bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Driver Model Based on Driver Response
Authors: Ali Faryal , Khan Zawar Hussain , Khan Fayaz Ahmad , Khattak Khurram Shehzad , Gulliver Thomas Aaron
Published: May 2022

In this paper, a new microscopic traffic model based on forward and rearward driver response is proposed. Driver response is characterized using the distance and time headways. Existing models such as the Intelligent Driver (ID) model characterize traffic flow based on a constant acceleration exponent. This exponent reflects uniform driver behaviour during different conditions which is unrealistic. Driver response is slow with a large distance headway and quick with a short time headway. Conversely, it is quick with a small distance headway and slow with a long time headway. Thus, a new microscopic traffic model is proposed which incorporates driver response. Results are given that show the proposed model provides better traffic stability than the ID model as this stability is based on traffic physics. Further, for effective utilization of road infrastructure, shorter time and longer distance headways are preferred. The performance of the ID and proposed models was evaluated over an 800 m circular road with a string of 15 vehicles for 120 s. These models are numerically discretized using the Euler scheme. The results obtained show that traffic queue dissemination with the proposed model is more realistic than with the ID model and the changes in density with the proposed model are smaller. This is because traffic dissemination with the proposed model is based on traffic parameters rather than a constant exponent.
Aluminium Assisted Nickel Alloying in Submerged Arc Welding of Carbon Steel: Application of Unconstrained Metal Powders
Authors: Coetsee Theresa , De Bruin Frederik
Published: May 2022

Nickel alloying of carbon steel is used to enhance steel strength and toughness. Nickel alloying of the weld metal via solid weld wire presents several difficulties as highlighted previously, such as work hardening of the solid weld wire in manufacturing and feeding through the SAW wire feeding mechanism, and expensive and time consuming manufacturing of multiple weld wire formulations. The application of nickel and aluminium powders in unconstrained format, meaning not as fluxed cored wire or as metal cored wire, is used to simplify weld metal alloying. Al powder is used to control the oxygen potential at the weld pool-molten flux interface. The results presented here show that the addition of Al powder to the weld metal enhances Ni yield to the weld metal, at 85%, compared to pre-alloyed powder Ni yields of 57–78% as applied in previous work. Carbon steel was alloyed to 6.9% Ni and 3.7% Al. Thermodynamic analysis is applied to elucidate the chemical interaction between Ni and Al, and its effects on Ni yield in the weld pool. Overall process productivity gains stem from weld metal alloying from unconstrained metal powders because the expensive and time consuming step of manufacturing alloyed wire and alloyed powder is eliminated.
Australian Bushfires (2019–2020): Aerosol Optical Properties and Radiative Forcing
Authors: Papanikolaou Christina-Anna , Kokkalis Panagiotis , Soupiona Ourania , Solomos Stavros , Papayannis Alexandros , Mylonaki Maria , Anagnou Dimitra , Foskinis Romanos , Gidarakou Marilena
Published: May 2022

In the present study, we present the aerosol optical properties and radiative forcing (RF) of the tropospheric and stratospheric smoke layers, observed by the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) satellite, during the extraordinary Australian biomass burning (BB) event in 2019–2020. These BB layers were studied and analyzed within the longitude range 140° E–20° W and the latitude band 20°–60° S, as they were gradually transported from the Australian banks to the South American continent. These layers were found to be trapped within the Andes circulation, staying for longer time periods in the same longitude region. The BB aerosols reached altitudes even up to 22 km amsl., and regarding their optical properties, they were found to be nearly spherical (particle linear depolarization ratio (PLDR) < 0.10) in the troposphere; while, in the stratosphere, they were more depolarizing with PLDR values reaching up to 0.20. Fine and ultrafine smoke particles were dominant in the stratosphere, according to the observed Ångström exponent, related to the backscatter coefficients obtained by the pair of wavelengths 532 and 1064 nm (Åb up to 3), in contrast to the Åb values in the troposphere (Åb < 1) indicative of the presence of coarser particles. As the aerosols fend off the source, towards North America, a slightly descending trend was observed in the tropospheric Åb values, while the stratospheric ones were lightly increased. A maximum aerosol optical depth (AOD) value of 0.54 was recorded in the lower troposphere over the fire spots, while, in the stratosphere, AOD values up to 0.29 were observed. Sharp changes of carbon monoxide (CO) and ozone (O3) concentrations were also recorded by the Copernicus Atmosphere Monitoring Service (CAMS) in various atmospheric heights over the study region, associated with fire smoke emissions. The tropospheric smoke layers were found to have a negative mean radiative effect, ranging from −12.83 W/m2 at the top of the atmosphere (TOA), to −32.22 W/m2 on the surface (SRF), while the radiative effect of the stratospheric smoke was estimated between −7.36 at the TOA to −18.51 W/m2 at the SRF.
Development of a Dust Source Map for WRF-Chem Model Based on MODIS NDVI
Authors: Spyrou Christos , Solomos Stavros , Bartsotas Nikolaos S. , Douvis Kostas C. , Nickovic Slobodan
Published: May 2022

