bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebellar control of fear learning via the cerebellar nuclei–Multiple pathways, multiple mechanisms?
Authors: Urrutia Desmaison Julie D. , Sala Romain W. , Ayyaz Ahsan , Nondhalee Pimpimon , Popa Daniela , Léna Clément
Published: May 2023

Fear learning is mediated by a large network of brain structures and the understanding of their roles and interactions is constantly progressing. There is a multitude of anatomical and behavioral evidence on the interconnection of the cerebellar nuclei to other structures in the fear network. Regarding the cerebellar nuclei, we focus on the coupling of the cerebellar fastigial nucleus to the fear network and the relation of the cerebellar dentate nucleus to the ventral tegmental area. Many of the fear network structures that receive direct projections from the cerebellar nuclei are playing a role in fear expression or in fear learning and fear extinction learning. We propose that the cerebellum, via its projections to the limbic system, acts as a modulator of fear learning and extinction learning, using prediction-error signaling and regulation of fear related thalamo-cortical oscillations.
Evaluation of nutritional status and clinical depression classification using an explainable machine learning method
Authors: Hosseinzadeh Kasani Payam , Lee Jung Eun , Park Chihyun , Yun Cheol-Heui , Jang Jae-Won , Lee Sang-Ah
Published: May 2023

Introduction

Depression is a prevalent disorder worldwide, with potentially severe implications. It contributes significantly to an increased risk of diseases associated with multiple risk factors. Early accurate diagnosis of depressive symptoms is a critical first step toward management, intervention, and prevention. Various nutritional and dietary compounds have been suggested to be involved in the onset, maintenance, and severity of depressive disorders. Despite the challenges to better understanding the association between nutritional risk factors and the occurrence of depression, assessing the interplay of these markers through supervised machine learning remains to be fully explored.

Methods

This study aimed to determine the ability of machine learning-based decision support methods to identify the presence of depression using publicly available health data from the Korean National Health and Nutrition Examination Survey. Two exploration techniques, namely, uniform manifold approximation and projection and Pearson correlation, were performed for explanatory analysis among datasets. A grid search optimization with cross-validation was performed to fine-tune the models for classifying depression with the highest accuracy. Several performance measures, including accuracy, precision, recall, F1 score, confusion matrix, areas under the precision-recall and receiver operating characteristic curves, and calibration plot, were used to compare classifier performances. We further investigated the importance of the features provided: visualized interpretation using ELI5, partial dependence plots, and local interpretable using model-agnostic explanations and Shapley additive explanation for the prediction at both the population and individual levels.

Results

The best model achieved an accuracy of 86.18% for XGBoost and an area under the curve of 84.96% for the random forest model in original dataset and the XGBoost algorithm with an accuracy of 86.02% and an area under the curve of 85.34% in the quantile-based dataset. The explainable results revealed a complementary observation of the relative changes in feature values, and, thus, the importance of emergent depression risks could be identified.

Discussion

The strength of our approach is the large sample size used for training with a fine-tuned model. The machine learning-based analysis showed that the hyper-tuned model has empirically higher accuracy in classifying patients with depressive disorder, as evidenced by the set of interpretable experiments, and can be an effective solution for disease control.
Plasma protein changes reflect colorectal cancer development and associated inflammation
Authors: Urbiola-Salvador Víctor , Jabłońska Agnieszka , Miroszewska Dominika , Huang Qianru , Duzowska Katarzyna , Drężek-Chyła Kinga , Zdrenka Marek , Śrutek Ewa , Szylberg Łukasz , Jankowski Michał , Bała Dariusz , Zegarski Wojciech , Nowikiewicz Tomasz , Makarewicz Wojciech , Adamczyk Agnieszka , Ambicka Aleksandra , Przewoźnik Marcin , Harazin-Lechowicz Agnieszka , Ryś Janusz , Filipowicz Natalia , Piotrowski Arkadiusz , Dumanski Jan P. , Li Bin , Chen Zhi
Published: May 2023

Introduction

Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of death worldwide. Efficient non-invasive blood-based biomarkers for CRC early detection and prognosis are urgently needed.

Methods

To identify novel potential plasma biomarkers, we applied a proximity extension assay (PEA), an antibody-based proteomics strategy to quantify the abundance of plasma proteins in CRC development and cancer-associated inflammation from few μL of plasma sample.

Results

Among the 690 quantified proteins, levels of 202 plasma proteins were significantly changed in CRC patients compared to age-and-sex-matched healthy subjects. We identified novel protein changes involved in Th17 activity, oncogenic pathways, and cancer-related inflammation with potential implications in the CRC diagnosis. Moreover, the interferon γ (IFNG), interleukin (IL) 32, and IL17C were identified as associated with the early stages of CRC, whereas lysophosphatidic acid phosphatase type 6 (ACP6), Fms-related tyrosine kinase 4 (FLT4), and MANSC domain-containing protein 1 (MANSC1) were correlated with the late-stages of CRC.

Discussion

Further study to characterize the newly identified plasma protein changes from larger cohorts will facilitate the identification of potential novel diagnostic, prognostic biomarkers for CRC.
Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia
Authors: Timofeeva Natalia , Ayres Mary L. , Baran Natalia , Santiago-O’Farrill Janice M. , Bildik Gamze , Lu Zhen , Konopleva Marina , Gandhi Varsha
Published: May 2023

Introduction

Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.

