bluuebunny/crossref_metadata_2025_split huggingface dataset:
GADD45A regulates subcutaneous fat deposition and lipid metabolism by interacting with Stat1
Authors: You Wenjing , Liu Shiqi , Li Jie , Tu Yuang , Shan Tizhong 
Published: October 2023

Abstract
Background
Obesity, characterized by excessive white adipose tissue expansion, is associated with several metabolic complications. Identifying new adipogenesis regulators may lead to effective therapies for obesity-induced metabolic disorders.

Results
Here, we identified the growth arrest and DNA damage-inducible A (GADD45A), a stress-inducible histone-folding protein, as a novel regulator of subcutaneous adipose metabolism. We found that GADD45A expression was positively correlated with subcutaneous fat deposition and obesity in humans and fatty animals. In vitro, the gain or loss function of GADD45A promoted or inhibited subcutaneous adipogenic differentiation and lipid accumulation, respectively. Using a Gadd45a-/- mouse model, we showed that compared to wild-type (WT) mice, knockout (KO) mice exhibited subcutaneous fat browning and resistance to high-fat diet (HFD)-induced obesity. GADD45A deletion also upregulated the expression of mitochondria-related genes. Importantly, we further revealed that the interaction of GADD45A with Stat1 prevented phosphorylation of Stat1, resulting in the impaired expression of Lkb1, thereby regulating subcutaneous adipogenesis and lipid metabolism.

Conclusions
Overall, our results reveal the critical regulatory roles of GADD45A in subcutaneous fat deposition and lipid metabolism. We demonstrate that GADD45A deficiency induces the inguinal white adipose tissue (iWAT) browning and protects mice against HFD-induced obesity. Our findings provide new potential targets for combating obesity-related metabolic diseases and improving human health.
PRC2 mediated KLF2 down regulation: a therapeutic and diagnostic axis during tumor progression
Authors: Taghehchian Negin , Maharati Amirhosein , Akhlaghipour Iman , Zangouei Amir Sadra , Moghbeli Meysam 
Published: October 2023

AbstractSurgery and chemo-radiotherapy are used as the common first-line treatment options in many cancers. However, tumor relapse is observed in many cancer patients following such first-line treatments. Therefore, targeted therapy according to the molecular cancer biology can be very important in reducing tumor recurrence. In this regard, a wide range of monoclonal antibodies against the growth factors and their receptors can offer more targeted treatment in cancer patients. However, due to the importance of growth factors in the normal biology of body cells, side effects can also be observed following the application of growth factor inhibitors. Therefore, more specific factors should be introduced as therapeutic targets with less side effects. Krüppel-like factors 2 (KLF2) belongs to the KLF family of transcription factors that are involved in the regulation of many cellular processes. KLF2 deregulations have been also reported during the progression of many tumors. In the present review we discussed the molecular mechanisms of KLF2 during tumor growth and invasion. It has been shown that the KLF2 as a tumor suppressor is mainly inhibited by the non-coding RNAs (ncRNAs) through the polycomb repressive complex 2 (PRC2) recruitment. This review is an effective step towards introducing the KLF2 as a suitable diagnostic and therapeutic target in cancer patients.
Space-time modelling of monthly malaria incidence for seasonal associated drivers and early epidemic detection in Southern Ethiopia
Authors: Kitawa Yonas Shuke , Asfaw Zeytu Gashaw 
Published: October 2023

Abstract
Background
Although Ethiopia has made great strides in recent years to reduce the threat of malaria, the disease remains a significant issue in most districts of the country. It constantly disappears in parts of the areas before reappearing in others with erratic transmission rates. Thus, developing a malaria epidemic early warning system is important to support the prevention and control of the incidence.

Methods
Space-time malaria risk mapping is essential to monitor and evaluate priority zones, refocus intervention, and enable planning for future health targets. From August 2013 to May 2019, the researcher considered an aggregated count of genus Plasmodium falciparum from 149 districts in Southern Ethiopia. Afterwards, a malaria epidemic early warning system was developed using model-based geostatistics, which helped to chart the disease’s spread and future management.

