bluuebunny/crossref_metadata_2025_split huggingface dataset:
The devastating earthquake that struck Turkey and Syria: Post‐traumatic stress disorder and mental health issues among the victims
Authors: Iqbal Amna , Sheikh Ayesha 
Published: April 2023

AbstractNatural catastrophes like earthquakes have the potential to be fatal by claiming lives and harming infrastructure, the environment, and mental health. Victims may experience symptoms such as anxiety, despondency, and post‐traumatic stress disorder. Recent earthquakes in Turkey and Syria caused enormous destruction and a high number of fatalities, which is growing by the day. The past examples of earthquakes in China, South Asia, and Turkey imply that there is a possibility that the victims may feel isolated and under psychological stress. Our article outlines the high strategies to minimise the risk of mental health problems among victims of Turkey and Syria.
Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials
Authors: Gong Jingqi Q. X. , Suleiman Ahmed A. , Menon Rajeev , Deng Rong , Mensing Sven , Salem Ahmed Hamed 
Published: April 2023

AbstractFollowing the decade‐long clinical investigation, venetoclax has accrued pharmacokinetic (PK) data across multiple populations and widely ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects with population PK modeling. Plasma concentration–time data were pooled from 3016 subjects enrolled in 41 phase 1, 2, and 3 clinical studies, including patients from 9 indications and healthy volunteers. A nonlinear mixed‐effect model was developed. Covariates were evaluated with full covariate modeling approach. A 2‐compartment model with 3 transit absorption compartments described the data well. The impact of moderate and strong cytochrome P450 (CYP) 3A inhibition on apparent clearance (CL/F), female sex on apparent volume of distribution, food effect on relative bioavailability, and dose nonlinearity was confirmed. Newly identified covariate effects include 48% lower CL/F in subjects with severe hepatic impairment, 61% higher bioavailability in Asian subjects. When multiple CYP3A inhibitors are taken simultaneously, a 49% decrease in CL/F was estimated with multiple moderate inhibitors, more substantial than the 22% decrease of a single moderate inhibitor. An 85% decrease in CL/F was indicated when at least 1 strong CYP3A inhibitor was taken in combination, comparable to that of a single strong inhibitor. A venetoclax cross‐indication population PK model with improved absorption‐phase characterization was developed. Covariate analyses suggested lower CL/F for subjects with severe hepatic impairment and higher bioavailability in Asian subjects. Further decrease in CL/F was indicated when multiple moderate CYP3A inhibitors are present, compared to a single moderate inhibitor.
A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults
Authors: Dioh Waly , Tourette Cendrine , Del Signore Susanna , Daudigny Louiza , Dupont Philippe , Balducci Christine , Dilda Pierre J. , Lafont René , Veillet Stanislas 
Published: April 2023

AbstractBackgroundSarcopenia is an age‐related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20‐Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study.MethodsThis study is a Single Ascending Dose (SAD) followed by a 14‐day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen‐III‐amino‐terminal propeptide (PIIINP), myoglobin, creatine‐kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels.ResultsBIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than dose‐proportionally. Mean half‐life was short (2.4–4.9 h), and mean renal clearance was comparable in all doses (4.05–5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%–15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK‐MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14‐deoxy‐20‐hydroxyecdysone and 14‐deoxypoststerone) were identified and quantified.ConclusionsBIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age‐related sarcopenia (SARA‐INT) and Phase 3 in Covid‐19 (COVA).
Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle
Authors: Zhao Wanni , Zhang Yansong , Lin Siyuan , Li Yajuan , Zhu Alan Jian , Shi Hanping , Liu Min 
Published: April 2023