Methods

To investigate the in vitro effects of CB-839 on CLL cells, we tested CB-839 alone and in combination with ibrutinib, venetoclax, or AZD-5991 on the HG-3 and MEC-1 CLL cell lines and on primary CLL lymphocytes.

Results

We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839–treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed.

Discussion

Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.
Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer
Authors: Yang Shicheng , Green Allen , Brown Needa , Robinson Alexis , Senat Merline , Testino Bryanna , Dinulescu Daniela M. , Sridhar Srinivas
Published: May 2023

Background

Ovarian cancer has long been known to be the deadliest cancer associated with the female reproductive system. More than 15% of ovarian cancer patients have a defective BRCA-mediated homologous recombination repair pathway that can be therapeutically targeted with PARP inhibitors (PARPi), such as Talazoparib (TLZ). The expansion of TLZ clinical approval beyond breast cancer has been hindered due to the highly potent systemic side effects resembling chemotherapeutics. Here we report the development of a novel TLZ-loaded PLGA implant (InCeT-TLZ) that sustainedly releases TLZ directly into the peritoneal (i.p.) cavity to treat patient-mimicking BRCA-mutated metastatic ovarian cancer (mOC).

Methods

InCeT-TLZ was fabricated by dissolving TLZ and PLGA in chloroform, followed by extrusion and evaporation. Drug loading and release were confirmed by HPLC. The in vivo therapeutic efficacy of InCeT-TLZ was carried out in a murine Brca2-/-p53R172H/-Pten-/- genetically engineered peritoneally mOC model. Mice with tumors were divided into four groups: PBS i.p. injection, empty implant i.p. implantation, TLZ i.p. injection, and InCeT-TLZ i.p. implantation. Body weight was recorded three times weekly as an indicator of treatment tolerance and efficacy. Mice were sacrificed when the body weight increased by 50% of the initial weight.

Results

Biodegradable InCeT-TLZ administered intraperitoneally releases 66 μg of TLZ over 25 days. In vivo experimentation shows doubled survival in the InCeT-TLZ treated group compared to control, and no significant signs of toxicity were visible histologically in the surrounding peritoneal organs, indicating that the sustained and local delivery of TLZ greatly maximized therapeutic efficacy and minimized severe clinical side effects. The treated animals eventually developed resistance to PARPi therapy and were sacrificed. To explore treatments to overcome resistance, in vitro studies with TLZ sensitive and resistant ascites-derived murine cell lines were carried out and demonstrated that ATR inhibitor and PI3K inhibitor could be used in combination with the InCeT-TLZ to overcome acquired PARPi resistance.

Conclusion

Compared to intraperitoneal PARPi injection, the InCeT-TLZ better inhibits tumor growth, delays the ascites formation, and prolongs the overall survival of treated mice, which could be a promising therapy option that benefits thousands of women diagnosed with ovarian cancer.
Light activation of the dopaminergic system occurs after eye-opening in the mouse retina
Authors: Jain Vrinda , Liang Phillip J. M. , Raja Sushmitha , Mikhael Meena , Cameron Morven A.
Published: May 2023

The neuromodulator dopamine plays a significant role in light adaptation, eye growth, and modulation of neuronal circuitry in the retina. Dopaminergic amacrine cells in the adult retina release dopamine in response to light stimulation, however, the light-induced activity of these cells in during postnatal development is not known. We assessed the activity of dopaminergic amacrine cells in the retina response to a light pulse in C57BL/6 wild-type animals across various postnatal ages. Expression of tyrosine hydroxylase (TH) in dopaminergic amacrine cells was apparent from postnatal day 3 (P3) and restricted to the dorso-temporal region; by P8 TH+ cells were uniformly distributed across the retina. TH cell density increased until P8 and then markedly decreased by P10 to then remain at this density into adulthood. Light-induced c-fos expression was observed in all light-pulsed retinae, however, no c-fos was ever found to be co-localised with TH prior to P12. At P14, one day after eye opening, 100% of TH cells co-localised with c-fos and this was maintained for all older ages analysed. Dopamine and its primary metabolite DOPAC were measured in the vitreous of animals P8-P30. Both analytes were found in the vitreous at all ages, however, a significant difference in dopamine concentration between dark and light-pulsed animals was only observed at P30. DOPAC concentration was found to be significantly light-induced from P16, and the amplitude of this difference increased over time. Our data suggests that dopaminergic cell activation and light-induced dopamine release in the retina is primarily driven by classical photoreceptors after eye-opening.
Effect of hip CPM on gross motor function and development of the hip joint: a single-center randomized controlled study on spastic cerebral palsy children with hip dysplasia
Authors: Wang Lulu , Zhang Nuochen , Fang Liwei , Cui Zhenzhen , Niu Huihui , Lv Fuli , Hu Dayong , Wu De
Published: May 2023

Objective

To investigate the effectiveness of hip continuous passive motion (hCPM) on hip development at skeletal maturity and gross motor function for spastic cerebral palsy children with hip dysplasia.

Methods

Prospective case–control research of hCPM with goal-directed training versus merely goal-directed training. On the basis of goal-directed training, the hCPM group used the hip joint CPM instrument (the external fixator was connected to the power device to make the hip joint carry out continuous passive movement) for 40–60 min, twice a day, and five times a week, and received continuous training for 8 weeks simultaneously. The control group received only goal-directed training for 8 weeks. Functional outcomes pertaining to the affected hip joints were assessed via gross motor function measure (GMFM), migration percentage (MP), acetabular index (AI), and Harris hip functional score (HHS) at the time of enrollment and the end of the intervention.

