bluuebunny/crossref_metadata_2025 huggingface dataset:
Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells
Authors: Letian Anudari , Lemma Eyoel Yemanaberhan , Cavaliere Paola , Dephoure Noah , Altorki Nasser K. , McGraw Timothy E.
Published: March 2023

Background

PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.g., mutant EGF receptor tumors) are generally poor responders. Although PD-L1 is best characterized as a transmembrane PD1 ligand, the emerging view is that PD-L1 has functions independent of activating PD1 signaling. It is not known whether these cell-intrinsic functions of PD-L1 are shared among non-transformed and transformed cells, if they vary among cancer molecular subtypes, or if they are impacted by anti-PD-L1 therapy.

Methods

Here we use quantitative microscopy techniques and APEX2 proximity mapping to describe the behavior of PD-L1 and to identify PD-L1's proximal proteome in human lung epithelial cells.

Results

Our data reveal growth factor control of PD-L1 recycling as a mechanism for acute and reversible regulation of PD-L1 density on the plasma membrane. In addition, we describe novel PD-L1 biology restricted to mutant EGFR cells. Anti-PD-L1 antibody treatment of mutant EGFR cells perturbs cell intrinsic PD-L1 functions, leading to reduced cell migration, increased half-life of EGFR and increased extracellular vesicle biogenesis, whereas anti-PD-L1 antibody does not induce these changes in wild type EGFR cells.

Conclusions

Growth factor acute regulation of PD-L1 trafficking, by contributing to the control of plasma membrane density, might contribute to the regulation of PD-L1's immune checkpoint activity, whereas the specific effects of anti-PD-L1 on mutant EGFR cells might contribute to the poor anti-PD-L1 response of mutant EGFR tumors.
Leisure-time physical activity trajectories from adolescence to adulthood in relation to several activity domains: a 27-year longitudinal study
Authors: Mathisen Frida Kathrine Sofie , Torsheim Torbjørn , Falco Coral , Wold Bente
Published: March 2023

Background

Insufficient physical activity (PA) levels among adolescents and adults make promoting PA a public health priority. Although most people exhibit low or decreasing levels of PA, other groups increase or maintain high levels of activity. These different groups may engage differently in activity domains during their leisure time. This study aimed to identify distinct trajectories of leisure-time vigorous physical activity (LVPA) and to explore whether these trajectories are characterised by differences in four activity domains (participation in organised sports clubs, diversity in leisure-time activities, outdoor recreation, and peer PA) over the life course.

Methods

Data were drawn from the Norwegian Longitudinal Health Behaviour Study. The sample of participants (n = 1103, 45.5% female) was surveyed 10 times from age 13 years in 1990 to age 40 years in 2017. LVPA trajectories were identified using latent class growth analysis, and mean differences in activity domains were studied using the one-step BCH approach.

Results

Four trajectories were identified: active (9%), increasingly active (12%), decreasingly active (25%), and low active (54%). Overall, this analysis showed a declining tendency in LVPA from age 13 to 40 years except for the increasingly active trajectory. Belonging to a trajectory with a higher LVPA level was related to higher mean levels of the included activity domains. Compared with those in the increasing trajectory, people belonging to the decreasing trajectory reported higher mean participation levels in and age at becoming a member of sports clubs, diversity in leisure-time activities, and best friend’s activity level during adolescence. However, in young adulthood, people in the increasingly active trajectory reported significantly higher mean levels for the same variables.

Conclusions

The development of LVPA from adolescence to adulthood is heterogeneous, suggesting the need for targeted health promotion initiatives. The largest trajectory group included more than 50 percent and was characterized by low levels of LVPA, less engagement in PA domains and fewer active friends. There seems to be little carry-over effect of engagement in organised sports in adolescence regarding level of LVPA later in life. Changes in social surroundings throughout the life span, such as having friends who are more or less engaged in PA, may assist or hinder health enhancing engagement in LVPA.
Identification of novel immune subtypes and potential hub genes of patients with psoriasis
Authors: Li Yingxi , Li Lin , Tian Yao , Luo Jing , Huang Junkai , Zhang Litao , Zhang Junling , Li Xiaoxia , Hu Lizhi
Published: March 2023

Background

Psoriasis is a common, chronic and relapsing immune-related inflammatory dermal disease. Patients with psoriasis suffering from the recurrences is mainly caused by immune response disorder. Thus, our study is aimed to identify novel immune subtypes and select targeted drugs for the precision therapy in different subtypes of psoriasis.

Methods

Differentially expressed genes of psoriasis were identified from the Gene Expression Omnibus database. Functional and disease enrichment were performed by Gene Set Enrichment Analysis and Disease Ontology Semantic and Enrichment analysis. Hub genes of psoriasis were selected from protein–protein interaction networks using Metascape database. The expression of hub genes was validated in human psoriasis samples by RT-qPCR and immunohistochemistry. Further, novel immune subtypes of psoriasis were identified by ConsensusClusterPlus package and its association with hub genes were calculated. Immune infiltration analysis was performed, and its candidate drugs were evaluated by Connectivity Map analysis.