We present the development of a physically-based dust source map for the GOCART-AFWA dust module in WRF-Chem model. The new parameterization is based on MODIS-NDVI and an updated emission strength map is computed every 15 days from the latest satellite observations. Modeling simulations for the period April–May 2017 over the Mediterranean, north Africa, and the Middle East are compared with observations of AOD at 31 AERONET stations. The new module is capable of reproducing the dust sources at finer detail. The overall performance of the model is improved, especially for stronger dust episodes with AOD > 0.25. For this threshold the model BIAS decreases from −0.20 to −0.02, the RMSE from 0.38 to 0.30, the Correlation Coefficient improves from 0.21 to 0.47, the fractional gross error (FGE) from 0.62 to 0.40, and the mean fractional bias (MFB) from −0.49 to −0.08. Similar improvement is also found for the lower AOD thresholds (>0.0 and >0.1), especially for the stations in Europe, the Mediterranean, Sahel, the Middle East, and Arabian Peninsula, which are mostly affected by dust transport during the experimental period. An overprediction of AOD, compared to the original dust-source scheme, is found for some stations in the Sahara desert, the Atlantic Ocean, and the Iberian Peninsula. In total, 124 out of the 170 statistical scores that are calculated indicate improvement of model performance.
Development of a Novel Bioaerosol Chamber to Determine Survival Rates of Airborne Staphylococci
Authors: Clauß Marcus , Linke Stefan , Tautz Christin , Bromann Sarah
Published: May 2022

Large amounts of microorganisms are emitted from animal houses into the environment via exhaust air. To assess the potential risks, the spread of microorganisms can be simulated with computer models. Such modeling usually does not take into account die-off rates, since there are hardly any reliable data so far on how long microorganisms can survive in outdoor air. Previous studies were conducted almost exclusively in closed chambers and usually only took into account the influence of individual environmental factors such as temperature or humidity. Therefore, a novel bioaerosol chamber was developed to quantify the survival rates of Staphylococci specific to livestock under outdoor air conditions. For evaluation, the survival rates of Staphylococcus xylosus were determined as a function of temperature, relative humidity, ozone concentration, and global radiation. Survival rates decreased with increasing temperature, decreasing relative humidity, increasing global radiation intensity, and increasing ozone concentration. At 12 min in the airborne state, die-off rates of more than 90% were observed, especially at high global radiation levels > 400 W/m2. The novel bioaerosol chamber enabled the investigation of the survival rates of airborne microorganisms over a certain period of time in a quasi-closed system and yet under real outdoor air conditions.
Exposure to Aerosols Emitted from Common Heating Combustion Sources Indoors—The Jordanian Case as an Example for Eastern Mediterranean Conditions
Authors: Hussein Tareq , Al-Jaghbeer Omar , Bqour Nizar , Zidan Bilal , Lahlouh Bashar
Published: May 2022

In Jordan, ~61% of total residential energy consumption is consumed by heating spaces using portable kerosene (K) and liquified petroleum gas (LPG) heaters. Here, we evaluated the indoor air quality (IAQ) versus the use of K and LPG heaters inside a test room reflecting the typical conditions of Jordanian dwellings during the winter season. The experimental setup included particle size distribution (diameter 0.01–25 µm) measurements, and we utilized a simple sectional indoor aerosol model (SIAM) to estimate the emission rate and lifetime of the combustion products in the test room. The particle number (PN) concentration during the LPG operation was 6 × 104–5.9 × 105 cm−3, depending on the setting at minimum, medium, or maximum. The K heater operation increased with the PN concentrations to a range of 4 × 105–8 × 105 cm−3. On average, the particle losses were 0.7–1.6 h−1 for micron particles (1–10 µm) and 0.8–0.9 h−1 for ultrafine particles (<0.1 µm). The emission rate from the LPG heater was 1.2 × 1010–2.8 × 1010 particles/s (6.6 × 106–8.0 × 106 particles/J), and that for the K heater was about 4.4 × 1010 particles/s (1.9 × 107 particles/J). The results call for the immediate need to apply interventions to improve the IAQ by turning to cleaner heating processes indoors.
Reproducibility of the 10-nm Solid Particle Number Methodology for Light-Duty Vehicles Exhaust Measurements
Authors: Lähde Tero , Giechaskiel Barouch , Martini Giorgio , Woodburn Joseph , Bielaczyc Piotr , Schreiber Daniel , Huber Mathias , Dimopoulos Eggenschwiler Panayotis , Fittavolini Corrado , Florio Salvatore , Pellegrini Leonardo , Schuster Norbert , Kirchner Ulf , Yamada Hiroyuki , Momique Jean-Claude , Monier Richard , Lai Yitu , Murtonen Timo , Vanhanen Joonas , Mamakos Athanasios , Dardiotis Christos , Otsuki Yoshinori , Spielvogel Jürgen
Published: May 2022

Many countries worldwide have introduced a limit for solid particles larger than 23 nm for the type approval of vehicles before their circulation in the market. However, for some vehicles, in particular for port fuel injection engines (gasoline and gas engines) a high fraction of particles resides below 23 nm. For this reason, a methodology for counting solid particles larger than 10 nm was developed in the Particle Measurement Programme (PMP) group of the United Nations Economic Commission for Europe (UNECE). There are no studies assessing the reproducibility of the new methodology across different laboratories. In this study we compared the reproducibility of the new 10 nm methodology to the current 23 nm methodology. A light-duty gasoline direct injection vehicle and two reference solid particle number measurement systems were circulated in seven European and two Asian laboratories which were also measuring with their own systems fulfilling the current 23 nm methodology. The hot and cold start emission of the vehicle covered a range of 1 to 15 × 1012 #/km with the ratio of sub-23 nm particles to the >23 nm emissions being 10–50%. In most cases the differences between the three measurement systems were ±10%. In general, the reproducibility of the new methodology was at the same levels (around 14%) as with the current methodology (on average 17%).
Further Study on C-Eigenvalue Inclusion Intervals for Piezoelectric Tensors
Authors: Wang Gang , Yang Xiaoxuan , Shao Wei , Hou Qiuling
Published: May 2022