Results

The case–control research included 65 participants (mean age = 46.20 months, SD = 17.09 months; Gross Motor Function Grading System level: III = 41, IV = 24) who were randomly selected to either the hCPM (n = 45) or the control group (n = 20). No differences were found in baseline (acquisition phase) GMFM, MP, AI, or HHS (t = −1.720, P = 0.090; t* = 1.836, P* = 0.071; t# = −1.517, P# = 0.139; t* = −1.310, P* = 0.195; t# = −1.084, P# = 0.097; t = −1.041, P = 0.301). At the 8-week follow-up, GMFM, MP, AI, and HHS significantly improved over baseline in the hCPM group (hCPM group: t = 18.59, 20.172*, 40.291#, 16.820*, 32.900#, 28.081; P < 0.001). Between-group differences at 8-week follow-up times points favored the hCPM group for GMFM (t = −2.637, P = 0.011), MP (t* = 2.615, P* = 0.014; t# = 3.000, P# = 0.006), AI (t* = 2.055, P* = 0.044; t# = 2.223, P# = 0.030), HHS (t = −4.685, P < 0.001) (*: left side; #: right side).

Conclusion

Spastic cerebral palsy children with hip dysplasia achieved meaningful functional improvement after 8 weeks of goal-directed training with hCPM therapy.
Changes in behavior and quality of life in German young children during the COVID-19 pandemic—results from the COVID kids bavaria study
Authors: Schillok Hannah , Coenen Michaela , Rehfuess Eva A. , Kuhlmann Pia H. , Matl Stefan , Kindermann Hannah , Maison Nicole , Eckert Jana , von Both Ulrich , Behrends Uta , Frühwald Michael C. , Neubert Antje , Woelfle Joachim , Melter Michael , Liese Johannes , Hübner Johannes , Klein Christoph , Kern Anna , Jung-Sievers Caroline
Published: May 2023

Introduction

The COVID-19 pandemic with its containment measures such as closures of schools and daycare facilities led to numerous restrictions in daily life, putting developmental opportunities and health-related quality of life in children at risk. However, studies show that not every family was impacted equally by the pandemic and that this exceptional health and societal situation reinforced pre-existing health inequalities among the vulnerable. Our study aimed at analyzing changes in behavior and health-related quality of life of children attending elementary schools and daycare facilities in Bavaria, Germany in spring 2021. We also sought to identify associated factors contributing to inequalities in quality of life.

Methods

Data from a multi-center, open cohort study (“COVID Kids Bavaria”) conducted in 101 childcare facilities and 69 elementary schools across all electoral districts of Bavaria were analyzed. Children attending these educational settings (aged 3-10 years) were eligible for participation in a survey on changes in behavior and health-related quality of life. The KINDLR questionnaire (based on children’s self-report and parental report) was administered about one year after the onset of the pandemic (spring 2021). Descriptive and logistic regression analyses and comparisons to pre-pandemic KiGGS (German Health Interview and Examination Survey for Children and Adolescents) data were undertaken.

Results

Among respondents, a high percentage of parents reported changes in their children's eating and sleeping behavior, sports and outdoor activities as well as altered screen time. Health-related quality of life in KINDLR analyses compared to pre-pandemic population averages were lower in all age groups (for 3–6-year-old KINDLR-total score: COVID Kids Bavaria MD 74.78 ± 10.57 vs KiGGS data 80.0 ± 8.1; 7-10 years-old KINDLR-total score: COVID Kids Bavaria MD 73.88 ± 12.03 vs KiGGS data 79.30 ± 9.0). No significant differences were detected with regard to associated factors, namely type of institution, sex of the child, migration background, household size and parental education.

Conclusion

These findings suggest a relevant impact of the COVID-19 pandemic on children’s behavior and health-related quality of life one year after the onset of the pandemic. Further analyses in large-scale longitudinal studies are needed to determine the effects of specific pandemic or crisis associated factors contributing to health inequalities.
Association of pharmaceutical care barriers and role ambiguity and role conflict of clinical pharmacists
Authors: Sun Qingran , Wan Chuchuan , Xu Zhaoqi , Huang Yuankai , Xi Xiaoyu
Published: May 2023

Objectives: This study aimed to understand current status of pharmaceutical care barriers and explore the impact of them on the role ambiguity and role conflict of clinical pharmacists in secondary and tertiary hospitals in mainland China.

Methods: The Chinese version of Role Conflict and Role Ambiguity Scale was used to measure clinical pharmacists’ role ambiguity and role conflict. A questionnaire for clinical pharmacists’ pharmaceutical care barriers was established to determine whether clinical pharmacists encounter barriers. Multiple linear regression model was used to analyze the influence of various pharmaceutical care barriers on the role ambiguity and role conflict of clinical pharmacists.

Results: 1,300 clinical pharmacists from 31 provinces were eventually included. The results revealed that commonly perceived barriers to pharmaceutical care by clinical pharmacists include the lack of financial compensation and dedicated time for pharmaceutical care. Barriers such as clinical pharmacists’ unawareness of the importance of pharmaceutical care increase the degree of clinical pharmacists’ role conflict. And the lack of financial compensation for pharmaceutical care decreases the degree of role ambiguity, while barriers such as the lack of dedicated time for pharmaceutical care, the failure to standardize the service procedures and contents of related documents in healthcare institutions increase the degree of role ambiguity.