Results

182 differentially expressed genes of psoriasis were identified from GSE14905 cohort, in which 99 genes were significantly up-regulated and 83 genes were down-regulated. We then conducted functional and disease enrichment in up-regulated genes of psoriasis. Five potential hub genes of psoriasis were obtained, including SOD2, PGD, PPIF, GYS1 and AHCY. The high expression of hub genes was validated in human psoriasis samples. Notably, two novel immune subtypes of psoriasis were determined and defined as C1 and C2. Bioinformatic analysis showed C1 and C2 had different enrichment in immune cells. Further, candidate drugs and mechanism of action that applicable to different subtypes were evaluated.

Conclusions

Our study identified two novel immune subtypes and five potential hub genes of psoriasis. These findings might give insight into the pathogenesis of psoriasis and provide effective immunotherapy regimens for the precise treatment of psoriasis.
Safety and efficacy of co-administration of CD19 and CD22 CAR-T cells in children with B-ALL relapse after CD19 CAR-T therapy
Authors: Li Wenjie , Ding Lixia , Shi Wenhua , Wan Xinyu , Yang Xiaomin , Yang Jing , Wang Tianyi , Song Lili , Wang Xiang , Ma Yani , Luo Chengjuan , Tang Jingyan , Gu Longjun , Chen Jing , Lu Jun , Tang Yanjing , Li Benshang
Published: March 2023

Background

CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in treating relapsed or refractory pediatric B-lineage acute lymphoblastic leukemia (B-ALL). However, poor results are obtained when the same product is reused in patients who relapse after CAR-T. Therefore, there is a need to explore the safety and efficacy of co-administration of CD19- and CD22-targeted CAR-T as a salvage second CAR-T therapy (CART2) in B-ALL patients who relapse after their first CD19 CAR-T treatment (CART1).

Methods

In this study, we recruited five patients who relapsed after CD19-targeted CAR-T. CD19- and CD22-CAR lentivirus-transfected T cells were cultured separately and mixed before infusion in an approximate ratio of 1:1. The total dose range of CD19 and CD22 CAR-T was 4.3 × 106–1.5 × 107/kg. Throughout the trial, we evaluated the patients’ clinical responses, side effects, and the expansion and persistence of CAR-T cells.

Results

After CART2, all five patients had minimal residual disease (MRD)-negative complete remission (CR). The 6- and 12-month overall survival (OS) rates were 100%. The median follow-up time was 26.3 months. Three of the five patients bridged to consolidated allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CART2 and remained in MRD-negative CR at the cut-off time. In patient No. 3 (pt03), CAR-T cells were still detected in the peripheral blood (PB) at 347 days post-CART2. Cytokine release syndrome (CRS) only occurred with a grade of ≤ 2, and no patients experienced symptoms of neurologic toxicity during CART2.

Conclusions

Mixed infusion of CD19- and CD22-targeted CAR-T cells is a safe and effective regimen for children with B-ALL who relapse after prior CD19-targeted CAR-T therapy. Salvage CART2 provides an opportunity for bridging to transplantation and long-term survival.

Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032211. Retrospectively registered: April 23, 2020.
PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer
Authors: Gao Sheng , Zhang Wensheng , Ma Jingjing , Ni Xiaojian
Published: March 2023

Background

Aberrant epigenetic remodeling events contribute to progression and metastasis of breast cancer (Bca). The specific mechanims that epigenetic factors rely on to mediate tumor aggressiveness remain unclear. We aimed to elucidate the roles of epigenetic protein PHF6 in breast tumorigenesis.

Methods

Published datasets and tissue samples with PHF6 staining were used to investigate the clinical relevance of PHF6 in Bca. CCK-8, clony formation assays were used to assess cell growth capacity. Cell migration and invasion abilities were measured by Transwell assay. The gene mRNA and protein levels were measured by quantitative real-time PCR and western blot. Chromatin immunoprecipitation (ChIP)-qPCR assays were used to investigate transcriptional relationships among genes. The Co-immunoprecipitation (Co-IP) assay was used to validate interactions between proteins. The CRISPR/Cas9 editing technology was used to construct double HIF knockout (HIF-DKO) cells. The subcutaneous xenograft model and orthotopic implantation tumor model were used to asess in vivo tumor growth.

Results

In this study, we utilized MTT assay to screen that PHF6 is required for Bca growth. PHF6 promotes Bca proliferation and migration. By analyzing The Cancer Genome Atlas breast cancer (TCGA-Bca) cohort, we found that PHF6 was significantly higher in tumor versus normal tissues. Mechanistically, PHF6 physically interacts with HIF-1α and HIF-2α to potentiate HIF-driven transcriptional events to initiate breast tumorigenesis. HIF-DKO abolished PHF6-mediated breast tumor growth, and PHF6 deficiency in turn impaired HIF transcriptional effects. Besides, hypoxia could also rely on YAP activation, but not HIF, to sustain PHF6 expressions in Bca cells. In addition, PHF6 recuits BPTF to mediate epigenetic remodeling to augment HIF transcriptional activity. Targeting PHF6 or BPTF inhibitor (AU1) is effective in mice models. Lastly, PHF6 correlated with HIF target gene expression in human breast tumors, which is an independent prognostic regulator.

