bluuebunny/crossref_metadata_2025 huggingface dataset:
VEGF and EGFR signaling pathways are involved in the baicalein attenuation of OVA-induced airway inflammation and airway remodeling in mice
Authors: Peng Wang , Xia Qinxuan , Zhang Yue , Cao Danfeng , Zheng Xiangrong
Published: January 2024

Background

Although Traditional Chinese Medicine (TCM) has been used for treating asthma for centuries, the understanding of its mechanism of action is still limited. Thus, the purpose of this study was to explore the possible therapeutic effects, and underlying mechanism of baicalein in the treatment of asthma.

Methods

Freely availabled atabases (e.g. OMIM, TTD, Genecards, BATMAN-TCM, STITCH 5.0, SEA, SwissTargetPrediction) and software (e.g. Ligplot 2.2.5 and PyMoL) were used for disease drug target prediction and molecular docking by network pharmacology. The efficacy and mechanism of action of baicalein in the treatment of asthma were validated using an ovalbumin (OVA)-induced asthma mouse model and molecular biology techniques.

Results

A total of 1655 asthma-related genes and 161 baicalein-related targets were identified from public databases. Utilizing common databases and software for network pharmacology and molecular docking analysis, seven potential target proteins for the therapeutic effects of baicalein on asthma were selected, including v-akt murine thymoma viral oncogene homolog 1 (AKT1), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase Src (SRC), mitogen-activated protein kinase 3 (MAPK3), matrix metallopeptidase 9 (MMP9), and MAPK1. In vivo, baicalein treatment via intraperitoneal injection at a dose of 50 mg/kg significantly reduced airway inflammation, collagen deposition, smooth muscle thickness, lung interleukin (IL)-4 and IL-13 levels, peripheral blood immunoglobulin (Ig)E levels, as well as the count and ratio of eosinophils in bronchoalveolar lavage fluid (BALF) in an OVA-induced asthma mouse model. Further validation by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analysis revealed that the VEGF and EGFR signaling pathways involving VEGFA, MAPK1, MAPK3, and EGFR were inhibited by baicalein in the asthma mouse model.

Conclusion

Baicalein attenuates airway inflammation and airway remodeling through inhibition of VEGF and EGFR signaling pathways in an OVA-induced asthma mouse model. This will provide a new basis for the development of baicalein as a treatment for asthma and highlights the potential of network pharmacology and molecular docking in drug discovery and development.
Features which discriminate between tuberculosis and haematologic malignancy as the cause of pleural effusions with high adenosine deaminase
Authors: Choe Junsu , Shin Sun Hye , Jeon Kyeongman , Huh Hee Jae , Park Hyung-Doo , Jeong Byeong-Ho
Published: January 2024

Background

Adenosine deaminase (ADA) is a useful biomarker for the diagnosis of tuberculous pleurisy (TBP). However, pleural effusions with high ADA can also be caused by other diseases, particularly hematologic malignant pleural effusion (hMPE). This study aimed to investigate the features that could differentiate TBP and hMPE in patients with pleural effusion ADA ≥ 40 IU/L.

Methods

This was a retrospective observational study of patients with pleural effusion ADA ≥ 40 IU/L, conducted at a Korean tertiary referral hospital with an intermediate tuberculosis burden between January 2010 and December 2017. Multivariable logistic regression analyses were performed to investigate the features associated with TBP and hMPE, respectively.

Results

Among 1134 patients with ADA ≥ 40 IU/L, 375 (33.1%) and 85 (7.5%) were diagnosed with TBP and hMPE, respectively. TBP and hMPE accounted for 59% (257/433) and 6% (27/433) in patients with ADA between 70 and 150 IU/L, respectively. However, in patients with ADA ≥ 150 IU/L, they accounted for 7% (9/123) and 19% (23/123), respectively. When ADA between 40 and 70 IU/L was the reference category, ADA between 70 and 150 IU/L was independently associated with TBP (adjusted odds ratio [aOR], 3.11; 95% confidence interval [CI], 1.95–4.95; P < 0.001). ADA ≥ 150 IU/L was negatively associated with TBP (aOR, 0.35; 95% CI, 0.14–0.90; P = 0.029) and positively associated with hMPE (aOR, 13.21; 95% CI, 5.67–30.79; P < 0.001). In addition, TBP was independently associated with lymphocytes ≥ 35% and a lactate dehydrogenase (LD)/ADA ratio < 18 in pleural effusion. hMPE was independently associated with pleural polymorphonuclear neutrophils < 50%, thrombocytopenia, and higher serum LD. A combination of lymphocytes ≥ 35%, LD/ADA < 18, and ADA < 150 IU/L demonstrated a sensitivity of 0.824 and specificity of 0.937 for predicting TBP.

Conclusion

In patients with very high levels of pleural effusion ADA, hMPE should be considered. Several features in pleural effusion and serum may help to more effectively differentiate TBP from hMPE.
CD147 induces asthmatic airway remodeling and activation of circulating fibrocytes in a mouse model of asthma
Authors: Li Zhao , Cheng Tao , Guo Yaning , Gao Rong , Ma Xuankun , Mao Xuecong , Han Xinpeng
Published: January 2024

Background

Airway remodeling is a poorly reversible feature of asthma which lacks effective therapeutic interventions. CD147 can regulate extracellular matrix (ECM) remodeling and tissue fibrosis, and participate in the pathogenesis of asthma. In this study, the role of CD147 in airway remodeling and activation of circulating fibrocytes was investigated in asthmatic mice.

