bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer
Authors: Johns Andrew C , Yang Mike , Wei Lai , Grogan Madison , Spakowicz Daniel , Patel Sandipkumar H , Li Mingjia , Husain Marium , Kendra Kari L , Otterson Gregory A , Rosko Ashley E , Andersen Barbara L , Carbone David P , Owen Dwight H , Presley Carolyn J
Published: April 2023

Objectives

Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults.

Materials and Methods

This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs.

Results

Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs.

Conclusion

Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.
Chytrids alleviate the harmful effect of heat and cyanobacteria diet on Daphnia via PUFA-upgrading
Authors: Abonyi András , Pilecky Matthias , Rasconi Serena , Ptacnik Robert , Kainz Martin J
Published: April 2023

Chytrid fungal parasites increase herbivory and dietary access to essential molecules, such as polyunsaturated fatty acids (PUFA), at the phytoplankton–zooplankton interface. Warming enhances cyanobacteria blooms and decreases algae-derived PUFA for zooplankton. Whether chytrids could support zooplankton with PUFA under global warming scenarios remains unknown. We tested the combined effect of water temperature (ambient: 18°C, heat: +6°C) and the presence of chytrids with Daphnia magna as the consumer, and Planktothrix rubescens as the main diet. We hypothesized that chytrids would support Daphnia fitness with PUFA, irrespective of water temperature. Heating was detrimental to the fitness of Daphnia when feeding solely on the Planktothrix diet. Chytrid-infected Planktothrix diet alleviated the negative impact of heat and could support Daphnia survival, somatic growth and reproduction. Carbon stable isotopes of fatty acids highlighted a ~3x more efficient n-3 than n-6 PUFA conversion by Daphnia feeding on the chytrid-infected diet, irrespective of temperature. The chytrid diet significantly increased eicosapentaenoic acid (EPA; 20:5n-3) and arachidonic acid (ARA; 20:4n-6) retention in Daphnia. The EPA retention remained unaffected, while ARA retention increased in response to heat. We conclude that chytrids support pelagic ecosystem functioning under cyanobacteria blooms and global warming via chytrids-conveyed PUFA toward higher trophic levels.
Cytosolic isocitrate dehydrogenase regulates plant stem cell maintenance in response to nutrient deficiency
Authors: Zhan Sijia , Zhang Qian , Yao Yuhan , Cui Yuchao , Huang Tao
Published: April 2023

WUSCHEL (WUS) and WUSCHEL-RELATED HOMEOBOX (WOX) proteins determine stem cell maintenance for continual plant growth and development under changing environmental conditions. Nutrient availability is an environmental factor that substantially controls plant growth and development. However, how plant stem cell homeostasis is regulated under nutrient deficiency remains to be elucidated. Here, we showed that cytosolic isocitrate dehydrogenase (ICDH) plays an important role in nutrient sensing of stem cells in Arabidopsis (Arabidopsis thaliana). Nutrient deficiency induced the cytoplasmic-to-nuclear translocation of cytosolic ICDH protein. ICDH can interact with WUS/WOX protein as a complex that further promotes WUS/WOX expression by binding to its promoter. WUS/WOX expression in the icdh-2 mutant was lower than that of wild-type plants under nutrient deficiency. Consistently, loss of ICDH function caused a more serious growth repression under nutrient deficiency that was independent of ICDH's catalytic activity. Therefore, cytosolic ICDH regulates stem cell homeostasis of plants in response to nutrient deficiency.
A point mutation in the gene encoding magnesium chelatase I subunit influences strawberry leaf color and metabolism
Authors: Ma Yang-Yang , Shi Jian-Cheng , Wang Dan-Juan , Liang Xia , Wei Feng , Gong Chun-Mei , Qiu Li-Juan , Zhou Hou-Cheng , Folta Kevin M , Wen Ying-Qiang , Feng Jia-Yue
Published: April 2023

