bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of multivariate design quantiles for drought characteristics using joint return period analysis, Vine copulas, and the systematic sampling method
Authors: Yang Jie , Yao Jun 
Published: April 2023

Abstract
The Wei River Basin has suffered from severe droughts. It is essential to build drought relief projects to cope with drought disasters. Traditionally, design quantiles have been estimated using univariate analysis, in which multiple characteristics of hydrological events are not considered. To design the more appropriate hydrological projects for the case study area, the Wei River Basin, it is essential to conduct research on multivariate analysis allowing multiple characteristics to be considered simultaneously. Here, the authors focus on hydrological drought (the basis for designing a hydrological project), and a framework to calculate the joint design quantiles of three drought characteristics is proposed. The most likely design quantiles relating to a specific return period, reflecting the highest occurrence probabilities among multiple combinations of variables, are derived by the maximum joint probability density function. Results show that compared to univariate analysis, design quantiles calculated via joint return period yield infrastructure with a smaller total storage capacity in the study area relating to a specific return period, i.e., reduces the economic input while maintaining the project safety. Proposed methods bring new sights to the design project. However, multi-method comparisons considering more uncertainties, inherent laws, investment, and other limited factors are still vital.
Effects of Glutathionylation on Guanylyltransferase Activity of NS5
N-terminal Capping Domain from Dengue, Japanese Encephalitis, and
Zika Viruses
Authors: Saisawang Chonticha , Reamtong Onrapak , Nachampa Isara , Petcharat Patchareebhorn , Priewkhiew Suphansa , Sakdee Somsri , Wongsantichon Jantana , J. Ketterman Albert 
Published: April 2023

Background:
Glutathionylation is a protein post-translational modification triggered by
oxidative stress. The susceptible proteins are modified by the addition of glutathione to specific
cysteine residues. Virus infection also induces oxidative stress in the cell, which affects cellular
homeostasis. It is not just the cellular proteins but the viral proteins that can also be modified by
glutathionylation events, thereby impacting the function of the viral proteins.

Objectives:
This study was conducted to identify the effects of modification by glutathionylation on
the guanylyltransferase activity of NS5 and identify the cysteine residues modified for the three
flavivirus NS5 proteins.

Methods:
The capping domain of NS5 proteins from 3 flaviviruses was cloned and expressed as
recombinant proteins. A gel-based assay for guanylyltransferase activity was performed using a GTP
analog labeled with the fluorescent dye Cy5 as substrate. The protein modification by
glutathionylation was induced by GSSG and evaluated by western blot. The reactive cysteine residues
were identified by mass spectrometry.

Results:
It was found that the three flavivirus proteins behaved in a similar fashion with increasing
glutathionylation yielding decreased guanylyltransferase activity. The three proteins also possessed
conserved cysteines and they appeared to be modified for all three proteins.

Conclusion:
The glutathionylation appeared to induce conformational changes that affect enzyme
activity. The conformational changes might also create binding sites for host cell protein interactions
at later stages of viral propagation with the glutathionylation event, thereby serving as a switch for
function change.
Purine Nucleosides and Analogues Bearing Chiral Substituents:
Medicinal Chemistry and Therapeutic Perspective
Authors: Drenichev Mikhail S. , Borokh Valentina N. 
Published: April 2023

Abstract:
Adenosine and its analogues play an important role as bioregulators of metabolic
processes in animal cells, affecting a variety of metabolic functions by acting
through the purinergic signaling system. Synthesis and structure-activity relationship for
some known purine nucleosides bearing chiral substituents are considered in this work.
These compounds represent a promising potential as drug prototypes for targeted therapy
of cancer, metabolic dysfunctions, and neuronal disorders due to their enhanced selectivity
to receptors of the purinergic signaling system. Derivatives of adenosine and guanosine
containing a chiral substituent also manifest antiviral activity.
Efficient Inhibition of Pathologic Angiogenesis using Combination Therapy of
Anti-Epcam and Anti-VEGFR2 Nanobodies
Authors: Karami Elmira , Azizi Parisa , Behdani Mahdi , Kazemi-Lomedasht Fatemeh 
Published: April 2023

Background:
EpCAM and VEGFR2 play an important role in angiogenesis and tumorigenesis. It is
currently of paramount importance to produce new drugs that can inhibit the angiogenesis and proliferation
of tumor cells. Nanobodies are potential drug candidates for cancer therapy due to their unique properties.

