bluuebunny/crossref_metadata_2025 huggingface dataset:
Quercetin inhibition of porcine intestinal alpha coronavirus in vitro and in vivo
Authors: Feng Yongzhi , Yi Heyou , Zheng Xiaoyu , Liu Xing , Gong Ting , Wu Dongdong , Song Zebu , Zheng Zezhong
Published: April 2024

Background

Porcine acute diarrhea syndrome coronavirus (SADS-CoV) is one of the novel pathogens responsible for piglet diarrhea, contributing to substantial economic losses in the farming sector. The broad host range of SADS-CoV raises concerns regarding its potential for cross-species transmission. Currently, there are no effective means of preventing or treating SADS-CoV infection, underscoring the urgent need for identifying efficient antiviral drugs. This study focuses on evaluating quercetin as an antiviral agent against SADS-CoV.

Results

In vitro experiments showed that quercetin inhibited SADS-CoV proliferation in a concentration-dependent manner, targeting the adsorption and replication stages of the viral life cycle. Furthermore, quercetin disrupts the regulation of the P53 gene by the virus and inhibits host cell cycle progression induced by SADS-CoV infection. In vivo experiments revealed that quercetin effectively alleviated the clinical symptoms and intestinal pathological damage caused by SADS-CoV-infected piglets, leading to reduced expression levels of inflammatory factors such as TLR3, IL-6, IL-8, and TNF-α.

Conclusions

Therefore, this study provides compelling evidence that quercetin has great potential and promising applications for anti- SADS-CoV action.
Transcriptomic profiling of an evolved Yarrowia lipolytica strain: tackling hexanoic acid fermentation to increase lipid production from short-chain fatty acids
Authors: Morales-Palomo Sergio , Navarrete Clara , Martínez José Luis , González-Fernández Cristina , Tomás-Pejó Elia
Published: April 2024

Background

Short-chain fatty acids (SCFAs) are cost-effective carbon sources for an affordable production of lipids. Hexanoic acid, the acid with the longest carbon chain in the SCFAs pool, is produced in anaerobic fermentation of organic residues and its use is very challenging, even inhibiting oleaginous yeasts growth.

Results

In this investigation, an adaptive laboratory evolution (ALE) was performed to improve Yarrowia lipolytica ACA DC 50109 tolerance to high hexanoic acid concentrations. Following ALE, the transcriptomic analysis revealed several genetic adaptations that improved the assimilation of this carbon source in the evolved strain compared to the wild type (WT). Indeed, the evolved strain presented a high expression of the up-regulated gene YALI0 E16016g, which codes for FAT1 and is related to lipid droplets formation and responsible for mobilizing long-chain acids within the cell. Strikingly, acetic acid and other carbohydrate transporters were over-expressed in the WT strain.

Conclusions

A more tolerant yeast strain able to attain higher lipid content under the presence of high concentrations of hexanoic acid has been obtained. Results provided novel information regarding the assimilation of hexanoic acid in yeasts.
Deciphering the prognostic features of bladder cancer through gemcitabine resistance and immune-related gene analysis and identifying potential small molecular drug PIK-75
Authors: Cai Tingting , Feng Tao , Li Guangren , Wang Jin , Jin Shengming , Ye Dingwei , Zhu Yiping
Published: April 2024

Background

Bladder cancer (BCa) stands out as a prevalent and highly lethal malignancy worldwide. Chemoresistance significantly contributes to cancer recurrence and progression. Traditional Tumor Node Metastasis (TNM) stage and molecular subtypes often fail to promptly identify treatment preferences based on sensitivity.

Methods

In this study, we developed a prognostic signature for BCa with uni-Cox + LASSO + multi-Cox survival analysis in multiple independent cohorts. Six machine learning algorithms were adopted to screen out the hub gene, RAC3. IHC staining was used to validate the expression of RAC3 in BCa tumor tissue. RT-qPCR and Western blot were performed to detect and quantify the mRNA and protein levels of RAC3. CCK8, colony formation, wound healing, and flow cytometry analysis of apoptosis were employed to determine cell proliferation, migration, and apoptosis. Molecular docking was used to find small target drugs, PIK-75. 3D cell viability assay was applied to evaluate the ATP viability of bladder cancer organoids before and after PIK-75 treated.

Results

The established clinical prognostic model, GIRS, comprises 13 genes associated with gemcitabine resistance and immunology. This model has demonstrated robust predictive capabilities for survival outcomes across various independent public cohorts. Additionally, the GIRS signature shows significant correlations with responses to both immunotherapy and chemotherapy. Leveraging machine learning algorithms, the hub gene, RAC3, was identified, and potential upstream transcription factors were screened through database analysis. IHC results showed that RAC3 was higher expressed in GEM-resistant BCa patients. Employing molecular docking, the small molecule drug PIK-75, as binding to RAC3, was identified. Experiments on cell lines, organoids and animals validated the biological effects of PIK-75 in bladder cancer.