Magnesium chelatase (MgCh) catalyzes the insertion of magnesium into protoporphyrin IX, a vital step in chlorophyll (Chl) biogenesis. The enzyme consists of 3 subunits, MgCh I subunit (CHLI), MgCh D subunit (CHLD), and MgCh H subunit (CHLH). The CHLI subunit is an ATPase that mediates catalysis. Previous studies on CHLI have mainly focused on model plant species, and its functions in other species have not been well described, especially with regard to leaf coloration and metabolism. In this study, we identified and characterized a CHLI mutant in strawberry species Fragaria pentaphylla. The mutant, noted as p240, exhibits yellow–green leaves and a low Chl level. RNA-Seq identified a mutation in the 186th amino acid of the CHLI subunit, a base conserved in most photosynthetic organisms. Transient transformation of wild-type CHLI into p240 leaves complemented the mutant phenotype. Further mutants generated from RNA-interference (RNAi) and CRISPR/Cas9 gene editing recapitulated the mutant phenotype. Notably, heterozygous chli mutants accumulated more Chl under low light conditions compared with high light conditions. Metabolite analysis of null mutants under high light conditions revealed substantial changes in both nitrogen and carbon metabolism. Further analysis indicated that mutation in Glu186 of CHLI does not affect its subcellular localization nor the interaction between CHLI and CHLD. However, intramolecular interactions were impaired, leading to reduced ATPase and MgCh activity. These findings demonstrate that Glu186 plays a key role in enzyme function, affecting leaf coloration via the formation of the hexameric ring itself, and that manipulation of CHLI may be a means to improve strawberry plant fitness and photosynthetic efficiency under low light conditions.
Multi-walled carbon nanotubes reversing the bone formation of bone marrow stromal cells by activating M2 macrophage polarization
Authors: Lin Runlian , Ge Kun , Fan Dehui , Li Jing , Zhou Guoqiang , Zhang Kaihan , Huang Yuanyu , Ma Lili , Zhang Jinchao
Published: April 2023

Multi-walled carbon nanotubes (MWCNTs) are an excellent bone tissue repair material both in vitro and in vivo. The interactions between MWCNTs and single type of cells of bone tissue, including osteoblasts, bone marrow stromal cells (BMSCs) or osteoclasts, have been extensively studied. However, the interactions between MWCNTs with different types of cells in the bone microenvironment remain elusive. Bone microenvironment is a complex system composed of different types of cells, which have interactions between each other. In this work, the effects of MWCNTs on bone microenvironment were firstly studied by culture of MWCNTs with BMSCs, osteoblasts, osteoclasts, macrophages and vascular endothelial cells, respectively. Then, co-culture systems of macrophages–BMSCs, macrophages–calvaria and macrophages–BMSCs–vascular endothelial cells were treated with MWCNTs, respectively. The osteogenic differentiation of BMSCs and osteoblasts was inhibited when these two types of cells were cultured with MWCNTs, respectively. Strikingly, when co-culture MWCNTs with BMSCs and macrophages, the osteogenesis of BMSCs was promoted by inducing the M2 polymerization of macrophages. Meanwhile, MWCNTs promoted the bone formation in the osteolysis model of calvaria ex vivo. In addition, the formation of osteoclasts was inhibited, and angiogenesis was increased when treated with MWCNTs. This study revealed the inconsistent effects of MWCNTs on single type of bone cells and on the bone microenvironment. The results provided basic research data for the application of MWCNTs in bone tissue repair.
The impact of traditional cardiovascular risk factor control on 7-year follow-up atherosclerosis progression in systemic lupus erythematosus
Authors: Papazoglou Nikolaos , Kravvariti Evrydiki , Konstantonis George , Sfikakis Petros P , Tektonidou Maria G
Published: April 2023

Objectives

The 2022 EULAR recommendations for cardiovascular risk management in patients with rheumatic disorders, including SLE, call for rigorous management of cardiovascular risk factors (CVRF). The impact of CVRF target attainment on atherosclerotic plaque progression hasn’t been previously evaluated in prospective ultrasound studies.

Methods

A total of 115 patients with SLE and 1:1 age and sex-matched healthy controls who had a baseline carotid and femoral ultrasound examination in our cardiovascular research unit were invited for a 7-year follow-up assessment of new plaque development. We aimed to compare the incidence of plaque progression between SLE patients and controls and reveal the extent to which it is affected by the attainment of European Society of Cardiology (ESC) targets for modifiable CVRFs (blood pressure, smoking status, body weight, lipids and physical activity), and disease-related features (disease duration, disease activity, autoantibodies, treatments).