AbstractBackgroundMalnutrition is implicated in human metabolic disorders, including hepatic steatosis and myosteatosis. The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient‐sensing mechanisms in the pathogenesis of steatosis.MethodsPlin2, a lipid droplet (LD) protein‐inhibiting lipolysis, is associated with steatosis in liver and muscle. Taking advantage of the Gal4‐UAS system, we used the Drosophila melanogaster wing imaginal disc as an in vivo model to study the regulation of Plin2 proteostasis and LD homeostasis. Drosophila Schneider 2 (S2) cells were used for western blotting, immunoprecipitation assays, amino acid‐binding assays and ubiquitination assays to further investigate the regulatory mechanisms of Plin2 in response to nutrient signals. Mouse AML12 hepatocytes, human JHH‐7 and SNU‐475 hepatoma cells were used for immunofluorescence, western blotting and immunoprecipitation to demonstrate that the mode of Plin2 regulation is evolutionarily conserved. In addition, we purified proteins from HEK293 cells and reconstituted in vitro cell‐free systems in amino acid‐binding assays, pulldown assays and ubiquitination assays to directly demonstrate the molecular mechanism by which Ubr1 senses amino acids to regulate Plin2 proteostasis.ResultsAs a lipolysis inhibitor, Plin2 was significantly elevated in liver (P < 0.05) and muscle (P < 0.05) in patients with steatosis. Consistently, we found that the ubiquitin moiety can be conjugated to any Lys residue in Plin2, ensuring robust clearance of Plin2 by protein degradation. We further demonstrated that the E3 ubiquitin ligase Ubr1 targets Plin2 for degradation in an amino acid‐dependent manner. Ubr1 uses two canonical substrate‐binding pockets, independent of each other, to bind basic and bulky hydrophobic amino acids, respectively. Mechanistically, amino acid binding allosterically activates Ubr1 by alleviating Ubr1's auto‐inhibition. In the absence of amino acids, or when the amino acid‐binding capacity of Ubr1 is diminished, Ubr1‐mediated Plin2 degradation is inactivated, leading to steatosis.ConclusionsWe identified Ubr1 as an amino acid sensor regulating Plin2 proteostasis, bridging the knowledge gap between steatosis and nutrient sensing. Our work may provide new strategies for the prevention and treatment of steatosis.
Prognostic significance of sarcopenia and severe vitamin D deficiency in patients with cirrhosis
Authors: Saeki Chisato , Kanai Tomoya , Ueda Kaoru , Nakano Masanori , Oikawa Tsunekazu , Torisu Yuichi , Saruta Masayuki , Tsubota Akihito 
Published: April 2023

AbstractBackground and AimSarcopenia and severe vitamin D deficiency are associated with malnutrition and poor prognosis. We investigated the impact of the comorbidity of Child–Pugh (CP) class B/C cirrhosis and the aforementioned complications on the prognosis of patients with cirrhosis.MethodsWe retrospectively evaluated 104 patients with cirrhosis. The cumulative survival rates were compared between patients with and without both or either of these disease conditions: CP class B/C and complications (sarcopenia or severe vitamin D deficiency). Sarcopenia was diagnosed according to the Japan Society of Hepatology criteria. Severe vitamin D deficiency was defined as levels of 25‐hydroxyvitamin D <10 ng/mL in serum.ResultsThe prevalence of CP class B/C, sarcopenia, and severe vitamin D deficiency was 26.9%, 38.5%, and 24.0%, respectively. Patients with both CP class B/C and sarcopenia had significantly lower survival rates than those without both (hazard ratio [HR] = 6.101; P < 0.001) and with either condition (HR = 6.137; P = 0.001). Similarly, patients with both CP class B/C and severe vitamin D deficiency or with either condition had significantly lower survival rates than those without both conditions (HR = 8.135 or 3.189; P < 0.001 or =0.025, respectively). CP class B/C (HR = 3.354; P = 0.006) and severe vitamin D deficiency (HR = 2.445; P = 0.044) were independent prognostic factors.ConclusionsThe coexistence of CP class B/C and sarcopenia or severe vitamin D deficiency worsened the prognosis of patients with cirrhosis. Nutritional assessments such as sarcopenia and vitamin D status should be considered to better evaluate disease conditions and patient prognosis.
HSV‐1 infection‐induced herpetic neuralgia involves a CCL5/CCR5‐mediated inflammation mechanism
Authors: Wu Songbin , Yang Shaomin , Li Rongzhen , Ba Xiyuan , Jiang Changyu , Xiong Donglin , Xiao Lizu , Sun Wuping 
Published: April 2023