Conclusions

Collectively, this study identified PHF6 as a prognostic epigenetic regulator for Bca, functioning as a HIF coactivator. The fundamental mechanisms underlying YAP/PHF6/HIF axis in breast tumors endowed novel epigenegtic targets for Bca treatment.
Multi-omics and experimental analysis unveil theragnostic value and immunological roles of inner membrane mitochondrial protein (IMMT) in breast cancer
Authors: Lin Hung-Yu , Wu Hsing-Ju , Chu Pei-Yi
Published: March 2023

Background

The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear.

Methods

Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings.

Results

High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression.

Conclusion

This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.
Gut microbiota mediated the individualized efficacy of Temozolomide via immunomodulation in glioma
Authors: Hou Xiaoying , Du Hongzhi , Deng Yufei , Wang Haiping , Liu Jinmi , Qiao Jialu , Liu Wei , Shu Xiji , Sun Binlian , Liu Yuchen
Published: March 2023

Background

Temozolomide (TMZ) is the preferred chemotherapy strategy for glioma therapy. As a second-generation alkylating agent, TMZ provides superior oral bio-availability. However, limited response rate (less than 50%) and high incidence of drug resistance seriously restricts TMZ’s application, there still lack of strategies to increase the chemotherapy sensitivity.

Methods

Luci-GL261 glioma orthotopic xenograft model combined bioluminescence imaging was utilized to evaluate the anti-tumor effect of TMZ and differentiate TMZ sensitive (S)/non-sensitive (NS) individuals. Integrated microbiomics and metabolomics analysis was applied to disentangle the involvement of gut bacteria in TMZ sensitivity. Spearman’s correlation analysis was applied to test the association between fecal bacteria levels and pharmacodynamics indices. Antibiotics treatment combined TMZ treatment was used to confirm the involvement of gut microbiota in TMZ response. Flow cytometry analysis, ELISA and histopathology were used to explore the potential role of immunoregulation in gut microbiota mediated TMZ response.

Results

Firstly, gut bacteria composition was significantly altered during glioma development and TMZ treatment. Meanwhile, in vivo anti-cancer evaluation suggested a remarkable difference in chemotherapy efficacy after TMZ administration. Moreover, 16s rRNA gene sequencing and non-targeted metabolomics analysis revealed distinct different gut microbiota and immune infiltrating state between TMZ sensitive and non-sensitive mice, while abundance of differential gut bacteria and related metabolites was significantly correlated with TMZ pharmacodynamics indices. Further verification suggested that gut microbiota deletion by antibiotics treatment could accelerate glioma development, attenuate TMZ efficacy and inhibit immune cells (macrophage and CD8α+ T cell) recruitment.

Conclusions

The current study confirmed the involvement of gut microbiota in glioma development and individualized TMZ efficacy via immunomodulation, hence gut bacteria may serve as a predictive biomarker as well as a therapeutic target for clinical TMZ application.
Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism
Authors: Lou Bowen , Wu Haoyu , Ott Hannes , Bennewitz Katrin , Wang Chen , Poschet Gernot , Liu Hui , Yuan Zuyi , Kroll Jens , She Jianqing
Published: March 2023

Background

Increased circulating uric acid (UA) concentration may disrupt cardiac function in heart failure patients, but the specific mechanism remains unclear. Here, we postulate that hyperuremia induces sterol regulatory element binding protein 1 (SREBP1), which in turn activate hepatic fatty acid biosynthesis response, leading to cardiac dysfunction.

Methods and results

Increased circulating uric acid was observed in heart failure patients and inversely correlated to cardiac function. Besides, uric acid correlated to circulating lipids profile based on metabolomics in heart failure patients. Using cultured human hepatoellular carcinomas (HepG2) and Tg(myl7:egfp) zebrafish, we demonstrated that UA regulated fatty acid synthase (FASN) via SREBP1 signaling pathway, leading to FFA accumulation and impaired energy metabolism, which could be rescued via SREBP1 knockdown. In ISO treated zebrafish, UA aggravated heart failure via increased cardiovascular cavity size, decreased heart beats, pericardial edema and long-stretched heart deformation.

Conclusions

Our findings suggest that UA-SREBP1-FASN signaling exacerbates cardiac dysfunction during FFA accumulation. Identification of this mechanism may help in treatment and prevention of heart failure.
Microglia/macrophages require vitamin D signaling to restrain neuroinflammation and brain injury in a murine ischemic stroke model
Authors: Cui Pan , Lu Wanting , Wang Junjie , Wang Fei , Zhang Xiyue , Hou Xiaodan , Xu Fang , Liang Yan , Chai Guoliang , Hao Junwei
Published: March 2023

