bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Risk Characteristics of Agricultural Drought Disaster Events Based on the Copula Function in Northeast China
Authors: Zhang Shujie , Wang Ping , Wang Dongni , Zhang Yushu , Ji Ruipeng , Cai Fu
Published: August 2022

Accurate feature identification of drought disaster events is required for proper risk management in agriculture. This study improved the crop water deficit index (CWDI) by including the daily meteorological, crop development stage, soil moisture content, and yield data for 1981–2020 in northeastern China. Two drought characteristic variables (drought duration and intensity) were extracted using the theory of runs to produce the improved crop water deficit index (CWDIwp). Thresholds for the bivariate indicators were also determined for agricultural drought events of varying severity. A joint distribution model for drought variables was constructed based on five types of Archimedean copulas. The joint probability and the joint recurrence period for agricultural drought events were analyzed for drought events with varying intensities in northeast China. The results suggest that the CWDIwp can reliably identify the onset, duration, and intensity of drought events over the study area and can be used to monitor agricultural drought events. The conditional probability of drought intensity (duration) decreased as the drought duration (intensity) threshold increased, whereas the drought recurrence period increased as the threshold for drought duration and intensity rose. In the period (1981–2020), drought intensity in the three Northeastern provinces showed an increasing trend in the order Jilin Province > Liaoning Province > Heilongjiang Province. The spatial distribution of the joint probability and the joint recurrence period was obvious, and the joint probability showed a decreasing distribution trend from west to east. The distribution trend for the joint probability was opposite to that of the joint recurrence period. Furthermore, the areas with high drought probability values corresponded to the areas with low values for the recurrence period, indicating that the drought occurrence probability was higher, and the recurrence period value was lower in the drought-prone areas. The high-risk drought areas (60–87%) were in western Liaoning and western Jilin, with a recurrence period of 1–3 years, whereas the low-risk areas (<40%) were located in the mountainous areas of eastern Liaoning and eastern Jilin. The joint probability and joint recurrence period for agricultural drought events of varying severity were quite different, with the probability following the order light drought > moderate drought > severe drought > extreme drought. The order for the recurrence period was light drought < moderate drought < severe drought < extreme drought. The results provide technical support for disaster prevention and mitigation in drought risk management.
The Influences of the Desert Photovoltaic Power Station on Local Climate and Environment: A Case Study in Dunhuang Photovoltaic Industrial Park, Dunhuang City, China in 2019
Authors: Hua Yaping , Chai Juan , Chen Long , Liu Puxing
Published: August 2022

Based on the meteorological observation data of air temperature, surface temperature and albedo data retrieved from remote sensing images inside and outside the photovoltaic station, as well as the measured soil moisture content and bulk density at different locations of the photovoltaic power station in 2019, the impact of large-scale desert photovoltaic power plants on climate and environment was studied. The results show that air temperature, surface temperature and albedo inside the photovoltaic power station are lower than those outside the station, which are obvious in winter and not obvious in summer. Therefore, the photovoltaic power station is a cold source and an energy sink. The soil moisture content under and between the photovoltaic arrays is larger than other sampling points, and the soil bulk density gradually decreases with the distance from the center of the photovoltaic power station. Therefore, future plans for desert photovoltaic power station construction should take into account the impacts on local climate and environment.
Naturally Equipped Urinary Exosomes Coated Poly (2−ethyl−2−oxazoline)−Poly (D, L−lactide) Nanocarriers for the Pre−Clinical Translation of Breast Cancer
Authors: Ni Jiang , Mi Yuanyuan , Wang Bei , Zhu Yuting , Ding Yang , Ding Yongjuan , Li Xia
Published: August 2022

Recently, biomimetic nanoparticles for tumor−targeted therapy have attracted intensifying interest. Although exosomes are an excellent biomimetic material, numerous challenges are still hindering its clinical applications, such as low yield, insufficient targeting efficiency, and high cost. In this work, urinary exosomes (UEs) with high expression of CD9 and CD47 were extracted from breast cancer patients by a non−invasive method. Here, a nanotechnology approach is reported for tumor homologous targeting via CD9 and phagocytosis escape via CD47 through UE−coated poly (2−ethyl−2−oxazoline)−poly (D, L−lactide) (PEOz−PLA) nanoparticles (UEPP NPs). The cytotoxic agent doxorubicin (DOX)−loaded UEPP (UEPP−D) NPs with an initial particle size of 61.5 nm showed a burst release under acidic condition mimicking the tumor microenvironment. In vitro experiments revealed that UEPP−D NPs exhibited significantly improved cellular uptake, cytotoxicity, and apoptosis in MCF−7 cell lines as compared to DOX−loaded PEOz−PLA nanoparticles (PP−D NPs) and free DOX. More importantly, anti−phagocytosis and pharmacokinetic studies confirmed that UEPP−D NPs had superior immune escape ability and significantly prolonged the drug’s bloodstream circulation in vivo. Finally, UEPP−D NPs showed a markedly higher antitumor efficacy and lower side−toxicity in MCF−7 tumor bearing nude mice model. Thus, this versatile nano−system with immune escape, homologous targeting, and rapid response release characteristics could be a promising tool for breast cancer treatment.
Changes in Liver Stiffness and Markers of Liver Synthesis and Portal Hypertension following Hepatitis C Virus Eradication in Cirrhotic Individuals
Authors: Armandi Angelo , Rosso Chiara , Troshina Giulia , Pérez Diaz Del Campo Nuria , Marinoni Chiara , Nicolosi Aurora , Caviglia Gian Paolo , Saracco Giorgio Maria , Bugianesi Elisabetta , Ciancio Alessia
Published: August 2022