Conclusions

The GIRS signature offers a valuable complement to the conventional anatomic TNM staging system and molecular subtype stratification in bladder cancer. The hub gene, RAC3, plays a crucial role in BCa and is significantly associated with resistance to gemcitabine. The small molecular drug, PIK-75 having the potential as a therapeutic agent in the context of gemcitabine-resistant and immune-related pathways.
GSH-responsive degradable nanodrug for glucose metabolism intervention and induction of ferroptosis to enhance magnetothermal anti-tumor therapy
Authors: Liao Zhen , Wen E. , Feng Yi
Published: April 2024

The challenges associated with activating ferroptosis for cancer therapy primarily arise from obstacles related to redox and iron homeostasis, which hinder the susceptibility of tumor cells to ferroptosis. However, the specific mechanisms of ferroptosis resistance, especially those intertwined with abnormal metabolic processes within tumor cells, have been consistently underestimated. In response, we present an innovative glutathione-responsive magnetocaloric therapy nanodrug termed LFMP. LFMP consists of lonidamine (LND) loaded into PEG-modified magnetic nanoparticles with a Fe3O4 core and coated with disulfide bonds-bridged mesoporous silica shells. This nanodrug is designed to induce an accelerated ferroptosis-activating state in tumor cells by disrupting homeostasis. Under the dual effects of alternating magnetic fields and high concentrations of glutathione in the tumor microenvironment, LFMP undergoes disintegration, releasing drugs. LND intervenes in cell metabolism by inhibiting glycolysis, ultimately enhancing iron death and leading to synthetic glutathione consumption. The disulfide bonds play a pivotal role in disrupting intracellular redox homeostasis by depleting glutathione and inactivating glutathione peroxidase 4 (GPX4), synergizing with LND to enhance the sensitivity of tumor cells to ferroptosis. This process intensifies oxidative stress, further impairing redox homeostasis. Furthermore, LFMP exacerbates mitochondrial dysfunction, triggering ROS formation and lactate buildup in cancer cells, resulting in increased acidity and subsequent tumor cell death. Importantly, LFMP significantly suppresses tumor cell proliferation with minimal side effects both in vitro and in vivo, exhibiting satisfactory T2-weighted MR imaging properties. In conclusion, this magnetic hyperthermia-based nanomedicine strategy presents a promising and innovative approach for antitumor therapy.

Graphical Abstract
Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice
Authors: Dong Jie , Kong Lingkai , Wang Shiqun , Xia Mao , Zhang Yenan , Wu Jingyi , Yang Fuming , Zuo Shuguang , Wei Jiwu
Published: April 2024

Background

Dysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol efflux and maintaining cellular cholesterol homeostasis. However, further exploration is needed to determine whether it inhibits TNBC metastasis by affecting cholesterol metabolism. Additionally, it is necessary to investigate whether ApoA1-based oncolytic virus therapy can be used to treat TNBC.

Methods

In vitro experiments and mouse breast cancer models were utilized to evaluate the molecular mechanism of ApoA1 in regulating cholesterol efflux and inhibiting breast cancer progression and metastasis. The gene encoding ApoA1 was inserted into the adenovirus genome to construct a recombinant adenovirus (ADV-ApoA1). Subsequently, the efficacy of ADV-ApoA1 in inhibiting the growth and metastasis of TNBC was evaluated in several mouse models, including orthotopic breast cancer, spontaneous breast cancer, and human xenografts. In addition, a comprehensive safety assessment of Syrian hamsters and rhesus monkeys injected with oncolytic adenovirus was conducted.

Results

This study found that dysregulation of cholesterol homeostasis is critical for the progression and metastasis of TNBC. In a mouse orthotopic model of TNBC, a high-cholesterol diet promoted lung and liver metastasis, which was associated with keratin 14 (KRT14), a protein responsible for TNBC metastasis. Furthermore, studies have shown that ApoA1, a cholesterol reverse transporter, inhibits TNBC metastasis by regulating the cholesterol/IKBKB/FOXO3a/KRT14 axis. Moreover, ADV-ApoA1 was found to promote cholesterol efflux, inhibit tumor growth, reduce lung metastasis, and prolonged the survival of mice with TNBC. Importantly, high doses of ADV-ApoA1 administered intravenously and subcutaneously were well tolerated in rhesus monkeys and Syrian hamsters.

Conclusions

This study provides a promising oncolytic virus treatment strategy for TNBC based on targeting dysregulated cholesterol metabolism. It also establishes a basis for subsequent clinical trials of ADV-ApoA1 in the treatment of TNBC.
Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET
Authors: Xia Shengkai , Duan Wenzhe , Xu Mingxin , Li Mengqi , Tang Mengyi , Wei Song , Lin Manqing , Li Encheng , Liu Wenwen , Wang Qi
Published: April 2024

Background

Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown.

