conducting an exploratory pilot study on how school leaders in North Carolina responded to changes wrought by the onset of the novel Coronavirus in early 2020. In many ways, North Carolina is a distinctive case because it exists in what is commonly referred to as the Urban/Rural Divide; but, it is also similar to other cases in that educators must be adaptable and flexible in a situation that is constantly in flux. Some early findings confirmed our hunches about how educators were faring in this new world we face. Other discoveries, however, were truly that: discoveries, leading us to two new areas of future research: 1) examining more deeply the weighty connections between past political decisions around public infrastructure (e.g., broadband) and many of the current crizes facing school leaders; and 2) continuing to expand our collection of cases that illustrate ways a broad collection of community stakeholders can emerge as educational leaders.
A Thematic Approach to Realize Multidisciplinary Community Service-Learning Education to Address Complex Societal Problems: A-Win-Win-Win Situation?
Authors: Tijsma Geertje , Urias Eduardo , Zweekhorst Marjolein
Published: February 2021

Universities are under increasing pressure to become more and better involved in society as part of their third mission, to which Community Service learning (CSL) can contribute. To date, most CSL projects are mono-disciplinary, single courses, often of a short-term nature. In order to address the increasingly complex problems facing society, there is a need to adopt multi–and interdisciplinary CSL approaches that allow for a range of perspectives. The article describes and analyzes how a thematic CSL approach was initiated at the VU Amsterdam starting from the needs of a local community. Once loneliness was identified as an important and relevant issue, the approach evolved in order to include multiple courses and internships from different programs offered by two faculties and various stakeholders and community organizations. Taking an action–research approach, the CSL team evaluated the process of its development, outcomes and contributions, as well as possible benefits and considerations. In addition to more tangible outcomes arising from many student projects, the approach assists in building new community networks, supports project continuity, deepens knowledge, encourages new collaborations, reduces CSL-created workload and finally increases student development, motivation and sense of ownership. Overall, it can be concluded that the thematic approach can contribute to addressing complex problems as it allows for multidisciplinary collaborations while not imposing too great a burden on the established curriculum. This makes the thematic CSL approach a valuable stepping stone in advancing CSL in universities, and so contribute to fulfilling their third mission.
Sodium-Glucose Co-Transporter 2 Inhibitors for Non-Alcoholic Fatty Liver Disease in Asian Patients With Type 2 Diabetes: A Meta-Analysis
Authors: Wong Chloe , Yaow Clyve Yu Leon , Ng Cheng Han , Chin Yip Han , Low Yi Fen , Lim Amanda Yuan Ling , Muthiah Mark Dhinesh , Khoo Chin Meng
Published: February 2021

Objective

Non-alcoholic fatty liver disease (NAFLD) is a very common disorder among patients with type 2 diabetes and may share causal relationship. Type 2 diabetes is a risk factor for progression and potential poor outcomes in NAFLD patients. This meta-analysis aimed to analyze the current evidence of sodium-glucose co-transporter-2 inhibitors (SGLT2i), a glucose-lowering drug to improve NAFLD in patients with Type 2 Diabetes.

Methods

Medline, Embase and Cochrane Central Register of Controlled Trials were searched for articles examining efficacy of SGLT2i on treatments of NAFLD in type 2 diabetes in July 2020, and articles were sieved. Continuous data were extracted in the form of mean and standard deviation and were pooled with standardized mean difference (SMD).

