bluuebunny/crossref_metadata_2025 huggingface dataset:
Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process
Authors: Dongol Anjila , Chen Xi , Zheng Peng , Seyhan Zehra Boz , Huang Xu-Feng
Published: December 2023

Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases.
RETRACTED ARTICLE: csi-miR-96-5p delivered by Clonorchis sinensis extracellular vesicles promotes intrahepatic cholangiocarcinoma proliferation and migration via the ferroptosis-related PTEN/SLC7A11/GPX4 axis
Authors: Wen Li-Jia , Yin Ji-Gang , Wang Yong-Xin , Liu Kai , Zhao Ji-Xue
Published: December 2023

Background

Clonorchis sinensis (CS) is classified as a group 1 carcinogen and can cause intrahepatic cholangiocarcinoma (ICC). CS extracellular vesicles (CsEVs) play important roles in mediating communication between parasitic helminths and humans. Ferroptosis is a novel cell death mechanism that is mainly induced by lipid peroxidation and iron overload. However, the role of CsEVs in the regulation of ferroptosis in ICC remains unclear. This study aimed to explore the role of CS-secreted miR-96-5p (csi-miR-96-5p) delivered by CsEVs in ICC progression and ferroptosis.

Methods

Tissue samples were collected from ICC patients with CS infection (CS-ICC) or without CS infection (NC-ICC). The levels of csi-miR-96-5p and PTEN gene were determined by quantitative polymerase chain reaction (qPCR) and western blotting, and survival analysis was performed. CsEVs were isolated and identified by ultracentrifugation and transmission electron microscopy. Lentiviruses were used to establish stable cell lines with csi-miR-96-5p mimic expression, PTEN overexpression (PTEN-EXO) and PTEN CRISPR/Cas9-based knockout (PTEN-KO) and their respective negative controls. Cell proliferation was assessed by performing Cell Counting Kit-8 assays in vitro and in a tumor xenograft model in vivo, and cell migration was assessed by performing Transwell assays. Erastin is used to induce ferroptosis. Ferroptosis levels were evaluated using biomarkers.

Results

High csi-miR-96-5p and low PTEN expression was observed in CS-ICC tissues and was associated with poor overall survival. csi-miR-96-5p was highly enriched in CsEVs and was taken up by ICC cells. csi-miR-96-5p mimics or PTEN-KO significantly promoted the growth and migration of ICC cells in vitro and in vivo, whereas PTEN-EXO exerted the opposite effect. Mechanistically, csi-miR-96-5p mimics or PTEN-KO inhibited erastin-induced ferroptosis, including reducing the accumulation of Fe2+, lipid reactive oxygen species, and malondialdehyde, increasing the GSH/GSSG ratio and levels of SLC7A11 and GPX4, whereas PTEN-EXOs exerted the opposite effect.

Conclusions

csi-miR-96-5p delivered by CsEVs reduced ferroptosis by regulating the expression of the PTEN/SLC7A11/GPX4 axis, thereby promoting ICC proliferation and migration. For the first time to our knowledge, we found that CS miRNAs could promote tumor development through ferroptosis.

Graphical Abstract
Association between serum PCSK9 and coronary heart disease in patients with type 2 diabetes mellitus
Authors: Huang Juan , Gu Jun-Xu , Wang Kun , Zhang Ai-Min , Hong Ting-Ting , Li Shan-Shan , Yao Xiao-Qin , Yang Ming , Yin Yue , Zhang Na , Su Ming , Hu Jia-Jia , Zhang Xue-Zhi , Jia Mei
Published: December 2023

Background and aims

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered a new biomarker for atherosclerosis, but its ability to predict cardiovascular outcomes has been controversial. This study aimed to address the lack of data on PCSK9, coronary heart disease (CHD) severity, and major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 2984 T2DM patients underwent selective coronary angiography, and their serum PCSK9 levels were measured using enzyme-linked immunosorbent assay. Correlation and logistic regression analyses were performed to investigate the association between PCSK9 expression and CHD severity. This study used Cox regression analysis to assess the association between circulating PCSK9 levels and the risk of MACEs.

Results

Circulating PCSK9 levels were significantly higher in the CHD group than in the non-CHD group [554.62 (265.11) ng/mL vs. 496.86 (129.05) ng/mL, p < 0.001]. Circulating PCSK9 levels positively correlated with CHD severity (diseased vessels: r = 0.35, p < 0.001; Gensini score: r = 0.46, p < 0.001). Elevated PCSK9 levels are an independent risk factor for CHD risk and severity (CHD group vs. non–CHD group: OR = 2.829, 95% CI: 1.771–4.520, p < 0.001; three vessel disease group vs. one vessel disease group: OR = 4.800, 95% CI: 2.387–9.652, p < 0.001; high GS group vs. low GS group: OR = 5.534, 95% CI: 2.733–11.208, p < 0.001). Through a six-year follow-up and multivariate Cox regression analysis, elevated circulating PCSK9 levels were found to be independently associated with MACEs in all participants (HR: 3.416, 5% CI: 2.485–4.697, p < 0.001; adjusted HR: 2.780, 95% CI: 1.930–4.004, p < 0.001).