Methods

The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies.

Results

MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice.

Conclusions

Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.
New benzimidazole derivative compounds with in vitro fasciolicidal properties
Authors: Valderas-García Elora , Castilla-Gómez de Agüero Verónica , González del Palacio Laura , Galli Giulio , Escala Nerea , Ruiz-Somacarrera Marta , González-Warleta Marta , del Olmo Esther , Balaña-Fouce Rafael , Martínez-Valladares María
Published: April 2024

Background

Control of the zoonotic food-borne parasiteFasciola hepaticaremains a major challenge in humans and livestock. It is estimated that annual economic losses due to fasciolosis can reach US$3.2 billion in agriculture and livestock. Moreover, the wide distribution of drug-resistant parasite populations and the absence of a vaccine threaten sustainable control, reinforcing the need for novel flukicides.

Methods

The present work analyses the flukicidal activity of a total of 70 benzimidazole derivatives on different stages ofF. hepatica. With the aim to select the most potent ones, and screenings were first performed on eggs at decreasing concentrations ranging from 50 to 5 µM and then on adult worms at 10 µM. Only the most effective compounds were also evaluated using a resistant isolate of the parasite.

Results

After the first screenings at 50 and 10 µM, four hit compounds (BZD31, BZD46, BZD56, and BZD59) were selected and progressed to the next assays. At 5 µM, all hit compounds showed ovicidal activities higher than 71% on the susceptible isolate, but only BZD31 remained considerably active (53%) when they were tested on an albendazol-resistant isolate, even with values superior to the reference drug, albendazole sulfoxide. On the other hand, BZD59 displayed a high motility inhibition when tested on adult worms from an albendazole-resistant isolate after 72 h of incubation.

Conclusions

BZD31 and BZD59 compounds could be promising candidates for the development of fasciolicidal compounds or as starting point for the new synthesis of structure-related compounds.

Graphical Abstract
The synergistic effect of obesity and dyslipidemia on hypertension: results from the STEPS survey
Authors: Mohseni Parisa , Khalili Davood , Djalalinia Shirin , Mohseni Hamideh , Farzadfar Farshad , Shafiee Arman , Izadi Neda
Published: April 2024

Background

Obesity and dyslipidemia are important risk factors for hypertension (HTN). When these two conditions coexist, they may interact in a synergistic manner and increase the risk of developing HTN and its associated complications. The aim of this study was to investigate the synergistic effect of general and central obesity with dyslipidemia on the risk of HTN.

Method

Data from 40,387 individuals aged 25 to 64 years were obtained from a repeated cross-sectional study examining risk factors for non-communicable diseases (STEPS) in 2007, 2011 and 2016. Body mass index (BMI) was calculated as a measure of general obesity and waist circumference (WC) as a measure of central obesity. Dyslipidemia was defined as the presence of at least one of the lipid abnormalities. Hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or current use of antihypertensive medication. To analyze the synergistic effect between obesity and dyslipidemia and HTN, the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI) were calculated. A weighted logistic regression model was performed to estimate the odds ratios (ORs) for the risk of HTN.

Results

The results showed an association between obesity, dyslipidemia and hypertension. The interaction between obesity and dyslipidemia significantly influences the risk of hypertension. In hypertensive patients, the presence of general obesity increased from 14.55% without dyslipidemia to 64.36% with dyslipidemia, while central obesity increased from 13.27 to 58.88%. This interaction is quantified by RERI and AP values of 0.15 and 0.06 for general obesity and 0.24 and 0.09 for central obesity, respectively. The corresponding SI of 1.11 and 1.16 indicate a synergistic effect. The OR also show that the risk of hypertension is increased in the presence of obesity and dyslipidemia.

Conclusion

Obesity and dyslipidemia are risk factors for HTN. In addition, dyslipidemia with central obesity increases the risk of HTN and has a synergistic interaction effect on HTN. Therefore, the coexistence of obesity and lipid abnormalities has many clinical implications and should be appropriately monitored and evaluated in the management of HTN.
RepEnTools: an automated repeat enrichment analysis package for ChIP-seq data reveals hUHRF1 Tandem-Tudor domain enrichment in young repeats
Authors: Choudalakis Michel , Bashtrykov Pavel , Jeltsch Albert
Published: April 2024

Background

Repeat elements (REs) play important roles for cell function in health and disease. However, RE enrichment analysis in short-read high-throughput sequencing (HTS) data, such as ChIP-seq, is a challenging task.