The advent of direct antiviral agents (DAAs) has radically changed the natural history of hepatitis C virus (HCV) chronic liver disease. Even patients with cirrhosis may display improvements in liver function or features of portal hypertension following viral eradication. The aim of this study was to assess whether a HCV cure would lead to improvements in cirrhotic patients using simple, readily available tools in clinical practice, together with liver stiffness (LS) measurement. This is a retrospective study of cirrhotic patients with cured HCV infection, with or without previous decompensation. Clinical and biochemical parameters as well as LS measurements were collected before antiviral treatment with DAAs and after 6 months following sustained virological response. Hepatic synthesis was assessed by serum albumin levels. Portal hypertension was indirectly assessed by platelet count. Liver function was determined by the CHILD score. A total of 373 cirrhotic patients with successful HCV eradication were retrospectively included. After 6 months of follow-up, a significantly higher proportion of patients showed improved liver function, shifting from the CHILD B/C to CHILD A group, (71.4%, p < 0.001). Similarly, LS improved from a median of 19.3 kPa (14.7–27) at the baseline vs. a median of 11.6 (7.7–16.8 kPa) at follow-up (p < 0.001). The proportion of patients who showed improved hepatic synthesis was 66.0%, which was statistically different when compared to that of patients who had a worsened condition (0.3%) (p < 0.001). Moreover, when classifying the cohort according to the RESIST-HCV score, we found that a significant proportion of patients shifted into the “low risk” group following DAA treatment (52% baseline vs. 45.6% at follow-up, p = 0.004). Even in the decompensated patients, LS improved from 1.6 to 2-fold from the baseline. Antiviral treatment is effective in improving indirect signs of hepatic synthesis and portal hypertension. Similarly, the LS values displayed significant improvements, even in decompensated patients.
Morphometric and Genetic Description of Trophic Adaptations in Cichlid Fishes
Authors: DeLorenzo Leah , DeBrock Victoria , Carmona Baez Aldo , Ciccotto Patrick J. , Peterson Erin N. , Stull Clare , Roberts Natalie B. , Roberts Reade B. , Powder Kara E.
Published: August 2022

Since Darwin, biologists have sought to understand the evolution and origins of phenotypic adaptations. The skull is particularly diverse due to intense natural selection on feeding biomechanics. We investigated the genetic and molecular origins of trophic adaptation using Lake Malawi cichlids, which have undergone an exemplary evolutionary radiation. We analyzed morphological differences in the lateral and ventral head shape among an insectivore that eats by suction feeding, an obligate biting herbivore, and their F2 hybrids. We identified variation in a series of morphological traits—including mandible width, mandible length, and buccal length—that directly affect feeding kinematics and function. Using quantitative trait loci (QTL) mapping, we found that many genes of small effects influence these craniofacial adaptations. Intervals for some traits were enriched in genes related to potassium transport and sensory systems, the latter suggesting co-evolution of feeding structures and sensory adaptations for foraging. Despite these indications of co-evolution of structures, morphological traits did not show covariation. Furthermore, phenotypes largely mapped to distinct genetic intervals, suggesting that a common genetic basis does not generate coordinated changes in shape. Together, these suggest that craniofacial traits are mostly inherited as separate modules, which confers a high potential for the evolution of morphological diversity. Though these traits are not restricted by genetic pleiotropy, functional demands of feeding and sensory structures likely introduce constraints on variation. In all, we provide insights into the quantitative genetic basis of trophic adaptation, identify mechanisms that influence the direction of morphological evolution, and provide molecular inroads to craniofacial variation.
Biological Maturation Predicts Dynamic Balance and Lower Limb Power in Young Football Players
Authors: Wilczyński Bartosz , Radzimiński Łukasz , Sobierajska-Rek Agnieszka , de Tillier Karol , Bracha Jakub , Zorena Katarzyna
Published: August 2022

Biological maturation has an increasingly important role in youth sports. The aim of the study was to evaluate the relationship between dynamic balance and lower limb power and biological maturation in young football players. Seventy-two healthy, young male elite football players (age: 10 ± 2) participated in the study. Dynamic balance was assessed using a modified Star Excursion Balance Test (mSEBT). Power of the lower limbs was examined by a Countermovement Jump test (CMJ) and Single Leg Hop for Distance (SLHD). Furthermore, anthropometry and biological maturation (age, peak height velocity, and maturity offset) were assessed. There was a strong positive correlation between vertical jump (r = 0.75), distance long jump (r = 0.84), and biological maturation. A moderate positive correlation was found between dynamic balance (mSEBT COM, PL, and PM) and maturity offset. There was a significant association between mSEBT, CMJ, and SLHD (p < 0.05). Moreover, maturity offset explained 75% of vertical jump and 74% of distance long jump performance, respectively, and 12% of dynamic balance. Biological maturation should be considered when assessing athletic performance, establishing rehabilitation, and sports training in youth football players.
Experimentally Deduced Criteria for Detection of Clinically Relevant Fusion 3′ Oncogenes from FFPE Bulk RNA Sequencing Data
Authors: Rabushko Elizaveta , Sorokin Maxim , Suntsova Maria , Seryakov Alexander P. , Kuzmin Denis V. , Poddubskaya Elena , Buzdin Anton A.
Published: August 2022