Conclusions

Serum PCSK9 levels were positively correlated with multi-vessel CHD and Gensini score. Elevated circulating PCSK9 levels are an independent risk factor for CHD and increased incidence of MACEs in T2DM.
A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide
Authors: Chatzikyriakou Prodromos , Brempou Dimitria , Quinn Mark , Fishbein Lauren , Noberini Roberta , Anastopoulos Ioannis N. , Tufton Nicola , Lim Eugenie S. , Obholzer Rupert , Hubbard Johnathan G. , Moonim Mufaddal , Bonaldi Tiziana , Nathanson Katherine L. , Izatt Louise , Oakey Rebecca J.
Published: December 2023

Background

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes.

Results

Out of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1.

Conclusions

Combined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.
Statins and cognitive decline in patients with Alzheimer’s and mixed dementia: a longitudinal registry-based cohort study
Authors: Petek Bojana , Häbel Henrike , Xu Hong , Villa-Lopez Marta , Kalar Irena , Hoang Minh Tuan , Maioli Silvia , Pereira Joana B. , Mostafaei Shayan , Winblad Bengt , Gregoric Kramberger Milica , Eriksdotter Maria , Garcia-Ptacek Sara
Published: December 2023

Background

Disturbances in brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer’s disease (AD). Lipid-lowering medications could interfere with neurodegenerative processes in AD through cholesterol metabolism or other mechanisms.

Objective

To explore the association between the use of lipid-lowering medications and cognitive decline over time in a cohort of patients with AD or mixed dementia with indication for lipid-lowering treatment.

Methods

A longitudinal cohort study using the Swedish Registry for Cognitive/Dementia Disorders, linked with other Swedish national registries. Cognitive trajectories evaluated with mini-mental state examination (MMSE) were compared between statin users and non-users, individual statin users, groups of statins and non-statin lipid-lowering medications using mixed-effect regression models with inverse probability of drop out weighting. A dose-response analysis included statin users compared to non-users.

Results

Our cohort consisted of 15,586 patients with mean age of 79.5 years at diagnosis and a majority of women (59.2 %). A dose-response effect was demonstrated: taking one defined daily dose of statins on average was associated with 0.63 more MMSE points after 3 years compared to no use of statins (95% CI: 0.33;0.94). Simvastatin users showed 1.01 more MMSE points (95% CI: 0.06;1.97) after 3 years compared to atorvastatin users. Younger (< 79.5 years at index date) simvastatin users had 0.80 more MMSE points compared to younger atorvastatin users (95% CI: 0.05;1.55) after 3 years. Simvastatin users had 1.03 more MMSE points (95% CI: 0.26;1.80) compared to rosuvastatin users after 3 years. No differences regarding statin lipophilicity were observed. The results of sensitivity analysis restricted to incident users were not consistent.

Conclusions

Some patients with AD or mixed dementia with indication for lipid-lowering medication may benefit cognitively from statin treatment; however, further research is needed to clarify the findings of sensitivity analyses.
Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts
Authors: Zhang Jingbo , Li Junjun , Qu Xiang , Liu Yuting , Harada Akima , Hua Ying , Yoshida Noriko , Ishida Masako , Tabata Akiko , Sun Lifu , Liu Li , Miyagawa Shigeru
Published: December 2023

Background

Heart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair.

Methods

We applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling.

Results

In vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group.

Conclusions

We developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model.

Graphical Abstract
Competing endogenous RNA network analysis of Turner syndrome patient-specific iPSC-derived cardiomyocytes reveals dysregulation of autosomal heart development genes by altered dosages of X-inactivation escaping non-coding RNAs
Authors: Luo Yumei , Chen Yapei , Ge Lingxia , Zhou Guanqing , Chen Yaoyong , Zhu Detu
Published: December 2023

Background

A 45,X monosomy (Turner syndrome, TS) is the only chromosome haploinsufficiency compatible with life. Nevertheless, the surviving TS patients still suffer from increased morbidity and mortality, with around one-third of them subjecting to heart abnormalities. How loss of one X chromosome drive these conditions remains largely unknown.

Methods

Here, we have generated cardiomyocytes (CMs) from wild-type and TS patient-specific induced pluripotent stem cells and profiled the mRNA, lncRNA and circRNA expression in these cells.