Objective:
This study aimed to investigate the combined inhibitory effect of anti-EpCAM and anti-VEGFR2
nanobodies in cancer cell lines.

Methods:
Inhibitory activity of anti-EpCAM and anti-VEGFR2 nanobodies on MDA-MB231, MCF7, and
HUVEC cells was investigated using both in vitro (MTT, migration, and tube formation assays) and in vivo
assays.

Results:
Results showed that the combination of anti-EpCAM and anti-VEGFR2 nanobodies efficiently inhibited
proliferation, migration, and tube formation of MDA-MB-231 cells compared to each individual nanobodies
(p < 0.05). In addition, the combination of anti-EpCAM and anti-VEGFR2 nanobodies efficiently inhibited
tumor growth and volume of Nude mice bearing MDA-MB-231 cells (p < 0.05).

Conclusion:
Taken together, the results indicate the potential of combination therapy as an efficient approach
to cancer therapy.
Nomilin Attenuates Lipopolysaccharide-Induced Inflammatory Response by Binding with Myeloid Differentiation Protein-2
Authors: Chen Yuting , Guo Song , Chen Guirong , Liu Chang , Zhang Mingbo , Wang Xiaobo 
Published: April 2023

Background:
Nomilin shows anti-inflammatory activity by inhibiting the activation of
the Toll-like receptor 4 (TLR 4)/NF-κB pathway. However, the key target of the anti-inflammatory
activity of nomilin has not been elaborated and needs further exploration.

Objective:
This study aimed to assess the drug potential of nomilin and its ability to target myeloid
differentiation protein 2 (MD-2) as a mechanism underlying the anti-inflammatory activity of
nomilin on the lipopolysaccharide (LPS)-TLR4/MD-2-NF-κB signaling pathways.

Methods:
The methods of ForteBio and molecular docking were used to investigate the internation
between MD-2 and nomilin. 3-(4,5)-Dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide
experiment was performed to test the effect of nomilin on cell viability. Enzyme-linked immunosorbent
assay, real-time polymerase chain reaction, and Western blot experiments were carried out
to assess the anti-inflammatory activity and possible mechanism of nomilin in vitro.

Results:
The results indicated that nomilin exhibited binding affinity with MD-2. Nomilin significantly
reduced the release and expression of NO, IL-6, TNF-α, and IL-1β induced by LPS in vitro.
It inhibited the expression of LPS-TLR4/MD-2-NF-κB signaling pathway proteins, such as TLR4,
Myd88, P65, P-P65, and iNOS.

Conclusion:
Our results suggested that nomilin had therapeutic potential and was bound to MD-2.
Nomilin exhibited anti-inflammatory activity by binding to the key protein MD-2 and inhibiting
the LPS-TLR4/MD-2-NF-κB signaling pathway.
Factors Influencing ADME Properties of Therapeutic Antisense Oligonucleotides:
Physicochemical Characteristics and Beyond
Authors: Jiang Rongrong , Hooshfar Shirin , Rebecca Eno Marsha , Yun Cassandra , Sonego Zimmermann Estevan , Shinkyo Raku 
Published: April 2023

Abstract:
Therapeutic antisense oligonucleotides (ASOs) represent a diverse array of chemically modified singlestranded
deoxyribonucleotides that work complementarily to affect their mRNA targets. They vastly differ from
conventional small molecules. These newly developed therapeutic ASOs possess unique absorption, distribution,
metabolism, and excretion (ADME) processes that ultimately determine their pharmacokinetic, efficacy and safety
profiles. The ADME properties of ASOs and associated key factors have not been fully investigated. Therefore,
thorough characterization and in-depth study of their ADME properties are critical to support drug discovery and
development processes for safe and effective therapeutic ASOs. In this review, we discussed the main factors affecting
the ADME characteristics of these novels and evolving therapies. The major changes to ASO backbone and sugar
chemistry, conjugation approaches, sites and routes of administration, etc., are the principal determinants of ADME
and PK profiles that consequentially impact their efficacy and safety profiles. In addition, species difference and DDI
considerations are important in understanding ADME profile and PK translatability but are less studied for ASOs.
We, therefore, have summarized these aspects based on current knowledge and provided discussions in this review.
We also give an overview of the current tools, technologies, and approaches available to investigate key factors that
influence the ADME of ASO drugs and provide future perspectives and knowledge gap analysis.
The Therapeutic Effects of Withaferin A against Cancer: Overview
and Updates
Authors: Abeesh Prathapan , Guruvayoorappan Chandrasekaran 
Published: April 2023