Drugs targeting receptor tyrosine kinase (RTK) oncogenic fusion proteins demonstrate impressive anti-cancer activities. The fusion presence in the cancer is the respective drug prescription biomarker, but their identification is challenging as both the breakpoint and the exact fusion partners are unknown. RNAseq offers the advantage of finding both fusion parts by screening sequencing reads. Paraffin (FFPE) tissue blocks are the most common way of storing cancer biomaterials in biobanks. However, finding RTK fusions in FFPE samples is challenging as RNA fragments are short and their artifact ligation may appear in sequencing libraries. Here, we annotated RNAseq reads of 764 experimental FFPE solid cancer samples, 96 leukemia samples, and 2 cell lines, and identified 36 putative clinically relevant RTK fusions with junctions corresponding to exon borders of the fusion partners. Where possible, putative fusions were validated by RT-PCR (confirmed for 10/25 fusions tested). For the confirmed 3′RTK fusions, we observed the following distinguishing features. Both moieties were in-frame, and the tyrosine kinase domain was preserved. RTK exon coverage by RNAseq reads upstream of the junction site were lower than downstream. Finally, most of the true fusions were present by more than one RNAseq read. This provides the basis for automatic annotation of 3′RTK fusions using FFPE RNAseq profiles.
Association of Serum GFAP with Functional and Neurocognitive Outcome in Sporadic Small Vessel Disease
Authors: Huss André , Abdelhak Ahmed , Mayer Benjamin , Tumani Hayrettin , Müller Hans-Peter , Althaus Katharina , Kassubek Jan , Otto Markus , Ludolph Albert C. , Yilmazer-Hanke Deniz , Neugebauer Hermann
Published: August 2022

Cerebrospinal fluid (CSF) and serum biomarkers are critical for clinical decision making in neurological diseases. In cerebral small vessel disease (CSVD), white matter hyperintensities (WMH) are an important neuroimaging biomarker, but more blood-based biomarkers capturing different aspects of CSVD pathology are needed. In 42 sporadic CSVD patients, we prospectively analysed WMH on magnetic resonance imaging (MRI) and the biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), chitinase3-like protein 1 (CHI3L1), Tau and Aβ1-42 in CSF and NfL and GFAP in serum. GFAP and CHI3L1 expression was studied in post-mortem brain tissue in additional cases. CSVD cases with higher serum NfL and GFAP levels had a higher modified Rankin Scale (mRS) and NIHSS score and lower CSF Aβ1-42 levels, whereas the CSF NfL and CHI3L1 levels were positively correlated with the WMH load. Moreover, the serum GFAP levels significantly correlated with the neurocognitive functions. Pathological analyses in CSVD revealed a high density of GFAP-immunoreactive fibrillary astrocytic processes in the periventricular white matter and clusters of CHI3L1-immunoreactive astrocytes in the basal ganglia and thalamus. Thus, besides NfL, serum GFAP is a highly promising fluid biomarker of sporadic CSVD, because it does not only correlate with the clinical severity but also correlates with the cognitive function in patients.
In Vitro Blood Clot Formation and Dissolution for Testing New Stroke-Treatment Devices
Authors: Wood Kayla , Stephens Sam E. , Xu Feng , Hazaa Alshaimaa , Meek James C. , Jensen Hanna K. , Jensen Morten O. , Wickramasinghe Ranil
Published: August 2022

Strokes are among the leading causes of death worldwide. Ischemic stroke, due to plaque or other buildup blocking blood flow to the brain, is the most common type. Although ischemic stroke is treatable, current methods have severe shortcomings with high mortality rates. Clot retrieval devices, for example, can result in physically damaged vessels and death. This study aims to create blood clots that are representative of those found in vivo and demonstrate a new method of removing them. Static blood clots were formed using a 9:1 ratio of whole sheep blood and 2.45% calcium chloride solution. This mixture was heated in a water bath at 37 °C for approximately one hour until solidified. Following clot solidification, human plasmin was introduced by various methods, including soaking, injection, and membrane perfusion, and the resulting dissolution percentages were determined. Different clot types, representative of the wide range found physiologically, were also manufactured and their dissolution characteristics evaluated. A method to reproducibly create blood clots, characteristic of those found in vivo, is essential for the production of stroke retrieval devices that can efficiently and effectively remove clots from patients with low mortality rates and little/no damage to the surrounding vessels.
Developing New Treatment Options for Castration-Resistant Prostate Cancer and Recurrent Disease
Authors: Wang Bo-Ren , Chen Yu-An , Kao Wei-Hsiang , Lai Chih-Ho , Lin Ho , Hsieh Jer-Tsong
Published: August 2022

Prostate cancer (PCa) is a major diagnosed cancer among men globally, and about 20% of patients develop metastatic prostate cancer (mPCa) in the initial diagnosis. PCa is a typical androgen-dependent disease; thus, hormonal therapy is commonly used as a standard care for mPCa by inhibiting androgen receptor (AR) activities, or androgen metabolism. Inevitably, almost all PCa will acquire resistance and become castration-resistant PCa (CRPC) that is associated with AR gene mutations or amplification, the presence of AR variants, loss of AR expression toward neuroendocrine phenotype, or other hormonal receptors. Treating CRPC poses a great challenge to clinicians. Research efforts in the last decade have come up with several new anti-androgen agents to prolong overall survival of CRPC patients. In addition, many potential targeting agents have been at the stage of being able to translate many preclinical discoveries into clinical practices. At this juncture, it is important to highlight the emerging strategies including small-molecule inhibitors to AR variants, DNA repair enzymes, cell survival pathway, neuroendocrine differentiation pathway, radiotherapy, CRPC-specific theranostics and immune therapy that are underway or have recently been completed.
LncRNA-Profile-Based Screening of Extracellular Vesicles Released from Brain Endothelial Cells after Oxygen–Glucose Deprivation
Authors: He Xiang , Zou Hecun , Lyu Qiang , Tang Yujing , Xiong Wenkui , Shang Fei-Fei
Published: August 2022