Results
Risk factors like precipitation, temperature, humidity, and nighttime light are significantly associated with malaria with different rates across the districts. Districts in the southwest, including Selamago, Bero, and Hamer, had higher rates of malaria risk, whereas in the south and centre like Arbaminch and Hawassa had moderate rates. The distribution is inconsistent and varies across time and space with the seasons.

Conclusion
Despite the importance of spatial correlation in disease risk mapping, it may occasionally be a good idea to generate epidemic early warning independently in each district to get a quick picture of disease risk. A system like this is essential for spotting numerous inconsistencies in lower administrative levels early enough to take corrective action before outbreaks arise.
Towards clinical application of GlycA and GlycB for early detection of inflammation associated with (pre)diabetes and cardiovascular disease: recent evidence and updates
Authors: Fung Erik , Chan Eunice Y. S. , Ng Kwan Hung , Yu Ka Man , Li Huijun , Wang Yulan 
Published: October 2023

Abstract
Summary
Cardiometabolic diseases are associated with low-grade inflammation early in life and persists into old age. The long latency period presents opportunities for early detection, lifestyle modification and intervention. However, the performance of conventional biomarker assays to detect low-grade inflammation has been variable, particularly for early-stage cardiometabolic disorder including prediabetes and subclinical atherosclerotic vascular inflammation. During the last decade, the application of nuclear magnetic resonance (NMR) spectroscopy for metabolic profiling of biofluids in translational and epidemiological research has advanced to a stage approaching clinical application. Proton (1H)-NMR profiling induces no destructible physical changes to specimens, and generates quantitative signals from deconvoluted spectra that are highly repeatable and reproducible. Apart from quantitative analysis of amino acids, lipids/lipoproteins, metabolic intermediates and small proteins, 1H-NMR technology is unique in being able to detect composite signals of acute-phase and low-grade inflammation indicated by glycosylated acetyls (GlycA) and N-acetylneuraminic acid (sialic acid) moieties (GlycB). Different from conventional immunoassays that target epitopes and are susceptible to conformational variation in protein structure and binding, GlycA and GlycB signals are stable over time, and maybe complementary as well as superior to high-sensitivity C-reactive protein and other inflammatory cytokines. Here we review the physicochemical principles behind 1H-NMR profiling of GlycA and GlycB, and the available evidence supporting their potential clinical application for the prediction of incident (pre)diabetes, cardiovascular disease, and adverse outcomes.
Immunization with a multi-antigen targeted DNA vaccine eliminates chemoresistant pancreatic cancer by disrupting tumor-stromal cell crosstalk
Authors: Qin Hongquan , Chen Jiali , Bouchekioua-Bouzaghou Katia , Meng Ya-Ming , Griera Jordi Bach , Jiang Xue , Kong Xiangzhan , Wang Minghui , Xu Qiuping , Wong Ping-Pui 
Published: October 2023

Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is characterised by limited responses to chemoimmunotherapy attributed to highly desmoplastic tumor microenvironment. Disrupting the tumor-stromal cell crosstalk is considered as an improved PDAC treatment strategy, whereas little progress has been made due to poor understanding of its underlying mechanism. Here, we examined the cellular role of melanoma associated antigen A isoforms (MAGEA) in regulating tumor-stromal crosstalk mediated chemoresistance.

Methods
We used clinical samples to explore the correlation between MAGEA expression and patient prognosis in multiple cancers. We utilized cancer cell lines, patient derived organoids and orthotopic PDAC model to examine the function of MAGEA in chemoresistance. We performed biochemical, proteome profiler array and transcriptional analysis to uncover a mechanism that governs tumor-stromal crosstalk. We developed a multi-MAGEA antigen targeted DNA vaccine and tested its effect on PDAC tumor growth.