Methods

Asthmatic mouse model was established by sensitizing and challenging mice with ovalbumin (OVA), and treated with anti-CD147 or Isotype antibody. The number of eosinophils in bronchoalveolar lavage fluid (BALF) was examined by microscope, and the levels of interleukin-4 (IL-4), IL-5 and IL-13 in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The number of CD45+ and collagen I (COL-I)+ circulating fibrocytes in BALF was detected by flow cytometry. Lung tissue sections were respectively stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS) or Masson trichrome staining, or used for immunohistochemistry of CD31 and immunohistofluorescence of α-smooth muscle actin (α-SMA), CD45 and COL-I. The protein expression of α-SMA, vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), Fibronectin, and COL-I was determined by western blotting.

Results

Anti-CD147 treatment significantly reduced the number of eosinophils and the levels of IL-4, IL-13, and IL-5 in BALF, and repressed airway inflammatory infiltration and airway wall thickening in asthmatic mice. Anti-CD147 treatment also reduced airway goblet cell metaplasia, collagen deposition, and angiogenesis in asthmatic mice, accompanied by inhibition of VEGF and α-SMA expression. The number of CD45+COL-I+ circulating fibrocytes was increased in BALF and lung tissues of OVA-induced asthmatic mice, but was decreased by anti-CD147 treatment. In addition, anti-CD147 treatment also reduced the protein expression of COL-I, fibronectin, and TGF-β1 in lung tissues of asthmatic mice.

Conclusion

OVA-triggered airway inflammation and airway remodeling in asthmatic mice can be repressed by anti-CD147 treatment, along with inhibiting the accumulation and activation of circulating fibrocytes.
A gene-based score for the risk stratification of stage IA lung adenocarcinoma
Authors: Xiong Yanlu , Ma Yongfu , Liu Kun , Lei Jie , Zhao Jinbo , Zhu Jianfei , Wang Wenchen , Wen Miaomiao , Wang Xuejiao , Sun Ying , Zhao Yabo , Han Yong , Jiang Tao , Liu Yang
Published: January 2024

Objective

We aim to molecularly stratify stage IA lung adenocarcinoma (LUAD) for precision medicine.

Methods

Twelve multi-institution datasets (837 cases of IA) were used to classify the high- and low-risk types (based on survival status within 5 years), and the biological differences were compared. Then, a gene-based classifying score (IA score) was trained, tested and validated by several machine learning methods. Furthermore, we estimated the significance of the IA score in the prognostic assessment, chemotherapy prediction and risk stratification of stage IA LUAD. We also developed an R package for the clinical application. The SEER database (15708 IA samples) and TCGA Pan-Cancer (1881 stage I samples) database were used to verify clinical significance.

Results

Compared with the low-risk group, the high-risk group of stage IA LUAD has obvious enrichment of the malignant pathway and more driver mutations and copy number variations. The effect of the IA score on the classification of high- and low-risk stage IA LUAD was much better than that of classical clinicopathological factors (training set: AUC = 0.9, validation set: AUC = 0.7). The IA score can significantly predict the prognosis of stage IA LUAD and has a prognostic effect for stage I pancancer. The IA score can effectively predict chemotherapy sensitivity and occult metastasis or invasion in stage IA LUAD. The R package IAExpSuv has a good risk probability prediction effect for both groups and single stages of IA LUAD.

Conclusions

The IA score can effectively stratify the risk of stage IA LUAD, offering good assistance in precision medicine.
Association between cigar use, with and without cigarettes, and incident diagnosed COPD: a longitudinal cohort study
Authors: Cook Steven , Buszkiewicz James H. , Levy David T. , Meza Rafael , Fleischer Nancy L.
Published: January 2024

Background

While regular cigar smoking is believed to carry similar health risks as regular cigarette smoking, the impact of cigar use, alone or in combination with cigarettes, on obstructive pulmonary disease (COPD) has not been well characterized. The purpose of this study was to examine the prospective association between exclusive and dual cigar and cigarette use and incident self-reported diagnosed COPD.

Methods

This study used data from Waves 1–5 (2013–2019) of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative survey of U.S. adults. Longitudinal data from adults aged 40 to 79 at Wave 1, without a pre-existing COPD diagnosis who participated at follow-up interview were analyzed. A time-varying current tobacco exposure, lagged by one wave and categorized as: (a) never/non-current use; (b) exclusive cigar use; (c) exclusive cigarette use; and (d) dual cigar/cigarette use. Multivariable models adjusted for demographics (age, sex, race or ethnicity, education), clinical risk factors (asthma, obesity), and smoking-related confounders (second-hand smoke exposure, other combustible tobacco product use, e-cigarette use, time since quitting, cigarette pack-years). The incidence of self-reported diagnosed COPD was estimated using discrete-time survival models, using a general linear modeling (GLM) approach with a binomial distribution and a complementary log-log link function.

Results

The analytic sample consisted of 9,556 adults with a mean (SD) age of 56 (10.4), who were predominately female (52.8%) and Non-Hispanic White (70.8%). A total of 906 respondents reported a diagnosis of COPD at follow-up. In the fully adjusted model, exclusive cigar use (adjusted hazard ratio (aHR) = 1.57, 95% CI: 0.77, 3.21) was not associated with increased COPD risk compared to non-use, while exclusive cigarette use (aHR = 1.48, 95% CI: 1.13, 1.93) and dual cigar/cigarette use (aHR = 1.88, 95% CI: 1.24, 2.85) were.