Brain microvascular endothelial cells (BMECs) linked by tight junctions play important roles in cerebral ischemia. Intercellular signaling via extracellular vesicles (EVs) is an underappreciated mode of cell–cell crosstalk. This study aims to explore the potential function of long noncoding RNAs (lncRNAs) in BMECs’ secreted EVs. We subjected primary human and rat BMECs to oxygen and glucose deprivation (OGD). EVs were enriched for RNA sequencing. A comparison of the sequencing results revealed 146 upregulated lncRNAs and 331 downregulated lncRNAs in human cells and 1215 upregulated lncRNAs and 1200 downregulated lncRNAs in rat cells. Next, we analyzed the genes that were coexpressed with the differentially expressed (DE) lncRNAs on chromosomes and performed Gene Ontology (GO) and signaling pathway enrichment analyses. The results showed that the lncRNAs may play roles in apoptosis, the TNF signaling pathway, and leukocyte transendothelial migration. Next, three conserved lncRNAs between humans and rats were analyzed and confirmed using PCR. The binding proteins of these three lncRNAs in human astrocytes were identified via RNA pulldown and mass spectrometry. These proteins could regulate mRNA stability and translation. Additionally, the lentivirus was used to upregulate them in human microglial HMC3 cells. The results showed NR_002323.2 induced microglial M1 activation. Therefore, these results suggest that BMECs’ EVs carry the lncRNAs, which may regulate gliocyte function after cerebral ischemia.
Higher Plasma Fibrinogen Level at Admission Is Associated with Post-Stroke Depression at Discharge
Authors: Zhu Juehua , Wang Li , Shao Han , Tang Xiang , Zhang Lulu , Zhou Yun , Jiang Yongjun , Fang Qi , Cai Xiuying
Published: August 2022

Background: Post-stroke depression (PSD) is a common complication of stroke, which seriously affects the functional outcome of patients. Systemic low-grade inflammation associated with PSD has been shown to occur at several months to years, however, whether these inflammatory markers predicted PSD at an acute stage of stroke is controversial. Method: A total of 625 patients with acute ischemic stroke (219 female, 35.40%) were included in this study. PSD was diagnosed using the 17-item Hamilton depression scale (HAMD) at 7 days following discharge (7–14 days after stroke onset). Multivariable logistic regression analysis was applied to build a prediction model for PSD at discharge. Discrimination and calibration of the model were assessed by C-index, calibration plot. Internal validation was conducted using bootstrapping validation. Results: At discharge of hospitalization, 95 patients (15.20%) were diagnosed with PSD. Multivariable logistic regression suggested that female gender (OR = 2.043, 95% CI = 1.287–3.245, p = 0.002), baseline NIHSS (OR = 1.108, 95% CI = 1.055–1.165, p < 0.001) and fibrinogen (OR = 1.388, 95% CI = 1.129–1.706, p = 0.002) were independent predictors for PSD at discharge. The cut-off of the fibrinogen plasma level was 3.08 g/L. These predictors were included in the nomogram. The model displayed good discrimination, with a C-index of 0.730 (95% CI = 0.683–0.777) and good calibration. Conclusion: Female gender, baseline stroke severity and a higher level of fibrinogen were independently associated with PSD at discharge. A nomogram based on these three predictors can be used to provide an individual, visual prediction of the risk probability of PSD.
The Eccentric Compression Performance of Spirally Stiffened Thin-Walled Square Concrete-Filled Steel Tubular Laminated Composite Members
Authors: Wang Zhenshan , Su Yanan , Wei Jun , Lu Junlong , Li Xiaolei
Published: August 2022

To enhance the local buckling resistance of thin-walled steel pipes and enhance their fire and corrosion resistance, a new spirally stiffened thin-walled square concrete-filled steel tubular laminated composite member with transverse ribs is proposed. Through the four forms of combined members for eccentric pressure testing, it was found that: ordinary thin-walled steel pipe concrete drum buckling is more severe; with spiral ribs, the buckling is limited between the stiffening ribs; and the deformation is significantly reduced. By addressing the problem of cooperative work between the inner and outer structural layers of new components, it was found that, after setting constraints such as steel bars, the integrity of the two can be ensured, and the stress performance is significantly improved; compared to ordinary steel pipe concrete, the load-carrying capacity is 17.9% higher, and the deformation capacity is roughly equivalent. Spiral ribs as a new form of spatial restraint, in addition to increasing the local bending stiffness, manifest an overall restraint role in limiting lateral deformation of the steel pipe, whereas the role of vertical stiffness is insignificant. Based on test evidence, the influences of the width to thickness ratio of spiral ribs and pitch were determined, and reasonable structural measures for the members were given. Through the N–M relationship curve, the limit of damage in compression and tension under eccentricity was obtained at an eccentricity of about 0.9. Finally, a method for calculating the eccentric compressive ultimate load capacity of this new composite member was proposed.
FEM-Based Evaluation of the Point Thermal Transmittance of Various Types of Ventilated Façade Cladding Fastening Systems
Authors: Petresevics Fanni , Nagy Balázs
Published: August 2022