Results

Here, we present RepEnTools, a software package for genome-wide RE enrichment analysis of ChIP-seq and similar chromatin pulldown experiments. Our analysis package bundles together various software with carefully chosen and validated settings to provide a complete solution for RE analysis, starting from raw input files to tabular and graphical outputs. RepEnTools implementations are easily accessible even with minimal IT skills (Galaxy/UNIX). To demonstrate the performance of RepEnTools, we analysed chromatin pulldown data by the human UHRF1 TTD protein domain and discovered enrichment of TTD binding on young primate and hominid specific polymorphic repeats (SVA, L1PA1/L1HS) overlapping known enhancers and decorated with H3K4me1-K9me2/3 modifications. We corroborated these new bioinformatic findings with experimental data by qPCR assays using newly developed primate and hominid specific qPCR assays which complement similar research tools. Finally, we analysed mouse UHRF1 ChIP-seq data with RepEnTools and showed that the endogenous mUHRF1 protein colocalizes with H3K4me1-H3K9me3 on promoters of REs which were silenced by UHRF1. These new data suggest a functional role for UHRF1 in silencing of REs that is mediated by TTD binding to the H3K4me1-K9me3 double mark and conserved in two mammalian species.

Conclusions

RepEnTools improves the previously available programmes for RE enrichment analysis in chromatin pulldown studies by leveraging new tools, enhancing accessibility and adding some key functions. RepEnTools can analyse RE enrichment rapidly, efficiently, and accurately, providing the community with an up-to-date, reliable and accessible tool for this important type of analysis.
Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons
Authors: Wu Shanshan , Wang Jing , Zhang Zicheng , Jin Xinchen , Xu Yang , Si Youwen , Liang Yixiao , Ge Yueping , Zhan Huidong , peng Li , Bi Wenkai , Luo Dandan , Li Mengzhu , Meng Bo , Guan Qingbo , Zhao Jiajun , Gao Ling , He Zhao
Published: April 2024

Background

SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency.

Methods

Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3−/−) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α.

Results

We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3−/− mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice.

Limitations

We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons.

Conclusions

These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.
Efficacy and safety of mesenchymal stem cell therapy for ovarian ageing in a mouse model
Authors: Pei Wendi , Fu Lin , Guo Wenhuan , Wang Yibo , Fan Yong , Yang Rui , Li Rong , Qiao Jie , Yu Yang
Published: April 2024

Background

Ovarian ageing is one of the major issues that impacts female fertility. Mesenchymal stem cell (MSC)-based therapy has made impressive progress in recent years. However, the efficacy and safety of MSCs, as nonautologous components, remain to be further verified.

Methods

Two common sources of MSCs, umbilical cord-derived MSCs (UC-MSCs) and adipose tissue-derived MSCs (AD-MSCs), were orthotopically transplanted into a mouse model of ovarian ageing to evaluate their therapeutic effects. The safety of the treatment was further evaluated, and RNA sequencing was performed to explore the underlying mechanisms involved.

Results

After orthotopic transplantation of MSCs into the ovary, the oestrous cycle, ovarian weight, number and proportion of primary follicles, granulosa cell proliferation, and angiogenesis were improved. The effects of AD-MSCs were superior to those of UC-MSCs in several indices, such as post-transplant granulosa cell proliferation, ovarian weight and angiogenesis. Moreover, the tumorigenesis, acute toxicity, immunogenicity and biodistribution of MSCs were evaluated, and both AD-MSCs and UC-MSCs were found to possess high safety profiles. Through RNA sequencing analysis, enhancement of the MAPK cascade was observed, and long-term effects were mainly linked to the activation of immune function.

Conclusions

Orthotopic transplantation of MSCs displays significant efficacy and high safety for the treatment of ovarian ageing in mice.
Sex differences and sex-specific regulation of motivated behavior by Melanin-concentrating hormone: a short review
Authors: Kuebler Isabel R. K. , Suárez Mauricio , Wakabayashi Ken T.
Published: April 2024

Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH’s role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.
Orthoceratoid and coleoid cephalopods from the Middle Triassic of Switzerland with an updated taxonomic framework for Triassic Orthoceratoidea
Authors: Pohle Alexander , Klug Christian
Published: April 2024

Orthoconic cephalopods are subordinate, but persistent, widespread and regionally abundant components of Triassic marine ecosystems. Here, we describe unpublished specimens from the Anisian (Middle Triassic) Besano Formation at Monte San Giorgio, Switzerland. They can be assigned to two major but unrelated lineages, the Coleoidea and the Orthoceratoidea. The orthoceratoids belong toTrematoceras elegans(Münster, 1841) and occur regularly within the Besano Formation, are uniform in size, and have few available morphological characters. In contrast, coleoids are more diverse and appear to be restricted to shorter intervals. A new coleoid is described asTicinoteuthis chuchichaeschtligen. et sp. nov. To better put the orthoceratoids of the Besano Formation into perspective, we also synthesise the current taxonomy of Triassic orthoceratoids on a global scale. The currently used scheme is largely outdated, with very little taxonomic progress in the past 100 years. Despite previous research showing the distinctness of Triassic orthoceratoids from Palaeozoic taxa, they are still commonly labelled as “Orthoceras” or “Michelinoceras”, which are confined to the Palaeozoic. We show that Triassic orthoceratoids probably belong to a single lineage, the Trematoceratidae, which can be assigned to the Pseudorthocerida based on the embryonic shell and endosiphuncular deposits. Many Triassic species can probably be assigned toTrematoceras, but there are at least two additional Triassic orthoceratoid genera,ParatrematocerasandPseudotemperoceras. Finally, we review the palaeobiogeographic and stratigraphic distribution of the group and outline possible future research directions.
Ground state normalized solutions to the Kirchhoff equation with general nonlinearities: mass supercritical case
Authors: Wang Qun , Qian Aixia
Published: April 2024