Results

10 articles involving 555 patients from seven randomized controlled trials (RCTs) and three cohort studies, were included in this meta-analysis. Our analysis revealed significant improvements in hepatic fat content (after treatment: -0.789 (-1.404 to -0.175), p = 0.012; compared with control: -0.923 (-1.562 to -0.285), p = 0.005), AST (After Treatment: -0.539 (-0.720 to -0.357), p < 0.001; compared with control: -0.421 (-0.680 to -0.161), p = 0.001), ALT (after treatment: -0.633 (-0.892 to -0.373), p < 0.001; compared with Control: -0.468 (-0.685 to -0.251), p < 0.001), body composition (BMI: after treatment: -0.225 (-0.456 to 0.005), p = 0.055; compared with Control: -1.092 (-2.032 to -0.153), p = 0.023), glycemic control (HbA1c: After Treatment: -0.701 (-1.098 to -0.303), p = 0.001; compared with control: -0.210 (-0.603 to 0.183), p = 0.295), lipid parameters (Triglycerides: after treatment: -0.230 (-0.409 to -0.052), p = 0.011; compared with control: -0.336 (-0.597 to -0.076), p = 0.011), inflammatory markers (serum ferritin: after treatment: -0.409 (-0.694 to -0.124), p = 0.005; compared with control: -0.814 (-1.688 to 0.059), p = 0.068) after SGLT2i treatment, and when compared against controls. There was a trend in the improvement in fibrosis markers after SGLT2i treatment.

Conclusions

SGLT2i is an effective treatment to improve NAFLD among patients with type 2 diabetes. Further studies are needed to understand the direct and indirect effects of SGLT2i on NAFLD and if SGLT2i could prevent the progression of NAFLD or NASH. SGLT2i could potentially be considered for patients with type 2 diabetes and NAFLD, if there are no contraindications.
Association Between Obesity and Short-And Long-Term Mortality in Patients With Acute Respiratory Distress Syndrome Based on the Berlin Definition
Authors: Zhang Wei , Wang Yadan , Li Weijie , Wang Jun
Published: February 2021

Purpose

Acute respiratory distress syndrome (ARDS) is one of the most common causes of death in intensive care units (ICU). Previous studies have reported the potential protective effect of obesity on ARDS patients. However, these findings are inconsistent, in which less was reported on long-term prognosis and diagnosed ARDS by Berlin definition. This study aimed to investigate the relationship between obesity and short-term and long-term mortality in patients with ARDS based on the Berlin Definition.

Methods

This is a retrospective cohort study from the Medical Information Mart for Intensive Care III (MIMIC-III) database, in which all the patients were diagnosed with ARDS according to the Berlin definition. The patients were divided into four groups according to the WHO body mass index (BMI) categories. The multivariable logistic regression and Cox regression analysis were used to investigate the relationship between BMI and short-term and long-term mortality.

Result

A total of 2,378 patients with ARDS were enrolled in our study. In-hospital mortality was 27.92%, and 1,036 (43.57%) patients had died after 1-year follow-up. After adjusting for confounders, the in-hospital and 1-year mortality risks of obese patients were significantly lower than those of normal weight (OR 0.72, 95%CI 0.55–0.94, P=0.0168; HR 0.80, 95%CI 0.68–0.94 P=0.0084; respectively), while those mortality risks of underweight patients were higher than normal weight patients (P=0.0102, P=0.0184; respectively). The smooth curve showed that BMI, which was used as a continuous variable, was negatively correlated with in-hospital and 1-year mortality. The results were consistent after being stratified by age, gender, race, type of admission, severity of organ dysfunction, and severity of ARDS. The Kaplan-Meier survival curves showed that obese patients had significant lower 1-year mortality than normal weight patients.

Conclusion

We found that obesity was associated with decreased risk of short-term and long-term mortality in patients with ARDS.
The BECCS Implementation Gap–A Swedish Case Study
Authors: Fuss Sabine , Johnsson Filip
Published: February 2021