Results

We observed lower beating frequencies and higher mitochondrial DNA copies per nucleus in TS-CMs. Moreover, we have identified a global transcriptome dysregulation of both coding and non-coding RNAs in TS-CMs. The differentially expressed mRNAs were enriched of heart development genes. Further competing endogenous RNA network analysis revealed putative regulatory circuit of autosomal genes relevant with mitochondrial respiratory chain and heart development, such as COQ10A, RARB and WNT2, mediated by X-inactivation escaping lnc/circRNAs, such as lnc-KDM5C-4:1, hsa_circ_0090421 and hsa_circ_0090392. The aberrant expressions of these genes in TS-CMs were verified by qPCR. Further knockdown of lnc-KDM5C-4:1 in wild-type CMs exhibited significantly reduced beating frequencies.

Conclusions

Our study has revealed a genomewide ripple effect of X chromosome halpoinsufficiency at post-transcriptional level and provided insights into the molecular mechanisms underlying heart abnormalities in TS patients.
Dynamics of Staphylococcus aureus in patients and the hospital environment in a tertiary care hospital in the Netherlands
Authors: van der Schoor Adriënne S. , Voor in ’t holt Anne F. , Zandijk Willemien H.A. , Bruno Marco J. , Gommers Diederik , van den Akker Johannes P.C. , Hendriks Johanna M. , Severin Juliëtte A. , Klaassen Corné H.W. , Vos Margreet C.
Published: December 2023

Background

The dynamics of Staphylococcus aureus in patients and the hospital environment are relatively unknown. We studied these dynamics in a tertiary care hospital in the Netherlands.

Methods

Nasal samples were taken from adult patients at admission and discharge. Isolates cultured from clinical samples taken before and during hospitalization from these patients were included. Environmental samples of patient rooms were taken over a three-year period. Finally, isolates from clinical samples from patients with an epidemiological link to S. aureus positive rooms were included. Staphylococcal protein A (spa) typing was performed.

Results

Nasal samples were taken from 673 patients. One hundred eighteen (17.5%) were positive at admission and discharge, 15 (2.2%) patients acquired S. aureus during hospitalization. Nineteen patients had a positive clinical sample during hospitalization, 15.9% of the S. aureus were considered as from an exogenous source. One hundred and forty (2.8%) environmental samples were S. aureus positive. No persistent contamination of surfaces was observed. Isolates were highly diverse: spa typing was performed for 893 isolates, identifying 278 different spa types, 161 of these spa types were observed only once.

Conclusion

Limited transmission could be identified between patients and the hospital environment, and from patient-to-patient. Exogenous acquisition was assumed to occur in 15% of clinical samples. Environmental contamination was infrequent, temporarily, and coincided with the strain from the patient admitted to the room at that time. MRSA was rare and not found in the environment.
Enterogenic Stenotrophomonas maltophilia migrates to the mammary gland to induce mastitis by activating the calcium-ROS-AMPK-mTOR-autophagy pathway
Authors: He Zhaoqi , Zhao Caijun , He Yuhong , Liu Zhuoyu , Fan Guyue , Zhu Kun , Wang Yiqi , Zhang Naisheng , Fu Yunhe , Hu Xiaoyu
Published: December 2023

Background

Mastitis is an inflammatory disease of the mammary gland that has serious economic impacts on the dairy industry and endangers food safety. Our previous study found that the body has a gut/rumen-mammary gland axis and that disturbance of the gut/rumen microbiota could result in ‘gastroenterogenic mastitis’. However, the mechanism has not been fully clarified. Recently, we found that long-term feeding of a high-concentrate diet induced mastitis in dairy cows, and the abundance of Stenotrophomonas maltophilia (S. maltophilia) was significantly increased in both the rumen and milk microbiota. Accordingly, we hypothesized that ‘gastroenterogenic mastitis’ can be induced by the migration of endogenous gut bacteria to the mammary gland. Therefore, this study investigated the mechanism by which enterogenic S. maltophilia induces mastitis.

Results

First, S. maltophilia was labelled with superfolder GFP and administered to mice via gavage. The results showed that treatment with S. maltophilia promoted the occurrence of mastitis and increased the permeability of the blood-milk barrier, leading to intestinal inflammation and intestinal leakage. Furthermore, tracking of ingested S. maltophilia revealed that S. maltophilia could migrate from the gut to the mammary gland and induce mastitis. Subsequently, mammary gland transcriptome analysis showed that the calcium and AMPK signalling pathways were significantly upregulated in mice treated with S. maltophilia. Then, using mouse mammary epithelial cells (MMECs), we verified that S. maltophilia induces mastitis through activation of the calcium-ROS-AMPK-mTOR-autophagy pathway.