We study the following nonlinear mass supercritical Kirchhoff equation: $$ - \biggl(a+b \int _{\mathbb{R}^{N}} \vert \nabla u \vert ^{2} \biggr) \triangle u+ \mu u=f(u) \quad \text{in } {\mathbb{R}^{N}}, $$
−

(
a
+
b

∫

R
N

|
∇
u

|
2

)

△
u
+
μ
u
=
f
(
u
)

in 

R
N

,
where $a ,b,m>0$
a
,
b
,
m
>
0
are prescribed, and the normalized constrain $\int _{\mathbb{R}^{N}}|u|^{2}\,dx =m$

∫

R
N

|
u
|

2

d
x
=
m
is satisfied in the case $1\leq N\leq 3$
1
≤
N
≤
3
. The nonlinearity f is more general and satisfies weak mass supercritical conditions. Under some mild assumptions, we establish the existence of ground state when $1\leq N\leq 3$
1
≤
N
≤
3
and obtain infinitely many radial solutions when $2\leq N\leq 3$
2
≤
N
≤
3
by constructing a particular bounded Palais–Smale sequence.
Psychometric properties of the cannabis abuse screening test (CAST) in a sample of Moroccans with cannabis use
Authors: El Malki Hicham , Moutawakkil Salma Ghofrane , El-Ammari Abdelfettah , Ragala Mohammed El Amine , El Hilaly Jaouad , El Gnaoui Samir , El Houari Fatima , El Rhazi Karima , Zarrouq Btissame
Published: April 2024

Background

The Cannabis Abuse Screening Test (CAST) is a widely used screening tool for identifying patterns of cannabis use that have negative health or social consequences for both the user and others involved. This brief screening instrument has been translated into multiple languages, and several studies examining its psychometric properties have been published. However, studies on the factorial validity and psychometric properties of a Moroccan version of the CAST are not yet available. The objective of this study is to validate the CAST, translated, and adapted to the Moroccan Arabic dialect among persons with cannabis use.

Methods

A total of 370 participants from an addictology center in Fez City, were selected over two phases to form the study sample. First, in phase I, exploratory factor analysis was employed to evaluate the factor structure in the pilot sample (n1 = 150). Subsequently, in the second phase (Phase II), confirmatory factor analysis was utilized to confirm this structure in the validation sample (n2 = 220). All statistical analyses were carried out using the R program.

Results

The CFA unveiled a three-factor structure that showed a good overall fit (χ2/df = 2.23, RMSEA = 0.07, SRMR = 0.02, CFI = 0.99, NFI = 0.98) and satisfactory local parameters (standardized factor loadings between 0.72 and 0.88). The model demonstrates satisfactory reliability and convergent validity, as evidenced by the acceptable values of composite reliability (CR) (0.76–0.88) and average variance extracted (AVE) (0.62–0.78), respectively. The square roots of the AVE exceeded the correlations of the factor pairs, and the heterotrait-monotrait (HTMT) ratio of the correlation values was below 0.85, indicating acceptable discriminant validity.

Conclusion

The reliability, convergent validity, and discriminant validity tests all demonstrated that the Moroccan version of the CAST performed well and can be considered a valid tool for screening of problematic cannabis use.
Validation of graph sequence clusters through multivariate analysis: application to Rovash scripts
Authors: Hosszú Gábor
Published: April 2024

This paper introduces the concept of pattern systems that evolve, with a focus on scripts, a specific type of pattern system. The study analyses the development of different script systems, known as scriptinformatics, with a focus on the historical Rovash scripts used in the Eurasian steppe. The aim is to assess the traditional classification of historical inscriptions, referred to as script relics, into distinct Rovash scripts. Clustering and ordination techniques were used to perform multivariate analyses on Rovash scripts and inscriptions. The study presents two new measures, the script-specific holophyletic index and the joint holophyletic index, for evaluating trees produced by hierarchical clustering. The results indicate that holophyletic indices can validate the traditional assignment of inscriptions to scripts through phylogenetic tree evaluation. This method can be extended to include pattern systems with evolutionary properties and graph sequences derived from them, as well as additional scripts and inscriptions.
A new ingredient to improve Chinese traditional hydraulic lime and its assessment on stone heritage conservation
Authors: Chen Weichang , Li Li
Published: April 2024