Abstract:
Cancer is a rapidly rising health problem among the global population, and
this burden causes a significant challenge for public health. Current chemotherapeutic
agents have different limitations, including drug resistance and severe side effects, and it
demands a robust approach to accessing promising anti-cancer therapeutics. The
natural compounds have been extensively studied to identify improved therapeutic
agents for cancer therapy. Withaferin A (WA) is a steroidal lactone found in Withania
somnifera and possesses anti-inflammatory, antioxidant, anti-angiogenesis, and anticancer
properties. Multiple studies have shown that WA treatment attenuated various
cancer hallmarks by inducing apoptosis and reducing angiogenesis and metastasis with
reduced side effects. WA is a promising agent for the treatment of various cancer, and it
targets various signaling pathways. With recent updates, the current review highlights
the therapeutic implications of WA and its molecular targets in different cancer.
CsHscB Derived from a Liver Fluke Clonorchis sinensis
Ameliorates Cholestatic Hepatic Fibrosis in a Mouse Model of
Sclerosing Cholangitis
Authors: Yu Qian , Koda Stephane , Xu Na , Li Jing , Wang Jian-Ling , Liu Man , Liu Ji-Xin , Zhang Yu , Yang Hui-Min , Zhang Bei-Bei , Li Xiang-Yang , Li Xiao-Cui , Tang Ren-Xian , Zheng Kui-Yang , Yan Chao 
Published: April 2023

Background:
Primary sclerosing cholangitis (PSC) is a chronic cholestatic
liver disease characterized by inflammatory fibrosis usually involving the whole biliary
tree. However, there are very limited treatment options to treat this disease. Our
previous study found a lipid-protein rCsHscB from a liver fluke - Clonorchis sinensis,
which had full capacities of immune regulation. Therefore, we investigated the role of
rCsHscB in a mouse model of sclerosing cholangitis induced by xenobiotic 3,5-
diethoxycarbonyl-1,4-dihydrocollidine (DDC) to explore whether this protein had potential
therapeutic value for PSC.

Methods:
Mice were fed 0.1% DDC for 4 weeks and treated with CsHscB (30
μg/mouse, intraperitoneal injection, once every 3 days); the control group was given an
equal amount of PBS or CsHscB under normal diet conditions. All the mice were
sacrificed at 4 weeks for the evaluation of biliary proliferation, fibrosis, and inflammation.

Results:
rCsHscB treatment attenuated DDC-induced liver congestion and enlargement
and significantly decreased the upregulation of serum AST and ALT levels. The
administration of rCsHscB to DDC-fed mice significantly decreased cholangiocyte
proliferation and pro-inflammatory cytokine production compared to mice fed with DDC
alone. Also, rCsHscB treatment showed a decreased expression of α-SMA in the liver
and other markers of liver fibrosis (Masson staining, Hydroxyproline content, and
collagen deposit). More interestingly, DDC-fed mice treated with rCsHscB showed a
significant up-regulation of PPAR-γ expression, which was similar to control mice,
indicating the involvement of PPAR-γ signaling in the protective action of rCsHscB.

Conclusion:
Overall, our data show that rCsHscB attenuates the progression of
cholestatic fibrosis induced by DDC and supports the potential for manipulating the
parasite-derived molecule to treat certain immune-mediated disorders.
GRP78 is Overexpressed in Non-small Cell Lung Cancer Tissues and is
Associated with High VEGF Expression in Squamous Cell Carcinoma: A
Pilot Study
Authors: Al-Keilani Maha , Alqudah Mohammad A. , Almomani Basima , Alrjoub Moath M. , Shhabat Batool A. , Alzoubi Karem 
Published: April 2023

Background:
Neovascularization is essential for the growth and progression of tumor tissues.
GRP78 is frequently overexpressed in various cancers and has been suggested as a proangiogenic
factor.

Purpose:
This study aimed to investigate the expression levels of GRP78 and to test for significant
relationships with the angiogenic markers, VEGF, and CD31.

Methods:
In this study, paraffin-embedded NSCLC tissue samples (71 adenocarcinomas and 23 squamous
cell carcinoma) were retrospectively collected from 94 patients with NSCLC. The expressions of
VEGF, CD31, and GRP78 were determined by immunohistochemistry.