Conclusion: Increased focus on enhancing financial compensation, responsibility cognition, education and training, and greater consideration of institutional factors could help clinical pharmacists better manage their work environments and provide higher-quality pharmaceutical care.
Deuterated buprenorphine retains pharmacodynamic properties of buprenorphine and resists metabolism to the active metabolite norbuprenorphine in rats
Authors: Janganati Venumadhav , Salazar Paloma , Parks Brian J. , Gorman Gregory S. , Prather Paul L. , Peterson Eric C. , Alund Alexander W. , Moran Jeffery H. , Crooks Peter A. , Brents Lisa K.
Published: May 2023

Introduction: An active metabolite of buprenorphine (BUP), called norbuprenorphine (NorBUP), is implicated in neonatal opioid withdrawal syndrome when BUP is taken during pregnancy. Therefore, reducing or eliminating metabolism of BUP to NorBUP is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Precision deuteration alters pharmacokinetics of drugs without altering pharmacodynamics. Here, we report the synthesis and testing of deuterated buprenorphine (BUP-D2).

Methods: We determined opioid receptor affinities of BUP-D2 relative to BUP with radioligand competition receptor binding assays, and the potency and efficacy of BUP-D2 relative to BUP to activate G-proteins via opioid receptors with [35S]GTPγS binding assays in homogenates containing the human mu, delta, or kappa opioid receptors. The antinociceptive effects of BUP-D2 and BUP were compared using the warm-water tail withdrawal assay in rats. Blood concentration versus time profiles of BUP, BUP-D2, and NorBUP were measured in rats following intravenous BUP-D2 or BUP injection.

Results: The synthesis provided a 48% yield and the product was ≥99% deuterated. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. BUP-D2 also activated opioid receptors and induced antinociception with equal potency and efficacy as BUP. The maximum concentration and the area under the curve of NorBUP in the blood of rats that received BUP-D2 were over 19- and 10-fold lower, respectively, than in rats that received BUP.

Discussion: These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and resists metabolism to NorBUP and therefore holds promise as an alternative to BUP.
Yue-bi-tang attenuates adriamycin-induced nephropathy edema through decreasing renal microvascular permeability via inhibition of the Cav-1/ eNOS pathway
Authors: Li Tingting , Cheng Su , Xu Lin , Lin Pinglan , Shao Minghai
Published: May 2023

Edema is one of the most typical symptoms of nephrotic syndrome. Increased vascular permeability makes a significant contribution to the progression of edema. Yue-bi-tang (YBT) is a traditional formula with excellent clinical efficacy in the treatment of edema. This study investigated the effect of YBT on renal microvascular hyperpermeability-induced edema in nephrotic syndrome and its mechanism. In our study, the content of target chemical components of YBT was identified using UHPLC-Q-Orbitrap HRMS analysis. A nephrotic syndrome model was replicated based on male Sprague-Dawley rats with Adriamycin (6.5 mg/kg) by tail vein injection. The rats were randomly divided into control, model, prednisone, and YBT (22.2 g/kg, 11.1 g/kg, and 6.6 g/kg) groups. After 14 d of treatment, the severity of renal microvascular permeability, edema, the degree of renal injury, and changes in the Cav-1/eNOS pathway were assessed. We found that YBT could regulate renal microvascular permeability, alleviate edema, and reduce renal function impairment. In the model group, the protein expression of Cav-1 was upregulated, whereas VE-cadherin was downregulated, accompanied by the suppression of p-eNOS expression and activation of the PI3K pathway. Meanwhile, an increased NO level in both serum and kidney tissues was observed, and the above situations were improved with YBT intervention. It thus indicates YBT exerts therapeutic effects on the edema of nephrotic syndrome, as it improves the hyperpermeability of renal microvasculature, and that YBT is engaged in the regulation of Cav-1/eNOS pathway-mediated endothelial function.
In-situ formed thermosensitive hydrogel amplifies statin-mediated immune checkpoint blockade for coordinated tumor chemo-immunotherapy
Authors: Liu Zefan , Zhang Yajun , Huang Jinyu , Wang Yan , Kang Xin
Published: May 2023

Small molecule drugs are the next-generation of immune checkpoint inhibitors (ICIs), but their in vivo therapeutic outcomes remain unsatisfactory for a long time. Herein, we proposed a combinatory regimen that delivered a small molecule ICI and an immunogenic cell death inducer in an in-situ formed hydrogel scaffold based on thermosensitive materials (Pluronic F127). This platform increased the tumor retention of administrated small molecules, creating more opportunities for the interaction between drugs and tumor cells. We found that atorvastatin (ATO) effectively downregulated the expression of programmed death ligand 1 (PD-L1) and reversed compensative PD-L1 upregulation after cyclophosphamide (CTX) chemotherapy on CT26 colon tumors. CTX not only killed tumor cells to reduce the tumor burden, but also release damage-associated molecular patterns (DAMPs) to stimulate T cell immunity, therefore amplifying statin-mediated immunotherapy. The platform reported in this study might be promising to overcome the limitation of small molecule ICIs with short retention time and potentiate tumor chemo-immunotherapy.
Pharmacist-led iodinated contrast media infusion risk assessment service
Authors: Jiang Huiyan , Li Yuan , Wu Xiaoyan , Yu Hongming , Zhang Xin , Ge Weihong , Yan Simin
Published: May 2023

Background: With the increasing development of medical imaging, the use of iodinated contrast media has become more widespread. Adverse reactions caused by iodinated contrast media have drawn much attention. Despite this, there is still a lack of unified standards for the safe infusion process of iodinated contrast media in clinical practice both domestically and internationally.