Ginger nut, AGA soil, and shell lime are the primary building limes used in traditional Chinese architectural sites. They have been widely researched and developed for restoring rock and soil heritage over the last decade. Previous studies have shown that these materials are compatible with weathered rock in terms of mechanical properties and environmental adaptability. In this study, metakaolinite was added to Chinese hydraulic limes to improve the mortar abilities. The basic properties and weather abilities of the mortars were evaluated. The characteristics of carbonation and hydration were analyzed over 900 days. The results indicated that the early strength improved and the contracting rate reduced when metakaolinite was added. The shell lime mortar was improved considerably compared with the modified ginger nut and AGA soil. The lime mortar content was determined using the X-ray diffraction results. The carbonation and hydration characteristics revealed that the metakaolinite aided the generation of hydraulic products (Ca2Al2SiO7·nH2O and β-CaSiO3·nH2O), particularly in the early stage. The microstructures were observed by scanning electron microscopy, which revealed more uniform and consolidated structures when metakaolinite was added.
Gene selection via improved nuclear reaction optimization algorithm for cancer classification in high-dimensional data
Authors: El-Mageed Amr A. Abd , Elkhouli Ahmed E. , Abohany Amr A. , Gafar Mona
Published: April 2024

RNA Sequencing (RNA-Seq) has been considered a revolutionary technique in gene profiling and quantification. It offers a comprehensive view of the transcriptome, making it a more expansive technique in comparison with micro-array. Genes that discriminate malignancy and normal can be deduced using quantitative gene expression. However, this data is a high-dimensional dense matrix; each sample has a dimension of more than 20,000 genes. Dealing with this data poses challenges. This paper proposes RBNRO-DE (Relief Binary NRO based on Differential Evolution) for handling the gene selection strategy on (rnaseqv2 illuminahiseq rnaseqv2 un edu Level 3 RSEM genes normalized) with more than 20,000 genes to pick the best informative genes and assess them through 22 cancer datasets. The k-nearest Neighbor (k-NN) and Support Vector Machine (SVM) are applied to assess the quality of the selected genes. Binary versions of the most common meta-heuristic algorithms have been compared with the proposed RBNRO-DE algorithm. In most of the 22 cancer datasets, the RBNRO-DE algorithm based on k-NN and SVM classifiers achieved optimal convergence and classification accuracy up to 100% integrated with a feature reduction size down to 98%, which is very evident when compared to its counterparts, according to Wilcoxon’s rank-sum test (5% significance level).
A novel neuroimmune modulation system for the treatment of rheumatoid arthritis
Authors: Bonaz Bruno
Published: April 2024

The vagus nerve has an anti-inflammatory effect through the inflammatory reflex, which inhibits the release of proinflammatory cytokines by macrophages. Recent pilot clinical trials, using implantable bioelectronic devices, have demonstrated the efficacy of vagus nerve stimulation in adult patients with rheumatoid arthritis and inflammatory bowel diseases as an alternative to drugs, which are not devoid of side effects and are costly. In this issue of Bioelectronic Medicine, Peterson et al. report the safety of novel implantable neuroimmune modulation device for treating rheumatoid arthritis (The RESET RA study), which I will discuss in this commentary.
Joint contrastive learning and belief rule base for named entity recognition in cybersecurity
Authors: Hu Chenxi , Wu Tao , Liu Chunsheng , Chang Chao
Published: April 2024

Named Entity Recognition (NER) in cybersecurity is crucial for mining information during cybersecurity incidents. Current methods rely on pre-trained models for rich semantic text embeddings, but the challenge of anisotropy may affect subsequent encoding quality. Additionally, existing models may struggle with noise detection. To address these issues, we propose JCLB, a novel model that Joins Contrastive Learning and Belief rule base for NER in cybersecurity. JCLB utilizes contrastive learning to enhance similarity in the vector space between token sequence representations of entities in the same category. A Belief Rule Base (BRB) is developed using regexes to ensure accurate entity identification, particularly for fixed-format phrases lacking semantics. Moreover, a Distributed Constraint Covariance Matrix Adaptation Evolution Strategy (D-CMA-ES) algorithm is introduced for BRB parameter optimization. Experimental results demonstrate that JCLB, with the D-CMA-ES algorithm, significantly improves NER accuracy in cybersecurity.
The outcome of genetic and non-genetic pediatric cardiomyopathies
Authors: AlAlakhfash Ali , Agati Luciano , Mazzesi Giuseppe , Elhobi Dalia , Alqwaiee Abdullah , Alhory Khalid , Almesned Abdulrahman , Alhasnan Zuhair , Alwadai Abdullah
Published: April 2024

Background

Pediatric cardiomyopathies (CMP) can be familial or idiopathic with increasing detection of genetic mutations. The study is a retrospective single-center review of cardiomyopathy patients from January 2011 to May 2020. Results of the genetic study, as well as the outcome, were reported. Patients were divided according to the type of CMP, age of presentation, and EF at presentation. Univariate and multivariate analysis and ROC and survival curves were done.