Vitamin D deficiency is associated with worse clinical outcomes after ischemic stroke; nevertheless, the pathophysiological mechanisms remain largely unexplored. In this study, we characterized the molecular mechanisms of how vitamin D signaling modulated stroke progression in male mouse ischemia–reperfusion stroke models. We found that vitamin D receptor (VDR) exhibited a predominant upregulation in peri-infarct microglia/macrophages following cerebral ischemia. Conditional Vdr inactivation in microglia/macrophages markedly augmented infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a more primed proinflammatory phenotype with substantial secretion of TNF-α and IFN-γ. These inflammatory cytokines further enhanced CXCL10 release from endothelial cells and blood–brain barrier disruption, and ultimately infiltration of peripheral T lymphocytes. Notably, blocking TNF-α and IFN-γ significantly ameliorated stroke phenotypes in Vdr conditional knockout mice. Collectively, VDR signaling in microglia/macrophages plays a crucial role in restraining ischemia-elicited neuroinflammation and stroke progression. Our findings delineate a novel mechanism underlying the association between vitamin D deficiency and poor stroke outcomes, and underline the significance of maintaining a functional vitamin D signaling in the management of acute ischemic stroke.
Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease
Authors: Grotemeyer Alexander , Fischer Judith F. , Koprich James B. , Brotchie Jonathan M. , Blum Robert , Volkmann Jens , Ip Chi Wang
Published: March 2023

Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4+ and CD8+ T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.

Graphical Abstract
Control of the temporal development of Alzheimer’s disease pathology by the MR1/MAIT cell axis
Authors: Wyatt-Johnson Season K. , Kersey Holly N. , Codocedo Juan F. , Newell Kathy L. , Landreth Gary E. , Lamb Bruce T. , Oblak Adrian L. , Brutkiewicz Randy R.
Published: March 2023

Background

Neuroinflammation is an important feature of Alzheimer’s disease (AD). Understanding which aspects of the immune system are important in AD may lead to new therapeutic approaches. We study the major histocompatibility complex class I-related immune molecule, MR1, which is recognized by an innate-like T cell population called mucosal-associated invariant T (MAIT) cells.

Methods

Having found that MR1 gene expression is elevated in the brain tissue of AD patients by mining the Agora database, we sought to examine the role of the MR1/MAIT cell axis in AD pathology. Brain tissue from AD patients and the 5XFAD mouse model of AD were used to analyze MR1 expression through qPCR, immunofluorescence, and flow cytometry. Furthermore, mice deficient in MR1 and MAIT cells were crossed with the 5XFAD mice to produce a model to study how the loss of this innate immune axis alters AD progression. Moreover, 5XFAD mice were also used to study brain-resident MAIT cells over time.

Results

In tissue samples from AD patients and 5XFAD mice, MR1 expression was substantially elevated in the microglia surrounding plaques vs. those that are further away (human AD: P < 0.05; 5XFAD: P < 0.001). In 5XFAD mice lacking the MR1/MAIT cell axis, the development of amyloid-beta plaque pathology occurred at a significantly slower rate than in those mice with MR1 and MAIT cells. Furthermore, in brain tissue from 5XFAD mice, there was a temporal increase in MAIT cell numbers (P < 0.01) and their activation state, the latter determined by detecting an upregulation of both CD69 (P < 0.05) and the interleukin-2 receptor alpha chain (P < 0.05) via flow cytometry.

Conclusions

Together, these data reveal a previously unknown role for the MR1/MAIT cell innate immune axis in AD pathology and its potential utility as a novel therapeutic target.
Associated factors for multidimensional attitudes and behaviors of reproductive health toward pregnancy among early and late adolescents in Tanzania: a cross-sectional study
Authors: Hirose Naoki , Sanmei Chen , Okamoto Mariko , Madeni Frida E. , Madeni Nicolaus , Teshima Ayaka , Ando Yasunobu , Takahama Koji , Yoshikawa Mayu , Kunimoto Yu , Shimpuku Yoko
Published: March 2023

Background

Adolescent pregnancy is a serious reproductive health problem in Tanzania. However, the risk factors for multidimensional attitudes and behaviors of reproductive health toward pregnancy in Tanzanian adolescents remain unexplored.

Methods

We collected baseline characteristics and information on attitudes and behaviors of reproductive health from 4161 Tanzanian adolescents in all 54 primary and secondary schools in the Korogwe district. We applied mixed effect multiple regression analyses stratified by sex to find the factors related to reproductive health attitudes and behaviors toward pregnancy.

Results

In female students, regarding the attitudes of reproductive health, higher age, hope for marriage in the future, a talk with a parent about sex or pregnancy, and a higher hope score were significantly associated with a lower score. For the behaviors of reproductive health, higher age, a talk with a parent about sex or pregnancy, time to talk with a parent about daily life, and a higher hope score were significantly associated with a lower score. In male students, regarding the attitudes of reproductive health, a higher hope score was significantly associated with a lower score. For the behaviors of reproductive health, higher age, time to talk with a parent about daily life, and a higher hope score was significantly associated with a lower score.

Conclusions

The heterogeneous factor-outcomes association between female and male students suggested that sex-specialized interventions may be required to change their risky attitudes or behaviors of reproductive health. Although we cannot conclude as points of intervention, our study suggested that it may be practical to improve parent-adolescents communication about sex or reproductive health and change adolescents’ views of pregnancy or marriage for gaining financial or social status.
Comparison of inequality in utilization of maternal healthcare services between Bangladesh and Pakistan: evidence from the demographic health survey 2017–2018
Authors: Misu Farjana , Alam Khurshid
Published: March 2023

Background

Inequality in maternal health has remained a challenge in many low-income countries, like Bangladesh and Pakistan. The study examines within-country and between-country inequality in utilization of maternal healthcare services for Bangladesh and Pakistan.