The prevalence of ventilated façade systems is not only due to their aesthetic properties but also due to the fact they provide mechanical and acoustic protection for the façade and reduce the energy demand of the building. However, it is essential to mention that the point thermal bridges of the fastening system with brackets and anchors are often neglected during simplified energy performance calculations and practical design tasks. The reason practitioners do not consider the brackets in the calculation is the lack of standards for the simplified calculation of point thermal transmittances, or there being no comprehensive, manufacturer-independent thermal bridge catalogue available. This study aims to evaluate the point thermal transmittances created by the brackets and anchors of the ventilated façade claddings by using 3D numerical thermal modelling. A broad point thermal bridge catalogue was created, considering multiple factors of the ventilated facades. The FEM-based results show that thermal breaks/isolators could reduce the point thermal transmittances by only 2 to 28%, depending on the material of the brackets and the isolators. The brackets’ material and geometrical properties/parameters could cause up to 70% of difference between corrected and uncorrected thermal transmittance values, as well as significant differences between the results if the brackets were applied to different kinds of masonry walls or reinforced concrete walls.
Quantification of Vertical Irregularities for Earthquake Resistant Reinforced Concrete Buildings
Authors: Nady Omar , Mahfouz Sameh Youssef , Taher Salah El-Din Fahmy
Published: August 2022

In modern urban construction, irregular buildings are increasingly constructed to fulfill architectural and functional requirements. However, these buildings revealed unfavorable seismic performance during the past earthquake records. When the seismic design codes deal with the issue of building irregularity, little attention is paid to the location of irregularity. In the current study, a detailed structural analysis was performed to investigate the effects of the location of mass, stiffness, setback, and combined irregularities on the structural seismic response of twelve irregular building models. Based on the dynamic properties of the building, an irregularity index is proposed to quantify the effects of the magnitude and location of various types of vertical irregularities. The proposed index was able to successfully quantify all types of vertical irregularities.
Hydrothermal Evaluation of Vernacular Housing: Comparing Case Studies of Waste PET Bottles, Stone, and Adobe Houses
Authors: Soto Flavio Roberto Ceja , Bueno José de Jesús Pérez , Mendoza López Maria Luisa , Chavela Martín Hernández , Ramos Martha Elva Pérez , Manzano-Ramírez Alejandro
Published: August 2022

This work shows the humidity and thermal evaluation of different case studies of houses. The analyses focused on room prototypes and houses built in different regions of Querétaro, México. Three different climatic zones were included with the evaluations of houses and prototypes. The assessments of internal and external parameters in residential buildings are also shown. The internal parameter measurements were done with hydro-thermometers and thermography images. Six structures were evaluated, one of the conventional housing materials and five of alternative or vernacular materials. The predicted mean vote (PMV) and the predicted percentage dissatisfied (PPD) were determined using the average temperature and relative humidity values, and they were considered to be dynamic because they can change depending on many factors. The six dwelling insulating properties were associated with their construction materials, design, location, and other factors. The six houses have many differences, but considering their behavior in their location, the two floor porous stone house got the best results. On the contrary, the flagstone house with a gabled roof of galvanized sheets had a cold perception despite many advantageous elements, failing to provide comfort in such a cold location. Contrasting these with other adobe constructions, the analyzed one had low thermal insulation, which was explained by its characteristics. PET and adobe uninhabited prototypes had medium to cold perceptions. The PET prototype has excellent and adjustable insulations, both on temperature and RH, considering the passive illumination and ventilation of its glass bottle skylights.
External Quality Assessment 2.0: The Importance of a Standardized Implementation of TILs for Daily and Trial Practices
Authors: Nauwelaers Inne , Laudus Nele , Peeters Dieter , Acs Balazs , Denkert Carsten , Michiels Stefan , Horlings Hugo , Siziopikou Kalliopi P. , Ely Scott , Zardavas Dimitrios , Mustimbo Roberts , Bartlett John , Floris Giuseppe , Hartman Johan , van Deurzen Carolien H. M. , Ceusters Dorien , Dequeker Els , Salgado Roberto
Published: August 2022

Increasing data suggests that an intact immune system is required for improvedoutcomes in patients with Human Epidermal Growth Factor Receptor 2 (HER2+) and Triple Negative Breast Cancer (TNBC) [...]
Proteomic Analysis of Prostate Cancer FFPE Samples Reveals Markers of Disease Progression and Aggressiveness
Authors: Lygirou Vasiliki , Fasoulakis Konstantinos , Stroggilos Rafael , Makridakis Manousos , Latosinska Agnieszka , Frantzi Maria , Katafigiotis Ioannis , Alamanis Christos , Stravodimos Konstantinos G. , Constantinides Constantinos A. , Vlahou Antonia , Zoidakis Jerome
Published: August 2022

Prostate cancer (PCa) is the second most common cancer in men. Diagnosis and risk assessment are widely based on serum Prostate Specific Antigen (PSA) and biopsy, which might not represent the exact degree of PCa risk. Towards the discovery of biomarkers for better patient stratification, we performed proteomic analysis of Formalin Fixed Paraffin Embedded (FFPE) prostate tissue specimens using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Comparative analysis of 86 PCa samples among grade groups 1–5 identified 301 significantly altered proteins. Additional analysis based on biochemical recurrence (BCR; BCR+ n = 14, BCR- n = 51) revealed 197 significantly altered proteins that indicate disease persistence. Filtering the overlapping proteins of these analyses, seven proteins (NPM1, UQCRH, HSPA9, MRPL3, VCAN, SERBP1, HSPE1) had increased expression in advanced grades and in BCR+/BCR- and may play a critical role in PCa aggressiveness. Notably, all seven proteins were significantly associated with progression in Prostate Cancer Transcriptome Atles (PCTA) and NPM1NPM1, UQCRH, and VCAN were further validated in The Cancer Genome Atlas (TCGA), where they were upregulated in BCR+/BCR-. UQCRH levels were also associated with poorer 5-year survival. Our study provides valuable insights into the key regulators of PCa progression and aggressiveness. The seven selected proteins could be used for the development of risk assessment tools.
Fabrication of WS2/WSe2 Z-Scheme Nano-Heterostructure for Efficient Photocatalytic Hydrogen Production and Removal of Congo Red under Visible Light
Authors: Tien Tsung-Mo , Chung Yu-Jen , Huang Chen-Tang , Chen Edward L.
Published: August 2022