The C-eigenpair of piezoelectric tensors finds applications in the area of the piezoelectric effect and converse piezoelectric effect. In this paper, we provide some characterizations of C-eigenvectors by exploring the structure of piezoelectric tensors, and establish sharp C-eigenvalue inclusion intervals via Cauchy–Schwartz inequality. Further, we propose the lower and upper bounds of the largest C-eigenvalue and evaluate the efficiency of the best rank-one approximation of piezoelectric tensors. Numerical examples are proposed to verify the efficiency of the obtained results.
Total Rainbow Connection Number of Some Graph Operations
Authors: Li Hengzhe , Ma Yingbin , Zhao Yan
Published: May 2022

In a graph H with a total coloring, a path Q is a total rainbow if all elements in V(Q)∪E(Q), except for its end vertices, are assigned different colors. The total coloring of a graph H is a total rainbow connected coloring if, for any x,y∈V(H), there is a total rainbow path joining them. The total rainbow connection number trc(H) of H is the minimum integer r such that there is a total rainbow-connected coloring of H using r colors. In this paper, we study the total rainbow connection number of several graph operations (specifically, adding an edge, deleting an edge, and the Cartesian product) for which the total rainbow connection number is upper-bounded by a linear function of its radius.
On the Generalized Gaussian Fibonacci Numbers and Horadam Hybrid Numbers: A Unified Approach
Authors: Yılmaz Fatih , Özkan Mustafa
Published: May 2022

In this paper, we consider an approach based on the elementary matrix theory. In other words, we take into account the generalized Gaussian Fibonacci numbers. In this context, we consider a general tridiagonal matrix family. Then, we obtain determinants of the matrix family via the Chebyshev polynomials. Moreover, we consider one type of tridiagonal matrix, whose determinants are Horadam hybrid polynomials, i.e., the most general form of hybrid numbers. Then, we obtain its determinants by means of the Chebyshev polynomials of the second kind. We provided several illustrative examples, as well.
Highly Porous Type II Collagen-Containing Scaffolds for Enhanced Cartilage Repair with Reduced Hypertrophic Cartilage Formation
Authors: Intini Claudio , Hodgkinson Tom , Casey Sarah M. , Gleeson John P. , O’Brien Fergal J.
Published: May 2022

The ability to regenerate damaged cartilage capable of long-term performance in an active joint remains an unmet clinical challenge in regenerative medicine. Biomimetic scaffold biomaterials have shown some potential to direct effective cartilage-like formation and repair, albeit with limited clinical translation. In this context, type II collagen (CII)-containing scaffolds have been recently developed by our research group and have demonstrated significant chondrogenic capacity using murine cells. However, the ability of these CII-containing scaffolds to support improved longer-lasting cartilage repair with reduced calcified cartilage formation still needs to be assessed in order to elucidate their potential therapeutic benefit to patients. To this end, CII-containing scaffolds in presence or absence of hyaluronic acid (HyA) within a type I collagen (CI) network were manufactured and cultured with human mesenchymal stem cells (MSCs) in vitro under chondrogenic conditions for 28 days. Consistent with our previous study in rat cells, the results revealed enhanced cartilage-like formation in the biomimetic scaffolds. In addition, while the variable chondrogenic abilities of human MSCs isolated from different donors were highlighted, protein expression analysis illustrated consistent responses in terms of the deposition of key cartilage extracellular matrix (ECM) components. Specifically, CI/II-HyA scaffolds directed the greatest cell-mediated synthesis and accumulation in the matrices of type II collagen (a principal cartilage ECM component), and reduced deposition of type X collagen (a key protein associated with hypertrophic cartilage formation). Taken together, these results provide further evidence of the capability of these CI/II-HyA scaffolds to direct enhanced and longer-lasting cartilage repair in patients with reduced hypertrophic cartilage formation.
Relationship between Performance and Inter-Limb Asymmetries Using Flywheel Resistance Device in Elite Youth Female Basketball Players
Authors: Fort-Vanmeerhaeghe Azahara , Benet-Vigo Ariadna , Montalvo Alicia , Arboix Adrià , Buscà Bernat , Arboix-Alió Jordi
Published: May 2022