Conclusions

In conclusion, the results showed that enterogenic S. maltophilia could migrate from the gut to the mammary gland via the gut-mammary axis and activate the calcium-ROS-AMPK-mTOR-autophagy pathway to induce mastitis. Targeting the gut-mammary gland axis may also be an effective method to treat mastitis.
Precise tilt measurement by seafloor borehole tiltmeters at the Nankai Trough subduction zone
Authors: Tsuji Shuhei , Araki Eiichiro , Yokobiki Takashi , Nishida Shuhei , Machida Yuya , Zumberge Mark , Takahashi Keisuke
Published: December 2023

In this study, geodetic and seismic phenomena occurring in the subduction zone were observed with two tiltmeters that were installed in seafloor boreholes drilled in the Kumano Basin in the Nankai Trough, southwest Japan. We used one electrolytic-type tiltmeter and one pendulum-type tiltmeter installed 6 and 19 m below the seafloor, respectively. The two tiltmeters have been continuously operated since 2019 and 2021, respectively. The records of the two tiltmeters showed microseisms, seismic signals of normal earthquakes, and variations that correlated well with the M2 tide (tidal response). The noise environment relative to existing seafloor observatories was assessed by comparing the power spectral densities of the tiltmeters and broadband seismometers in the seismic frequency band. The two tiltmeters and the seismometers showed similar spectral peaks in the microseism band, and at lower frequencies below 10–2 Hz, the pendulum tiltmeter had a noise level that was up to 20 dB lower than that of the broadband seismometers. The tidal responses of the tiltmeters were analyzed to reveal corresponding mechanisms because a large amplitude of the tidal response makes it difficult to detect geodetic phenomena. Considerable azimuthal dependence was observed in the NW–SE direction for both tiltmeters. The principal direction was approximately the same as the down-slope direction of the local bathymetry. This tendency was thus interpreted to be caused by the differences in the thickness of the sedimentary layer along the direction of the slope. Furthermore, the validity of the tilt measurements for the two tiltmeters was demonstrated by in-situ loading experiments, where the theoretical response of an elastic half-space medium was computed and compared with the experimental results. The results of the loading experiments can be explained using theoretical values with a set of realistic elastic moduli.

Graphical Abstract
Efficacy and safety of praziquantel treatment against Schistosoma mansoni infection among pre-school age children in southern Ethiopia
Authors: Tadele Tafese , Astatkie Ayalew , Tadesse Birkneh Tilahun , Makonnen Eyasu , Aklillu Eleni , Abay Solomon Mequanente
Published: December 2023

Background

Preventive chemotherapy with a single dose of praziquantel given to an all-at-risk population through mass drug administration is the cornerstone intervention to control and eliminate schistosomiasis as a public health problem. This intervention mainly targets school age children, and pre-school age children (pre-SAC) are excluded from receiving preventive chemotherapy, partly due to scarcity of data on praziquantel treatment outcomes.

Methods

We conducted active efficacy and safety surveillance of praziquantel treatment among 240 Schistosoma mansoni-infected pre-SAC who received a single dose of praziquantel (40 mg/kg) in southern Ethiopia. The study outcomes were egg reduction rates (ERR) and cure rates (CRs) four weeks after treatment using the Kato–Katz technique and treatment-associated adverse events (AEs) that occurred within 8 days post-treatment.

Results

The overall ERR was 93.3% (WHO reference threshold ≥ 90%), while the CR was 85.2% (95% CI = 80.0–89.5%). Baseline S. mansoni infection intensity was significantly associated with CRs, 100% among light infected than moderate (83.4%) or heavy (29.4%) infected children. An increase of 100 in baseline S. mansoni egg count per gram of stool resulted in a 26% (95% CI: 17%, 34%) reduction in the odds of cure. The incidence of experiencing at least one type of AE was 23.1% (95% CI: 18.0%, 29.0%). Stomachache, diarrhea, and nausea were the most common AEs. AEs were mild-to-moderate grade and transient. Pre-treatment moderate (ARR = 3.2, 95% CI: 1.69, 6.14) or heavy infection intensity (ARR = 6.5, 95% CI: 3.62, 11.52) was a significant predictor of AEs (p < 0.001). Sex, age, or soil-transmitted helminth coinfections were not significant predictors of CR or AEs.

Conclusions

Single-dose praziquantel is tolerable and effective against S. mansoni infection among pre-SAC, and associated AEs are mostly mild-to-moderate and transient. However, the reduced CR in heavily infected and AEs in one-fourth of S. mansoni-infected pre-SAC underscores the need for safety and efficacy monitoring, especially in moderate-to-high infection settings. Integrating pre-SACs in the national deworming programs is recommended to accelerate the elimination of schistosomiasis as a public health problem.
The role of leadership level in college students’ facial emotion recognition: evidence from event-related potential analysis
Authors: Gu Huang , Du Shunshun , Jin Peipei , Wang Chengming , He Hui , Zhao Mingnan
Published: December 2023