Results

We reported 229 patients under 14 years of age with a diagnosis of cardiomyopathy, most commonly DCM (160 patients (70%)) followed by HCM (26.2%). 52% presented at 6 months of age or less and 119 (52%) required ICU admission at presentation. The genetic and or metabolic disorder was confirmed in 21.4% of patients, most commonly VLCAD defect (16, 7%) and ELAC2 gene defect (10, 4.4%). During the disease course, 88 patients (38.4%) died (48 with DCM, 39 with HCM, and 1 with RCM). An EF of 20% or less at presentation and presentation at 6 months of age or less carries a risk for mortality in patients with DCM and HCM, respectively (RR 3.88 and 2.06 and OR of 11.09 and 4.35, respectively). Death was more common among HCM patients especially patients with positive genetic abnormality compared with patients with DCM.

Conclusions

The mortality for CMP in children reaches up to 40%, (30% in DCM and 65% in HCM patients). Mortality was higher in those with HCM, DCM with EF of 20% or less, and HCM presented at 6 months of age or less. Whole-exome and/or whole-genome sequencing is advised for all patients of CMP and at-risk family members.
Design and implementation of a Primary Health Care (PHC) Toolbox for improving the impact of support from Global Development Partners
Authors: Spasenoska Dijana , Grundy John , Omam Lundi-Anne , Chaudhri Irtaza Ahmad , Khalid Faraz , O’Connell Thomas S. , Tampe Tova
Published: April 2024

Primary Health Care (PHC) is the most equitable and cost-effective way to enhance the health of populations and improve health security and is a requirement for achieving universal health coverage (UHC). Vital to advancing the PHC agenda is effective global health partnerships, particularly with Global Health Initiatives (GHIs) which provide financial support for improving population health. Despite progress, GHI support at times remained parallel to rather than embedded in national health strategies. To improve the impact of GHI support, World Health Organization (WHO) member states requested specific guidance to better align GHI support to national health strategies and PHC principles. We present the PHC-GHI Toolbox as a comprehensive set of resources for use by countries to apply the PHC approach to development of plans for securing and optimally utilizing funding received from GHIs, such as Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM); and the Global Financing Facility (GFF) as well as other donors. The PHC-GHI Toolbox includes a PHC resource database, GHI-specific overviews, a database of health system strengthening (HSS) investments, COVID-19 funding rapid assessment tool, and a focal point database for identifying expert technical assistance. This paper describes the process undertaken for Toolbox development and outlines its potential applications.
PmWebSpec: An Application to Create and Manage CDISC-Compliant Pharmacometric Analysis Dataset Specifications
Authors: Chen Lu , Dombrowsky Erin , Boyle Baylea , Tang Chengke , Thanneer Neelima
Published: April 2024

A well-documented pharmacometric (PMx) analysis dataset specification ensures consistency in derivations of the variables, naming conventions, traceability to the source data, and reproducibility of the analysis dataset. Lack of standards in creating the dataset specification can lead to poor quality analysis datasets, negatively impacting the quality of the PMx analysis. Standardization of the dataset specification within an individual organization helps address some of these inconsistencies. The recent introduction of the Clinical Data Interchange Standards Consortium (CDISC) Analysis Data Model (ADaM) Population Pharmacokinetic (popPK) Implementation Guide (IG) further promotes industry-wide standards by providing guidelines for the basic data structure of popPK analysis datasets. However, manual implementation of the standards can be labor intensive and error-prone. Hence, there is still a need to automate the implementation of these standards. In this paper, we present PmWebSpec, an easily deployable web-based application to facilitate the creation and management of CDISC-compliant PMx analysis dataset specifications. We describe the application of this tool through examples and highlight its key features including pre-populated dataset specifications, built-in checks to enforce standards, and generation of an electronic Common Technical Document (eCTD)-compliant data definition file. The application increases efficiency, quality and semi-automates PMx analysis dataset, and specification creation and has been well accepted by pharmacometricians and programmers internally. The success of this application suggests its potential for broader usage across the PMx community.

Graphical Abstract
Medication-Overuse Headache
Authors: Rizzoli Paul
Published: April 2024

Objective

Medication-overuse headache (MOH) has been described for almost 100 years and is characterized as a daily or near-daily headache that usually presents in patients with preexisting primary headache disorders who are overusing one or more acute or symptomatic headache medications. This article reviews the diagnosis and management of patients with MOH.