Results

Eighty-six SLE patients and 42 controls had a 7-year follow-up carotid and femoral plaque examination. New plaque development was observed in 32/86 patients vs 8/42 controls (P = 0.037). Patients with SLE had a 4-fold higher risk for plaque progression than controls (OR: 4.16, CI: 1.22, 14.19, P = 0.023), adjusting for potential confounders. Multivariate regression analyses showed a 50% decrease in plaque progression for every modifiable CVRF fulfilling ESC targets (OR: 0.56, CI: 0.34, 0.93, P = 0.026).

Conclusion

Patients with SLE develop a rapid progression of atherosclerotic plaques which may be drastically reduced by CVRF target attainment according to ESC guidelines.
Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with granulomatosis with polyangiitis
Authors: Lintermans Lucas L , Stegeman Coen A , Muñoz-Elías Ernesto J , Tarcha Eric J , Iadonato Shawn P , Rutgers Abraham , Heeringa Peter , Abdulahad Wayel H
Published: April 2023

Objectives

Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186.

Methods

Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry.

Results

ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs.

Conclusions

Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.
Sleep Problems, Suicidal Ideation, and Psychopathology in First-Episode Psychosis
Authors: Ayers Nolan , McCall William V , Miller Brian J
Published: April 2023

Background and Hypothesis

Insomnia occurs frequently in the clinical course of schizophrenia. A growing literature has found associations between insomnia, suicidal ideation and behavior, and psychopathology in schizophrenia. We explored associations between sleep problems, suicidal ideation, and psychopathology in a cohort of patients with first-episode psychosis.

Study Design

We performed a secondary analysis of data for n = 403 subjects with data from the Recovery After an Initial Schizophrenia Episode study using regression models.

Study Results

The prevalence of sleep problems and suicidal ideation at baseline was 57% and 15%, respectively. After controlling for potential confounders, in the study baseline sleep problems were associated with increased odds of suicidal ideation with evidence of a dose-dependent relationship (OR = 2.25, 95% CI 1.15–4.41, P = .018). Over 24 months, sleep problems at any time point were associated with an over 3-fold increased odds of concurrent suicidal ideation (OR = 3.21, 95% CI 1.45–7.14, P = .004). Subjects with persistent sleep problems were almost 14 times more likely to endorse suicidal ideation at least once over the study than those without sleep problems (OR = 13.8, 95% CI 6.5–53.4, P < .001). Sleep problems were also a predictor of higher Positive and Negative Syndrome Scale total (β = 0.13–0.22), positive (β = 0.14–0.25), and general (β = 0.16–0.27) subscale scores at baseline and multiple follow-up visits (P < .01 for each).

Conclusions

Sleep problems are highly prevalent and associated with suicidal ideation and greater psychopathology in first-episode psychosis. Formal assessment and treatment of insomnia appear relevant to the clinical care of patients with psychosis as a predictor of suicidal ideation and symptom severity.
Parental Leave Reforms in South Korea, 1995–2021: Policy Translation and Institutional Legacies
Authors: Kim Yeonjin , Lundqvist Åsa
Published: April 2023

This article aims to explore how policy translation and institutional legacies have shaped South Korean parental leave policies between 1995 and 2021. It draws on a document analysis of central political documents and interviews with a number of key policy actors in South Korea. The findings show that reforms of parental leave policies were implemented according to four major rationales: maternity protection; combating low-fertility rates; (working mothers’) work–family life reconciliation; and, finally, men's involvement in childcare. Swedish parental leave policies, especially the introduction of the quota system (the “daddy month”), served as inspiration. The current design of Korean parental leave differs, however, from that of Sweden, and is analyzed as a result of localized reforms surrounding plummeting fertility rates and institutional legacies, mainly connected to the organization of the labor market.
Single-Cell RNA Sequencing ofSox17-Expressing Lineages Reveals Distinct Gene Regulatory Networks and Dynamic Developmental Trajectories
Authors: Trinh Linh T , Osipovich Anna B , Liu Bryan , Shrestha Shristi , Cartailler Jean-Philippe , Wright Christopher V E , Magnuson Mark A
Published: April 2023