While the role of emotion in leadership practice is well-acknowledged, there is still a lack of clarity regarding the behavioral distinctions between individuals with varying levels of leadership and the underlying neurocognitive mechanisms at play. This study utilizes facial emotion recognition in conjunction with electroencephalograms to explore the temporal dynamics of facial emotion recognition processes among college students with high and low levels of leadership. The results showed no significant differences in the amplitude of P1 during the early stage of facial emotion recognition between the two groups. In the middle stage of facial emotion recognition, the main effect of group was significant on the N170 component, with higher N170 amplitude evoked in high-leadership students than low-leadership students. In the late stage of facial emotion recognition, low-leadership students evoked greater LPP amplitude in the temporal-parietal lobe when recognizing happy facial emotions compared to high-leadership students. In addition, time–frequency results revealed a difference in the alpha frequency band, with high-leadership students exhibiting lower alpha power than low-leadership students. The results suggest differences in the brain temporal courses of facial emotion recognition between students with different leadership levels, which are mainly manifested in the middle stage of structural encoding and the late stage of delicate emotional processing during facial emotion recognition.
Nanoemulsion drug delivery system loaded with imiquimod: a QbD-based strategy for augmenting anti-cancer effects
Authors: Jadhav Shital Tanaji , Salunkhe Vijay Rajaram , Bhinge Somnath Devidas
Published: December 2023

Background

Skin cancer is becoming a public health concern due to increased exposure to environmental pollutants and UV rays, among other factors. In India, skin neoplasms constitute 2–3% of all human cancer cases, whereas in the USA, 2–3 million cases of non-melanoma skin cancer are reported annually. Various drugs are available in the market for treating skin cancer. Imiquimod (IMQ) is one such drug approved by the USFDA for managing basal cell malignancy, external genital warts, and actinic keratosis. The conventional dosage form of IMQ cream has several side effects that can lead to therapy interruption. Therefore, the present work aims to develop an IMQ nanoemulsion with improved solubility, in vitro drug release and stability. Nanoemulsion was formulated using oleic acid/rose oil, with polysorbate 20/propylene glycol selected as the oil phase and Smix, respectively. Optimization carried out using a 32 factorial design with the aid of a quadratic model. Characterization was conducted for parameters, namely viscosity, pH, drug content, globule size, zeta potential and entrapment efficiency. Thermodynamic stability studies were conducted to assess the stability of the formulation. Furthermore, the optimized system was subjected to TEM analysis, in vitro drug release and in vitro cytotoxicity assay (MTT assay).

Results

Nanoemulsions were found to be in the size range of 152.80–470.13 nm and exhibited a spherical shape. Zeta potential values ranged from − 28.93 to − 58.48 mV. DSC measurements indicated the complete solubilization of IMQ in the nanoemulsion system. The optimized formulation F1 displayed the following characteristics: a globule size < 200 nm, a zeta potential > − 55 mV, a polydispersity index < 0.2, % drug content of 102.89 ± 1.06, % entrapment efficiency of 97.59 ± 0.24, a pH of 4.77 ± 0.06, and a viscosity of 4.06 ± 0.06 poise. In vitro IMQ release studies of nanoemulsion and commercial cream showed approximately 70% and 34% drug release, respectively, at the end of 8 h. Moreover, the in vitro cytotoxicity assay depicted that F1 exhibited greater cytotoxic potential compared to the commercial formulation against the A431 cell line.

Conclusion

The present investigation showed a significant improvement in in vitro drug release of the BCS class IV drug IMQ and enhanced cytotoxic activity against cancerous cells. IMQ-loaded nanoemulsion represents a promising vehicle for delivering treatment to the skin for treating skin cancer.

Graphical abstract
Molecular and physiological responses to salt stress in salinity-sensitive and tolerant Hibiscus rosa-sinensis cultivars
Authors: Trivellini Alice , Carmassi Giulia , Scatena Guido , Vernieri Paolo , Ferrante Antonio
Published: December 2023

Ornamental plants are used to decorate urban and peri-urban areas, and during their cultivation or utilisation, they can be exposed to abiotic stress. Salinity is an abiotic stress factor that limits plant growth and reduces the ornamental value of sensitive species. In this study, transcriptomic analysis was conducted to identify genes associated with tolerance or sensitivity to salinity in two hibiscus (Hibiscus rosa-sinensis L.) cultivars, ‘Porto’ and ‘Sunny wind’. The physiological and biochemical parameters of plants exposed to 50, 100, or 200 mM NaCl and water (control) were monitored. Salinity treatments were applied for six weeks. After four weeks, differences between cultivars were clearly evident and ‘Porto’ was more tolerant than ‘Sunny wind’. The tolerant cultivar showed lower electrolyte leakage and ABA concentrations, and higher proline content in the leaves. Accumulation of Na in different organs was lower in the flower organs of ‘Porto’. At the molecular level, several differential expressed genes were observed between the cultivars and flower organs. Among the highly expressed DEGs, coat protein, alcohol dehydrogenase, and AP2/EREBP transcription factor ERF-1. Among the downregulated genes, GH3 and NCED were the most interesting. The differential expression of these genes may explain the salt stress tolerance of ‘Porto’.