The purposes of this study were to quantify inter-limb asymmetries from unilateral jumps, change of direction (COD) speed, and flywheel resistance skill tests and to examine their relationship with physical performance in a sample of elite youth female basketball players. Eleven female basketball players (age = 17.56 ± 0.60 year; body mass = 75.13 ± 12.37 kg; height = 1.83 ± 0.08 m; BMI = 22.42 ± 2.28; sports experience = 6.31 ± 1.73 year; years post-peak height velocity = 4.79 ± 0.68 year) performed a battery of fitness tests in the post-season consisting of the Single Leg Countermovement Jump in vertical (SLCJ-V), horizontal (SLCJ-H), and lateral (SLCJ-L) directions, 135° and 90° COD tests, and four skills (acceleration step, deceleration step, sidestep, and crossover step) with an flywheel resistance device. The results showed significant differences between the higher performing and lower performing limbs across all tasks (p < 0.05). The mean asymmetry index values ranged from 1.26% (COD 135°) to 11.75% (SLC-V). Inter-limb asymmetries were greatest during the flywheel resistance skills. Spearman’s correlations (ρ) for all tests were only significant for inter-limb asymmetries during the sidestep test and reduced performance in SLCJ-L (ρ = −0.61; p = 0.046) and all COD deficits (ρ range = −0.72 to −0.81). The findings of the present study showed that inter-limb asymmetries are task-specific in female youth basketball players and suggest that the use of flywheel devices can be included in the battery of tests to detect inter-limb asymmetry.
Effect of Bis(maltolato)oxovanadium(IV) on Zinc, Copper, and Manganese Homeostasis and DMT1 mRNA Expression in Streptozotocin-Induced Hyperglycemic Rats
Authors: Sánchez-González Cristina , Moreno Laura , Aranda Pilar , Montes-Bayón María , Llopis Juan , Rivas-García Lorenzo
Published: May 2022

Our aim was to examine whether vanadium (IV) corrects alterations in zinc, copper and manganese homeostasis, observed in streptozotocin-induced hyperglycemic rats, and whether such changes are related to divalent metal transporter 1 (DMT1) mRNA expression, and antioxidant and proinflammatory parameters. Four groups of Wistar rats were examined: control; hyperglycemic (H); hyperglycemic treated with 1 mg V/day (HV); and hyperglycemic treated with 3 mg V/day (HVH). Vanadium was supplied in drinking water as bis(maltolato)oxovanadium(IV) for five weeks. Zinc, copper and manganese were measured in food, excreta, serum and tissues. DMT1 mRNA expression was quantified in the liver. Hyperglycemic rats showed increased Zn and Cu absorption and content in the liver, serum, kidneys and femurs; DMT1 expression also increased (p < 0.05 in all cases). HV rats showed no changes compared to H rats other than decreased DMT1 expression (p < 0.05). In the HVH group, decreased absorption and tissular content of studied elements (p < 0.05 in all cases) and DMT1 expression compared to H (p < 0.05) were observed. Liver zinc, copper and manganese content correlated positively with glutathione peroxidase activity and negatively with catalase activity (p < 0.05 in both cases). In conclusion, treatment with 3 mg V/d reverted the alterations in zinc and copper homeostasis caused by hyperglycemia, possibly facilitated by decreased DMT1 expression.
Nonoperative Treatment of Finger Flexor Tenosynovitis in Sport Climbers—A Retrospective Descriptive Study Based on a Clinical 10-Year Database
Authors: Mohn Sabrina , Spörri Jörg , Mauler Flavien , Kabelitz Method , Schweizer Andreas
Published: May 2022

The aim of this study was to describe the nonoperative treatment outcomes of finger flexor tenosynovitis in sport climbers and to evaluate the association with baseline measures and therapy contents. Sixty-five sport climbers (49 males, mean age 34.1 years) diagnosed with tenosynovitis of the finger flexors were retrospectively asked about injury triggers, therapy contents and outcomes. Pulley thickness was measured by ultrasound. All patients were initially treated conservatively, and only one of the patients needed further therapy (single injection with hyaluronic acid); none of them underwent surgical treatment. The most frequently applied therapy was climbing-related load reduction (91%). The treatment resulted in a statistically significant reduction in pain intensity during climbing (before/after therapy ratio [Visual Analog Scale (VAS)/VAS] = 0.62, 95% CI = 0.55, 0.68). The average duration of the symptoms was 30.5 weeks (range 1–120 weeks). In a multiple linear regression analysis, initial daily life pain intensity and a climbing level higher than 7b according to the French/sport grading scale were the only predictive parameters for the relative change in pain intensity and symptom duration, respectively. All patients were able to resume climbing, with 75% regaining or even exceeding their initial climbing level. The good to excellent outcomes and no correlation between particular therapy contents and therapy outcome may suggest that finger flexor tenosynovitis in sport climbers has a favorable natural course without requiring invasive therapy. However, further cohort studies and, ultimately, randomized controlled trials are needed to conclusively confirm our promising observations.
Effectiveness of Adapted Taekwondo, Multi-Component Training and Walking Exercise on Health Status in Independent Older Women: Study Protocol for a Randomized Controlled Trial (TKD & Aging Project)
Authors: Valdés-Badilla Pablo , Herrera-Valenzuela Tomás , Guzmán-Muñoz Eduardo , Branco Braulio Henrique Magnani , Zapata-Bastias José , Lucero Boris , Castillo-Retamal Franklin
Published: May 2022