Objectives: Establishing a risk management service system to better predict the risks associated with iodinated contrast media infusion, reduce the incidence of adverse reactions and minimize patient harm.

Method: A prospective interventional study was carried out from April 2021 to December 2021 at Nanjing Drum Tower Hospital in China. During this study, a service system was established to manage the risks associated with the infusion of iodinated contrast media. Personalized risk identification and assessment were performed by a pharmacist-led multidisciplinary team before iodinated contrast media infusion. Early warning, prevention, and adverse reaction management were performed according to different risk levels during and after infusion.

Results: A multidisciplinary team led by pharmacists was established to evaluate the risks associated with infusion of iodinated contrast media. A total of 157 patients with risk factors related to the iodinated contrast media were screened out, which prevented 22 serious adverse events and enhanced the quality of medical care. All participants expressed high satisfaction with the service.

Conclusion: Through practical exploration, the pharmacist-led multidisciplinary team can provide advance warning and effectively limit the risks of adverse reactions caused by iodinated contrast media to a preventable and controllable level. This approach serves as a valuable reference for developing strategies and schemes to reduce the incidence of such reactions. Therefore, we encourage the implementation of this intervention in other areas of China.
The mechanism of oxytocin and its receptors in regulating cells in bone metabolism
Authors: Feixiang Liu , Yanchen Feng , Xiang Li , Yunke Zhang , Jinxin Miao , Jianru Wang , Zixuan Lin
Published: May 2023

Oxytocin (OT) is a neuropeptide known to affect social behavior and cognition. The epigenetic modification of the oxytocin receptor (OTR) via DNA methylation stimulates parturition and breast milk secretion and inhibits craniopharyngioma, breast cancer, and ovarian cancer growth significantly as well as directly regulates bone metabolism in their peripheral form rather than the central form. OT and OTR can be expressed on bone marrow mesenchymal stem cells (BMSCs), osteoblasts (OB), osteoclasts (OC), osteocytes, chondrocytes, and adipocytes. OB can synthesize OT under the stimulation of estrogen as a paracrine–autocrine regulator for bone formation. OT/OTR, estrogen, and OB form a feed-forward loop through estrogen mediation. The osteoclastogenesis inhibitory factor (OPG)/receptor activator of the nuclear factor kappa-B ligand (RANKL) signaling pathway is crucially required for OT and OTR to exert anti-osteoporosis effect. Downregulating the expression of bone resorption markers and upregulating the expression of the bone morphogenetic protein, OT could increase BMSC activity and promote OB differentiation instead of adipocytes. It could also stimulate the mineralization of OB by motivating OTR translocation into the OB nucleus. Moreover, by inducing intracytoplasmic Ca2+ release and nitric oxide synthesis, OT could regulate the OPG/RANKL ratio in OB and exert a bidirectional regulatory effect on OC. Furthermore, OT could increase the activity of osteocytes and chondrocytes, which helps increase bone mass and improve bone microstructure. This paper reviews recent studies on the role of OT and OTR in regulating cells in bone metabolism as a reference for their clinical use and research based on their reliable anti-osteoporosis effects.
Co-delivery of doxorubicin and hydroxychloroquine via chitosan/alginate nanoparticles for blocking autophagy and enhancing chemotherapy in breast cancer therapy
Authors: Zhang Hui , Xue Qingwen , Zhou Zihan , He Ningning , Li Shangyong , Zhao Cheng
Published: May 2023

Breast cancer (BC) is the most common malignancy in women worldwide, and the standard treatment is chemotherapy or radiotherapy after surgery. In order to reduce the side effects of chemotherapy, various nanoparticles (NPs) have been discovered and synthesized, which has become a promising treatment for BC. In this study, a co-delivery nanodelivery drug system (Co-NDDS) was designed and synthesized with 2,3-dimercaptosuccinic acid (DMSA) coated Fe3O4 NPs as core encapsulated into chitosan/alginate nanoparticles (CANPs) shell, doxorubicin (DOX) and hydroxychloroquine (HCQ) as loading drugs. Smaller NPs carrying DOX (FeAC-DOX NPs) were loaded into larger NPs containing HCQ (FeAC-DOX@PC-HCQ NPs) by ionic gelation and emulsifying solvent volatilization methods. The physicochemical properties of this Co-NDDS were characterised, followed by in vitro studies of the anticancer effects and mechanisms using two different BC cell lines, MCF-7 cells and MDA-MB-231 cells. The results indicated that the Co-NDDS showcases exemplary physicochemical qualities and encapsulation capacity, facilitating accurate intracellular release through pH-sensitive attributes. Importantly, NPs can significantly increase the in vitro cytotoxicity of co-administered drugs and effectively inhibit the autophagy level of tumour cells. The Co-NDDS constructed in this study provides a promising strategy for the treatment of BC.
Association of periconceptional or pregnancy exposure of HPV vaccination and adverse pregnancy outcomes: a systematic review and meta-analysis with trial sequential analysis
Authors: Yan Xiaoli , Li Hongyu , Song Bin , Huang Ge , Chang Qing , Wang Dan , Yan Ping
Published: May 2023

Objective: To evaluate whether periconceptional or pregnancy exposure of human papillomavirus (HPV) vaccination would increase the risk of adverse pregnancy outcomes.