Graphical Abstract
Posterior sampling with convolutional neural network-based plug-and-play regularization with applications to poststack seismic inversion
Authors: Izzatullah Muhammad , Alkhalifah Tariq , Romero Juan , Corrales Miguel , Luiken Nick , Ravasi Matteo
Published: December 2023

Uncertainty quantification is a crucial component in any geophysical inverse problem, as it provides decision makers with valuable information about the inversion results. Seismic inversion is a notoriously ill-posed inverse problem, due to the band-limited and noisy nature of seismic data; as such, quantifying the uncertainties associated with the ill-posed nature of this inversion process is essential for qualifying the subsequent interpretation and decision-making processes. Selecting appropriate prior information is a crucial — yet nontrivial — step in probabilistic inversion because it influences the ability of sampling-based inference algorithms to provide geologically plausible posterior samples. However, the necessity to encapsulate prior knowledge into a probability distribution can greatly limit our ability to define expressive priors. To address this limitation and following in the footsteps of the plug-and-play (PnP) methodology for deterministic inversion, we develop a regularized variational inference framework that performs posterior inference by implicitly regularizing the Kullback-Leibler divergence loss — a measure of the distance between the approximated and target probabilistic distributions — with a convolutional neural network-based denoiser. We call this new algorithm PnP Stein variational gradient descent and determine its ability to produce high-resolution trustworthy samples that realistically represent subsurface structures. Our method is validated on synthetic and field poststack seismic data.
Multiplexed Serum Steroid Profiling Reveals Metabolic Signatures of Subtypes in Congenital Adrenal Hyperplasia
Authors: Shim Jaeyoon , Ahn Chang Ho , Park Seung Shin , Noh Jongsung , Lee Chaelin , Lee Sang Won , Kim Jung Hee , Choi Man Ho
Published: December 2023

Context

Altered metabolic signatures on steroidogenesis may characterize individual subtypes of congenital adrenal hyperplasia (CAH), but conventional diagnostic approaches are limited to differentiate subtypes.

Objective

We explored metabolic characterizations and identified multiple diagnostic biomarkers specific to individual subtypes of CAH.

Methods

Liquid chromatography-mass spectrometry-based profiling of 33 adrenal steroids was developed and applied to serum samples obtained from 67 CAH patients and 38 healthy volunteers.

Results

Within- and between-run precisions were 95.4% to 108.3% and 94.1% to 110.0%, respectively, while all accuracies were <12% and the correlation coefficients (r2) were > 0.910. Metabolic ratios corresponding to 21-hydroxylase characterized 21-hydroxylase deficiency (21-OHD; n = 63) from healthy controls (area under the curve = 1.0, P < 1 × 10−18 for all) and other patients with CAH in addition to significantly increased serum 17α-hydroxyprogesterone (P < 1 × 10−16) and 21-deoxycortisol (P < 1 × 10−15) levels. Higher levels of mineralocorticoids, such as corticosterone (B) and 18-hydroxyB, were observed in 17α-hydroxylase deficiency (17α-OHD; N = 3), while metabolic ratio of dehydroepiandrosterone sulfate to pregnenolone sulfate was remarkably decreased against all subjects. A patient with 11β-hydroxylase deficiency (11β-OHD) demonstrated significantly elevated 11-deoxycortisol and its metabolite tetrahydroxy-11-deoxyF, with reduced metabolic ratios of 11β-hydroxytestosterone/testosterone and 11β-hydroxyandrostenedione/androstenedione. The steroid profiles resulted in significantly decreased cortisol metabolism in both 21-OHD and 17α-OHD but not in 11β-OHD.

Conclusion

The metabolic signatures with specific steroids and their corresponding metabolic ratios may reveal individual CAH subtypes. Further investigations with more substantial sample sizes should be explored to enhance the clinical validity.
Textual heritage and digital archives – the case of the Hyakugo Archive in Kyoto
Authors: GERLINI Edoardo
Published: December 2023

What are the effects and significance of inscribing an archive or group of documents in a heritage list? In light of the positive effects of digital technology on archival science, should all archives and past documents be considered “heritage,” or are some more significant than others? What are the implications and benefits of a heritage archive? Is creating a digital database of a specific archive considered part of heritage conservation? Is the term "heritagization" or "heritage making" a synonym for preservation or conservation? In this article, I will attempt to answer some of these questions from the point of view of premodern literature, drawing on recent researches in heritage studies, specifically in the subfield of "critical heritage studies. After briefly introducing the current state of heritage scholarship, I will present the definition of "textual heritage" that I developed during my most recent project. Secondly, to reflect on how the concept of textual heritage can affect our understanding of historical archives, I will present the case of the Hyakugo Archive of Toji Temple (Kyoto, Japan), a collection of 19,000 documents dating from the eight to the eighteenth century, which was inscribed on the UNESCO Memory of the World List in 2005 and has been fully digitized and made available to the public via the Internet. I will examine a particular historical event that occurred during the 17th century, which can be viewed as a re-birth of this archive as a cultural heritage and reflect on the implications of this event for the survival of the archive itself and its use today.
The genome sequence of Ashworth’s Rustic, Xestia ashworthii (Doubleday, 1855)
Authors: Mulley John F. , Lees David C. ,   Natural History Museum Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: December 2023