During early embryogenesis, the transcription factor SOX17 contributes to hepato-pancreato-biliary system formation and vascular-hematopoietic emergence. To better understand Sox17 function in the developing endoderm and endothelium, we developed a dual-color temporal lineage-tracing strategy in mice combined with single-cell RNA sequencing to analyze 6934 cells from Sox17-expressing lineages at embryonic days 9.0-9.5. Our analyses showed 19 distinct cellular clusters combined from all 3 germ layers. Differential gene expression, trajectory and RNA-velocity analyses of endothelial cells revealed a heterogenous population of uncommitted and specialized endothelial subtypes, including 2 hemogenic populations that arise from different origins. Similarly, analyses of posterior foregut endoderm revealed subsets of hepatic, pancreatic, and biliary progenitors with overlapping developmental potency. Calculated gene-regulatory networks predict gene regulons that are dominated by cell type-specific transcription factors unique to each lineage. Vastly different Sox17 regulons found in endoderm versus endothelial cells support the differential interactions of SOX17 with other regulatory factors thereby enabling lineage-specific regulatory actions.
Circumcision and Sexual Medicine
Authors: Bernaschina-Rivera Sebastián A , López-Chaim Alexandra I , Cordero-Pacheco José A , Fernández-Crespo Raúl , Quesada-Olarte José , Carrión Rafael
Published: April 2023

Introduction

Male circumcision is one of the most frequently performed and debated urological procedures due to its possible implications for sexual health.

Objectives

The objective of this article is to review the literature on male circumcision and reconcile the scientific evidence to improve the quality of care, patient education, and clinician decision-making regarding the effects on sexual function of this procedure.

Methods

A review of the published literature regarding male circumcision was performed on PubMed. The criteria for selecting resources prioritized systematic reviews and cohort studies pertinent to sexual dysfunction, with a preference for recent publications.

Results

Despite the conflicting data reported in articles, the weight of the scientific evidence suggests there is not sufficient data to establish a direct association between male circumcision and sexual dysfunction.

Conclusion

This review provides clinicians with an updated summary of the best available evidence on male circumcision and sexual dysfunction for evidenced-based quality of care and patient education.
Substance abuse and male sexual dysfunction: what lies beneath?
Authors: Mostafa Taymour , Alghobary Moheiddin
Published: April 2023

Introduction

Substance abuse has become a worldwide health problem, leading to numerous consequences such as social problems among family members, abnormal behavior, adverse health effects, and psychological problems as well as economic consequences.

Objectives

We sought to assess the relationship between substance abuse and male sexual health.

Methods

A search was carried out in the following databases: PubMed, MeSH (Medical Subject Headings), Science Direct, Scopus, Cochrane Library, EMBASE, CINAHL, Academic Search Complete, and the Egyptian Knowledge Bank. The following keywords were used to assess the outcomes for relevant associations: illicit drugs, addiction, substance abuse, sexual health, erectile dysfunction, ejaculatory disorders, impotence, orgasm disorders, and sexual performance.

Results

The initial literature search identified a total of 148 articles in all searched databases. After removal of duplicate studies and application of inclusion/exclusion criteria, 75 reported studies were retained for review, including 38 case-control studies and 37 cross-sectional studies. These articles were classified into the following categories according to the type of abused substance addressed: cannabis/marihuana, 16 articles; opioids, 13 articles; heroin, 11 articles; cocaine, 5 articles; tramadol, 6 articles; ketamine, 2 articles; ecstasy, 4 articles; amphetamine, 2 articles; khat, 7 articles; androgen anabolic steroids, 2 articles; and polydrugs, 7 articles. Most of these recruited articles demonstrated a negative impact of the addressed substance on male sexual health, with variable levels.