The IPCC has assessed a variety of pathways that could still lead to achievement of the ambitious climate targets set in the Paris Agreement. However, the longer time that climate action is delayed, the more the achievement of this goal will depend on Carbon Dioxide Removal (CDR) technologies and practices. In the models behind these pathways, the main CDR technology is Bioenergy combined with Carbon Capture and Storage (BECCS). We review the role that BECCS could play in reaching net-zero targets based on the existing 1.5°C scenarios. Such scenarios presented in the literature typically have BECCS at a GtCO2per year scale. We also assess the potentials and obstacles for BECCS implementation at the national level, applying Sweden as a case study. Given that BECCS deployment has scarcely started and, thus, is far from capturing 1 GtCO2per year, with lead times on the scale of multiple years, we conclude that there will be a large implementation gap unless BECCS development is immediately intensified, emissions are reduced at a much faster pace or removals realized through other CDR measures. In the national case study, we show that Sweden has favorable conditions for BECCS in that it has large point sources of biogenic emissions, and that BECCS has been identified as one potential “supplementary measure” for reaching the Swedish target of net-zero emissions in 2045. Yet, work on planning for BECCS implementation has started only recently and would need to be accelerated to close the implementation gap between the present advancement and the targets for BECCS proposed in a recent public inquiry on the roles of supplementary measures. An assessment of two ramp-up scenarios for BECCS demonstrates that it should in principle be possible to reach the currently envisaged deployment scales, but this will require prompt introduction of political and economic incentives. The main barriers are thus not due to technological immaturity, but are rather of a socio-economic, political and institutional nature.
Divalent Nonaqueous Metal-Air Batteries
Authors: Lu Yi-Ting , Neale Alex R. , Hu Chi-Chang , Hardwick Laurence J.
Published: February 2021

In the field of secondary batteries, the growing diversity of possible applications for energy storage has led to the investigation of numerous alternative systems to the state-of-the-art lithium-ion battery. Metal-air batteries are one such technology, due to promising specific energies that could reach beyond the theoretical maximum of lithium-ion. Much focus over the past decade has been on lithium and sodium-air, and, only in recent years, efforts have been stepped up in the study of divalent metal-air batteries. Within this article, the opportunities, progress, and challenges in nonaqueous rechargeable magnesium and calcium-air batteries will be examined and critically reviewed. In particular, attention will be focused on the electrolyte development for reversible metal deposition and the positive electrode chemistries (frequently referred to as the “air cathode”). Synergies between two cell chemistries will be described, along with the present impediments required to be overcome. Scientific advances in understanding fundamental cell (electro)chemistry and electrolyte development are crucial to surmount these barriers in order to edge these technologies toward practical application.
First-Principles Design of Rutile Oxide Heterostructures for Oxygen Evolution Reactions
Authors: Lim Hyeong Yong , Park Sung O , Kim Su Hwan , Jung Gwan Yeong , Kwak Sang Kyu
Published: February 2021

The oxygen evolution reaction (OER) plays a key role in the determination of overall water-splitting rate. Lowering the high overpotential of the OER of transition metal oxides (TMOs), which are used as conventional OER electrocatalysts, has been the focus of many studies. The OER activity of TMOs can be tuned via the strategic formation of a heterostructure with another TMO substrate. We screened 11 rutile-type TMOs (i.e., MO2; M = V, Cr, Mn, Nb, Ru, Rh, Sn, Ta, Os, Ir, and Pt) on a rutile (110) substrate using density functional theory calculations to determine their OER activities. The conventional volcano approach based on simple binding energies of reaction intermediates was implemented; in addition, the electrochemical-step symmetry index was employed to screen heterostructures for use as electrode materials. The results show that RuO2 and IrO2 are the most promising catalysts among all candidates. The scaling results provide insights into the intrinsic properties of the heterostructure as well as materials that can be used to lower the overpotential of the OER.
Data-Driven-Based Forecasting of Two-Phase Flow Parameters in Rectangular Channel
Authors: Huang Qingyu , Yu Yang , Zhang Yaoyi , Pang Bo , Wang Yafeng , Chen Di , Pang Zhixin
Published: February 2021

In the current nuclear reactor system analysis codes, the interfacial area concentration and void fraction are mainly obtained through empirical relations based on different flow regime maps. In the present research, the data-driven method has been proposed, using four machine learning algorithms (lasso regression, support vector regression, random forest regression and back propagation neural network) in the field of artificial intelligence to predict some important two-phase flow parameters in rectangular channels, and evaluate the performance of different models through multiple metrics. The random forest regression algorithm was found to have the strongest ability to learn from the experimental data in this study. Test results show that the prediction errors of the random forest regression model for interfacial area concentrations and void fractions are all less than 20%, which means the target parameters have been forecasted with good accuracy.
Design and Performance of an Innovative Hybrid Constructed Wetland for Sustainable Pig Slurry Treatment in Small Farms
Authors: Torrens Antonina , Folch Montserrat , Salgot Miquel
Published: February 2021