Methods: The PubMed, Web of Science, Embase, the Cochrane Library of clinical trials were searched from inception to March 2023. We computed relative risk (RR) and 95% confidence intervals (CIs) and prediction intervals (PIs) regarding the association between HPV vaccination in periconceptional period or during pregnancy and the risks of adverse pregnancy outcomes by using R software Version 4.1.2 and STATA Version 12.0. A trial sequential analysis (TSA) was performed with TSA v0.9.5.10 Beta software.

Results: Four randomized controlled trials (RCTs) and eight cohort studies were included in this meta-analysis. Analysis of RCTs showed that HPV vaccination in periconceptional period or during pregnancy did not increase the risks of spontaneous abortion (RR = 1.152, 95% CI: 0.909–1.460, 95% PI: 0.442–3.000), birth defects (RR = 1.171, 95% CI: 0.802–1.709, 95% PI: 0.320–4.342), stillbirth (RR = 1.053, 95% CI: 0.616–1.800, 95% PI: 0.318–3.540), preterm birth (RR = 0.940, 95% CI: 0.670–1.318) and ectopic pregnancy (RR = 0.807, 95% CI: 0.353–1.842, 95% PI: 0.128–5.335). In cohort studies, periconceptional or pregnancy exposures of HPV vaccine were not associated with the increased risk of spontaneous abortion (RR = 0.987, 95% CI: 0.854–1.140, 95% PI: 0.652–1.493), birth defects (RR = 0.960, 95% CI: 0.697–1.322, 95% PI: 0.371–2.480), stillbirth (RR = 1.033, 95% CI: 0.651–1.639, 95% PI: 0.052–21.064), small size for gestational age (SGA) (RR = 0.971, 95% CI: 0.873–1.081, 95% PI: 0.657–1.462) and preterm birth (RR = 0.977, 95% CI: 0.874–1.092, 95% PI: 0.651–1.444).

Conclusion: HPV vaccine exposures in periconceptional period or during pregnancy did not increase the risks of adverse pregnancy outcomes, including spontaneous abortion, birth defects, stillbirth, SGA, preterm birth and ectopic pregnancy.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42023399777.
Potential impact of mepolizumab in stepping down anti-osteporotic treatment in corticosteroid-dependent asthma
Authors: Domingo Christian , Sogo Ana , Casado Enrique , Martínez-Moragón Eva , Blanco-Aparicio Marina , Carrillo Teresa , Bañas-Conejero David , Sánchez-Herrero María-Guadalupe
Published: May 2023

Oral corticosteroids (OCS) are commonly used for the acute management of severe asthma exacerbations or as maintenance therapy; however, chronic use is associated with significant toxicities, e.g., osteoporosis. In the REal worlD Effectiveness and Safety (REDES) study of mepolizumab in a multicentric Spanish cohort of asthma patients, mepolizumab effectively reduced clinically severe asthma exacerbations and decreased OCS dependence. This post-hoc analysis further evaluates mepolizumab’s de-escalation effect on OCS dose. Patients enrolled in REDES who had OCS consumption data available for 12 months pre- and post-mepolizumab treatment were included in this analysis. Primary outcomes were to determine the change in the proportion of patients eligible for anti-osteoporotic treatment due to the changes in OCS consumption before and after 1 year of mepolizumab treatment. All analyses are descriptive. Approximately one-third (98/318; 30.8%) of patients in REDES were on maintenance OCS at the time of mepolizumab treatment initiation. In REDES, mean cumulative OCS exposure decreased by 54.3% after 1 year of treatment. The proportion of patients on high-dose OCS (≥7.5 mg/day) fell from 57.1% at baseline to 28.9% after 12 months of mepolizumab treatment. Thus, 53.6% of OCS-dependent asthma patients treated with mepolizumab would cease to be candidates for anti-osteoporotic treatment according to guidelines thresholds.
Ultra-high efficiency bremsstrahlung production in the interaction of direct laser-accelerated electrons with high-Z material
Authors: Tavana P. , Bukharskii N. , Gyrdymov M. , Spillmann U. , Zähter Ş. , Cikhardt J. , Borisenko N. G. , Korneev Ph. , Jacoby J. , Spielmann C. , Andreev N. E. , Günther M. M. , Rosmej O. N.
Published: May 2023