Conclusions

Exclusive cigarette use and dual cigar/cigarette use were associated with diagnosed incident COPD. These results suggest that cigars, when used in combination with cigarettes, may be associated with poorer COPD health outcomes. Dual use may promote a higher likelihood of inhaling cigar smoke, and future research would benefit from examining whether inhalation of cigar smoke increases COPD risk.
Inspiratory-expiratory variation of pleural line thickness in neonates with and without acute respiratory failure
Authors: Loi Barbara , Barra Pasquale Fabio , Vivalda Laura , Raimondi Francesco , De Luca Daniele
Published: January 2024

Background

There are relatively few data about the ultrasound evaluation of pleural line in patients with respiratory failure. We measured the pleural line thickness during different phases of the respiratory cycle in neonates with and without acute respiratory failure as we hypothesized that this can significantly change.

Methods

Prospective, observational, cohort study performed in an academic tertiary neonatal intensive care unit recruiting neonates with transient tachypnoea of the neonate (TTN), respiratory distress syndrome (RDS) or neonatal acute respiratory distress syndrome (NARDS). Neonates with no lung disease (NLD) were also recruited as controls. Pleural line thickness was measured with high-frequency ultrasound at end-inspiration and end-expiration by two different raters.

Results

Pleural line thickness was slightly but significantly higher at end-expiration (0.53 [0.43–0.63] mm) than at end-inspiration (0.5 [0.4–0.6] mm; p = 0.001) for the whole population. End-inspiratory (NLD: 0.45 [0.38–0.53], TTN: 0.49 [0.43–0.59], RDS: 0.53 [0.41–0.62], NARDS: 0.6 [0.5–0.7] mm) and -expiratory (NLD: 0.47 [0.42–0.56], TTN: 0.48 [0.43–0.61], RDS: 0.53 [0.46–0.65], NARDS: 0.61 [0.54–0.72] mm) thickness were significantly different (overall p = 0.021 for both), between the groups although the absolute differences were small. The inter-rater agreement was optimal (ICC: 0.95 (0.94–0.96)). Coefficient of variation was 2.8% and 2.5% for end-inspiratory and end-expiratory measurements, respectively. These findings provide normative data of pleural line thickness for the most common forms of neonatal acute respiratory failure and are useful to design future studies to investigate possible clinical applications.
"In their own words": delineating the contours of dyspnea invisibility in patients with advanced chronic obstructive pulmonary disease from quantitative discourse analysis
Authors: Dedonder Jonathan , Gelgon Christelle , Guerder Antoine , Nion Nathalie , Lavault Sophie , Morélot-Panzini Capucine , Gonzalez-Bermejo Jésus , Benoit Laelia , Similowski Thomas , Serresse Laure
Published: January 2024

Background

Dyspnea conveys an upsetting or distressing experience of breathing awareness. It heavily weighs on chronic respiratory disease patients, particularly when it persists despite maximal treatment of causative abnormalities. The physical, psychological and social impacts of persistent dyspnea are ill-appreciated by others. This invisibility constitutes a social barrier and impedes access to care. This study aimed to better understand dyspnea invisibility in patients with chronic obstructive pulmonary disease (COPD) through quantitative discourse analysis.

Methods

We conducted a lexicometric analysis (lemmatization, descending hierarchical classification, multicomponent analysis, similarity analysis) of 11 patients' discourses (6 men, severe COPD; immediate postexacerbation rehabilitation) to identify semantic classes and communities, which we then confronted with themes previously identified using interpretative phenomenological analysis (IPA).

Results

Class#1 ("experience and need for better understanding"; 38.9% of semantic forms, 50% of patients) illustrates the gap that patients perceive between their experience and what others see, confirming the importance of dyspnea invisibility in patients' concerns. Class#2 ("limitations"; 28.7% of forms) and Class#3 (management"; 13.1% of forms) point to the weight of daily limitations in performing basic activities, of the need to accept or adapt to the constraints of the disease. These three classes matched previously identified IPA-derived themes. Class#4 ("hospitalization"; 18.2% of forms) points to the importance of interactions with the hospital, especially during exacerbations, which constitutes novel information.

Conclusions

Lexicometry confirms the importance of dyspnea invisibility as a burden to COPD patients.
The complement cascade in lung injury and disease
Authors: Detsika M. G. , Palamaris K. , Dimopoulou I. , Kotanidou A. , Orfanos S. E.
Published: January 2024

Background

The complement system is an important arm of immune defense bringing innate and adaptive immunity. Although originally regarded as a major complementary defense mechanism against pathogens, continuously emerging evidence has uncovered a central role of this complex system in several diseases including lung pathologies.

Main body

Complement factors such as anaphylatoxins C3a and C5a, their receptors C3aR, C5aR and C5aR2 as well as complement inhibitory proteins CD55, CD46 and CD59 have been implicated in pathologies such as the acute respiratory distress syndrome, pneumonia, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, and lung cancer. However, the exact mechanisms by which complement factors induce these diseases remain unclear. Several complement-targeting monoclonal antibodies are reported to treat lung diseases.