Simple and suitable treatment of swine slurry from small farms is paramount especially in sensitive areas. This paper evaluates the viability of an innovative nature-based technology hybrid system (a Vertical Flow Constructed Wetland followed by a Horizontal Flow Constructed Wetland both planted with reeds – Phragmites australis) to treat swine slurry for further land application or discharge in water bodies with reduced nitrogen impact. Physicochemical parameters, bacterial indicators, surface deposits and biomass inside the filters were monitored. The hybrid configuration offered a dual function for simultaneous solid-liquid separation and biological treatment. Removal of organic matter and suspended solids was very high (>80% for SS and >75% for COD and BOD5) while the overall nitrogen load removal was 65%, due to the combined nitrification/denitrification processes, thus effectively reducing swine slurry nitrogen content. The influence of temperature and design and operational parameters on the treatment efficiency and the hydraulic behavior were also studied. The vertical constructed wetland achieved good hydraulic performance with no clogging problems, despite high pollutant loads. Some of the pollutants were retained and mineralized in the surface deposit layer, increasing around 20 cm each year. This organic biosolid layer improved filtration efficiency. The high ammonia contents interfered with the growth of Phragmites australis, while the high concentration of suspended solids and organic matter determine the operation and design to be implemented.
Ancient Burial Mounds Provide Safe Havens for Grassland Specialist Plants in Transformed Landscapes—A Trait-Based Analysis
Authors: Deák Balázs , Rádai Zoltán , Bátori Zoltán , Kelemen András , Lukács Katalin , Kiss Réka , Maák István Elek , Valkó Orsolya
Published: February 2021

Due to the intensified land use in transformed landscapes, grassland biodiversity is often restricted to habitat fragments inadequate for arable use or for urban development. In continental parts of Eurasia, the ~600,000 ancient burial mounds (called “kurgans”) built by nomadic tribes of the steppes are amongst the most widespread landmarks providing refuge for dry grassland species. In our study by using plant functional groups and functional traits, we aimed at gaining insight into the ecological and evolutionary processes shaping the structure and the composition of assemblages of grassland specialist plant species on kurgans embedded in the agricultural landscapes of East-Hungary. As a comparison, we also studied roadside verges and pristine extensive grasslands in the same region. We found that despite their small size, due to the lack of human disturbances and high microhabitat diversity kurgans can maintain a high species richness and percentage cover of specialists, especially when compared to verges. We revealed that assemblages of specialist plants on kurgans are characterized by traits typical to terrestrial habitat islands such as self-compatibility, large seed mass and tall stature. Kurgans and extensive grasslands were characterized by higher functional diversity (both at the level of single traits and multi-trait based functional dispersion) which is probably due to the higher level of environmental heterogeneity compared to the homogeneous environment in verges.
Comparison of Gene Editing Versus Conventional Breeding to Introgress the POLLED Allele Into the Tropically Adapted Australian Beef Cattle Population
Authors: Mueller Maci L. , Cole John B. , Connors Natalie K. , Johnston David J. , Randhawa Imtiaz A. S. , Van Eenennaam Alison L.
Published: February 2021