We present a genome assembly from an individual male Xestia ashworthii (Ashworth’s Rustic; Arthropoda; Insecta; Lepidoptera; Noctuidae). The genome sequence is 726.3 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the z sex chromosome. The mitochondrial genome has also been assembled and is 15.39 kilobases in length.
A Sequential Follower Refinement Algorithm for Robust Surgery Scheduling
Authors: Bansal Ankit , Richard Jean-Philippe , Berg Bjorn P. , Huang Yu-Li
Published: December 2023

An algorithm for the two-stage robust optimization surgery-to-operating room allocation problem is presented. The second-stage problem is an integer linear program whose convex hull is approximated using three types of specialized valid inequalities and Chvátal-Gomory cuts. The resulting linear relaxation of the second-stage problem is then dualized and integrated into the first-stage problem. The resulting mixed integer linear program, which is an approximation of the original problem, is then solved using a commercial solver. If the solution of this model is not optimal for the second-stage problem, valid inequalities for the second-stage problem are generated, yielding a type of column-generation based approach that we refer to as the sequential follower refinement (SFR) algorithm. Data from an academic medical center are used to compare the computational performance of SFR with the constraint and column generation (C&CG) algorithm, which is the only exact approach that has been specifically applied for this problem in the literature. An extensive numerical study of SFR and its computational characteristics is presented that shows that SFR yields better-quality solutions compared with C&CG, even as the termination criterion of SFR is met much sooner, especially for problems involving higher number of surgeries.

History: Accepted by Paul Brooks, Area Editor for Applications in Biology, Medicine, & Healthcare.

Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0191 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0191 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
Frontiers: Shrinkflation Aversion: When and Why Product Size Decreases Are Seen as More Unfair than Equivalent Price Increases
Authors: Evangelidis Ioannis
Published: December 2023

This research shows that consumers judge product downsizing to be more unfair than equivalent price increases.
Thiazide diuretics and primary hyperparathyroidism
Authors: Mifsud Simon , Montanaro Gabriella , Craus Sarah , Mifsud Emma L , Gruppetta Mark
Published: December 2023

Thiazide diuretics exert a natriuretic and diuretic effect by inhibiting sodium reabsorption in the distal convoluted tubule. Furthermore, thiazide diuretics affect renal calcium handling by increasing calcium reabsorption, leading to hypocalciuria. The effect that thiazide diuretics exert on parathyroid hormone secretion is controversial. Some studies found parathyroid hormone levels were suppressed with the use of thiazide diuretics, while others found that thiazides were associated with initial parathyroid hormone suppression followed by raised parathyroid hormone levels. This makes the relationship between thiazide diuretics and primary hyperparathyroidism interesting. If a patient is taking thiazide diuretics, this may make it harder to establish the aetiology of hypercalcaemia and may unmask normocalcaemic or mild primary hyperparathyroidism. Thiazide diuretics may have a beneficial role in the diagnosis of patients with concomitant hyperparathyroidism and hypercalciuria by distinguishing secondary hyperparathyroidism caused by hypercalciuria from normocalcaemic primary hyperparathyroidism. In addition, thiazide diuretics may have a role in managing patients with primary hyperparathyroidism who have an indication for parathyroidectomy in view of significant hypercalciuria, but are unfit for surgery.
ANÁLISE SWOT APLICADA A PARTIR DE UM PROCESSO AVALIATIVO DO CURSO DE ENGENHARIA AGRONÔMICA: UM ESTUDO DE CASO
Authors: Sabbag Omar Jorge , Teixeira Filho Marcelo Carvalho Minhoto
Published: December 2023

O estudo teve por objetivo efetuar a análise SWOT para identificar pontos de melhoria a partir de informações de um relatório de avaliação do curso. Metodologicamente, foi efetuada a análise SWOT a partir de informações de um relatório de avaliação do Conselho Estadual de Educação para o ano de 2015, dividido em seis elementos avaliativos de ensino e baseado em uma análise qualitativa por amostragem intencional. A técnica SWOT foi realizada em plataforma Excel, contendo 10 vetores correspondentes aos pontos fortes e fracos do curso, bem como seis vetores correspondentes às ameaças e oportunidades. Os resultados mostram uma graduação com potencial de desenvolvimento, visando à melhoria contínua. Conclui-se que a Engenharia Agronômica apresenta oportunidades que podem atenuar as ameaças, propiciando novos caminhos para um curso mais adequado às novas demandas da sociedade.
Batwing elimination algorithm based on the Haar wavelet in white-light interferometry
Authors: Li Yinrui , Yang Yingzhe , Liang Yiyong
Published: December 2023