Conclusions

The complement system contributes to the progression of the acute and chronic lung diseases. Better understanding of the underlying mechanisms will provide groundwork to develop new strategy to target complement factors for treatment of lung diseases.
ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy
Authors: Soumoy Laura , Genbauffe Aline , Mouchart Lena , Sperone Alexandra , Trelcat Anne , Mukeba-Harchies Léa , Wells Mathilde , Blankert Bertrand , Najem Ahmad , Ghanem Ghanem , Saussez Sven , Journe Fabrice
Published: January 2024

Despite advancements in treating metastatic melanoma, many patients exhibit resistance to targeted therapies. Our study focuses on ATP1A1, a sodium pump subunit associated with cancer development. We aimed to assess ATP1A1 prognostic value in melanoma patients and examine the impact of its ligand, bufalin, on melanoma cell lines in vitro and in vivo. High ATP1A1 expression (IHC) correlated with reduced overall survival in melanoma patients. Resistance to BRAF inhibitor was linked to elevated ATP1A1 levels in patient biopsies (IHC, qPCR) and cell lines (Western blot, qPCR). Additionally, high ATP1A1 mRNA expression positively correlated with differentiation/pigmentation markers based on data from The Cancer Genome Atlas (TCGA) databases and Verfaillie proliferative gene signature analysis. Bufalin specifically targeted ATP1A1 in caveolae, (proximity ligation assay) and influenced Src phosphorylation (Western blot), thereby disrupting multiple signaling pathways (phosphokinase array). In vitro, bufalin induced apoptosis in melanoma cell lines by acting on ATP1A1 (siRNA experiments) and, in vivo, significantly impeded melanoma growth using a nude mouse xenograft model with continuous bufalin delivery via an osmotic pump. In conclusion, our study demonstrates that ATP1A1 could serve as a prognostic marker for patient survival and a predictive marker for response to BRAF inhibitor therapy. By targeting ATP1A1, bufalin inhibited cell proliferation, induced apoptosis in vitro, and effectively suppressed tumor development in mice. Thus, our findings strongly support ATP1A1 as a promising therapeutic target, with bufalin as a potential agent to disrupt its tumor-promoting activity.
In vitro delayed response to dihydroartemisinin of malaria parasites infecting sickle cell erythocytes
Authors: Gnondjui Albert A. , Toure Offianan A. , Ako Berenger A. , Koui Tossea S. , Assohoun Stanislas E. , Gbessi Eric A. , N’Guessan Landry T. , Tuo Karim , Beourou Sylvain , Assi Serge-Brice , Yapo Francis A. , Sanogo Ibrahima , Jambou Ronan
Published: January 2024

Background

Decreased efficacy of artemisinin-based combination therapy (ACT) forPlasmodium falciparummalaria has been previously reported in patients with sickle cell disease (SCD). The main purpose of this study was to investigate the in vitro susceptibility of isolates to dihydro-artemisinin (DHA) to provide a hypothesis to explain this treatment failure.

Methods

Isolates were collected from patients attending health centres in Abidjan with uncomplicatedP. falciparummalaria. The haemoglobin type has been identified and in vitro drug sensitivity tests were conducted with the ring stage assay and maturation inhibition assay.

Results

134 isolates were obtained. Parasitaemia and haemoglobin levels at inclusion were lower in patients with haemoglobin HbSS and HbSC than in patients with normal HbAA. After ex vivo RSA and drug inhibition assays, the lowest rate of parasitic growth was found with isolates from HbAS red cells. Conversely, a significantly higher survival rate of parasites ranging from 15 to 34% were observed in isolates from HbSS. Isolates with in vitro reduced DHA sensitivity correlate with lower RBC count and haematocrit and higher parasitaemia at inclusion compared to those with isolates with normal DHA sensitivity. However, this decrease of in vitro sensitivity to DHA was not associated with Kelch 13-Propeller gene polymorphism.

Conclusion

This study highlights an in vitro decreased sensitivity to DHA, for isolates collected from HbSS patients, not related to the Pfkelch13 gene mutations. These results are in line with recent studies pointing out the role of the redox context in the efficacy of the drug. Indeed, SCD red cells harbour a highly different ionic and redox context in comparison with normal red cells. This study offers new insights into the understanding of artemisinin selective pressure on the malaria parasite in the context of haemoglobinopathies in Africa.
Mosquito control by abatement programmes in the United States: perspectives and lessons for countries in sub-Saharan Africa
Authors: Ochomo Eric , Rund Samuel S. C. , Mthawanji Rosheen S. , Antonio-Nkondjio Christophe , Machani Maxwell , Samake Siriman , Wolie Rosine Z. , Nsango Sandrine , Lown Laurel Anne , Matoke-Muhia Damaris , Kamau Luna , Lukyamuzi Edward , Njeri Jane , Chabi Joseph , Akrofi Otubea Owusu , Ntege Charles , Mero Victor , Mwalimu Charles , Kiware Samson , Bilgo Etienne , Traoré Mohamed Moumine , Afrane Yaw , Hakizimana Emmanuel , Muleba Mbanga , Orefuwa Emma , Chaki Prosper , Juma Elijah Omondi
Published: January 2024

Africa and the United States are both large, heterogeneous geographies with a diverse range of ecologies, climates and mosquito species diversity which contribute to disease transmission and nuisance biting. In the United States, mosquito control is nationally, and regionally coordinated and in so much as the Centers for Disease Control (CDC) provides guidance, the Environmental Protection Agency (EPA) provides pesticide registration, and the states provide legal authority and oversight, the implementation is usually decentralized to the state, county, or city level. Mosquito control operations are organized, in most instances, into fully independent mosquito abatement districts, public works departments, local health departments. In some cases, municipalities engage independent private contractors to undertake mosquito control within their jurisdictions. In sub–Saharan Africa (SSA), where most vector-borne disease endemic countries lie, mosquito control is organized centrally at the national level. In this model, the disease control programmes (national malaria control programmes or national malaria elimination programmes (NMCP/NMEP)) are embedded within the central governments’ ministries of health (MoHs) and drive vector control policy development and implementation. Because of the high disease burden and limited resources, the primary endpoint of mosquito control in these settings is reduction of mosquito borne diseases, primarily, malaria. In the United States, however, the endpoint is mosquito control, therefore, significant (or even greater) emphasis is laid on nuisance mosquitoes as much as disease vectors. The authors detail experiences and learnings gathered by the delegation of African vector control professionals that participated in a formal exchange programme initiated by the Pan-African Mosquito Control Association (PAMCA), the University of Notre Dame, and members of the American Mosquito Control Association (AMCA), in the United States between the year 2021 and 2022. The authors highlight the key components of mosquito control operations in the United States and compare them to mosquito control programmes in SSA countries endemic for vector-borne diseases, deriving important lessons that could be useful for vector control in SSA.
Social inequalities in early childhood language development during the COVID-19 pandemic: a descriptive study with data from three consecutive school entry surveys in Germany
Authors: Hoffmann Stephanie , Tschorn Mira , Spallek Jacob
Published: January 2024