Dehorning is the process of physically removing horns to protect animals and humans from injury, but the process is costly, unpleasant, and faces increasing public scrutiny. Genetic selection for polled (hornless), which is genetically dominant to horned, is a long-term solution to eliminate the need for dehorning. However, due to the limited number of polled Australian Brahman bulls, the northern Australian beef cattle population remains predominantly horned. The potential to use gene editing to produce high-genetic-merit polled cattle was recently demonstrated. To further explore the concept, this study simulated introgression of the POLLED allele into a tropically adapted Australian beef cattle population via conventional breeding or gene editing (top 1% or 10% of seedstock bulls/year) for 3 polled mating schemes and compared results to baseline selection on genetic merit (Japan Ox selection index, $JapOx) alone, over the course of 20 years. The baseline scenario did not significantly decrease the 20-year HORNED allele frequency (80%), but resulted in one of the fastest rates of genetic gain ($8.00/year). Compared to the baseline, the conventional breeding scenarios where polled bulls were preferentially used for breeding, regardless of their genetic merit, significantly decreased the 20-year HORNED allele frequency (30%), but resulted in a significantly slower rate of genetic gain ($6.70/year, P ≤ 0.05). The mating scheme that required the exclusive use of homozygous polled bulls, resulted in the lowest 20-year HORNED allele frequency (8%), but this conventional breeding scenario resulted in the slowest rate of genetic gain ($5.50/year). The addition of gene editing the top 1% or 10% of seedstock bull calves/year to each conventional breeding scenario resulted in significantly faster rates of genetic gain (up to $8.10/year, P ≤ 0.05). Overall, our study demonstrates that, due to the limited number of polled Australian Brahman bulls, strong selection pressure on polled will be necessary to meaningfully increase the number of polled animals in this population. Moreover, these scenarios illustrate how gene editing could be a tool for accelerating the development of high-genetic-merit homozygous polled sires to mitigate the current trade-off of slower genetic gain associated with decreasing HORNED allele frequency in the Australian Brahman population.
Trained Immunity-Based Vaccine in B Cell Hematological Malignancies With Recurrent Infections: A New Therapeutic Approach
Authors: Ochoa-Grullón Juliana , Benavente Cuesta Celina , González Fernández Ataúlfo , Cordero Torres Gustavo , Pérez López Cristina , Peña Cortijo Ascensión , Conejero Hall Laura , Mateo Morales Marta , Rodríguez de la Peña Antonia , Díez-Rivero Carmen M. , Rodríguez de Frías Edgard , Guevara-Hoyer Kissy , Fernández-Arquero Miguel , Sánchez-Ramón Silvia
Published: February 2021

Infectious complications are a major cause of morbidity and mortality in B-cell hematological malignancies (HM). Prophylaxis for recurrent infections in HM patients with antibody deficiency consists of first-line antibiotics and when unsuccessful, gammaglobulin replacement therapy (IgRT). Recent knowledge of trained immunity-based vaccines (TIbV), such as the sublingual polybacterial formulation MV130, has shown a promising strategy in the management of patients with recurrent infections. We sought to determine the clinical benefit of MV130 in a cohort of HM patients with recurrent respiratory tract infections (RRTIs) who underwent immunization with MV130 for 3 months. Clinical information included the frequency of infections, antibiotic use, number of visits to the GP and hospitalizations previous and after MV130 immunotherapy. Improvement on infection rate was classified as: clear (>60% reduction of infection), partial (26%–60%) and low (≤25%) improvement. Fifteen HM patients (aged 42 to 80 years; nine females) were included in the study. All patients reduced their infection rate. Analysis of paired data revealed that the median (range, min - max) of respiratory infectious rate significantly decreased from 4.0 (8.0–3.0) to 2.0 (4.0–0.0) (p<0.001) at 12 months of MV130. A clear clinical improvement was observed in 53% (n = 8) of patients, partial improvement in 40% (n = 6) and low improvement in 7% (n = 1). These data correlated with a decrease on antibiotic consumption from 3.0 (8.0–1.0) to 1.0 (2.0–0.0) (p = 0.002) during 12 months after initiation of treatment with MV130. The number of infectious-related GP or emergency room visits declined from 4.0 (8.0–2.0) to 2.0 (3.0–0.0) (p<0.001), in parallel with a reduction in hospital admissions due to infections (p = 0.032). Regarding safety, no adverse events were observed. On the other hand, immunological assessment of serum IgA and IgG levels demonstrated an increase in specific antibodies to MV130-contained bacteria following MV130 immunotherapy. In conclusion, MV130 may add clinical benefit reducing the rate of infections and enhancing humoral immune responses in these vulnerable patients.
Multipathogen Analysis of IgA and IgG Antigen Specificity for Selected Pathogens in Milk Produced by Women From Diverse Geographical Regions: The INSPIRE Study
Authors: McGuire Michelle K. , Randall Arlo Z. , Seppo Antti E. , Järvinen Kirsi M. , Meehan Courtney L. , Gindola Debela , Williams Janet E. , Sellen Daniel W. , Kamau-Mbuthia Elizabeth W. , Kamundia Egidioh W. , Mbugua Samwel , Moore Sophie E. , Prentice Andrew M. , Foster James A. , Otoo Gloria E. , Rodríguez Juan M. , Pareja Rossina G. , Bode Lars , McGuire Mark A. , Campo Joseph J.
Published: February 2021