This study protocol aims to analyze and compare the effects of an adapted taekwondo program with respect to multi-component training and walking exercise on health status in independent older women. Secondarily, we analyze the variability of the inter-individual response and compare it according to the designated training system. The sample will consist of 64 women between 60 and 65 years, randomly assigned to experimental group 1 (n = 16; adapted taekwondo), experimental group 2 (n = 16; multi-component training), experimental group 3 (n = 16, walking exercise) or control group (n = 16; no intervention). The experimental groups will perform the designated training for three sessions (60 min per session) per week over 16-weeks, while the control group will not receive any treatment. The main outcome will provide information about (i) blood pressure, (ii) lipid profile, (iii) frequency of food consumption, (iv) body composition, (v) cognitive status, (vi) brain activity, (vii) health-related quality of life (HRQoL) and (viii) physical-functional fitness. Our hypothesis indicates that adapted taekwondo produces more significant effects and greater inter-individual responses in cognitive status, brain activity, HRQoL, and postural balance than the others training methods. If this intervention proves effective, it could be an alternative for older women.
Running Footwear and Impact Peak Differences in Recreational Runners
Authors: Roggio Federico , Trovato Bruno , Zanghì Marta , Petrigna Luca , Testa Gianluca , Pavone Vito , Musumeci Giuseppe
Published: May 2022

Running is a physical activity and the investigation of its biomechanical aspects is crucial both to avoid injuries and enhance performance. Recreational runners may be liable to increased stress over the body, particularly to lower limb joints. This study investigates the different running patterns of recreational runners by analyzing characteristics of the footwear impact peak, spatiotemporal, and kinematic parameters among those that present with a peak impact and those that do not, with a 3D markerless system. Thirty recreational runners were divided into two groups: impact peak group (IP) (n = 16) and no impact peak group (n = 14) (n-IP). Kinematic and spatiotemporal parameters showed a large Cohen’s d effect size between the groups. The mean hip flexion was IP 40.40° versus n-IP 32.30° (d = −0.82). Hip extension was IP 30.20° versus n-IP 27.70° (d = −0.58), and ankle dorsiflexion was IP 20.80°, versus n-IP 13.37° (d = −1.17). Stride length was IP 117.90 cm versus n-IP 105.50 cm (d = −0.84). Steps per minute was IP group 170 spm, versus n-IP 163 spm (d = −0.51). The heel-to-toe drop was mainly 10–12 mm for the IP group and 4–6 mm for the n-IP group. Recreational runners whose hip extension is around 40°, ankle dorsiflexion around 20°, and initial foot contact around 14°, may be predisposed to the presence of an impact peak.
Use of Eisenia fetida as a Biological Risk Marker in a Qualitative Eco Assessment Test of a Romanian Watercourse
Authors: Cristina Romeo T. , Baroga Mihai , Dumitrescu Eugenia , Muselin Florin , Doma Alexandru O. , Manea Dan , Banatean-Dunea Ioan
Published: May 2022

The qualitative trials were conducted by exposing earthworms to diverse contaminants sources using standard earthworms’ avoidance tests (considered useful ab initio indicators). For two years, we observed the Jiu River pollution points. We observed soil traits in 15 sampling points from two neighboring Romanian counties where Jiu River flows, by evaluating the risk of pollution on Eisenia fetida earthworms. The ISO: 11268-2:2015 acute static test was used, following the ethological and bodily features of E. fetida earthworms for 14 days, and then the results obtained for clean soils vs. those presumed polluted were statistically analyzed. Results disclosed statistically significant values (p < 0.05) for the two-way ANOVA and Tukey multiple comparisons tests used for the soil samples thought to be polluted. The mortality percentages by location/replica/year/county find out a high statistical correlation documenting observations related to soil samples gathered from 10 m (p < 0.01) and 30 m (p < 0.001). Compared with the control, the statistical analysis of Relative Growth Rate (RGR) (p < 0.05) and Specific Growth Rate (SGR) (p < 0.01) confirmed that, in the case of soil samples collected from 10 and 30 m from the Jiu River’s axis, the earthworms did not gain weight, qualitatively attesting the pollution suspicion/presence of chemical factors potentially pernicious for earthworms.
Mining of Cloned Disease Resistance Gene Homologs (CDRHs) in Brassica Species and Arabidopsis thaliana
Authors: Cantila Aldrin Y. , Neik Ting X. , Tirnaz Soodeh , Thomas William J. W. , Bayer Philipp E. , Edwards David , Batley Jacqueline
Published: May 2022

Various diseases severely affect Brassica crops, leading to significant global yield losses and a reduction in crop quality. In this study, we used the complete protein sequences of 49 cloned resistance genes (R genes) that confer resistance to fungal and bacterial diseases known to impact species in the Brassicaceae family. Homology searches were carried out across Brassica napus, B. rapa, B. oleracea, B. nigra, B. juncea, B. carinata and Arabidopsis thaliana genomes. In total, 660 cloned disease R gene homologs (CDRHs) were identified across the seven species, including 431 resistance gene analogs (RGAs) (248 nucleotide binding site-leucine rich repeats (NLRs), 150 receptor-like protein kinases (RLKs) and 33 receptor-like proteins (RLPs)) and 229 non-RGAs. Based on the position and distribution of specific homologs in each of the species, we observed a total of 87 CDRH clusters composed of 36 NLR, 16 RLK and 3 RLP homogeneous clusters and 32 heterogeneous clusters. The CDRHs detected consistently across the seven species are candidates that can be investigated for broad-spectrum resistance, potentially providing resistance to multiple pathogens. The R genes identified in this study provide a novel resource for the future functional analysis and gene cloning of Brassicaceae R genes towards crop improvement.
AI-Aided Design of Novel Targeted Covalent Inhibitors against SARS-CoV-2
Authors: Tang Bowen , He Fengming , Liu Dongpeng , He Fei , Wu Tong , Fang Meijuan , Niu Zhangming , Wu Zhen , Xu Dong
Published: May 2022