Methods

The study used the latest Demographic Health Surveys (DHS, 2017–2018) datasets of Bangladesh and Pakistan for women aged 15–49 years who had given at least one live birth in three years preceding the survey. Equity strata were identified from the literature and conformed by binary logistic regressions. For ordered equity strata with more than two categories, the relative concentration index (RCI), absolute concentration index (ACI) and the slope index of inequality (SII) were calculated to measure inequalities in the utilization of four maternal healthcare services. For two-categories equity strata, rate ratio (RR), and rate difference (RD) were calculated. Concentration curves and equiplots were constructed to visually demonstrate inequality in maternal healthcare services.

Results

In Bangladesh, there was greater inequality in skilled birth attendance (SBA) based on wealth (RCI: 0.424, ACI: 0.423, and SII: 0.612), women’s education (RCI: 0.380, ACI: 0.379 and SII: 0.591), husband’s education (RCI: 0.375, ACI: 0.373 and SII: 0.554) and birth order (RCI: − 0.242, ACI: − 0.241, and SII: -0.393). According to RCI, ACI, and SII, there was inequality in Pakistan for at least four ANC visits by the skilled provider based on wealth (RCI: 0.516, ACI: 0.516 and SII: 0.738), women’s education (RCI: 0.470, ACI: 0.470 and SII: 0.757), and husband’s education (RCI: 0.380, ACI: 0.379 and SII: 0.572). For Bangladesh, the RR (1.422) and RD (0.201) imply more significant urban–rural inequality in SBA. In Pakistan, urban–rural inequality was greater for at least four ANC visits by the skilled provider (RR: 1.650 and RD 0.279).

Conclusion

Inequality in maternal healthcare is greater among the underprivileged group in Pakistan than in Bangladesh. In Bangladesh, the SBA is the most inequitable maternal healthcare, while for Pakistan it is at least four ANC visits by the skilled provider. Customized policies based on country context would be more effective in bridging the gap between the privileged and underprivileged groups.
Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice
Authors: Gong Xue , Shen Haitao , Guo Liuling , Huang Ce , Su Tingting , Wang Hao , Feng Shengyu , Yang Shanshan , Huo Fenjiao , Liu Haifeng , Zhu Jianbo , Zhu Jian-Kang , Li Hongbin , Liu Hailiang
Published: March 2023

Background

Glycyrrhizic acid (GA), a saponin compound often used as a flavoring agent, can elicit anti-inflammatory and anti-tumor effects, and alleviate aging. However, the specific mechanism by which GA alters immune cell populations to produce these beneficial effects is currently unclear.

Results

In this study, we systematically analyzed single-cell sequencing data of peripheral blood mononuclear cells from young mice, aged mice, and GA-treated aged mice. Our in vivo results show that GA reduced senescence-induced increases in macrophages and neutrophils, and increased numbers of lymphoid lineage subpopulations specifically reduced by senescence. In vitro, GA significantly promoted differentiation of Lin−CD117+ hematopoietic stem cells toward lymphoid lineages, especially CD8+ T cells. Moreover, GA inhibited differentiation of CD4+ T cells and myeloid (CD11b+) cells by binding to S100 calcium-binding protein 8 (S100A8) protein. Overexpression of S100A8 in Lin− CD117+ hematopoietic stem cells enhanced cognition in aged mice and the immune reconstitution of severely immunodeficient B-NDG (NOD.CB17-Prkdcscid/l2rgtm1/Bcgen) mice.

Conclusions

Collectively, GA exerts anti-aging effects by binding to S100A8 to remodel the immune system of aged mice.
Validating stroke-induced bilateral ankle coordination deficits using bilateral ankle measure relationship with motor functions in lower limbs
Authors: Chang Jia-Lan , Chen Hung-Ju , Chen Po-Yin , Chou Li-Wei , Lai Chien-Hung , Lu Yueh-Hsun , Chiang Shang-Lin , Lin Chia-Huei , Wang Xin-Miao , Lin Chueh-Ho
Published: March 2023

Background

Coordinated control between the bilateral ankle joints plays an important role in performing daily life functions, such as walking and running. However, few studies have explored the impact of stroke on movement disorders that decrease the coordination control of the bilateral extremities and may decrease daily activities that require coordination control of the bilateral ankles. This study aimed to investigate the coordination control of the bilateral ankles using a novel bilateral ankle measurement system and evaluate the relationship of bilateral movement coordination control deficits with motor and functional performances of the lower extremities in patients with stroke.

Methods

Twenty-one healthy adults (36.5 ± 13.2 y/o) and 19 patients with chronic stroke (58.7 ± 10.5 y/o) were enrolled. A novel measurement device with embedded rotary potentiometers was used to evaluate bilateral ankle coordination control. Participants were asked to move their dominant (non-paretic) foot from dorsiflexion to plantarflexion position and non-dominant (paretic) foot from dorsiflexion to plantarflexion position (condition 1) simultaneously, and vice versa (condition 2). Alternating time and angle for coordination control with movements of both ankles were calculated for each condition. Motor and functional performance measurements of the lower extremities included the lower-extremity portion of the Fugl-Meyer assessment (FMA-LE), Berg Balance Test (BBS), Timed Up and Go Test (TUG), and Barthel Index (BI).