Breastfeeding provides defense against infectious disease during early life. The mechanisms underlying this protection are complex but likely include the vast array of immune cells and components, such as immunoglobulins, in milk. Simply characterizing the concentrations of these bioactives, however, provides only limited information regarding their potential relationships with disease risk in the recipient infant. Rather, understanding pathogen and antigen specificity profiles of milk-borne immunoglobulins might lead to a more complete understanding of how maternal immunity impacts infant health and wellbeing. Milk produced by women living in 11 geographically dispersed populations was applied to a protein microarray containing antigens from 16 pathogens, including diarrheagenicE. coli,Shigellaspp., Salmonella entericaserovar Typhi,Staphylococcus aureus,Streptococcus pneumoniae, Mycobacterium tuberculosisand other pathogens of global health concern, and specific IgA and IgG binding was measured. Our analysis identified novel disease-specific antigen responses and suggests that some IgA and IgG responses vary substantially within and among populations. Patterns of antibody reactivity analyzed by principal component analysis and differential reactivity analysis were associated with either lower-to-middle-income countries (LMICs) or high-income countries (HICs). Antibody levels were generally higher in LMICs than HICs, particularly forShigellaand diarrheagenicE. coliantigens, although sets ofS. aureus,S. pneumoniae, and someM. tuberculosisantigens were more reactive in HICs. Differential responses were typically specific to canonical immunodominant antigens, but a set of nondifferential but highly reactive antibodies were specific to antigens possibly universally recognized by antibodies in human milk. This approach provides a promising means to understand how breastfeeding and human milk protect (or do not protect) infants from environmentally relevant pathogens. Furthermore, this approach might lead to interventions to boost population-specific immunity in at-risk breastfeeding mothers and their infants.
Peptidoglycan Switches Off the TLR2-Mediated Sperm Recognition and Triggers Sperm Localization in the Bovine Endometrium
Authors: Elesh Ibrahim Fouad , Marey Mohamed Ali , Zinnah Mohammed Ali , Akthar Ihshan , Kawai Tomoko , Naim Fayrouz , Goda Wael , Rawash Abdel Rahman A. , Sasaki Motoki , Shimada Masayuki , Miyamoto Akio
Published: February 2021

In mammals, the uterine mucosal immune system simultaneously recognizes and reacts to most bacteria as well as allogenic sperm mainly through the Toll-like receptors (TLR)2/4 signaling pathway. Here, we characterized the impact of pathogen-derived TLR2/4 ligands (peptidoglycan (PGN)/lipopolysaccharide (LPS)) on the immune crosstalk of sperm with the bovine endometrial epithelium. The real-time PCR analysis showed that the presence of low levels of PGN, but not LPS, blocked the sperm-induced inflammatory responses in bovine endometrial epithelial cells (BEECs) in vitro. Immunoblotting analysis revealed that PGN prevented the sperm-induced phosphorylation of JNK in BEECs. Activation or blockade of the TLR2 system in the endometrial epithelium verified that TLR2 signaling acts as a commonly-shared pathway for PGN and sperm recognition. The impairment of endometrial sperm recognition, induced by PGN, subsequently inhibited sperm phagocytosis by polymorphonuclear neutrophils (PMNs). Moreover, using an ex vivo endometrial explant that more closely resembles those in vivo conditions, showed that sperm provoked a mild and reversible endometrial tissue injury and triggered PMN recruitment into uterine glands, while PGN inhibited these events. Of note, PGN markedly increased the sperm attachment to uterine glands, and relatively so in the surface epithelium. However, addition of the anti-CD44 antibody into a PGN-sperm-explant co-culture completely blocked sperm attachment into glands and surface epithelia, indicating that the CD44 adhesion molecule is involved in the PGN-triggered sperm attachment to the endometrial epithelium. Together, these findings demonstrate that, the presence of PGN residues disrupts sperm immune recognition and prevents the physiological inflammation induced by sperm in the endometrial epithelium via the MyD88-dependent pathway of TLR2 signaling, possibly leading to impairment of uterine clearance and subsequent embryo receptivity.
The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA
Authors: Kumar Vijay
Published: February 2021