Conclusion

Substance abuse has negative impacts on male sexual health that should be addressed. More studies conducted with proper methodological and statistical approaches, including logistic regression analysis, are needed to predict the effects of specific substances, considering the rapidly growing effects of non–substance-use disorders on male sexual health.
Pathogenic LRRK2 compromises the subcellular distribution of lysosomes in a Rab12‐RILPL1‐dependent manner
Authors: Ito Kyohei , Araki Miho , Katai Yuta , Nishimura Yuki , Imotani Sota , Inoue Haruki , Ito Genta , Tomita Taisuke
Published: April 2023

Mutations in leucine‐rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). Recent studies have shown that LRRK2 physiologically phosphorylates several Rab family proteins including Rab12 and that this phosphorylation is accelerated by the pathogenic mutations in LRRK2, although the significance in the PD pathogenesis remains unknown. Here we examined the effect of the overexpression of LRRK2 on the distribution of organelles in cultured cells and found that lysosomes become clustered in a perinuclear region upon the overexpression of pathogenic mutant LRRK2 in a manner dependent on its kinase activity. The perinuclear clustering of lysosomes was abolished by knocking out RAB12 as well as its effector protein RILPL1. Re‐expression of Rab12 in RAB12 knockout cells suggested that the phosphorylation at Ser106 of Rab12 is required for the perinuclear clustering of lysosomes. Moreover, phosphorylated Rab12 was also accumulated on the clustered lysosomes, and the phosphorylation of Rab12 increased its interaction with RILPL1, leading us to conclude that the increase in the phosphorylation of Rab12 by pathogenic LRRK2 compromised intracellular lysosomal transport via the enhanced interaction of Rab12 with RILPL1. These data suggest the involvement of abnormal regulation of lysosomal transport in the LRRK2‐mediated pathogenesis of PD.
WWC2 expression in the testis: Implications for spermatogenesis and male fertility
Authors: Höffken Verena , Di Persio Sara , Laurentino Sandra , Wyrwoll Margot J. , Terwort Nicole , Hermann Anke , Röpke Albrecht , Oud Manon S. , Wistuba Joachim , Kliesch Sabine , Pavenstädt Hermann J. , Tüttelmann Frank , Neuhaus Nina , Kremerskothen Joachim
Published: April 2023

The family of WWC proteins is known to regulate cell proliferation and organ growth control via the Hippo signaling pathway. As WWC proteins share a similar domain structure and a common set of interacting proteins, they are supposed to fulfill compensatory functions in cells and tissues. While all three WWC family members WWC1, WWC2, and WWC3 are found co‐expressed in most human organs including lung, brain, kidney, and liver, in the testis only WWC2 displays a relatively high expression. In this study, we investigated the testicular WWC2 expression in spermatogenesis and male fertility. We show that the Wwc2 mRNA expression level in mouse testes is increased during development in parallel with germ cell proliferation and differentiation. The cellular expression of each individual WWC family member was evaluated in published single‐cell mRNA datasets of murine and human testes demonstrating a high WWC2 expression predominantly in early spermatocytes. In line with this, immunohistochemistry revealed cytosolic WWC2 protein expression in primary spermatocytes from human testes displaying full spermatogenesis. In accordance with these findings, markedly lower WWC2 expression levels were detected in testicular tissues from mice and men lacking germ cells. Finally, analysis of whole‐exome sequencing data of male patients affected by infertility and unexplained severe spermatogenic failure revealed several heterozygous, rare WWC2 gene variants with a proposed damaging function and putative impact on WWC2 protein structure. Taken together, our findings provide novel insights into the testicular expression of WWC2 and show its cell‐specific expression in spermatocytes. As rare WWC2 variants were identified in the background of disturbed spermatogenesis, WWC2 may be a novel candidate gene for male infertility.
Cardiac PDGFRα+interstitial cells generate spontaneous inward currents that contribute to excitability in the heart
Authors: Zheng Haifeng , Peri Lauren , Ward Grace K. , Sanders Kenton M. , Ward Sean M.
Published: April 2023