AbstractHerpetic‐related neuralgia (HN) caused by varicella‐zoster virus (VZV) infection is one of the most typical and common neuropathic pain in the clinic. However, the potential mechanisms and therapeutic approaches for the prevention and treatment of HN are still unclear. This study aims to provide a comprehensive understanding of the molecular mechanisms and potential therapeutic targets of HN. We used an HSV‐1 infection‐induced HN mouse model and screened the differentially expressed genes (DEGs) in the DRG and spinal cord using an RNAseq technique. Moreover, bioinformatics methods were used to figure out the signaling pathways and expression regulation patterns of the DEGs enriched. In addition, quantitative real‐time RT‐PCR and western blot were carried out to further confirm the expression of DEGs. HSV‐1 inoculation in mice resulted in mechanical allodynia, thermal hyperalgesia, and cold allodynia, following the infection of HSV‐1 in both DRG and spinal cord. Besides, HSV‐1 inoculation induced an up‐regulation of ATF3, CGRP, and GAL in DRG and activation of astrocytes and microglia in the spinal cord. Moreover, 639 genes were upregulated, 249 genes were downregulated in DRG, whereas 534 genes were upregulated and 12 genes were downregulated in the spinal cord of mice 7 days after HSV‐1 inoculation. GO and KEGG enrichment analysis suggested that immune responses and cytokine‐cytokine receptor interaction are involved in DRG and spinal cord neurons in mice after HSV‐1 infection. In addition, CCL5 and its receptor CCR5 were significantly upregulated in DRG and spinal cord upon HSV‐1 infection in mice. And blockade of CCR5 exhibited a significant analgesic effect and suppressed the upregulation of inflammatory cytokines in DRG and spinal cord induced by HSV‐1 infection in mice. HSV‐1 infection‐induced allodynia and hyperalgesia in mice through dysregulation of immune response and cytokine‐cytokine receptor interaction mechanism. Blockade of CCR5 alleviated allodynia and hyperalgesia probably through the suppression of inflammatory cytokines. Therefore, CCR5 could be a therapeutic target for the alleviation of HSV‐1 infection‐induced HN.
Dynamic immunogenicity after primary and booster inactivated SARS‐CoV‐2 vaccination in people living with HIV: A longitudinal observational study
Authors: Lu Ting , Chen Zhiwei , Cao Yu , Ao Ling , Li Zisheng , Gu Xiaoyi , Ren Xingqian , Wang Yixuan , Zhang Gaoli , Xiang Dejuan , Chen Min , Cai Dachuan , Hu Peng , Zhang Dazhi , Peng Mingli , Shi Xiaofeng , Ren Hong 
Published: April 2023

AbstractPeople living with HIV (PLWH) have poor outcomes from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2); vaccination reduces the associated mortality. The humoral immune response dynamics after booster inactivated vaccinations in PLWH remain unclear. In this longitudinal observational study, 100 PLWH after primary inactivated SARS‐CoV‐2 vaccination were consecutively recruited and followed up. After booster vaccination (BV), neutralizing antibodies (NAbs) were detected at 1 month from all the PLWH, and the titer increased sixfold compared to that associated with the primary vaccination (PV), similar to that in healthy controls after BV. The NAbs titer declined over time after BV, but remained higher at 6 months than after PV. The NAbs response was elevated after BV with CD4 count <200 cells/μL, it was the poorest among the different CD4 cell count subgroups. Similar results were observed for anti‐RBD‐IgG responses. Moreover, RBD‐specific MBCs were significantly elevated after BV in PLWH. No serious AEs were observed after BV in PLWH. In conclusion, booster inactivated SARS‐CoV‐2 vaccination is well tolerated and can elicit robust and durable humoral responses in PLWH. PLWH may benefit from a third dose of the inactivated vaccine.
Urine‐based detection of HPV for cervical cancer screening: Time for standardized tests
Authors: Li Guorong , Lamsisi Maryame , Chenafi Sara , Moniod Louise , Benlghazi Abdelhamid , Ennaji Moulay Mustapha , Chauleur Céline , Bourlet Thomas 
Published: April 2023