The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.
Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity
Authors: Binder Christian , Sellberg Felix , Cvetkovski Filip , Berg Stefan , Berglund Erik , Berglund David
Published: February 2021

The glycoprotein CD2 is expressed on T and NK cells and contributes to cell-cell conjugation, agonistic signaling and actin cytoskeleton rearrangement. CD2 has previously been shown to have an important function in natural NK cell cytotoxicity but to be expendable in antibody-mediated cytotoxicity. Siplizumab is a monoclonal anti-CD2 IgG1 antibody that is currently undergoing clinical trials in the field of transplantation. This study investigated the effect of CD2 binding and Fc γ receptor binding by siplizumab (Fc-active) and Fc-silent anti-CD2 monoclonal antibodies in allogeneic mixed lymphocyte reaction and autologous lymphocyte culture. Further, induction of NK cell fratricide and inhibition of natural cytotoxicity as well as antibody-dependent cytotoxicity by these agents were assessed. Blockade of CD2 via monoclonal antibodies in the absence of Fc γ receptor binding inhibited NK cell activation in allogeneic mixed lymphocyte reaction. In contrast, siplizumab increased NK cell activation in both mixed lymphocyte reaction and autologous lymphocyte culture due to FcγRIIIA binding. However, experiments using purified NK cells did not show an inhibitory effect of CD2 blockade on natural cytotoxicity or antibody-dependent cytotoxicity. Lastly, it was shown that siplizumab induces NK cell fratricide. Concluding, siplizumab is a promising biopharmaceutical drug candidate for depletion of T and NK cells with minimal off-target effects.
Interaction Between MDSC and NK Cells in Solid and Hematological Malignancies: Impact on HSCT
Authors: Tumino Nicola , Di Pace Anna Laura , Besi Francesca , Quatrini Linda , Vacca Paola , Moretta Lorenzo
Published: February 2021

Myeloid derived suppressor cells (MDSC) are heterogeneous populations that through the release of soluble factors and/or by cell-to-cell interactions suppress both innate and adaptive immune effector cells. In pathological conditions, characterized by the presence of inflammation, a partial block in the differentiation potential of myeloid precursors causes an accumulation of these immunosuppressive cell subsets both in peripheral blood and in tissues. On the contrary, NK cells represent a major player of innate immunity able to counteract tumor growth. The anti-tumor activity of NK cells is primarily related to their cytolytic potential and to the secretion of soluble factors or cytokines that may act on tumors either directly or indirectly upon the recruitment of other cell types. NK cells have been shown to play a fundamental role in haploidentical hemopoietic stem cell transplantation (HSCT), for the therapy of high-risk leukemias. A deeper analysis of MDSC functional effects demonstrated that these cells are capable, through several mechanisms, to reduce the potent GvL activity exerted by NK cells. It is conceivable that, in this transplantation setting, the MDSC-removal or -inactivation may represent a promising strategy to restore the anti-leukemia effect mediated by NK cells. Thus, a better knowledge of the cellular interactions occurring in the tumor microenvironment could promote the development of novel therapeutic strategies for the treatment of solid and hematological malignances.
Regulatory T Cell Heterogeneity in the Thymus: Impact on Their Functional Activities
Authors: Santamaria Jérémy C. , Borelli Alexia , Irla Magali
Published: February 2021