High performance of laser-driven sources of radiation is in focus of research aimed at the study of high energy density matter, pair production and neutron generation using kJ PW-laser systems. In this work, we present a highly efficient approach to generate an ultra-high flux, high-energy bremsstrahlung in the interaction of direct laser-accelerated (DLA) electrons with a several-millimeters-thick high-Z converter. A directed beam of direct laser-accelerated electrons with energies up to 100 MeV was produced in the interaction of a sub-ps laser pulse of moderate relativistic intensity with long-scale plasma of near-critical density obtained by irradiation of low-density polymer foam with an ns laser pulse. In the experiment, tantalum isotopes generated via photonuclear reactions with threshold energies above 40 MeV were observed. The Geant4 Monte Carlo code, with the measured electron energy and angular distribution as input parameters, was used to characterize the bremsstrahlung spectrum responsible for the registered yields of isotopes from 180Ta to 175Ta. It is shown that when the direct laser-accelerated electrons interact with a tantalum converter, the directed bremsstrahlung with an average photon energy of 18 MeV and ∼2⋅1011 photons per laser shot in the energy range of giant dipole resonance (GDR) and beyond (≥7.5 MeV) is produced. This results in an ultra-high photon flux of ∼6 × 1022 sr−1·s−1 and a record conversion efficiency of 2% of the focused laser energy into high-energy bremsstrahlung.
Pathophysiological role of BACH transcription factors in digestive system diseases
Authors: Song Qianben , Mao Xin , Jing Mengjia , Fu Yu , Yan Wei
Published: May 2023

BTB and CNC homologous (BACH) proteins, including BACH1 and BACH2, are transcription factors that are widely expressed in human tissues. BACH proteins form heterodimers with small musculoaponeurotic fibrosarcoma (MAF) proteins to suppress the transcription of target genes. Furthermore, BACH1 promotes the transcription of target genes. BACH proteins regulate physiological processes, such as the differentiation of B cells and T cells, mitochondrial function, and heme homeostasis as well as pathogenesis related to inflammation, oxidative-stress damage caused by drugs, toxicants, or infections; autoimmunity disorders; and cancer angiogenesis, epithelial-mesenchymal transition, chemotherapy resistance, progression, and metabolism. In this review, we discuss the function of BACH proteins in the digestive system, including the liver, gallbladder, esophagus, stomach, small and large intestines, and pancreas. BACH proteins directly target genes or indirectly regulate downstream molecules to promote or inhibit biological phenomena such as inflammation, tumor angiogenesis, and epithelial-mesenchymal transition. BACH proteins are also regulated by proteins, miRNAs, LncRNAs, labile iron, and positive and negative feedback. Additionally, we summarize a list of regulators targeting these proteins. Our review provides a reference for future studies on targeted drugs in digestive diseases.
Persistence of auditory modulation of wind-induced escape behavior in crickets
Authors: Lu Anhua , Fukutomi Matasaburo , Shidara Hisashi , Ogawa Hiroto
Published: May 2023

Animals, including insects, change their innate escape behavior triggered by a specific threat stimulus depending on the environmental context to survive adaptively the predators’ attack. This indicates that additional inputs from sensory organs of different modalities indicating surrounding conditions could affect the neuronal circuit responsible for the escape behavior. Field crickets, Gryllus bimaculatus, exhibit an oriented running or jumping escape in response to short air puff detected by the abdominal mechanosensory organ called cerci. Crickets also receive a high-frequency acoustic stimulus by their tympanal organs on their frontal legs, which suggests approaching bats as a predator. We have reported that the crickets modulate their wind-elicited escape running in the moving direction when they are exposed to an acoustic stimulus preceded by the air puff. However, it remains unclear how long the effects of auditory inputs indicating surrounding contexts last after the sound is terminated. In this study, we applied a short pulse (200 ms) of 15-kHz pure tone to the crickets in various intervals before the air-puff stimulus. The sound given 200 or 1000 ms before the air puff biased the wind-elicited escape running backward, like the previous studies using the longer and overlapped sound. But the sounds that started 2000 ms before and simultaneously with the air puff had little effect. In addition, the jumping probability was higher only when the delay of air puff to the sound was 1000 ms. These results suggest that the cricket could retain the auditory memory for at least one second and alter the motion choice and direction of the wind-elicited escape behavior.
Alkaline ceramidase (ClAC) inhibition enhances heat stress response in Cyrtorhinus lividipennis (Reuter)
Authors: Chen Min , Shi Xiao-Xiao , Wang Ni , Zhang Chao , Shi Zhe-Yi , Zhou Wen-Wu , Zhu Zeng-Rong
Published: May 2023

Ceramidases (CDases) are vital sphingolipid enzymes involved in organismal growth and development. They have been reported as key mediators of thermal stress response. However, whether and how CDase responds to heat stress in insects remain unclear. Herein, we identified two CDase genes, C. lividipennis alkaline ceramidase (ClAC) and neutral ceramidase (ClNC), by searching the transcriptome and genome databases of the mirid bug, Cyrtorhinus lividipennis, an important natural predator of planthoppers. Quantitative PCR (qPCR) analysis showed that both ClNC and ClAC were highly expressed in nymphs than in adults. ClAC was especially highly expressed in the head, thorax, and legs, while ClNC was widely expressed in the tested organs. Only the ClAC transcription was significantly affected by heat stress. Knocking down ClAC increased the C. lividipennis nymph survival rate under heat stress. The transcriptome and lipidomics data showed that the RNA interference-mediated suppression of ClAC significantly upregulated the transcription level of catalase (CAT) and the content of long-chain base ceramides, including C16-, C18-, C24-, and C31- ceramides. In C. lividipennis nymphs, ClAC played an important role in heat stress response, and the upregulation of nymph survival rate might be caused by variation in the ceramide levels and transcriptional changes in CDase downstream genes. This study improves our understanding of the physiological functions of insect CDase under heat stress and provides valuable insights into the nature enemy application.
A novel estimate of biological aging by multiple fitness tests is associated with risk scores for age-related diseases
Authors: Manca A. , Fiorito G. , Morrone M. , Boi A. , Mercante B. , Martinez G. , Ventura L. , Delitala A. P. , Cano A. , Catte M. G. , Solinas G. , Melis F. , Ginatempo F. , Deriu F.
Published: May 2023

Introduction: Recent research highlights the need for a correct instrument for monitoring the individual health status, especially in the elderly. Different definitions of biological aging have been proposed, with a consistent positive association of physical activity and physical fitness with decelerated aging trajectories. The six-minute walking test is considered the current gold standard for estimating the individual fitness status in the elderly.