AbstractCervical cancer is preventable because it has an established etiology, mainly attributed to a detectable pathogen, human papillomavirus (HPV). In 2018, the world health organization issued an unprecedented call for global action to eliminate cervical cancer by 2030. The adaptation of regular screening programs is fundamental to achieve the goal of cervical cancer elimination. However, it is still difficult to achieve satisfactory coverage rates of screening in developing countries as well as in developed countries because many women are reluctant to participate in gynecologic examination. HPV detection in urine is a convenient, widely acceptable by women and relatively affordable without the necessity for clinical visits to improve the coverage rates of cervical cancer screening. Unfortunately, the clinical implementation of urine‐based tests for HPV detection has been hindered by the lack of standardized tests. Further optimization of protocols and standardization of urinary HPV detection are expected to be realized. With the advantages of urine sampling to overcome cost, personal, and cultural barriers, time has come for the standardized tests to facilitate a wide clinical implementation of urinary HPV detection that will significantly contribute to the WHO's goal, that is, to eliminate the cervical cancer globally.
Biocontrol of Trichoderma gamsii induces soil suppressive and growth‐promoting impacts and rot disease‐protecting activities
Authors: Valan Arasu Mariadhas , Vijayaraghavan Ponnuswamy , Al‐Dhabi Naif Abdullah , Choi Ki Choon , Moovendhan Meivelu 
Published: April 2023

AbstractPlant growth‐promoting rhizosphere of associated fungi is often used to improve productivity and crop health. Some biocontrol fungi showed less disease protection efficiency due to environmental factors. Hence, the analysis of biocontrol fungi strains in the field is valuable to analyze their performance in the natural environment. The main objective of this study is to isolate the growth‐promoting, rot disease‐protecting activities of Trichoderma gamsii RH4 obtained from the rhizosphere of black gram (Vigna mungo). In this study, we evaluated the protective role of 13 fungal strains, including T. gamsii against Fusarium oxysporum in the laboratory experiment (antagonistic assay), greenhouse. The growth‐promoting activity of the isolated 13 fungal strains was initially screened and the lytic property was assayed. The T. gamsii showed excellent growth‐promoting and lytic properties. Lytic enzyme assays revealed a significant difference in the enzyme yield than other isolates (p < 0.05). The influence of selected plant‐growth‐promoting fungal strains on the suppression of F. oxysporum rot and wilt black gram was analyzed. Results revealed that these fungal isolates improved black gram growth in greenhouse and significantly reduced wilt and rot disease. The improved growth and yield registered in this study proved growth‐promoting and biocontrol properties. The potent T. gamsii was applied in the open field and its effect on green gram was observed. The field trial experiment revealed several growth‐promoting effects such as the weight and length of the root and shoot system. The isolated native T. gamsii has the potential to improve the biocontrol properties against rot disease.
Effects of probiotics in rats with experimental metabolic syndrome and periodontitis: An investigation of the intestine–adipose tissue axis
Authors: Moreira André L. G. , Silva Pedro H. F. , Salvador Sérgio L. , Ishikawa Karin H. , Ferreira Graziele C. , Tanus‐Santos José E. , Mayer Marcia P. A. , de Souza Sérgio L. S. , Furlaneto Flávia A. C. , Messora Michel R. 
Published: April 2023

AbstractBackgroundThis study evaluated the systemic (intestine and adipose tissue) and local (periodontal tissues) impact of probiotic therapy in rats with metabolic syndrome (MS) associated or not with periodontitis (PE).MethodsForty‐eight rats received a high‐fat diet for induction of MS for 16 weeks. They were subdivided into groups with (+) and without (−) PE, receiving (*) or not (**) receiving probiotics (PROB): MS (−**), MSP (−*), MSPE (+**), and MSPEP (+*). PROB administration (Bifidobacterium animalis subsp. lactis HN019) started on the 8th week of the study and PE was induced on the 14th week by placing ligature on the animals’ lower first molars. Euthanasia occurred in the 16th week. Biomolecular, immunoenzymatic assays, and histomorphometric analyses were performed. The data obtained were statistically analyzed (ANOVA, Tukey, p < 0.05).ResultsThe MSPEP group exhibited reduced alveolar bone loss when compared with the MSPE group, as well as lower levels of hepatic steatosis and proteinuria (p < 0.05). In the intestinal environment, the MSPE group exhibited significantly lower villus height and crypt depth, as well as a greater increase in Bacillota when compared with the MSPEP group (p < 0.05). The MSPEP group showed lower adipokine gene expression (LEPR, NAMPT, and FABP4) in adipose tissue than the MSPE group (p < 0.05).ConclusionThe probiotic B. lactis HN019 reduced the severity of experimental periodontitis and modulated the expression of lipogenic genes and intestinal morphological and microbiological parameters in rats with MS.
Rheology on novel viscoelastic trimeric octadecyl zwitterionic surfactant micelle solutions
Authors: Xu Wenting , Han Xiaoyang , Fang Bo , He Jinlan , Wu Huinan , Xin Hui 
Published: April 2023