Background

Social health inequalities are still of great public health importance in modern societies. The COVID-19 pandemic may have affected social inequalities in people's health due to containment measures. As these measures particularly affected children, they might have been particularly vulnerable to increased social inequalities. The aim of the study was to describe health inequalities during the pandemic based on language delay (LD) in children in order to inform public health interventions for a population at risk of long-term health and education inequalities.

Methods

Data of 5–7 year old children from three consecutive school entry surveys in the German federal state of Brandenburg were used, including data compulsorily collected before the pandemic (2018/2019: n = 19,299), at the beginning of the pandemic (2019/2020: n = 19,916) and during the pandemic (2020/2021: n = 19,698). Bivariate and multivariate binary regression analyses [OR, 95% CI] cross-sectionally examined the relationship between the prevalence of LD [yes/no] and social inequalities, operationalized by family socioeconomic position [SEP low/middle/high], migration background [native-German language/non-native German language] and length of kindergarten attendance [< 4 years/ ≥ 4 years]. Factors contributing to inequality in LD were examined by socioeconomic stratification.

Results

Cross-sectionally, LD prevalence has decreased overall (2018/2019: 21.1%, 2019/2020: 19.2%, 2020/2021: 18.8%), and among children from both high SEP and native German-speaking families. As LD prevalence increased among children from families with low SEP and remained stable among non-native German speakers, social inequalities in LD prevalence increased slightly during the pandemic i) by low SEP (2018/2019: OR = 4.41, 3.93–4.94; 2020/2021: OR = 5.12, 4.54–5.77) and ii) by non-German native language (2018/2019: OR = 2.22, 1.86–2.66; 2020/2021: OR = 2.54, 2.19–2.95). During the pandemic, both migration background and kindergarten attendance determined LD prevalence in the high and middle SEP strata. However, the measured factors did not contribute to LD prevalence in children from families with low SEP.

Conclusion

Social inequalities in LD increased due to opposing trends in prevalence comparing low and high SEP families. To promote health equity across the life course, early childhood should be of interest for tailored public health actions (e.g. through targeted interventions for kindergarten groups). Further analytical studies should investigate determinants (e.g., parental investment).
Repurposed drugs in combinations exert additive anti-chikungunya virus activity: an in-vitro study
Authors: Davuluri Kusuma Sai , Ghanghav Rajnandini , Ahire Gunwant , Kakade Mahadeo , Cherian Sarah , Alagarasu Kalichamy , Parashar Deepti
Published: January 2024

Chikungunya virus (CHIKV) infection causes chikungunya, a viral disease that currently has no specific antiviral treatment. Several repurposed drug candidates have been investigated for the treatment of the disease. In order to improve the efficacy of the known drugs, combining drugs for treatment is a promising approach. The current study was undertaken to explore the antiviral activity of a combination of repurposed drugs that were reported to have anti-CHIKV activity. We explored the effect of different combinations of six effective drugs (2-fluoroadenine, emetine, lomibuvir, enalaprilat, metyrapone and resveratrol) at their non-toxic concentrations against CHIKV under post infection treatment conditions in Vero cells. Focus-forming unit assay, real time RT-PCR, immunofluorescence assay, and western blot were used to determine the virus titre. The results revealed that the combination of 2-fluoroadenine with either metyrapone or emetine or enalaprilat exerted inhibitory activity against CHIKV under post-infection treatment conditions. The effect of these drug combinations was additive in nature compared to the effect of the individual drugs. The results suggest an additive anti-viral effect of these drug combinations against CHIKV. The findings could serve as an outline for the development of an innovative therapeutic approach in the future to treat CHIKV-infected patients.
Prevalence of KIG-grades 3–5 in an orthodontic practice in North Rhine Westphalia compared with results of the DMS•6 and with KZBV data
Authors: Kinzinger Gero Stefan Michael , Hourfar Jan , Lisson Jörg Alexander
Published: January 2024

Background and aim

The prevalence of tooth and jaw malocclusions in 8- to 9-year-olds was surveyed in a nationwide setting as part of the orthodontic module of the Sixth German Study on Oral Health (DMS•6), using the orthodontic indication groups (KIG) as index. Aim of this study was the detection of the prevalence of malocclusions requiring treatment according to the KIG index in statutorily insured patients of an orthodontic practice in North Rhine Westphalia, Germany, and to compare results with corresponding DMS•6 and KZBV data.

Patients and methods

Between 2017–2021, n = 953 statutorily insured patients called for an initial consultation and subsequent determination of the KIG-classification and -grades. The malocclusions were classified and graded in the highest possible KIG-grade according to valid SHI guidelines. Multiple classifications were not recorded. KIG-grade > 3 according to the valid guidelines was detected in n = 815 patients. Since the DMS•6 does not contain information on KIG classifications "U" and "S", their inclusion was waived despite evaluation, leaving data from n = 683 patients for analysis and comparison.