Latest Developments

The International Classification of Headache Disorders criteria for MOH have changed over time. The worldwide prevalence appears to be between 1% and 2%. Together, headache disorders, including MOH, are currently ranked as the second leading cause of years lived with disability in the Global Burden of Disease world health survey. Significant neurophysiologic changes are seen in the brains of patients with MOH, including functional alterations in central pain processing and modulating systems and central sensitization. Research supports updates to the principles of management, including weaning off the overused medication, preventive therapy, biobehavioral therapy, and patient education.

Essential Points

MOH is a fairly common and treatable secondary headache disorder that produces significant disability and a substantial reduction in quality of life. The costs related to lost income and disability are substantial. MOH is intimately related to chronic migraine, which continues to be underrecognized and undertreated. Treatment focuses on both the institution of effective preventive migraine therapy and the reduction or removal of the overused medications. Educational efforts directed toward both providers and patients have been shown to be effective in reducing the effect of MOH.
Pathophysiology of Migraine
Authors: Karsan Nazia
Published: April 2024

Objective

This article provides an overview of the current understanding of migraine pathophysiology through insights gained from the extended symptom spectrum of migraine, neuroanatomy, migraine neurochemistry, and therapeutics.

Latest Developments

Recent advances in human migraine research, including human experimental migraine models and functional neuroimaging, have provided novel insights into migraine attack initiation, neurochemistry, neuroanatomy, and therapeutic substrates. It has become clear that migraine is a neural disorder, in which a wide range of brain areas and neurochemical systems are implicated, producing a heterogeneous clinical phenotype. Many of these neural pathways are monoaminergic and peptidergic, such as those involving calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide. We are currently witnessing an exciting era in which specific drugs targeting these pathways have shown promise in treating migraine, including some studies suggesting efficacy before headache has even started.

Essential Points

Migraine is a brain disorder involving both headache and altered sensory, limbic, and homeostatic processing. A complex interplay between neurotransmitter systems, physiologic systems, and pain processing likely occurs. Targeting various therapeutic substrates within these networks provides an exciting avenue for future migraine therapeutics.
Preventive Treatment of Migraine
Authors: Lipton Richard B.
Published: April 2024

OBJECTIVE

This article describes strategies for the preventive treatment of migraine including the emerging role of calcitonin gene-related peptide (CGRP)-targeted therapies and introduces novel paradigms for the preventive treatment of migraine.

LATEST DEVELOPMENTS

Multiple migraine medications targeting CGRP have been introduced since 2018, including injectable monoclonal antibodies (ie, eptinezumab, erenumab, fremanezumab, and galcanezumab) and oral small-molecule CGRP receptor antagonists (ie, ubrogepant, rimegepant, atogepant, and zavegepant). With the exceptions of ubrogepant and zavegepant, which are approved only as acute treatments, all of these agents have demonstrated efficacy in the preventive treatment of migraine; the monoclonal antibodies and atogepant have evidence of effectiveness in adults with either episodic or chronic migraine. The safety and tolerability profiles of CGRP-targeted therapies in migraine are favorable.

ESSENTIAL POINTS

The goals of preventive migraine therapy include reducing the frequency, severity, duration, and disability associated with attacks, reducing the need for acute treatment and the risk of medication overuse, enhancing self-efficacy and health-related quality of life, and reducing headache-related distress and interictal burden. Six drugs targeting CGRP (four monoclonal antibodies and two gepants) are now available for the preventive treatment of episodic migraine in adults. The efficacy of CGRP-targeted medications in the acute and preventive treatment of migraine, together with good safety and tolerability, has led to the emergence of new approaches to preventive treatment.
Solidarity as a Political Determinant of Health: Insights from EU Competition Policy
Authors: Guy Mary
Published: April 2024

Context: The connection between law and political determinants of health is not well understood, but nevertheless it is suggested that the two are inseparable, and this represents an upstream level with scope for influencing other determinants of health (particularly social determinants). Solidarity underpins European health care systems, and given its clear link with redistribution, it can be seen as a means for addressing health inequities. As such, solidarity may be seen as a political determinant of health in the specific context of European Union (EU) competition policy.

Methods: A range of EU case law, treaty provisions, and European Commission publications relating to EU competition policy are analyzed.

Findings: Solidarity is typically juxtaposed as antithetical to competition and thus as underpinning exceptions to the applicability of prohibitions on anticompetitive agreements, abuse of dominance, and state aid. Case law indicates an additional dynamic between definitions of solidarity at the EU and national levels.

Conclusions: This analysis leads to two groups of considerations when framing solidarity as a political determinant of health in the EU competition policy context: first, the predominance of solidarity suggests it may shape competition reforms; second, the EU–member state dynamic indicates less EU-level reach into national competition reforms in health care than may be expected.