In this study, a novel tungsten disulfide/tungsten diselenide (WS2/WSe2) heterojunction photocatalyst by a facile hydrothermal process with great capable photocatalytic efficiency for hydrogen evolution from water and organic compound removal was discussed. The WS2/WSe2 heterojunction photocatalyst to form heterojunctions to inhibit the quick recombination rate of photo-response holes and electrons is reflected to be a useful method to enhance the capability of photocatalysis hydrogen production. The hydrogen production rate of the WS2/WSe2 photocatalyst approach is 3856.7 μmol/g/h, which is 12 and 11 folds the efficiency of bare WS2 and WSe2, respectively. Moreover, the excellent photocatalytic performance for Congo Red (CR) removal (92.4%) was 2.4 and 2.1 times higher than those of bare WS2 and WSe2, respectively. The great photocatalytic efficiency was owing to the capable electrons and holes separation of WS2/WSe2 and the construction of Z-scheme heterostructure, which possessed vigorous photocatalytic oxidation and reduction potentials. The novel one-dimensional structure of WS2/WSe2 heterojunction shortens the transport pathway of photo-induced electrons and holes. This work provided an insight to the pathway of interfacial separation and transferring for induced charge carriers, which can refer to the interfacial engineering of developed nanocomposite photocatalysts. It possessed great capable photocatalytic efficiency of hydrogen production and organic dye removal. This study offers an insight to the route of interfacial migration and separation for induced charge carriers to generating clean hydrogen energy and solve environmental pollution issue.
The High ‘Lipolytic Jump’ of Immobilized Amano A Lipase from Aspergillus niger in Developed ‘ESS Catalytic Triangles’ Containing Natural Origin Substrates
Authors: Siódmiak Tomasz , Dulęba Jacek , Kocot Natalia , Wątróbska-Świetlikowska Dorota , Marszałł Michał
Published: August 2022

Lipase Amano A from Aspergillus niger (AA-ANL) is among the most commonly applied enzymes in biocatalysis processes, making it a significant scientific subject in the pharmaceutical and medical disciplines. In this study, we investigated the lipolytic activity of AA-ANL immobilized onto polyacrylic support IB-150A in 23 oils of natural origin containing various amounts of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs). The created systems were expressed as an ‘ESS catalytic triangle’. A distinct ‘jump’ (up to 2400%) of lipolytic activity of immobilized AA-ANL compared to free lipase and hyperactivation in mostly tested substrates was observed. There was a ‘cutoff limit’ in a quantitative mutual ratio of ω-PUFAs/MUFAs, for which there was an increase or decrease in the activity of the immobilized AA-ANL. In addition, we observed the beneficial effect of immobilization using three polyacrylic supports (IB-150A, IB-D152, and IB-EC1) characterized by different intramolecular interactions. The developed substrate systems demonstrated considerable hyperactivation of immobilized AA-ANL. Moreover, a ‘lipolytic jump’ in the full range of tested temperature and pH was also observed. The considerable activity of AA-ANL-IB-150A after four reuse cycles was demonstrated. On the other hand, we observed an essential decrease in stability of immobilized lipase after 168 h of storage in a climate chamber. The tested kinetic profile of immobilized AA-ANL confirmed the decreased affinity to the substrate relative to lipase in the free form.
Biochemical and Physical Characterization of Immobilized Candida rugosa Lipase on Metal Oxide Hybrid Support
Authors: Ramlee Nurfadhila Nasya , Md Illias Rosli , A. Rahman Roshanida , Toemen Susilawati , Selvasembian Rangabhashiyam , Ahmad Rabi’atul Adawiyah , Abdul Manas Nor Hasmaliana , Wan Azelee Nur Izyan
Published: August 2022

Enzyme immobilization on inorganic materials is gaining more attention with the potential characteristics of high-surface-area-to-volume ratios, increasing the efficiency of enzyme loading on the support. Metal oxide hybrid support was prepared by a wetness impregnation of five metal precursors, including CaO, CuO, MgO, NiO, and ZnO, on Al2O3 and used as a support for the immobilization of Candida rugosa lipase (CRL) by adsorption. Maximum activity recovery (70.6%) and immobilization efficiency (63.2%) were obtained after optimization of five parameters using response surface methodology (RSM) by Box–Behnken design (BBD). The biochemical properties of immobilized CRL showed high thermostability up to 70 °C and a wide range in pH stability (pH 4–10). TGA-DTA and FTIR analysis were conducted, verifying thermo-decomposition of lipase and the presence of an amide bond. FESEM-EDX showed the homogeneous distribution and high dispersion of magnesium and CRL on MgO-Al2O3, while a nitrogen adsorption–desorption study confirmed MgO-Al2O3 as a mesoporous material. CRL/MgO-Al2O3 can be reused for up to 12 cycles and it demonstrated high tolerance in solvents (ethanol, isopropanol, methanol, and tert-butanol) compared to free CRL.
Electrophysiology of Endolysosomal Two-Pore Channels: A Current Account
Authors: Patel Sandip , Yuan Yu , Chen Cheng-Chang , Jaślan Dawid , Gunaratne Gihan , Grimm Christian , Rahman Taufiq , Marchant Jonathan S.
Published: August 2022