Foxp3+ regulatory T cells (Treg) maintain the integrity of the organism by preventing excessive immune responses. These cells protect against autoimmune diseases but are also important regulators of other immune responses including inflammation, allergy, infection, and tumors. Furthermore, they exert non-immune functions such as tissue repair and regeneration. In the periphery, Foxp3+ Treg have emerged as a highly heterogeneous cell population with distinct molecular and functional properties. Foxp3+ Treg mainly develop within the thymus where they receive instructive signals for their differentiation. Recent studies have revealed that thymic Treg are also heterogeneous with two distinct precursors that give rise to mature Foxp3+ Treg exhibiting non-overlapping regulatory activities characterized by a differential ability to control different types of autoimmune reactions. Furthermore, the thymic Treg cell pool is not only composed of newly developing Treg, but also contain a large fraction of recirculating peripheral cells. Here, we review the two pathways of thymic Treg cell differentiation and their potential impact on Treg activity in the periphery. We also summarize our current knowledge on recirculating peripheral Treg in the thymus.
Effects of Electrical Pulse Stimulation on Behaviour and Survival of Marine Benthic Invertebrates
Authors: Boute Pim G. , Soetaert Maarten , Reid Navarro José A. , Lankheet Martin J.
Published: February 2021

Electrical pulse trawling is an alternative to conventional beam trawling for common sole (Solea solea), with the potential for higher revenues and less impact on the marine ecosystem. Concerns exist, however, that benthic invertebrates might be seriously affected by pulse fishing. Even if direct injuries and mortality were limited, changes in behaviour might compromise their survival, with potentially large impacts on food webs. Here, we investigate effects of electrical pulses on locomotion behaviour and 14-days survival of six invertebrate species from four phyla that may encounter pulse fishing gears. Electrical stimulation consisted of a Pulsed Bipolar Current at 200 V m–1, 30 Hz, 0.33 ms pulse width, and 3 s duration. We quantified species-specific behaviours before, during, and after electrical stimulation and compared these to a non-exposed control group. Responses during stimulation varied from no visible effect (echinoderms) to squirming (sea mouse) and retractions (whelk and crustaceans). Within 30 s after stimulation, all animals resumed normal behavioural patterns, without signs of lasting immobilisation. Starfish, serpent star, whelk and sea mouse showed no change in movement patterns after stimulation, whereas flying crab and hermit crab showed significant changes in activity that were indicative of increased shelter behaviour. For none of the species, survival at 14-days after stimulation was negatively affected. These findings suggest that changes in locomotion behaviour due to electrical stimulation as used in pulse trawling are unlikely to substantially compromise survival of the investigated species.
Deep-Sea Nematodes of the Mozambique Channel: Evidence of Random Community Assembly Dynamics in Seep Sediments
Authors: Macheriotou Lara , Rigaux Annelien , Olu Karine , Zeppilli Daniela , Derycke Sofie , Vanreusel Ann
Published: February 2021

Cold seeps occur globally in areas where gases escape from the seafloor, occasionally resulting in the formation of topographic depressions (pockmarks), characterised by unique physicochemical conditions such as anoxic and sulphuric sediments. Free-living marine nematodes tend to dominate the meiofaunal component in such environments, often occurring at extremely high densities and low richness; the mechanisms defining community assembly in areas of fluid seepage, however, have received little attention. Here we focus on a low-activity pockmark at 789 m in the Mozambique Channel (MC). We assessed the diversity, co-occurrence patterns and phylogenetic community structure of nematodes at this bathyal site to that of a nearby reference area as well as abyssal sediments using metabarcoding. In addition, we compared our molecularly-derived diversity estimates to replicate samples identified morphologically. Overall, nematode Amplicon Sequence Variants (ASVs) and generic richness were similar between Pockmark and Abyssal sediments, but lower compared to the Reference area. Although more than half the genera were shared, over 80% of ASVs were unique within each area and even within each replicate core. Even though both methodologies differentiated the Pockmark from the Reference and Abyssal sites, there was little overlap between the molecularly and morphologically identified taxa, highlighting the deficit of reference sequences for deep-sea nematodes in public databases. Phylogenetic community structure at higher taxonomic levels was clustered and did not differ between the three areas yet analysis within three shared and dominant genera (Acantholaimus, Desmoscolex, Halalaimus), revealed randomness with respect to phylogeny as well as co-occurrence which was exclusive to the Pockmark area. These patterns point to the influence of neutral dynamics at this locality resulting from the stochastic sampling of early colonizing taxa, the successional stage at sampling and/or the functional redundancy within the investigated genera.