Results

Compared with the healthy group, alternating time was shorter in the stroke group by 8.3% (p = 0.015), and the alternating angles of conditions 1 and 2 were significantly higher than those of the healthy group by 1.4° (p = 0.001) and 2.5° (p = 0.013), respectively. The alternating angle in condition 2 showed moderate correlations with TUG (r = 0.512; p = 0.025), 10-m walk (r = 0.747; p < 0.001), gait speed (r =  − 0.497 to − 0.491; p < 0.05), length (r =  − 0.518 to − 0.551; p < 0.05), and BI (r =  − 0.457; p = 0.049).

Conclusion

Stroke decreases alternating time, increases alternating angle, and shows bilateral ankle coordination control deficits temporally and spatially. A higher alternating angle is moderately to highly associated with motor function and lower limb function in patients with stroke.
Marek’s disease in chicken farms from Northwest Ethiopia: gross pathology, virus isolation, and molecular characterization
Authors: Birhan Mastewal , Gelaye Esayas , Ibrahim Saddam Mohammed , Berhane Nega , Abayneh Takele , Getachew Belayneh , Zemene Aragaw , Birie Kassahun , Deresse Getaw , Adamu Kassaye , Dessalegn Bereket , Gessese Abebe Tesfaye , Kinde Mebrie Zemene , Bitew Molalegne
Published: March 2023

Marek’s disease virus (MDV) is a highly contagious, immunosuppressive, and oncogenic chicken pathogen causing marek’s disease (MD). In this outbreak-based study, 70 dual-purpose chickens that originated from poultry farms in Northwest Ethiopia and suspected of MD were sampled for pathological and virological study from January 2020 to June 2020. Clinically, affected chickens showed inappetence, dyspnea, depression, shrunken combs, and paralysis of legs, wings, and neck, and death. Pathologically, single or multiple greyish white to yellow tumor-like nodular lesions of various size were appreciated in visceral organs. In addition, splenomegaly, hepatomegaly, renomegaly, and sciatic nerve enlargement were observed. Twenty-seven (27) pooled clinical samples i.e. 7 pooled spleen samples and 20 pooled feathers samples were aseptically collected. Confluent monolayer of Chicken Embryo Fibroblast cells was inoculated with a suspension of pathological samples. Of this, MDV-suggestive cytopathic effects were recorded in 5 (71.42%) and 17 (85%) pooled spleen and feather samples respectively. Molecular confirmation of pathogenic MDV was conducted using conventional PCR amplifying 318 bp of ICP4 gene of MDV-1, of which, 40.9% (9/22) tested positive. In addition, 5 PCR-positive samples from various farms were sequenced further confirming the identity of MDV. The ICP4 partial gene sequences were submitted to GenBank with the following accession numbers: OP485106, OP485107, OP485108, OP485109, and OP485110. Comparative phylogenetics showed, two of the isolates from the same site, Metema, seem to be clonal complexes forming distinct cluster. The other three isolates, two from Merawi and one from Debretabor, appear to represent distinct genotypes although the isolate from Debretabor is closer to the Metema clonal complex. On the other hand, the isolates from Merawi appeared genetically far related to the rest of the 3 isolates and clustered with Indian MDV strains included in the analysis. This study presented the first molecular evidence of MDV in chicken farms from Northwest Ethiopia. Biosecurity measures should strictly be implemented to hinder the spread of the virus. Nationwide studies on molecular characteristics of MDV isolates, their pathotypes, and estimation of the economic impact associated with the disease may help justify production and use of MD vaccines within the country.
Usefulness of intravoxel incoherent motion MRI for visualizing slow cerebrospinal fluid motion
Authors: Yamada Shigeki , Hiratsuka Shinnosuke , Otani Tomohiro , Ii Satoshi , Wada Shigeo , Oshima Marie , Nozaki Kazuhiko , Watanabe Yoshiyuki
Published: March 2023

Background

In the cerebrospinal fluid (CSF) dynamics, the pulsations of cerebral arteries and brain is considered the main driving force for the reciprocating bidirectional CSF movements. However, measuring these complex CSF movements on conventional flow-related MRI methods is difficult. We tried to visualize and quantify the CSF motion by using intravoxel incoherent motion (IVIM) MRI with low multi-b diffusion-weighted imaging.

Methods

Diffusion-weighted sequence with six b values (0, 50, 100, 250, 500, and 1000 s/mm2) was performed on 132 healthy volunteers aged ≥ 20 years and 36 patients with idiopathic normal pressure hydrocephalus (iNPH). The healthy volunteers were divided into three age groups (< 40, 40 to < 60, and ≥ 60 years). In the IVIM analysis, the bi-exponential IVIM fitting method using the Levenberg–Marquardt algorithm was adapted. The average, maximum, and minimum values of ADC, D, D*, and fraction of incoherent perfusion (f) calculated by IVIM were quantitatively measured in 45 regions of interests in the whole ventricles and subarachnoid spaces.