Results

During the study period, n = 235 patients (34.4%) had KIG-classification "D". More than 10% were classified as "K" (120 patients, 17.6%), "P" (98 patients, 14.2%), "M" (89 patients, 13.0%), and "E" (81 patients, 11.9%). Of 16 possible classifications with KIG-grade > 3, "D4" was the most common with 26.6% (182 patients). The results confirm the findings from the multicentric DMS•6 from2021 and corresponding KZBV data from 2020.

Conclusions

Sagittal deviations described by classifications "D" and "M" represent with 47.4% almost half of the malocclusions with treatment need. KIG-grade D4 is the most frequent classification. There were no regional deviations of the prevalence of KIG-grades 3–5 in the district of Viersen / North Rhine compared with the national average, not even when scrutinizing a five-year-period.
The prognostic role of PD-L1 expression and the presence of polyomavirus in Merkel cell carcinoma cases
Authors: Siqueira Stella Meireles , Campos-do-Carmo Gabriella , da Silva Paulo Ricardo Garcia , Small Isabele Ávila , De Melo Andreia Cristina
Published: January 2024

Background

Merkel cell carcinoma (MCC) comprises a rare malignant primary skin tumor presenting neuroendocrine differentiation. Recently, agents blocking the programmed cell death protein 1 and programmed cell death protein ligand 1 pathway (PD-1/PD-L1) have demonstrated objective and durable tumor regressions in patients presenting advanced MCC. This study aimed to describe the sociodemographic, clinical, and histopathological characteristics of MCC patients, also assessing the prevalence of PD-L1 expression and Merkel cell Polyomavirus (MCPyV), as well as their prognostic roles.

Methods

Data from patients diagnosed with MCC between 1996 and 2019 at a reference cancer center in Rio de Janeiro, southeastern Brazil, were evaluated in a retrospective study. Tumor samples were tested for MCPyV and PD-L1 employing immunohistochemistry. Survival analyses were carried out employing the Kaplan–Meier method and curves were compared using the log-rank test. A multiple semiparametric Cox model was used. Values p < 0.05 were considered significant.

Results

A total of 65 patients were included in the study, with a mean age at diagnosis of 72 (standard deviation 13.9). A total of 56.9% (37/65) of the patients were male, 86.2% (56/65) were white, and 56.9% (37/64) were illiterate or with incomplete elementary school. MCPyV immunohistochemistry was positive in 29 cases (44.6%) and PD-L1 positivity was ≥ 1% in 42 cases (64.6%). Significant associations between MCPyV and PD-L1 expression ≥ 1% (p = 0.003) and PD-L1 expression ≥ 5% (p = 0.005) were noted. Concerning the multivariate analysis, only education level and advanced MCC stage indicated statistically significant worse progression-free survival. Regarding overall survival (OS), being male, education level and advanced stage comprised risk factors. The estimated OS at 60 months for stages I to III was of 48.9% and for stage IV, 8.9%.

Conclusions

This is the first large Brazilian cohort to assess the prevalence of MCPyV in MCC tumors, as well as PD-L1 expression and their associations. No correlations were noted between MCPyV infection or PD-L1 expression and survival rates.
Genomic surveillance of Anopheles mosquitoes on the Bijagós Archipelago using custom targeted amplicon sequencing identifies mutations associated with insecticide resistance
Authors: Moss Sophie , Pretorius Elizabeth , Ceesay Sainey , Hutchins Harry , da Silva Eunice Teixeira , Ndiath Mamadou Ousmane , Jones Robert T. , Vasileva Hristina , Phelan Jody , Acford-Palmer Holly , Collins Emma , Rodrigues Amabelia , Krishna Sanjeev , Clark Taane G. , Last Anna , Campino Susana
Published: January 2024

Background

Insecticide resistance is reducing the efficacy of vector control interventions, consequently threatening efforts to control vector-borne diseases, including malaria. Investigating the prevalence of molecular markers of resistance is a useful tool for monitoring the spread of insecticide resistance in disease vectors. The Bijagós Archipelago (Bijagós) in Guinea-Bissau is a region of stable malaria transmission where insecticide-treated nets are the mainstay for malaria control. However, the prevalence of molecular markers of insecticide resistance in malaria vectors is not well understood.

Methods

A total of 214 Anopheles mosquitoes were analysed from 13 islands across the Bijagós. These mosquitoes were collected using CDC light traps in November 2019, during the peak malaria transmission season. High-throughput multiplex amplicon sequencing was used to investigate the prevalence of 17 different molecular markers associated with insecticide resistance in four genes: vgsc, rdl, ace1 and gste2.

Results

Of the 17 screened mutations, four were identified in mosquitoes from the Bijagós: vgsc L995F (12.2%), N1570Y (6.2%) and A1746S (0.7%) and rdl A269G (1.1%). This study is the first to report the L995F knock-down resistance (kdr)-west allele in Anopheles melas on the Archipelago. An additional eight non-synonymous single-nucleotide polymorphisms were identified across the four genes which have not been described previously. The prevalences of the vgsc L995F and N1570Y mutations were higher on Bubaque Island than on the other islands in this study; Bubaque is the most populous island in the archipelago, with the greatest population mobility and connection to continental Guinea-Bissau.