Results
We establish MAGEA as a regulator of the tumor-stromal crosstalk in PDAC. We provide strong clinical evidence indicating that high MAGEA expression, including MAGEA2, MAGEA3 and MAGEA10, correlates with worse chemotherapeutic response and poor prognosis in multiple cancers, while their expression is up-regulated in chemoresistant PDAC patient derived organoids and cancer cell lines. Mechanistically, MAGEA2 prohibits gemcitabine-induced JNK-c-Jun-p53 mediated cancer cell apoptosis, while gemcitabine stimulated pancreatic stellate cells secretes GDF15 to further enhance the gemcitabine resistance of MAGEA2 expressing cells by activating GFRAL-RET mediated Akt and ERK1/2 dependent survival pathway. Strikingly, immunization with a DNA vaccine that targeting multiple MAGEA antigens, including MAGEA2, MAGEA3 and MAGEA10, elicits robust immune responses against the growth of gemcitabine resistant tumors.

Conclusions
These findings suggest that targeting MAGEA-mediated paracrine regulation of chemoresistance by immunotherapy can be an improved pancreatic cancer treatment strategy.
Knockdown of NR3C1 inhibits the proliferation and migration of clear cell renal cell carcinoma through activating endoplasmic reticulum stress–mitophagy
Authors: Yan Minbo , Wang Jinhua , Wang Haojie , Zhou Jun , Qi Hao , Naji Yaser , Zhao Liangyu , Tang Yuxin , Dai Yingbo 
Published: October 2023

Abstract
Background
Clear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1’s carcinogenic effects in ccRCC.

Methods
Expression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways.

Results
The expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05).

Conclusions
This study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC.

Graphical Abstract
“Actually, the psychological wounds are more difficult than physical injuries:” a qualitative analysis of the impacts of attacks on health on the personal and professional lives of health workers in the Syrian conflict
Authors: Abbara Aula , Rayes Diana , Tappis Hannah , Hamze Mohamed , Wais Reham , Alahmad Hesham , Almhawish Naser , Rubenstein Leonard , Haar Rohini 
Published: October 2023

Abstract
Introduction
Attacks on healthcare in armed conflict have far-reaching impacts on the personal and professional lives of health workers, as well as the communities they serve. Despite this, even in protracted conflicts such as in Syria, health workers may choose to stay despite repeated attacks on health facilities, resulting in compounded traumas. This research explores the intermediate and long-term impacts of such attacks on healthcare on the local health professionals who have lived through them with the aim of strengthening the evidence base around such impacts and better supporting them.

Methods
We undertook purposive sampling of health workers in northwest and northeast Syria; we actively sought to interview non-physician and female health workers as these groups are often neglected in similar research. In-depth interviews (IDIs) were conducted in Arabic and transcribed into English for framework analysis. We used an a priori codebook to explore the short- and long-term impacts of attacks on the health workers and incorporated emergent themes as analysis progressed.

Results
A total of 40 health workers who had experienced attacks between 2013 and 2020 participated in IDIs. 13 were female (32.5%). Various health cadres including doctors, nurses, midwives, pharmacists, students in healthcare and technicians were represented. They were mainly based in Idlib (39.5%), and Aleppo (37.5%) governorates. Themes emerged related to personal and professional impacts as well as coping mechanisms. The key themes include firstly the psychological harms, second the impacts of the nature of the attacks e.g. anticipatory stress related to the ‘double tap’ nature of attacks as well as opportunities related to coping mechanisms among health workers.