The cell types and conductance that contribute to normal cardiac functions remain under investigation. We used mice that express an enhanced green fluorescent protein (eGFP)‐histone 2B fusion protein driven off the cell‐specific endogenous promoter forPdgfrato investigate the distribution and functional role of PDGFRα+cells in the heart. Cardiac PDGFRα+cells were widely distributed within the endomysium of atria, ventricle, and sino‐atrial node (SAN) tissues. PDGFRα+cells formed a discrete network of cells, lying in close apposition to neighboring cardiac myocytes in mouse and Cynomolgus monkey (Macaca fascicularis) hearts. Expression of eGFP in nuclei allowed unequivocal identification of these cells following enzymatic dispersion of muscle tissues. FACS purification of PDGFRα+cells from the SAN and analysis of gene transcripts by qPCR revealed that they were a distinct population of cells that expressed gap junction transcripts,Gja1andGjc1. Cardiac PDGFRα+cells generated spontaneous transient inward currents (STICs) and spontaneous transient depolarizations (STDs) that reversed at 0 mV. Reversal potential was maintained whenECl = −40 mV. [Na+]oreplacement and FTY720 abolished STICs, suggesting they were due to a non‐selective cation conductance (NSCC) carried by TRPM7. PDGFRα+cells also express β2‐adrenoceptor gene transcripts,Adrb2. Zinterol, a selective β2‐receptor agonist, increased the amplitude and frequency of STICs, suggesting these cells could contribute to adrenergic regulation of cardiac excitability. PDGFRα+cells in cardiac muscles generate inward currents via an NSCC. STICs generated by these cells may contribute to the integrated membrane potentials of cardiac muscles, possibly affecting the frequency of pacemaker activity.
MiR‐24‐3p regulates the differentiation of adipose‐derived stem cells toward pericytes and promotes fat grafting vascularization
Authors: Cai Zhongming , Li Zihao , Wei Qing , Yang Fangfang , Li Tian , Ke Chen , He Yucang , Wang Jingping , Ni Binting , Lin Ming , Li Liqun
Published: April 2023

Adipose‐derived stem cells (ADSCs) enhance fat graft survival by promoting neovascularization. The mechanism that promotes ADSCs differentiation toward pericytes was not known. We treated ADSCs with conditional medium (CM) from endothelial cells (ECs) or human recombinant transforming growth factor β (TGF‐β) to induce differentiation into pericytes. Pericytes markers, including platelet‐derived growth factor receptor β (PDGFRβ), alpha‐smooth muscle actin (α‐SMA), and desmin, were examined. Pericytes differentiation markers, migration, and their association with ECs were examined in ADSCs transfected with miR‐24‐3p mimics and inhibitors. Bioinformatics target prediction platforms and luciferase assays were used to investigate whether PDGFRβ was directly targeted by miR‐24‐3p. In vivo, fat mixed with ADSCs transfected with miR‐24‐3p mimics or inhibitors was implanted subcutaneously on the lower back region of nude mice. Fat grafts were harvested and analyzed at 2, 4, 6, and 8 weeks. Results showed that endogenous TGF‐β derived from CM from EC or human recombinant TGF‐β promoted migration, association with ECs, and induced expression of pericyte markers (PDGFRβ, α‐SMA, Desmin) in ADSCs. MiR‐24‐3p directly targeted PDGFRβ in ADSCs by lucifer reporter assays. Inhibition of miR‐24‐3p promoted pericytes differentiation, migration, and association with ECs in ADSCs. Inhibition of miR‐24‐3p in ADSCs promoted survival, integrity, adipocyte viability, vascularization, pericytes association with ECs, and reduced fibrosis, whereas overexpression of miR‐24‐3p in ADSCs yielded the opposite results. Collectively, TGF‐β released by ECs induced ADSCs differentiation toward pericytes through miR‐24‐3p. Downregulation of miR‐24‐3p in ADSCs induced survival, integrity, adipocyte viability, vascularization, pericytes association with ECs, and reduced fibrosis after fat grafting.
Knockout of miR‐184 in zebrafish leads to ocular abnormalities by elevating p21 levels
Authors: Zhang Jing , Li Ping , Sun Luqian , Jiang Ning , Guo Wenya , Wang Jungai , Gao Fen , Li Jing , Li Hui , Zhang Jun , Mu Hongmei , Hu Yanzhong , Cui Xiukun
Published: April 2023