Conclusions

This study provides the first surveillance data for genetic markers present in malaria vectors from islands across the Bijagós Archipelago. Overall prevalence of insecticide resistance mutations was found to be low. However, the identification of the vgsc L995F and N1570Y mutations associated with pyrethroid resistance warrants further monitoring. This is particularly important as the mainstay of malaria control on the islands is the use of pyrethroid insecticide-treated nets.

Graphical Abstract
Experimental genetic crosses in tsetse flies of the livestock pathogen Trypanosoma congolense savannah
Authors: Peacock Lori , Kay Chris , Bailey Mick , Gibson Wendy
Published: January 2024

Background

In tropical Africa animal trypanosomiasis is a disease that has severe impacts on the health and productivity of livestock in tsetse fly-infested regions. Trypanosoma congolense savannah (TCS) is one of the main causative agents and is widely distributed across the sub-Saharan tsetse belt. Population genetics analysis has shown that TCS is genetically heterogeneous and there is evidence for genetic exchange, but to date Trypanosoma brucei is the only tsetse-transmitted trypanosome with experimentally proven capability to undergo sexual reproduction, with meiosis and production of haploid gametes. In T. brucei sex occurs in the fly salivary glands, so by analogy, sex in TCS should occur in the proboscis, where the corresponding portion of the developmental cycle takes place. Here we test this prediction using genetically modified red and green fluorescent clones of TCS.

Methods

Three fly-transmissible strains of TCS were transfected with genes for red or green fluorescent protein, linked to a gene for resistance to the antibiotic hygromycin, and experimental crosses were set up by co-transmitting red and green fluorescent lines in different combinations via tsetse flies, Glossina pallidipes. To test whether sex occurred in vitro, co-cultures of attached epimastigotes of one red and one green fluorescent TCS strain were set up and sampled at intervals for 28 days.

Results

All interclonal crosses of genetically modified trypanosomes produced hybrids containing both red and green fluorescent proteins, but yellow fluorescent hybrids were only present among trypanosomes from the fly proboscis, not from the midgut or proventriculus. It was not possible to identify the precise life cycle stage that undergoes mating, but it is probably attached epimastigotes in the food canal of the proboscis. Yellow hybrids were seen as early as 14 days post-infection. One intraclonal cross in tsetse and in vitro co-cultures of epimastigotes also produced yellow hybrids in small numbers. The hybrid nature of the yellow fluorescent trypanosomes observed was not confirmed by genetic analysis.

Conclusions

Despite absence of genetic characterisation of hybrid trypanosomes, the fact that these were produced only in the proboscis and in several independent crosses suggests that they are products of mating rather than cell fusion. The three-way strain compatibility observed is similar to that demonstrated previously for T. brucei, indicating that a simple two mating type system does not apply for either trypanosome species.

Graphical Abstract
[68 Ga]Ga-FAPI-04 PET/CT may be a predictor for early treatment response in rheumatoid arthritis
Authors: Pan Qingqing , Yang Huaxia , Zhou Ziyue , Li Min , Jiang Xu , Li Fang , Luo Yaping , Li Mengtao
Published: January 2024

Background

The identification of biomarkers predicting the treatment response of rheumatoid arthritis (RA) is important. [68 Ga]Ga-FAPI-04 showed markedly increased uptake in the joints of patients with RA. The purpose of this study is to investigate whether [68 Ga]Ga-FAPI-04 PET/CT can be a predictor of treatment response in RA.

Results

Nineteen patients diagnosed with RA in the prospective cohort study were finally enrolled. Both total synovitis uptake (TSU) and metabolic synovitis volume (MSV) in [68 Ga]Ga-FAPI-04 and [18F]FDG PET/CT of the responders were significantly higher than those in non-responders according to Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) response criteria at 3-months’ follow-up (P < 0.05). The PET joint count (PJC) detected in [68 Ga]Ga-FAPI-04 and [18F]FDG PET/CT were also significantly higher in CDAI responders than non-responders (P = 0.016 and 0.045, respectively). The clinical characteristics of disease activity at baseline did not show significant difference between the responders and non-responders, except CRP (P = 0.035 and 0.033 in CDAI and SDAI response criteria, respectively). The baseline PJCFAPI, TSUFAPI and MSVFAPI > cutoff values in [68 Ga]Ga-FAPI-04 PET/CT successfully discriminated CDAI and SDAI responders and non-responders at 3-months’ follow-up.

Conclusion

[68 Ga]Ga-FAPI-04 uptake at baseline were significantly higher in early responders than those in non-responders.

Trial registration ClinicalTrials. NCT04514614. Registered 13 August 2020, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000A4PN&selectaction=Edit&uid=U0001JRW&ts=2&cx=-x9t7cp
The effect of innovative mindset and behavior on innovation performance and competitive advantage: a case of halal SMEs owner-managers from Malaysian energy-intensive industry
Authors: Jaaffar Amar Hisham , Abd Majid Nurshahirah , Kasavan Saraswathy , Isa Aerni , Alwi Mohd Nur Ruzainy , Zahari Abdul Rahman
Published: January 2024

Malaysia was ranked 32nd on the Global Competitiveness Index in 2022, which denotes that the level of R&D and productivity in SMEs in Malaysia needs to be improved. Therefore, more research is needed to ensure it remains competitive in the global halal marketplace by using innovative concepts as a culture to promote energy-intensive halal SMEs. This study examines the sequential influence of an innovative mindset, behavior, and performance on competitive advantage among SME owner-managers embarking on halal businesses. Data were gathered from SME owner-managers from the halal energy-intensive industry by conducting a self-administered and online-based survey involving 140 respondents. Data were analyzed with the partial least squares technique (SmartPLS 3.0). The results of this study show that innovative behavior was a direct result of an innovative mindset. On the other hand, innovative behavior produced innovation performance, which in turn produced a competitive advantage. This study shows that SMEs owner-managers of halal energy-intensive industries need possess both innovative behavior and innovative attitude as valuable assets. Moreover, a key component in their ability to gain a competitive advantage is their performance in innovation.
FDI and economic growth in Indonesia: a provincial and sectoral analysis
Authors: Fazaalloh Al Muizzuddin
Published: January 2024