Methods: In this study, we investigated the possibility of overcoming the main limitations of assessing fitness status based on a single measure. As a result, we developed a novel measure of fitness status based on multiple fitness tests. In 176 Sardinian individuals aged 51–80 years we collected the results of eight fitness tests to measure participants’ functional mobility, gait, aerobic condition, endurance, upper and lower limb strength, and static and dynamic balance. In addition, the participants’ state of health was estimated through validated risk scores for cardiovascular diseases, diabetes, mortality, and a comorbidity index.

Results: Six measures contributing to fitness age were extracted, with TUG showing the largest contribution (beta = 2.23 SDs), followed by handgrip strength (beta = −1.98 SDs) and 6MWT distance (beta = −1.11 SDs). Based on fitness age estimates, we developed a biological aging measure using an elastic net model regression as a linear combination of the results of the fitness tests described above. Our newly developed biomarker was significantly associated with risk scores for cardiovascular events (ACC-AHA: r = 0.61; p = 0.0006; MESA: r = 0.21; p = 0.002) and mortality (Levine mortality score: r = 0.90; p = 0.0002) and outperformed the previous definition of fitness status based on the six-minute walking test in predicting an individual health status.

Discussion: Our results indicate that a composite measure of biological age based on multiple fitness tests may be helpful for screening and monitoring strategies in clinical practice. However, additional studies are needed to test standardisation and to calibrate and validate the present results.
24-h movement behaviour, thermal perception, thirst, and heat management strategies of children and adults during heat alerts: a pilot study
Authors: Ravanelli Nicholas , Morris Nathan , Morrison Shawnda A.
Published: May 2023

Background: Heat waves caused by climate change are increasingly challenging the wellbeing of individuals across the lifespan. Current efforts to understand the thermal perceptions and behaviours of people throughout the lifespan during heat waves are limited.

Methods: Since June 2021, the Active Heatwave project has been recruiting households to better understand how individuals perceive, cope, and behave during heat waves. Using our novel web platform, participants were prompted to answer our Heat Alert Survey on days when a participants geolocation corresponded to a broadcasted local heat alert. Participants provided 24-h movement behaviour, thirst, thermal perception, and cooling strategies via validated questionnaires.

Results: A total of 285 participants (118 children) from 60 distinct weather station locations globally participated between June and September 2021 and 2022. At least 1 heat alert (834 total) were identified from 95% (57/60) of the weather stations. Children reported spending more time performing vigorous intensity exercise compared to adults (p < 0.05), but no differences in thermal sensation, thermal comfort, or thirst sensation (all p > 0.31) were observed. For thirst management, 88% of respondents used water to relieve thirst, although notably, 15% of adults reported using alcohol. Regardless of age, staying indoors was the most common heat management strategy, whereas visiting cooling centres was the least.

Conclusion: The present study presents a proof-of-concept combining local heat alert notifications with e-questionnaires for collecting near-real-time perceptual and behavioural data for both children and adults during heat waves. The observed patterns of behaviour suggest that present public heat-health guidelines are often ignored, children engage in fewer heat management strategies compared to adults, and these disparities highlight the need to improve public health communication and knowledge dissemination around promoting effective and accessible cooling solutions for children and adults.
Seasonal variations in carbon, nitrogen, and phosphorus of Pinus yunnanenis at different stand ages
Authors: Liang Siyi , Tan Tian , Wu Danzi , Li Chaojun , Jing Huiqing , Wu Junwen
Published: May 2023

The seasonal variations in carbon (C), nitrogen (N), and phosphorus (P) at the organ level of Pinus yunnanenis during different season are poorly understood. In this study, the C, N, P, and their stoichiometric ratios in various organs of P. yunnanensis during the four seasons are discussed. The middle and young aged P. yunnanensis forests in central Yunnan province, China were chosen, and the contents of C, N, and P in fine roots (<2 mm), stems, needles, and branches were analyzed. The results showed that the C, N, P contents and their ratios in P. yunnanensis were significantly influenced by season and organ, less affected by age. The C content of the middle-aged and young forests decreased continuously from spring to winter, whereas N and P first decreased and then increased. No significant allometric growth relationships were observed between P-C of the branches or stems in the young and middle-aged forests, whereas a significant allometric growth relationship existed for N-P of needles in the young stands, indicating that the P-C and N-P nutrient distribution patterns shows different trends in the organ level in different age stands. The pattern of P allocation between organs shows differences in stand age, with more allocation to needles in middle-aged stands and more allocation to fine roots in young stands. The N:P ratio in needles was less than 14, indicating that P. yunnanensis was mainly limited by N and increasing the application of N fertilizer would be beneficial for the productivity of this stand. The results will be helpful to nutrient management in P. yunnanensis plantation.