Conclusion
Violence against healthcare in Syria has had profound and lasting impacts on the health workforce due to the relentless and intentional targeting of healthcare facilities. They not only face the challenges of providing care for a conflict-affected population but are also part of the community themselves. They also face ethical dilemmas in their work leading to moral distress and moral injury. Donors must support funding for psychosocial support for health workers in Syria and similar contexts; the focus must be on supporting and enhancing existing context-specific coping strategies.
scIBD: a self-supervised iterative-optimizing model for boosting the detection of heterotypic doublets in single-cell chromatin accessibility data
Authors: Zhang Wenhao , Jiang Rui , Chen Shengquan , Wang Ying 
Published: October 2023

AbstractApplication of the widely used droplet-based microfluidic technologies in single-cell sequencing often yields doublets, introducing bias to downstream analyses. Especially, doublet-detection methods for single-cell chromatin accessibility sequencing (scCAS) data have multiple assay-specific challenges. Therefore, we propose scIBD, a self-supervised iterative-optimizing model for boosting heterotypic doublet detection in scCAS data. scIBD introduces an adaptive strategy to simulate high-confident heterotypic doublets and self-supervise for doublet-detection in an iteratively optimizing manner. Comprehensive benchmarking on various simulated and real datasets demonstrates the outperformance and robustness of scIBD. Moreover, the downstream biological analyses suggest the efficacy of doublet-removal by scIBD.
Deep learning-assisted high-content screening identifies isoliquiritigenin as an inhibitor of DNA double-strand breaks for preventing doxorubicin-induced cardiotoxicity
Authors: Chen Xuechun , Liu Changtong , Zhao Hong , Zhong Yigang , Xu Yizhou , Wang Yi 
Published: October 2023

Abstract
Background
Anthracyclines including doxorubicin are essential components of many cancer chemotherapy regimens, but their cardiotoxicity severely limits their use. New strategies for treating anthracycline-induced cardiotoxicity (AIC) are still needed. Anthracycline-induced DNA double-strand break (DSB) is the major cause of its cardiotoxicity. However, DSB-based drug screening for AIC has not been performed possibly due to the limited throughput of common assays for detecting DSB. To discover new therapeutic candidates for AIC, here we established a method to rapidly visualize and accurately evaluate the intranuclear anthracycline-induced DSB, and performed a screening for DSB inhibitors.

Results
First, we constructed a cardiomyocyte cell line stably expressing EGFP-53BP1, in which the formation of EGFP-53BP1 foci faithfully marked the doxorubicin-induced DSB, providing a faster and visible approach to detecting DSB. To quantify the DSB, we used a deep learning-based image analysis method, which showed the better ability to distinguish different cell populations undergoing different treatments of doxorubicin or reference compounds, compared with the traditional threshold-based method. Subsequently, we applied the deep learning-assisted high-content screening method to 315 compounds and found three compounds (kaempferol, kaempferide, and isoliquiritigenin) that exert cardioprotective effects in vitro. Among them, the protective effect of isoliquiritigenin is accompanied by the up-regulation of HO-1, down-regulation of peroxynitrite and topo II, and the alleviation of doxorubicin-induced DSB and apoptosis. The results of animal experiments also showed that isoliquiritigenin maintained the myocardial tissue structure and cardiac function in vivo. Moreover, isoliquiritigenin did not affect the killing of HeLa and MDA-MB-436 cancer cells by doxorubicin and thus has the potential to be a lead compound to exert cardioprotective effects without affecting the antitumor effect of doxorubicin.

Conclusions
Our findings provided a new method for the drug discovery for AIC, which combines phenotypic screening with artificial intelligence. The results suggested that isoliquiritigenin as an inhibitor of DSB may be a promising drug candidate for AIC.
Assessment of the diagnostic performance of serological tests in areas where Leishmania infantum and Leishmania tarentolae occur in sympatry
Authors: Iatta Roberta , Carbonara Mariaelisa , Morea Anna , Trerotoli Paolo , Benelli Giovanni , Nachum-Biala Yaarit , Mendoza-Roldan Jairo Alfonso , Cavalera Maria Alfonsa , Baneth Gad , Bandi Claudio , Zatelli Andrea , Otranto Domenico 
Published: October 2023

Abstract
Background
Visceral leishmaniosis caused by infection with the zoonotic protozoan Leishmania infantum is a life-threatening disease affecting dogs and humans. The sympatric occurrence of L. infantum and Leishmania tarentolae in an area of southern Italy endemic for canine leishmaniosis, where dogs are also exposed to the latter species, suggests the persistence of herpetophilic L. tarentolae in a non-permissive host, therefore raising questions about the performance of serological diagnostic tests routinely employed.