Foreign direct investment (FDI) plays an essential role in growing the economy, where this role runs through two things, namely capital accumulation and technology transfer. However, in the literature, previous research findings are still inconclusive to show positive contributions of FDI on economic growth. Furthermore, while the impact of FDI on economic growth has been studied using sectoral data, there has been less research done using data at the provincial and sectoral levels. This study aims to analyze the impact of foreign direct investment (FDI) on economic growth employing sectoral data at the provincial level (33 provinces) in Indonesia over 2010–2019. Based on the fixed effects estimator, our estimation results prove that, in general, FDI significantly positively impacts economic growth in the Indonesian provinces. We also find that FDI in the mining, manufacturing, water, gas and electricity, hotels and restaurants, and real estate sectors has a significant positive effect on economic growth. Meanwhile, only FDI in the agricultural sector has a significant negative impact. Our estimation results confirm that FDI in the manufacturing sector contributes positively and has a considerable impact. The results are robust to the GMM System estimator, which considers the endogeneity problem.
The role of regulatory B cells in immune regulation and childhood allergic asthma
Authors: Kliem Caroline Vanessa , Schaub Bianca
Published: January 2024

Background

As the most common chronic disease in childhood, asthma displays a major public health problem worldwide with the incidence of those affected rising. As there is currently no cure for allergic asthma, it is mandatory to get a better understanding of the underlying molecular mechanism.

Main body

By producing IgE antibodies upon allergen contact, B cells play a pivotal role in allergic asthma. Besides that, IL-10-secreting B cell subsets, namely regulatory B cells (Bregs), are reported in mice and humans to play a role in allergic asthma. In humans, several Breg subsets with distinct phenotypic and functional properties are identified among B cells at different maturational and differentiation stages that exert anti-inflammatory functions by expressing several suppressor molecules. Emerging research has focused on the role of Bregs in allergic asthma as well as their role for future diagnostic and preventive strategies.

Conclusion

Knowledge about the exact function of human Bregs in allergic asthma is still very limited. This review aims to summarize the current knowledge on Bregs. We discuss different human Breg subsets, several ways of Breg induction as well as the mechanisms through which they exert immunoregulatory functions, and their role in (childhood) allergic asthma.
Immobilization of Thermomyces lanuginosus lipase in a novel polysaccharide-based hydrogel by a two-step crosslinking method and its use in the lauroylation of α-arbutin
Authors: Chen Ming , She Weina , Zhao Xin , Chen Cheng , Zhu Benwei , Sun Yun , Yao Zhong
Published: January 2024

The Thermomyces lanuginosus lipase (TLLs) was successfully immobilized within a novel hydrogel matrix through a two-step crosslinking method. TLLs were initially crosslinked through the Schiff base reaction by oxidized carboxymethyl cellulose (OCMC). The water-soluble OCMC@TLLs complex was subsequently crosslinked by carboxymethyl chitosan (CMCSH) in a microfluidic apparatus to form the CMCHS/OCMC@TLLs microspheres. The CD (Circular Dichroism, CD) and FT-IR (Fourier Transform infrared spectroscopy, FT-IR) spectra demonstrated that the crosslinking of TLLs with OCMC resulted in a less significant impact on their structure compared to that with glutaraldehyde. CMCHS/OCMC@TLLs showed decreased catalytic performance due to the mass transfer resistance, while its thermal stability was greatly improved. The CMCHS/OCMC@TLLs were used to catalyze the lauroylation of arbutin in tetrahydrofuran. After 12 h of reaction under optimal conditions, the yield of 6′-O-lauryl arbutin reached an impressive 92.12%. The prepared 6′-O-lauryl arbutin has high lipophilicity and exhibits similar tyrosinase inhibitory activity and higher antioxidant activity compared to its parent compound.

Graphical Abstract
A circuitous route for in vitro multi-enzyme cascade production of cytidine triphosphate to overcome the thermodynamic bottleneck
Authors: Li Zonglin , Zhong Yahui , Qing Zhoulei , Li Zhimin
Published: January 2024

Cytidine triphosphate (CTP), as a substance involved in the metabolism of phospholipids, proteins and nucleic acids, has precise drug effects and is a direct precursor for the synthesis of drugs such as citicoline. In this study, we established an in vitro six-enzyme cascade system to generate CTP. To avoid thermodynamic bottlenecks, we employed a circuitous and two-stage reaction strategy. Using cytidine as the key substrate, the final product CTP is obtained via the deamination and uridine phosphorylation pathways, relying on the irreversible reaction of cytidine triphosphate synthase to catalyze the amination of uridine triphosphate. Several extremophilic microbial-derived deaminases were screened and characterized, and a suitable cytidine deaminase was selected to match the first-stage reaction conditions. In addition, directed evolution modification of the rate-limiting enzyme CTP synthetase in the pathway yielded a variant that successfully relieved the product feedback inhibition, along with a 1.7-fold increase in activity over the wild type. After optimizing the reaction conditions, we finally carried out the catalytic reaction at an initial cytidine concentration of 20 mM, and the yield of CTP exceeded 82% within 10.0 h.

Graphical Abstract