Results

Compared with healthy controls aged ≥ 60 years, the iNPH group had significantly lower mean f values in all the parts of the lateral and 3rd ventricles, whereas significantly higher mean f value in the bilateral foramina of Luschka. In the bilateral Sylvian fossa, which contain the middle cerebral bifurcation, the mean f values increased gradually with increasing age, whereas those were significantly lower in the iNPH group. In the 45 regions of interests, the f values in the bilateral foramina of Luschka were the most positively correlated with the ventricular size and indices specific to iNPH, whereas that in the anterior part of the 3rd ventricle was the most negatively correlated with the ventricular size and indices specific to iNPH. Other parameters of ADC, D, and D* were not significantly different between the two groups in any locations.

Conclusions

The f value on IVIM MRI is useful for evaluating small pulsatile complex motion of CSF throughout the intracranial CSF spaces. Patients with iNPH had significantly lower mean f values in the whole lateral ventricles and 3rd ventricles and significantly higher mean f value in the bilateral foramina of Luschka, compared with healthy controls aged ≥ 60 years.
Morphological and mitochondrial changes in murine choroid plexus epithelial cells during healthy aging
Authors: Scarpetta Valentina , Bodaleo Felipe , Salio Chiara , Agarwal Amit , Sassoè-Pognetto Marco , Patrizi Annarita
Published: March 2023

Background

Choroid plexuses (ChPs) are intraventricular structures mainly composed by specialized epithelial cells interconnected by tight junctions that establish the blood-cerebrospinal fluid (CSF) barrier. ChPs are essential to produce CSF and transport solutes from and into the brain. Deterioration of ChP function and morphology has been correlated to worsening of neurodegenerative disorders. We here map morpho-functional changes in the ChP epithelial cells during healthy aging, starting from young adult to 2-years old mice.

Methods

We used a multi-tiered approach, including transmission electron microscopy (TEM), immunohistochemistry, RT-qPCR, Western Blot and 2-photon microscopy (2-PM) at multiple timepoints ranging from young adult to 2-years old mice.

Results

We identified distinct morpho-functional modifications in epithelial cells of ChP starting from 8 to 12 months of age, which mostly remained stable up to 2 years. These changes include flattening of the epithelium, reduction of microvilli length and an augmentation of interrupted tight junctions. We also found a decrease in mitochondria density together with elongation of mitochondria in older mice. Morphological mitochondrial rearrangements were accompanied by increased superoxide levels, decreased membrane potential and decreased mitochondrial motility in aged mice. Interestingly, most of the age-related changes were not accompanied by modification of protein and/or gene expression levels and aged mitochondria effectively responded to acute pharmacological stressful stimuli.

Conclusions

Our study suggests a long-term progression of multiple morpho-functional features of the mouse choroid plexus epithelium during adulthood followed by structural remodeling during the aging process. These findings can lead to a better understanding on how functional and morphological rearrangements of ChP are correlated during aging.
Estimates of the permeability of extra-cellular pathways through the astrocyte endfoot sheath
Authors: Koch Timo , Vinje Vegard , Mardal Kent-André
Published: March 2023

Background

Astrocyte endfoot processes are believed to cover all micro-vessels in the brain cortex and may play a significant role in fluid and substance transport into and out of the brain parenchyma. Detailed fluid mechanical models of diffusive and advective transport in the brain are promising tools to investigate theories of transport.

Methods

We derive theoretical estimates of astrocyte endfoot sheath permeability for advective and diffusive transport and its variation in microvascular networks from mouse brain cortex. The networks are based on recently published experimental data and generated endfoot patterns are based on Voronoi tessellations of the perivascular surface. We estimate corrections for projection errors in previously published data.

Results

We provide structural-functional relationships between vessel radius and resistance that can be directly used in flow and transport simulations. We estimate endfoot sheath filtration coefficients in the range $$L_p=2\times 10^{-11}\,\hbox {m}\,\hbox {Pa}^{-1}\,\hbox {s}^{-1}$$

L
p

=
2
×

10

-
11

m

Pa

-
1

s

-
1

to $$3\times 10^{-10} \,\hbox {m}\,\hbox {Pa}^{-1}\,\hbox {s}^{-1}$$

3
×

10

-
10

m

Pa

-
1

s

-
1

, diffusion membrane coefficients for small solutes in the range $$C_M= 5 \times 10^{2}\,\hbox {m}^{-1}$$

C
M

=
5
×

10
2

m

-
1

to $$6\times 10^{3}\,\hbox {m}^{-1}$$

6
×

10
3

m

-
1

, and gap area fractions in the range 0.2–0.6%, based on a inter-endfoot gap width of 20 nm.