Results:
High expression levels of VEGF and GRP78 were observed in 65 and 74 cases, respectively.
Thirty-six patients expressed high CD31 levels. Adenocarcinomas expressed higher levels of the three
proteins than squamous cell carcinomas (p-value < 0.05). Moreover, a statistically significant association
was found between the expression levels of VEGF and CD31 (p-value = 0.001) and VEGF and
GRP78 (p-value=0.028).

Conclusion:
GRP78 overexpression was revealed in most of the investigated samples. The positive
association between VEGF and GRP78 may indicate the proangiogenic role of GRP78 in lung cancer.
Moreover, the positive association between VEGF and CD31 expression levels suggests that VEGF
may cooperate with CD31 to promote angiogenesis in NSCLC.
Recent Advances in Organic Synthesis Using Glycerol as a Green Media
Authors: Narasimhamurthy Kereyagalahally H. , Joy Muthipeedika Nibin , Sajith Ayyiliath M. , Santra Sougata , Zyryanov Grigory V. , Swaroop Toreshettahally R. , Rangappa Kanchugarakoppal S. 
Published: April 2023

Abstract:
Various catalytic and non-catalytic organic transformations are carried out in glycerol media
with superior efficiency over commonly employed organic solvents. The success of glycerol as a
green media is due to its exceptional H-bonding properties, which result in enhanced reactivity in
many organic transformations. In addition, its highly polar nature and non-toxic properties, recyclability,
large availability as an organic waste from the biodiesel industry, high boiling point, low vapor
pressure and low price further extend the scope of this solvent as green media. In this review, we present
the potential use of glycerol as a green solvent in many organic transformations in two sections:
cyclization reactions and miscellaneous reactions.
Total and Partial Replacement of Meat by Mycoprotein in Hamburger: Physico-Chemical, Nutritional, Mechanical, and Overall Acceptability
Authors: Hashempour-Baltork Fataneh , Farshi Parastou , Jannat Behrooz , Dadgarnejad Manouchehr , Asgharian Ramin , Khosravi-Darani Kianoush , Hosseini Hedayat 
Published: April 2023

Aim:
Processed meats are considered the most consumable products worldwide. However,
there are several limitations related to these products such as health and environmental issues,
and the high energy, time, and cost needed for their production, thus manufacturers are looking
for effective alternatives for processed meats. Mycoprotein can be a useful approach for meat
substitution.

Introduction:
This study’s objective was the partial and total replacement of meat with mycoproteins
in the formulation of burgers and to investigate the characteristics of these novel formulations
for comparison with the control sample (full meat burger).

Methods:
Cooking loss, mechanical, physicochemical, nutritional, color, and sensory properties
were determined.

Results:
The results indicated that mycoprotein substitution could improve health and nutritional
properties as a result of including high-value protein and lower lipid content (mostly unsaturated
fatty acids). However, the beef burger had better mechanical properties such as cohesiveness,
hardness, springiness, and gumminess compared to mycoprotein-containing burgers. Higher OBC
(oil binding capacity) and WBC (water binding capacity) of mycoprotein were responsible for filling
the interstitial spaces within the protein matrix and reducing the textural attributes. Thus, using
less oil and water in mycoprotein-containing formulations is recommended. Moreover, the
cooking loss percentage decreased by increasing the mycoprotein content of burgers, which has
economic advantages. According to sensory evaluations, no significant changes (p>0.05) were
shown in the overall acceptance and taste scores of the burgers.

Conclusions:
Mycoproteins are potential compounds to be used as promising ingredients for the
complete substitution of meat in the burger.
Micronutrients throughout the Life Cycle: Needs and Functions in Health and Disease
Authors: Kumar Mohit , Kumar Devesh , Sharma Ankita , Bhadauria Shivam , Thakur Anil , Bhatia Amit 
Published: April 2023