Two-pore channels TPC1 and TPC2 are ubiquitously expressed pathophysiologically relevant proteins that reside on endolysosomal vesicles. Here, we review the electrophysiology of these channels. Direct macroscopic recordings of recombinant TPCs expressed in enlarged lysosomes in mammalian cells or vacuoles in plants and yeast demonstrate gating by the Ca2+-mobilizing messenger NAADP and/or the lipid PI(3,5)P2. TPC currents are regulated by H+, Ca2+, and Mg2+ (luminal and/or cytosolic), as well as protein kinases, and they are impacted by single-nucleotide polymorphisms linked to pigmentation. Bisbenzylisoquinoline alkaloids, flavonoids, and several approved drugs demonstrably block channel activity. Endogenous TPC currents have been recorded from a number of primary cell types and cell lines. Many of the properties of endolysosomal TPCs are recapitulated upon rerouting channels to the cell surface, allowing more facile recording through conventional electrophysiological means. Single-channel analyses have provided high-resolution insight into both monovalent and divalent permeability. The discovery of small-molecule activators of TPC2 that toggle the ion selectivity from a Ca2+-permeable (NAADP-like) state to a Na+-selective (PI(3,5)P2-like) state explains discrepancies in the literature relating to the permeability of TPCs. Identification of binding proteins that confer NAADP-sensitive currents confirm that indirect, remote gating likely underpins the inconsistent observations of channel activation by NAADP.
Cell-Level Spatio-Temporal Model for a Bacillus Calmette–Guérin-Based Immunotherapy Treatment Protocol of Superficial Bladder Cancer
Authors: Lazebnik Teddy
Published: August 2022

Bladder cancer is one of the most widespread types of cancer. Multiple treatments for non-invasive, superficial bladder cancer have been proposed over the last several decades with a weekly Bacillus Calmette–Guérin immunotherapy-based therapy protocol, which is considered the gold standard today. Nonetheless, due to the complexity of the interactions between the immune system, healthy cells, and cancer cells in the bladder’s microenvironment, clinical outcomes vary significantly among patients. Mathematical models are shown to be effective in predicting the treatment outcome based on the patient’s clinical condition at the beginning of the treatment. Even so, these models still have large errors for long-term treatments and patients that they do not fit. In this work, we utilize modern mathematical tools and propose a novel cell-level spatio-temporal mathematical model that takes into consideration the cell–cell and cell–environment interactions occurring in a realistic bladder’s geometric configuration in order to reduce these errors. We implement the model using the agent-based simulation approach, showing the impacts of different cancer tumor sizes and locations at the beginning of the treatment on the clinical outcomes for today’s gold-standard treatment protocol. In addition, we propose a genetic-algorithm-based approach to finding a successful and time-optimal treatment protocol for a given patient’s initial condition. Our results show that the current standard treatment protocol can be modified to produce cancer-free equilibrium for deeper cancer cells in the urothelium if the cancer cells’ spatial distribution is known, resulting in a greater success rate.
Differential Paralog-Specific Expression of Multiple Small Subunit Proteins Cause Variations in Rpl42/eL42 Incorporation in Ribosome in Fission Yeast
Authors: Li Wenzhu , Zhang Jing , Cheng Wenpeng , Li Yuze , Feng Jinwen , Qin Jun , He Xiangwei
Published: August 2022

Ribosomes within a cell are commonly viewed as biochemically homogenous RNA–protein super-complexes performing identical functions of protein synthesis. However, recent evidence suggests that ribosomes may be a more dynamic macromolecular complex with specialized roles. Here, we present extensive genetic and molecular evidence in the fission yeast S. pombe that the paralogous genes for many ribosomal proteins (RPs) are functionally different, despite that they encode the same ribosomal component, often with only subtle differences in the sequences. Focusing on the rps8 paralog gene deletions rps801d and rps802d, we showed that the mutant cells differ in the level of Rpl42p in actively translating ribosomes and that their phenotypic differences reside in the Rpl42p level variation instead of the subtle protein sequence difference between Rps801p and Rps802p. Additional 40S ribosomal protein paralog pairs also exhibit similar phenotypic differences via differential Rpl42p levels in actively translating ribosomes. Together, our work identifies variations in the Rpl42p level as a potential form of ribosome heterogeneity in biochemical compositions and suggests a possible connection between large and small subunits during ribosome biogenesis that may cause such heterogeneity. Additionally, it illustrates the complexity of the underlying mechanisms for the genetic specificity of ribosome paralogs.
FGF10 Therapeutic Administration Promotes Mobilization of Injury-Activated Alveolar Progenitors in a Mouse Fibrosis Model
Authors: Lv Yu-Qing , Cai Ge-Fu , Zeng Ping-Ping , Dhlamini Qhaweni , Chen Le-Fu , Chen Jun-Jie , Lyu Han-Deng , Mossahebi-Mohammadi Majid , Ahmadvand Negah , Bellusci Saverio , Li Xiaokun , Chen Chengshui , Zhang Jin-San
Published: August 2022