The drug repurposing of known approved drugs (e.g., lopinavir/ritonavir) has failed to treat SARS-CoV-2-infected patients. Therefore, it is important to generate new chemical entities against this virus. As a critical enzyme in the lifecycle of the coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive target for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with a fragment-based drug design (ADQN–FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from the lead compounds based on our structure-based optimization policy (SBOP). All of the 47 lead compounds obtained directly with our AI model and related derivatives based on the SBOP are accessible in our molecular library. These compounds can be used as potential candidates by researchers to develop drugs against SARS-CoV-2.
The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease
Authors: Tian Yu , Zhao Mengxi , Chen Yiyi , Yang Mo , Wang Yilong
Published: May 2022

There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.
Dopamine D2 and Serotonin 5-HT1A Dimeric Receptor-Binding Monomeric Antibody scFv as a Potential Ligand for Carrying Drugs Targeting Selected Areas of the Brain
Authors: Kowalik Agata , Majerek Mateusz , Mrowiec Krzysztof , Solich Joanna , Faron-Górecka Agata , Woźnicka Olga , Dziedzicka-Wasylewska Marta , Łukasiewicz Sylwia
Published: May 2022

Targeted therapy uses multiple ways of ensuring that the drug will be delivered to the desired site. One of these ways is an encapsulation of the drug and functionalization of the surface. Among the many molecules that can perform such a task, the present work focused on the antibodies of single-chain variable fragments (scFvs format). We studied scFv, which specifically recognizes the dopamine D2 and serotonin 5-HT1A receptor heteromers. The scFvD2–5-HT1A protein was analyzed biochemically and biologically, and the obtained results indicated that the antibody is properly folded and non-toxic and can be described as low-immunogenic. It is not only able to bind to the D2–5-HT1A receptor heteromer, but it also influences the cAMP signaling pathway and—when surfaced on nanogold particles—it can cross the blood–brain barrier in in vitro models. When administered to mice, it decreased locomotor activity, matching the effect induced by clozapine. Thus, we are strongly convinced that scFvD2–5-HT1A, which was a subject of the present investigation, is a promising targeting ligand with the potential for the functionalization of nanocarriers targeting selected areas of the brain.
The 26S Proteasome Switches between ATP-Dependent and -Independent Mechanisms in Response to Substrate Ubiquitination
Authors: Manfredonia Abramo J. , Kraut Daniel A.
Published: May 2022

The ubiquitin–proteasome system is responsible for the bulk of protein degradation in eukaryotic cells. Proteins are generally targeted to the 26S proteasome through the attachment of polyubiquitin chains. Several proteins also contain ubiquitin-independent degrons (UbIDs) that allow for proteasomal targeting without the need for ubiquitination. Our laboratory previously showed that UbID substrates are less processively degraded than ubiquitinated substrates, but the mechanism underlying this difference remains unclear. We therefore designed two model substrates containing both a ubiquitination site and a UbID for a more direct comparison. We found UbID degradation to be overall less robust, with complete degradation only occurring with loosely folded substrates. UbID degradation was unaffected by the nonhydrolyzable ATP analog ATPγS, indicating that UbID degradation proceeds in an ATP-independent manner. Stabilizing substrates halted UbID degradation, indicating that the proteasome can only capture UbID substrates if they are already at least transiently unfolded, as confirmed using native-state proteolysis. The 26S proteasome therefore switches between ATP-independent weak degradation and ATP-dependent robust unfolding and degradation depending on whether or not the substrate is ubiquitinated.
KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities
Authors: Cela Ilaria , Dufrusine Beatrice , Rossi Claudia , Luini Alberto , De Laurenzi Vincenzo , Federici Luca , Sallese Michele
Published: May 2022

KDEL receptors (KDELRs) are ubiquitous seven-transmembrane domain proteins encoded by three mammalian genes. They bind to and retro-transport endoplasmic reticulum (ER)-resident proteins with a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence or variants thereof. In doing this, KDELR participates in the ER quality control of newly synthesized proteins and the unfolded protein response. The binding of KDEL proteins to KDELR initiates signaling cascades involving three alpha subunits of heterotrimeric G proteins, Src family kinases, protein kinases A (PKAs), and mitogen-activated protein kinases (MAPKs). These signaling pathways coordinate membrane trafficking flows between secretory compartments and control the degradation of the extracellular matrix (ECM), an important step in cancer progression. Considering the basic cellular functions performed by KDELRs, their association with various diseases is not surprising. KDELR mutants unable to bind the collagen-specific chaperon heat-shock protein 47 (HSP47) cause the osteogenesis imperfecta. Moreover, the overexpression of KDELRs appears to be linked to neurodegenerative diseases that share pathological ER-stress and activation of the unfolded protein response (UPR). Even immune function requires a functional KDELR1, as its mutants reduce the number of T lymphocytes and impair antiviral immunity. Several studies have also brought to light the exploitation of the shuttle activity of KDELR during the intoxication and maturation/exit of viral particles. Based on the above, KDELRs can be considered potential targets for the development of novel therapeutic strategies for a variety of diseases involving proteostasis disruption, cancer progression, and infectious disease. However, no drugs targeting KDELR functions are available to date; rather, KDELR has been leveraged to deliver drugs efficiently into cells or improve antigen presentation.
IRW (Isoleucine–Arginine–Tryptophan) Improves Glucose Tolerance in High Fat Diet Fed C57BL/6 Mice via Activation of Insulin Signaling and AMPK Pathways in Skeletal Muscle
Authors: de Campos Zani Stepheny C. , Son Myoungjin , Bhullar Khushwant S. , Chan Catherine B. , Wu Jianping
Published: May 2022