miR‐184 is one of the most abundant miRNAs expressed in the lens and corneal tissue. Mutations in the seed region of miR‐184 are responsible for inherited anterior segment dysgenesis. Animal models recapitulating miR‐184‐related anterior segment dysgenesis are still lacking, and the molecular basis of ocular abnormalities caused by miR‐184 dysfunction has not been well elucidated in vivo. In the present study, we constructed a miR‐184−/− zebrafish line by destroying both two dre‐mir‐184 paralogs with CRISPR‐Cas9 technology. Although there were no gross developmental defects, the miR‐184−/− zebrafish displayed microphthalmia and cataract phenotypes. Cytoskeletal abnormalities, aggregation of γ‐crystallin, and lens fibrosis were induced in miR‐184−/− lenses. However, no obvious corneal abnormalities were observed in miR‐184−/− zebrafish. Instead of apoptosis, deficiency of miR‐184 led to aberrant cell proliferation and a robust increase in p21 levels in zebrafish eyes. Inhibition of p21 by UC2288 compromised the elevation of lens fibrosis markers in miR‐184−/− lenses. RNA‐seq demonstrated that levels of four transcriptional factors HSF4, Sox9a, CTCF, and Smad6a, all of which could suppress p21 expression, were reduced in miR‐184−/− eyes. The predicted zebrafish miR‐184 direct target genes (e.g., atp1a3a and nck2a) were identified and verified in miR‐184−/− eye tissues. The miR‐184−/− zebrafish is the first animal model mimicking miR‐184‐related anterior segment dysgenesis and could broaden our understanding of the roles of miR‐184 in eye development.
Recommending Drug Combinations using Reinforcement Learning to target Genes/proteins that cause Stroke: A comprehensive Systematic Review and Network Meta-analysis
Authors: Boush Mahnaz , Kiaei Ali A. , Safaei Danial , Abadijou Sadegh , Salari Nader , Mohammadi Masoud
Published: April 2023

Objectives

(Importance)Cerebrovascular accident (Stroke) is a term used in medicine to describe cutting off blood supply to a portion of the brain, which causes tissue damage in the brain. Clots of blood that form in the brain’s blood vessels and ruptures in the brain’s blood vessels are the root causes of cerebrovascular accidents. Dizziness, numbness, weakness on one side of the body, and difficulties communicating verbally, writing, or comprehending language are the symptoms of this condition. Smoking, being older and having high blood pressure, diabetes, high cholesterol, heart disease, a history of cerebrovascular accident in the family, atherosclerosis (which is the buildup of fatty material and plaque inside the coronary arteries), or high cholesterol all contribute to an increased risk of having a cerebrovascular accident.(Objective)This paper analyzes available studies on Cerebrovascular accident medication combinations.

Evidence acquisition

(Data sources)This systematic review and network meta-analysis analyzed the Science Direct, Embase, Scopus, PubMed, Web of Science (ISI), and Google Scholar databases without a lower time limit and up to July 2022. A network meta-analysis examines the efficacy of this drug combination on genes/proteins that serve as progression targets for cerebrovascular accidents.

Results and Conclusion

In scenarios 1 through 3, the p-values for the suggested medication combination and Cerebrovascular accident were 0.036633, 0.007763, and 0.003638, respectively. Scenario I is the combination of medications initially indicated for treating a cerebrovascular accident. The recommended combination of medications for cerebrovascular accidents is ten times more effective. This systematic review and network meta-analysis demonstrate that the recommended medication combination decreases the p-value between cerebrovascular accidents and the genes as potential progression targets, thereby enhancing the treatment for cerebrovascular accidents. The optimal combination of medications improves community health and decreases per-person management costs.

Highlights

Combined drugs that make the p-value between Stroke and target genes close to 1

Using Reinforcement Learning to recommend drug combination

A comprehensive systematic review of recent works

A Network meta-analysis to measure the comparative efficacy

Considered drug interactions
No causal association between inguinal hernia and aortic aneurysm using Mendelian randomization analysis
Authors: Yao Sicheng , Ci Hongbo
Published: April 2023

Aortic aneurysm (AA) is a serious disease that affects the aging population worldwide. Potential risk factors such as inguinal hernia has been suggested by conventional studies could contribute to AA. The aim of our study was to clarify the causal association between inguinal hernia and AA using Mendelian randomization (MR) analysis. Summary statistics data for the associations of inguinal hernia were derived from a recently published large genome-wide association study including 18,791 inguinal hernia cases and 93,955 controls in UK Biobank. Corresponding data of AA were extracted from FinnGen, comprising 7,603 cases and 317,899 controls. The causal association was assessed using MR-egger, weighted median, and inverse variance weighting methods, and compared to observational estimates previously published. Our analysis found no convincing causal effect between genetically predicted inguinal hernia and the risk of AA (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 0.85–1.31,p= 0.65), AAA (OR = 1.15, 95% CI = 0.92–1.46,p= 0.22), and TAA (OR = 1.05, 95% CI = 0.85–1.30,p= 0.67). The results are in contrast to previous observational evidence suggesting a harmful effect of inguinal hernia.
Effects of previous infection, vaccination, and hybrid immunity against symptomatic Alpha, Beta, and Delta infections
Authors: Altarawneh Heba N. , Chemaitelly Hiam , Ayoub Houssein H. , Tang Patrick , Hasan Mohammad R. , Yassine Hadi M. , Al-Khatib Hebah A. , Al Thani Asmaa A. , Coyle Peter , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J.
Published: April 2023