Methods
The diagnostic performance of serological tests such as the immunofluorescence antibody test (IFAT), two commercial immunoenzymatic assays (i.e. NovaTec VetLine Leishmania ELISA® and rK39 ICT®) and an in-house enzyme-linked immunosorbent assay (ELISA) was evaluated in healthy dogs seropositive to L. infantum, whereas the only IFAT available was used to detect antibodies to L. tarentolae.

Results
With the IFAT, out of a total of 104 dogs tested, 15 were seronegative for L. infantum of which three were L. tarentolae seropositive‚ and 89 were L. infantum seropositive. Of the latter 89 dogs, representing the highest proportion of seropositive animals (85.6%) detected by IFAT‚ 66 were also seropositive for L. tarentolae. Cohen's kappa (κ) agreement coefficient between the IFAT results and those of all the other tests was very low, and the IFAT results were significantly different from those of all the other serological tests as calculated by Cochran's Q-test. Analysis using the Bayesian latent class (Bayes-LCA) showed that the in-house ELISA and IFAT contributed the most towards identifying infected and non-infected dogs, respectively. The IFAT test showed low positive predictive value (59.5%), but high negative predictive value (100%).

Conclusions
These results demonstrate that the IFAT for L. infantum, although highly sensitive, may not be considered a useful diagnostic test due to its low specificity. Therefore, an accurate serological tool with high specificity is mandatory for avoiding cross-reaction in epidemiological contexts where the two species of Leishmania occur in sympatry.

Graphical Abstract
Association of N-terminal pro-B-type natriuretic peptide levels and mortality risk in acute myocardial infarction across body mass index categories: an observational cohort study
Authors: Wang Man , Cao Ning , Zhou Li , Su Wen , Chen Hui , Li Hongwei 
Published: October 2023

Abstract
Background
The prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) across body mass index (BMI) categories in patients with acute myocardial infarction (AMI) is unclear. We aimed to assess the predictive value of NT-proBNP levels and identify the best cutoff values for mortality risk prediction across BMI categories in AMI.

Methods
We analyzed 4677 patients with AMI from the Cardiovascular Centre Beijing Friendship Hospital Database Bank. Patients were classified into underweight (< 18.5 kg/m2), normal-weight (18.5–23.9 kg/m2), overweight (24–27.9 kg/m2), and obese (≥ 28 kg/m2) groups. The association between NT-proBNP (ln-transformed) and mortality was investigated using Cox regression and stratified by BMI.

Results
During follow-up (13,787 person-years of observation), 718 patients died, averaging 52.1 events per 1000 person-years. NT-proBNP levels were inversely correlated with BMI (β = − 0.096, P < 0.001). After adjustment, NT-proBNP was independently associated with all-cause mortality (hazard ratio [HR] per 1-SD: 1.82; 95% confidence interval [CI] 1.60–2.07) in patients with AMI. Similar findings were observed in analyses stratified by BMI category, except for the underweight group. Adding NT-proBNP to conventional risk models improved risk discrimination in normal-weight, overweight, and obese patients (C-index changes of 0.036, 0.042, and 0.032, respectively) and classification of patients into predicted mortality risk categories (net reclassification improvement 0.263, 0.204, and 0.197, respectively). The best NT-proBNP cutoff values for 5-year mortality risk prediction across BMI categories were 5710, 4492, 2253, and 1300 pg/ml.

Conclusion
NT-proBNP level was an independent prognostic factor for mortality in patients with AMI and varied according to BMI. The best NT-proBNP cutoff values for mortality risk prediction reduced as BMI increased.