IRW (Isoleucine–Arginine–Tryptophan), has antihypertensive and anti-inflammatory properties in cells and animal models and prevents angiotensin-II- and tumor necrosis factor (TNF)-α-induced insulin resistance (IR) in vitro. We investigated the effects of IRW on body composition, glucose homeostasis and insulin sensitivity in a high-fat diet (HFD) induced insulin resistant (IR) model. C57BL/6 mice were fed HFD for 6 weeks, after which IRW was incorporated into the diet (45 or 15 mg/kg body weight (BW)) until week 14. IRW45 (at a dose of 45 mg/kg BW) reduced BW (p = 0.0327), fat mass gain (p = 0.0085), and preserved lean mass of HFD mice (p = 0.0065), concomitant with enhanced glucose tolerance and reduced fasting glucose (p < 0.001). In skeletal muscle, IRW45 increased insulin-stimulated protein kinase B (AKT) phosphorylation (p = 0.0132) and glucose transporter 4 (GLUT4) translocation (p < 0.001). Angiotensin 2 receptor (AT2R) (p = 0.0024), phosphorylated 5′-AMP-activated protein kinase (AMPKα) (p < 0.0124) and peroxisome proliferator-activated receptor gamma (PPARγ) (p < 0.001) were enhanced in skeletal muscle of IRW45-treated mice, as was the expression of genes involved in myogenesis. Plasma angiotensin converting enzyme-2 (ACE2) activity was increased (p = 0.0016). Uncoupling protein-1 in white adipose tissue (WAT) was partially restored after IRW supplementation. IRW improves glucose tolerance and body composition in HFD-fed mice and promotes glucose uptake in skeletal muscle via multiple signaling pathways, independent of angiotensin converting enzyme (ACE) inhibition.
Multi-Omics Approaches for the Prediction of Clinical Endpoints after Immunotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review
Authors: Bourbonne Vincent , Geier Margaux , Schick Ulrike , Lucia François
Published: May 2022

Immune checkpoint inhibitors (ICI) have revolutionized the management of locally advanced and advanced non-small lung cancer (NSCLC). With an improvement in the overall survival (OS) as both first- and second-line treatments, ICIs, and especially programmed-death 1 (PD-1) and programmed-death ligands 1 (PD-L1), changed the landscape of thoracic oncology. The PD-L1 level of expression is commonly accepted as the most used biomarker, with both prognostic and predictive values. However, even in a low expression level of PD-L1, response rates remain significant while a significant number of patients will experience hyperprogression or adverse events. The dentification of such subtypes is thus of paramount importance. While several studies focused mainly on the prediction of the PD-L1 expression status, others aimed directly at the development of prediction/prognostic models. The response to ICIs depends on a complex physiopathological cascade, intricating multiple mechanisms from the molecular to the macroscopic level. With the high-throughput extraction of features, omics approaches aim for the most comprehensive assessment of each patient. In this article, we will review the place of the different biomarkers (clinical, biological, genomics, transcriptomics, proteomics and radiomics), their clinical implementation and discuss the most recent trends projecting on the future steps in prediction modeling in NSCLC patients treated with ICI.
Systemic Inflammation Predicts Alzheimer Pathology in Community Samples without Dementia
Authors: Cherbuin Nicolas , Walsh Erin I. , Leach Liana , Brüstle Anne , Burns Richard , Anstey Kaarin J. , Sachdev Perminder S. , Baune Bernhard T.
Published: May 2022

Neuroinflammation and oxidative stress (OS) are implicated in the pathophysiology of Alzheimer’s disease (AD). However, it is unclear at what stage of the disease process inflammation first becomes manifest. The aim of this study was to investigate the associations between specific plasma markers of inflammation and OS, tau, and Amyloid-β 38, 40, and 42 levels in cognitively unimpaired middle-age and older individuals. Associations between inflammatory states identified through principal component analysis and AD biomarkers were investigated in middle-age (52–56 years, n = 335, 52% female) and older-age (72–76 years, n = 351, 46% female) participants without dementia. In middle-age, a component reflecting variation in OS was most strongly associated with tau and to a lesser extent amyloid-β levels. In older-age, a similar component to that observed in middle-age was only associated with tau, while another component reflecting heightened inflammation independent of OS, was associated with all AD biomarkers. In middle and older-age, inflammation and OS states are associated with plasma AD biomarkers.
Comparative Profiling of TG2 and Its Effectors in Human Relapsing Remitting and Progressive Multiple Sclerosis
Authors: Pearse Damien D. , Hefley Andrew B. , Morales Alejo A. , Ghosh Mousumi
Published: May 2022