White-light scanning interferometry is a mature non-contact three-dimensional shape detection method. However, the batwing effect is an inherent problem that causes systematic error. In this paper, we proposed an algorithm for detecting and eliminating the batwing effect based on the Haar wavelet transforms without any prior knowledge of the sample surface. It is verified by simulation and experiment that the proposed algorithm can effectively eliminate the batwing effect and does not increase the time complexity significantly.
Low loss and ultra-broadband design of an integrated 3  dB power splitter centered at 2  µm
Authors: Liu Zhiming , Dong Yue , Xu Yin , Zhang Bo , Ni Yi
Published: December 2023

Because chemical gas is sensitive to absorption in the 2 µm band, and 2 µm matches the absorption band of the remote sensing material, many remote sensors and optical sensors are designed to operate in the 2 µm wavelength region. In this paper, we designed an integrated 3 dB power splitter centered at 2 µm. The study of this device is built on a silicon-on-insulator (SOI) platform. We introduced a subwavelength grating (SWG) to improve the performance of the device. We used the three-dimensional finite-difference time-domain (3D FDTD) method to analyze the effect of the structure on the power splitter. The insertion loss (IL) of the fundamental TE mode is only 0.04 dB at 2 µm and its bandwidth of IL <0.45dB is 940 nm (1570–2510 nm). It is suitable for multidomain and all-band photonic integrated circuits at 2 µm.
Fiber-cavity ring-down temperature sensor using a transmissive configuration combined with the heterodyne detection technique
Authors: Kuroda Keiji , Ikeguchi Taiki , Oka Hisaki
Published: December 2023

A fiber Bragg grating temperature sensor based on the cavity ring-down technique is reported. A quasi-linear fiber cavity is proposed to reduce optical loss in the cavity instead of a conventional fiber-loop configuration. The heterodyne detection technique is applied to sensitively detect weak pulses from the cavity. A combination of the quasi-linear fiber cavity and heterodyne detection allows the sensitive detection of the decaying pulse trains and high-resolution measurement of the wavelength shift of the Bragg grating induced by the temperature change. A temperature resolution of about 0.01°C is achieved.
Changes to the shape, orientation and packing of red cells as a function of retinal capillary size
Authors: Bedggood Phillip , Ding Yifu , Metha Andrew
Published: December 2023

The free diameter of a red blood cell exceeds the lumen diameter of capillaries in the central nervous system, requiring significant deformation of cells. However the deformations undertaken in vivo are not well established due to the difficulty in observing cellular capillary flow in living human tissue. Here, we used high resolution adaptive optics imaging to non-invasively track 17,842 red blood cells in transit through 121 unique capillary segments of diameter 8 µm or less in the retina of 3 healthy human subjects. Within each vessel, a 2D en face profile was generated for the “average cell”, whose shape was then inferred in 3D based on the key assumption of a circular capillary cross-section. From this we estimated the average volume, surface area, orientation, and separation between red cells within each capillary tube. Our results showed a network filtration effect, whereby narrower vessels were more likely to contain smaller cells (defined by surface area, which is thought not to vary during a cell’s passage through the vascular system). A bivariate linear model showed that for larger cells in narrower vessels: cells re-orient themselves to align with the flow axis, their shape becomes more elongated, there are longer gaps between successive cells, and remarkably, that cell volume is less which implies the ejection of water from cells to facilitate capillary transit. Taken together, these findings suggest that red cells pass through retinal capillaries with some reluctance. A biphasic distribution for cell orientation and separation was evident, indicating a “tipping point” for vessels narrower than approx. 5 µm. This corresponds closely to the typical capillary lumen diameter, and may maximize sensitivity of cellular flow to small changes in diameter. We suggest that the minimization of unnecessary oxygen exchange, and hence of damage via reactive oxygen pathways, may have provided evolutionary pressure to ensure that capillary lumens are generally narrower than red blood cells.
Applications of the OCATA time domain digital twin: from QoT estimation to failure management
Authors: Devigili M. , Ruiz M. , Costa N. , Castro C. , Napoli A. , Pedro J. , Velasco L.
Published: December 2023

Optical in-phase and quadrature (IQ) constellations enclose valuable information regarding the optical elements traversed by the optical signal. Such information can be extracted and exploited by algorithms and models within an optical layer digital twin. In this paper, we investigate the feasibility of extracting information from IQ constellations and its use for both accurate quality of transmission (QoT) estimation and efficient failure management within. First, we observe the correlations between the measured QoT of lightpaths and the value of specific features extracted from IQ constellation samples collected from the optical receiver and design deep neural network (DNN) models for QoT estimation. Next, specific DNN models and algorithms that exploit IQ constellation features are proposed for soft-failure detection, identification, and severity estimation. Results from both simulation and experiments show noticeable accuracy on the estimation of QoT and on the prediction of failures affecting the transmitter, optical filters, and amplifiers.