Conclusions

The astrocyte endfoot sheath surrounding microvessels forms a secondary barrier to extra-cellular transport, separating the extra-cellular space of the parenchyma and the perivascular space outside the endothelial layer. The filtration and membrane diffusion coefficients of the endfoot sheath are estimated to be an order of magnitude lower than those of the extra-cellular matrix while being two orders of magnitude higher than those of the vessel wall.
ROS generation and p-38 activation contribute to montmorillonite-induced corneal toxicity in vitro and in vivo
Authors: Liu Jia , Yang Shubin , Zhao Laien , Jiang Feng , Sun Jianchao , Peng Shengjun , Zhao Ruikang , Huang Yanmei , Fu Xiaoxuan , Luo Rongrui , Jiang Yu , Li Zelin , Wang Nan , Fang Tengzheng , Zhang Zhuhong
Published: March 2023

Background

Montmorillonite (Mt) and its derivatives are now widely used in industrial and biomedical fields. Therefore, safety assessments of these materials are critical to protect human health after exposure; however, studies on the ocular toxicity of Mt are lacking. In particular, varying physicochemical characteristics of Mt may greatly alter their toxicological potential. To explore the effects of such characteristics on the eyes, five types of Mt were investigated in vitro and in vivo for the first time, and their underlying mechanisms studied.

Results

The different types of Mt caused cytotoxicity in human HCEC-B4G12 corneal cells based on analyses of ATP content, lactate dehydrogenase (LDH) leakage, cell morphology, and the distribution of Mt in cells. Among the five Mt types, Na-Mt exhibited the highest cytotoxicity. Notably, Na-Mt and chitosan-modified acidic Na-Mt (C-H-Na-Mt) induced ocular toxicity in vivo, as demonstrated by increases corneal injury area and the number of apoptotic cells. Na-Mt and C-H-Na-Mt also induced reactive oxygen species (ROS) generation in vitro and in vivo, as indicated by 2′,7′-dichlorofluorescin diacetate and dihydroethidium staining. In addition, Na-Mt activated the mitogen-activated protein kinase signaling pathway. The pretreatment of HCEC-B4G12 cells with N-acetylcysteine, an ROS scavenger, attenuated the Na-Mt-induced cytotoxicity and suppressed p38 activation, while inhibiting p38 activation with a p38-specific inhibitor decreased Na-Mt-induced cytotoxicity.

Conclusions

The results indicate that Mt induces corneal toxicity in vitro and in vivo. The physicochemical properties of Mt greatly affect its toxicological potential. Furthermore, ROS generation and p38 activation contribute at least in part to Na-Mt-induced toxicity.
Cognitive function in recovered COVID-19 Lebanese patients with schizophrenia
Authors: Haddad Chadia , Chamoun Angela , Sacre Hala , Hallit Souheil , Salameh Pascale , Calvet Benjamin
Published: March 2023

Introduction

It remains unclear whether COVID-19 which is an infectious disease caused by the SARS-CoV-2 virus is associated with the deterioration of cognitive function among patients with schizophrenia. This study aimed to evaluate changes in cognitive function before and after COVID-19 and associated factors among patients with schizophrenia at the Psychiatric Hospital of the Cross (HPC).

Methods

A prospective cohort study was conducted among 95 patients with schizophrenia followed from mid-2019 until June 2021 at the Psychiatric Hospital of the Cross (HPC). This cohort was divided into a group diagnosed with COVID-19 (n = 71) and another not diagnosed with COVID-19 (n = 24). The questionnaire included the Brief Assessment of Cognition in Schizophrenia (BACS), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), and Activities of Daily Living (ADL).

Results

The repeated-measures ANOVA showed no significant effect of time and the interaction between time and being diagnosed or not with COVID-19 on cognition. However, being diagnosed or not with COVID-19 had a significant effect on global cognitive function (p = 0.046), verbal memory (p = 0.046), and working memory (p = 0.047). The interaction between being diagnosed with COVID-19 and cognitive impairment at baseline was significantly associated with a higher cognitive deficit (Beta = 0.81; p = 0.005). Clinical symptoms, autonomy, and depression were not associated with the cognition (p > 0.05 for all).

Conclusion

COVID-19 disease affected global cognition and memory: patients diagnosed with COVID-19 had more deficits in these domains than those without COVID-19. Further studies are necessary to clarify the variation of cognitive function among schizophrenic patients with COVID-19.
Suicide and COVID-19: a rapid scoping review
Authors: Barlattani Tommaso , D’Amelio Chiara , Capelli Francesco , Mantenuto Simonetta , Rossi Rodolfo , Socci Valentina , Stratta Paolo , Di Stefano Ramona , Rossi Alessandro , Pacitti Francesca
Published: March 2023

There is considerable interest in exploring effects of coronavirus disease 2019 (COVID-19) pandemic on mental health. Suicide is one of the leading causes of mortality worldwide and changes in daily life brought by the pandemic may be additional risk factors in people with pre-existing mental disorders. This rapid PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) scoping review aims to identify and analyze current evidence about the relation between COVID-19 pandemic outbreak, along with COVID-19 disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, and suicide in individuals with previously diagnosed mental disorders. First, we conducted a comprehensive review of the literature, then proceeded to discuss findings in a narrative way. Tables were constructed and articles sorted according to the studies’ methodologies. 53 papers were eventually identified as eligible, among which 33 are cross-sectional studies, 9 are longitudinal studies, and 11 studies using other methodologies. Despite suffering from a mental disorder is a risk factor for suicidal behavior per se, the advent of COVID-19 pandemic may exacerbate this relation. Nevertheless, data addressing a clear correlation between suicidal behavior and the pandemic outbreak are still controversial. Longitudinal analysis using validated suicide scales and multicenter studies could provide deeper insight and knowledge about this topic.