AbstractIn this work, a novel trimeric octadecyl zwitterionic surfactant (TOCC) was successfully synthesized. TOCC was compounded with sodium salicylate (NaSal) for an optimized formulation to form viscoelastic micelles. The effects of NaSal concentration, pH, and temperature on the rheological properties of TOCC and TOCC/NaSal micelle solutions were investigated. The flow curves for both TOCC and TOCC/NaSal micelle solutions can be fitted with the Carreau–Yasuda model. Zero shear viscosity of TOCC/NaSal micelle solution increased and then decreased with increasing NaSal concentration, and the same trend was observed for viscoelasticity. Some micelle solutions exhibited significant thixotropy with stress overshoot. The optimal composition of the TOCC/NaSal micelle solution obtained was 5.0/0.5 wt%. Frequency sweep in the form of Cole–Cole plots indicated that the viscoelastic modulus of the TOCC/NaSal micelle solution fitted the Maxwell model at low and medium frequencies. With increasing pH, 5.0 wt% TOCC micelle solution had the maximum zero shear viscosity at pH = 6.9. The steady‐state viscosities of different concentrations of TOCC micelle solutions reached their maximum at neutral conditions (pH = 6.5 ~ 7.0). Viscoelastic modulus of 5.0 wt% TOCC and TOCC/NaSal (5.0/0.5 wt%) micelle solutions decreased with increasing temperature, and thermal thixotropy was observed in both micelle solutions. The novel TOCC and TOCC/NaSal micelle solutions enrich the variety of trimeric surfactants and viscoelastic micelle solutions. This study provides a rheological reference for the applications of viscoelastic trimeric surfactants in smart materials and oil fields.
Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducingROS‐dependent apoptosis and ferroptosis
Authors: Lai Xiang‐Yu , Shi Yu‐Mei , Zhou Ming‐Ming 
Published: April 2023

AbstractThe application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs), such as gefitinib, has shifted lung cancer treatment from empirical chemotherapy to targeted molecular therapy. However, acquired drug resistance is inevitable in almost all non‐small cell lung cancer (NSCLC) patients treated with gefitinib. Combined treatment with dihydroartemisinin (DHA) and gefitinib produced a better inhibitory effect on lung adenocarcinoma than gefitinib treatment alone; however, the specific mechanism remains unclear. In this study, we aimed to assess the underlying mechanism of this combination treatment. We prepared gefitinib‐resistant A549 cells and investigated whether apoptosis and ferroptosis were involved in the sensitizing effect of DHA. Treatment with 5 μM gefitinib resulted in rupturing and floatation of A549 cells in the medium, while A549‐GR cells were found to be insusceptible to gefitinib. However, treatment with DHA substantially inhibited the proliferation of A549‐GR cells in a dose‐dependent manner accompanied by increased apoptosis and ferroptosis. The accumulated reactive oxygen species (ROS) was crucial for the inhibitory effect of DHA on A549‐GR cells. Moreover, cellular autophagy was significantly upregulated post‐DHA treatment. The combined treatment of DHA and gefitinib resulted in inhibition of proliferation of A549, H1975, and HCC827 cells, and ROS accumulation and a remarkable induction of apoptosis was observed in A549‐GR cells. DHA significantly induced apoptosis and ferroptosis in a dose‐dependent manner and exhibited high cellular toxicity on A549‐GR cells when combined with gefitinib.