Background:Micronutrients play a vital role in the maintenance and proper functioning of body tissues. Micronutrients broadly consist of minerals and vitamins. These vitamins and minerals are of supreme importance in the treatment of an eclectic variety of diseases and are obligatory for many metabolic processes.Objective:The objective of this review is to give a comprehensive overview on the role of micronutrients in the treatment of broad-spectrum diseases and also give insightful knowledge regarding the numerous food sources for obtaining nutrients, their dietary reference values, and their deficiencies. In this review, the authors have also highlighted the role of micronutrients in COVID- 19.Findings:A properly balanced diet provides an acceptable amount of nutrients in the body. Deficiency and excessive nutrients in an individual’s diet may cause diseases or abnormal conditions. An improper diet may be responsible for the occurrence of deficiencies in iron, calcium, and iodine. Minerals like iron, boron, calcium, cobalt, phosphorous, and vitamins like K, E, A, D, and Riboflavin can cure and treat fatal diseases like Alzheimer’s, bone development conditions, osteoporosis, anemia, inflammatory bowel, and HIV Infections.Conclusion:Micronutrients are essential for metabolism and tissue function. Sufficient consumption is thus required, but providing additional supplements to persons who do not require them may be detrimental. Large-scale studies of varied micronutrient dosages with accurate outcome indicators are needed to optimize intakes in different patient groups and the general population at large. In this review, the authors have highlighted the crucial role of micronutrients in health and disease.
Esters of Quinoxaline-7-Carboxylate 1,4-di-N-Oxide as Potential Inhibitors
of Glycolytic Enzymes of Entamoeba histolytica: In silico Approach
Authors: Soto-Sánchez Jacqueline , Pérez-Mora Salvador , Ospina-Villa Juan David , Zavala-Ocampo Lizeth Mariel 
Published: April 2023

Background:
Esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate
QdNOs) derivatives are compounds that inhibit the growth of Entamoeba histolytica, the causative
agent of amebiasis. Although these compounds cause changes in the redistribution of glycogen
deposits within the parasite, it is unknown whether these compounds interact with enzymes of the
glycolytic pathway.

Objective:
The aim of this study was to test the binding affinity of these compounds to pyrophosphate-
dependent phosphofructokinase (PPi-PFK), triosephosphate isomerase (TIM), and pyruvate
phosphate dikinase (PPDK) from E. histolytica as a possible mechanism of action.

Methods:
The molecular docking study of the 7-carboxylate QdNOs derivatives and the proteins
was performed using AutoDock/Vina software. Molecular dynamics simulation was performed for
100 ns.

Results:
Among all the selected compounds, T-072 exhibited the best binding affinity to EhPPi-
PFK and EhTIM proteins, while T-006 interacted best with EhPPDK. ADMET analysis revealed
that T-072 was non-toxic, while T-006 could become harmful to the host. In addition, molecular
dynamics showed that T-072 has stable interaction with EhPPi-PFK and EhTIM.

Conclusion:
Including all aspects, these data indicated that these compounds might inhibit the
activity of key enzymes in energy metabolism leading to parasite death. Furthermore, these compounds
may be a good starting point for the future development of new potent antiamebic agents.
In vitro Culture and Multilocus Genotyping of Giardia duodenalis
Trophozoites Obtained from Human Fecal Samples in Southwest of Iran
Authors: Yousefi Hossein Ali , Asgarian Fatemeh , Tavalla Mehdi , Ghafari Shokouh , Kohansal Kobra 
Published: April 2023

Introduction:
The enteric protozoa, Giardia duodenalis (G. duodenalis), consists of
eight distinct assemblages (A-H) with identical morphological characteristics and a direct life
cycle. Successful axenic cultivation of this parasite is an important preliminary step for biological,
drug resistance and phylogenetic studies. Moreover, G. duodenalis exhibits great genetic and
biotypic diversity.

Aim:
The current study aimed to evaluate in vitro culture and multilocus genotyping of G.
duodenalis trophozoites obtained from human fecal samples in southwest Iran.

Methods:
Thirty human fecal specimens containing G. duodenalis cysts were collected from
Ahvaz city (southwest of Iran). The purification of cysts was carried out by the sucrose flotation
technique. The cysts were inoculated in a modified TYI-S-33 medium and was daily monitored
for the development and viability of trophozoites. After extracting DNA, gdh, bg and tpi genes
were evaluated using molecular techniques (the semi-nested PCR for gdh gene and the nested
PCR for tpi and bg genes). Eventually, the amplified fragments were sequenced and then, the
phylogenetic tree was drawn.

Results:
Of 30, the trophozoites were encysted from five samples. All three genes were detected
in two cases of five samples using molecular techniques. The multilocus phylogenetic analysis
demonstrated that all the two samples belonged to assemblage A and sub-assemblage AІІ.

Conclusion:
Our findings indicated the presence of different numbers of trophozoites with variable
development and survival rates in modified TYI-S-33 medium. Furthermore, the multilocus genotyping
showed that these trophozoites belonged to assemblage A and sub-assemblage AІІ.