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with dire consequences and in urgent need of improved therapies. Compelling evidence indicates that damage or dysfunction of AT2s is of central importance in the development of IPF. We recently identified a novel AT2 subpopulation characterized by low SFTPC expression but that is enriched for PD-L1 in mice. These cells represent quiescent, immature AT2 cells during normal homeostasis and expand upon pneumonectomy (PNX) and were consequently named injury-activated alveolar progenitors (IAAPs). FGF10 is shown to play critical roles in lung development, homeostasis, and injury repair demonstrated in genetically engineered mice. In an effort to bridge the gap between the promising properties of endogenous Fgf10 manipulation and therapeutic reality, we here investigated whether the administration of exogenous recombinant FGF10 protein (rFGF10) can provide preventive and/or therapeutic benefit in a mouse model of bleomycin-induced pulmonary fibrosis with a focus on its impact on IAAP dynamics. C57BL/6 mice and SftpcCreERT2/+; tdTomatoflox/+ mice aged 8–10 weeks old were used in this study. To induce the bleomycin (BLM) model, mice were intratracheally (i.t.) instilled with BLM (2 μg/g body weight). BLM injury was induced after a 7-day washout period following tamoxifen induction. A single i.t. injection of rFGF10 (0.05 μg/g body weight) was given on days 0, 7, 14, and 21 after BLM injury. Then, the effects of rFGF10 on BLM-induced fibrosis in lung tissues were assessed by H&E, IHC, Masson’s trichrome staining, hydroxyproline and Western blot assays. Immunofluorescence staining and flow cytometry was used to assess the dynamic behavior of AT2 lineage-labeled SftpcPos (IAAPs and mature AT2) during the course of pulmonary fibrosis. We observed that, depending on the timing of administration, rFGF10 exhibited robust preventive or therapeutic efficacy toward BLM-induced fibrosis based on the evaluation of various pathological parameters. Flow cytometric analysis revealed a dynamic expansion of IAAPs for up to 4 weeks following BLM injury while the number of mature AT2s was drastically reduced. Significantly, rFGF10 administration increased both the peak ratio and the duration of IAAPs expansion relative to EpCAMPos cells. Altogether, our results suggest that the administration of rFGF10 exhibits therapeutic potential for IPF most likely by promoting IAAP proliferation and alveolar repair.
Suppression of Linear Ubiquitination Ameliorates Cytoplasmic Aggregation of Truncated TDP-43
Authors: Zhang Qiang , Terawaki Seigo , Oikawa Daisuke , Okina Yoshinori , Usuki Yoshinosuke , Ito Hidefumi , Tokunaga Fuminori
Published: August 2022

TAR DNA-binding protein 43 (TDP-43) is a predominant component of inclusions in the brains and spines of patients with amyotrophic lateral sclerosis (ALS). The progressive accumulation of inclusions leads to proteinopathy in neurons. We have previously shown that Met1(M1)-linked linear ubiquitin, which is specifically generated by the linear ubiquitin chain assembly complex (LUBAC), is colocalized with TDP-43 inclusions in neurons from optineurin-associated familial and sporadic ALS patients, and affects NF-κB activation and apoptosis. To examine the effects of LUBAC-mediated linear ubiquitination on TDP-43 proteinopathies, we performed cell biological analyses using full-length and truncated forms of the ALS-associated Ala315→Thr (A315T) mutant of TDP-43 in Neuro2a cells. The truncated A315T mutants of TDP-43, which lack a nuclear localization signal, efficiently generated cytoplasmic aggregates that were colocalized with multiple ubiquitin chains such as M1-, Lys(K)48-, and K63-chains. Genetic ablation of HOIP or treatment with a LUBAC inhibitor, HOIPIN-8, suppressed the cytoplasmic aggregation of A315T mutants of TDP-43. Moreover, the enhanced TNF-α-mediated NF-κB activity by truncated TDP-43 mutants was eliminated in the presence of HOIPIN-8. These results suggest that multiple ubiquitinations of TDP-43 including M1-ubiquitin affect protein aggregation and inflammatory responses in vitro, and therefore, LUBAC inhibition ameliorates TDP-43 proteinopathy.
CHST7 Methylation Status Related to the Proliferation and Differentiation of Pituitary Adenomas
Authors: Dong Wei , Shi Wenjian , Liu Yongliang , Li Jingwu , Zhang Yu , Dong Guilan , Dong Xiaoliu , Gao Hua
Published: August 2022

Pituitary adenomas (PAs) are the second most common primary brain tumor and may develop from any of the cell lineages responsible for producing the different pituitary hormones. DNA methylation is one of the essential epigenetic mechanisms in cancers, including PAs. In this study, we measured the expression profile and promoter methylation status of carbohydrate sulfotransferase 7 (CHST7) in patients with PA; then, we investigated the effect of the CHST7 methylation status on the proliferation and differentiation of PAs. The volcano map and Metascape results showed that the levels of CHST7 were related to the lineages’ differentiation and the cell adhesion of PAs, and patients with low CHST7 had greater chances of having an SF-1 lineage (p = 0.002) and optic chiasm compression (p = 0.007). Reactome pathway analysis revealed that most of the DEGs involved in the regulation of TP53 regulated the transcription of cell cycle genes (HSA-6791312 and HSA6804116) in patients with high CHST7. Correlation analysis showed that CHST7 was significantly correlated with the eIF2/ATF4 pathway and mitochondrion-related genes. The AUC of ROC showed that CHST7 (0.288; 95% CI: 0.187–0.388) was superior to SF-1 (0.555; 95% CI: 0.440–0.671) and inferior to FSHB (0.804; 95% CI: 0.704–0.903) in forecasting the SF-1 lineage (p < 0.001). The SF-1 lineage showed a higher methylation frequency for CHST7 than the Pit-1 and TBX19 lineages (p = 0.009). Furthermore, as the key molecule of the hypothalamic–pituitary–gonadal axis, inhibin βE (INHBE) was positively correlated with the levels of CHST7 (r = 0.685, p < 0.001). In summary, CHST7 is a novel pituitary gland specific protein in SF-1 lineage adenomas with a potential role in gonadotroph cell proliferation and lineage differentiation in PAs.