Multiple Sclerosis (MS) is a chronic CNS autoimmune disease characterized by immune-mediated demyelination, axon loss, and disability. Dysregulation of transglutaminase-2 (TG2) has been implicated in disease initiation and progression. Herein, TG2 expression in post-mortem human brain tissue from Relapsing Remitting MS (RRMS) or Progressive MS (PMS) individuals were examined and correlated with the presence of TG2 binding partners and effectors implicated in the processes of inflammation, scar formation, and the antagonism of repair. Tissues from Relapsing-Remitting Multiple Sclerosis (RRMS; n = 6), Progressive Multiple Sclerosis (PMS; n = 5), and non-MS control (n = 6) patients underwent immunohistochemistry for TG2, PLA2, COX-2, FN, CSPG, and HSPG. TG2 was strongly upregulated in active RRMS and PMS lesions, within blood vessels and the perivascular tissue of sclerotic plaques. TG2 colocalization was observed with GFAP+ astrocytes and ECM, including FN, HSPG, and CSPG, which also increased in either RRMS or PMS lesions. Although TG2 was not colocalized with inflammatory mediators COX-2 and PLA2, or the macrophage-microglia marker Iba1, its increased expression correlated with their elevation in active RRMS and PMS lesions. In summary, the correlation of strong TG2 induction in either RRMS or PMS with some of its binding partners but not others implicates potentially different roles for TG2 in disparate MS forms that may warrant further investigation.
DNA Methylation and Gene Expression in Blood and Adipose Tissue of Adult Offspring of Women with Diabetes in Pregnancy—A Validation Study of DNA Methylation Changes Identified in Adolescent Offspring
Authors: Manitta Eleonora , Fontes Marques Irene Carolina , Stokholm Bredgaard Sandra , Kelstrup Louise , Houshmand-Oeregaard Azadeh , Dalsgaard Clausen Tine , Groth Grunnet Louise , Reinhardt Mathiesen Elisabeth , Torp Dalgaard Louise , Barrès Romain , Vaag Allan Arthur , Damm Peter , Hjort Line
Published: May 2022

Maternal gestational diabetes and obesity are associated with adverse outcomes in offspring, including increased risk of diabetes and cardiovascular diseases. Previously, we identified a lower DNA methylation degree at genomic sites near the genes ESM1, MS4A3, and TSPAN14 in the blood cells of adolescent offspring exposed to gestational diabetes and/or maternal obesity in utero. In the present study, we aimed to investigate if altered methylation and expression of these genes were detectable in blood, as well in the metabolically relevant subcutaneous adipose tissue, in a separate cohort of adult offspring exposed to gestational diabetes and obesity (O-GDM) or type 1 diabetes (O-T1D) in utero, compared with the offspring of women from the background population (O-BP). We did not replicate the findings of lower methylation of ESM1, MS4A3, and TSPAN14 in blood from adults, either in O-GDM or O-T1D. In contrast, in adipose tissue of O-T1D, we found higher MS4A3 DNA methylation, which will require further validation. The adipose tissue ESM1 expression was lower in O-GDM compared to O-BP, which in turn was not associated with maternal pre-pregnancy BMI nor the offspring’s own adiposity. Adipose tissue TSPAN14 expression was slightly lower in O-GDM compared with O-BP, but also positively associated with maternal pre-pregnancy BMI, as well as offspring’s own adiposity and HbA1c levels. In conclusion, the lower DNA methylation in blood from adolescent offspring exposed to GDM could not be confirmed in the present cohort of adult offspring, potentially due to methylation remodeling with increased aging. In offspring adipose tissue, ESM1 expression was associated with maternal GDM, and TSPAN14 expression was associated with both maternal GDM, as well as pre-pregnancy BMI. These altered expression patterns are potentially relevant to the concept of developmental programming of cardiometabolic diseases and require further studies.
Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes
Authors: Chung Goh-Eun , Han Kyungdo , Lee Kyu-Na , Cho Eun-Ju , Bae Jung-Ho , Yang Sun-Young , Yu Su-Jong , Choi Seung-Ho , Yim Jeong-Yoon , Heo Nam-Ju
Published: May 2022

Background: We investigated the combined effect of chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD) on the risk of cardiovascular disease (CVD) in patients with type 2 diabetes. Methods: Data were obtained from the Korean National Health Insurance Service. Patients with diabetes who participated in health screenings from 2009 to 2011 were included. The fatty liver index (FLI) was used as a surrogate marker for NAFLD. Results: During a mean follow-up of 6.9 years, 40,863 incidents of myocardial infarction (MI), 58,427 strokes, and 116,977 deaths were reported in 1,607,232 patients with type 2 diabetes. After adjusting for conventional risk factors, patients with CKD and NAFLD showed the highest risk of MI and stroke (hazard ratio (HR) = 1.49; 95% confidence interval (CI): 1.42–1.57 and stroke, HR = 1.48; 95% CI: 1.41–1.54, respectively) compared with those without either CKD or NAFLD. Both overall and cardiovascular mortality were highest in the CKD/NAFLD group compared with other groups (HR = 2.00; 95% CI: 1.94–2.06, and HR = 2.20; 95% CI: 2.07–2.35, respectively). Advanced liver fibrosis was significantly associated with an increased risk of CVD in patients with NAFLD. Proteinuria was significantly associated with incidence of CVD events in patients with CKD. Conclusions: The combination of CKD and NAFLD was associated with an increased risk of CVD and mortality in patients with type 2 diabetes. Close monitoring and appropriate management of CKD and NAFLD may be warranted to prevent CVD in these patients.