Background

Protection against SARS-CoV-2 symptomatic infection and severe COVID-19 of previous infection, mRNA two-dose vaccination, mRNA three-dose vaccination, and hybrid immunity of previous infection and vaccination were investigated in Qatar for the Alpha, Beta, and Delta variants.

Methods

Six national, matched, test-negative, case-control studies were conducted between January 18-December 18, 2021 on a sample of 239,120 PCR-positive tests and 6,103,365 PCR-negative tests.

Results

Effectiveness of previous infection against Alpha, Beta, and Delta reinfection was 89.5% (95% CI: 85.5-92.3%), 87.9% (95% CI: 85.4-89.9%), and 90.0% (95% CI: 86.7-92.5%), respectively. Effectiveness of two-dose BNT162b2 vaccination against Alpha, Beta, and Delta infection was 90.5% (95% CI, 83.9-94.4%), 80.5% (95% CI: 79.0-82.0%), and 58.1% (95% CI: 54.6-61.3%), respectively. Effectiveness of three-dose BNT162b2 vaccination against Delta infection was 91.7% (95% CI: 87.1-94.7%). Effectiveness of hybrid immunity of previous infection and two-dose BNT162b2 vaccination was 97.4% (95% CI: 95.4-98.5%) against Beta infection and 94.5% (95% CI: 92.8-95.8%) against Delta infection. Effectiveness of previous infection and three-dose BNT162b2 vaccination was 98.1% (95% CI: 85.7-99.7%) against Delta infection. All five forms of immunity had >90% protection against severe, critical, or fatal COVID-19 regardless of variant. Similar effectiveness estimates were observed for mRNA-1273.

Conclusions

All forms of natural and vaccine immunity prior to Omicron introduction provided strong protection against infection and severe COVID-19. Hybrid immunity conferred the strongest protection and its level was consistent with previous-infection immunity and vaccine immunity acting independently of each other.
Genetic tools for the study of the mangrove killifish, Kryptolebias marmoratus,an emerging vertebrate model for phenotypic plasticity
Authors: Li Cheng-Yu , Boldt Helena , Parent Emily , Ficklin Jax , James Althea , Anlage Troy J. , Boyer Lena M. , Pierce Brianna R. , Siegfried Kellee , Harris Matthew P. , Haag Eric S.
Published: April 2023

Kryptolebias marmoratus(Kmar), a teleost fish of the order Cyprinodontiformes, has a suite of unique phenotypes and behaviors not observed in other fishes. Many of these phenotypes are discrete and highly plastic –varying over time within an individual, and in some cases reversible. Kmar and its interfertile sister species,K. hermaphroditus, are the only known self-fertile vertebrates. This unusual sexual mode has the potential to provide unique insights into the regulation of vertebrate sexual development, and also lends itself to genetics. Kmar is easily adapted to the lab and requires little maintenance. However, its internal fertilization and small clutch size limits its experimental use. To support Kmar as a genetic model, we compared alternative husbandry techniques to maximize recovery of early cleavage-stage embryos. We find that frequent egg collection enhances yield, and that protease treatment promotes the greatest hatching successes from diapause. We completed a forward mutagenesis screen and recovered several mutant lines that serve as important tools for genetics in this model. Several will serve as useful viable recessive markers for marking crosses. Importantly, the mutantkissylipslays embryos at twice the rate of wild-type. Combining frequent egg collection with thekissylipsmutant background allows for a substantial enhancement of early embryo yield. These improvements were sufficient to allow experimental analysis of early development and the successful mono- and bi-allelic targeted knockout of an endogenoustyrosinasegene with CRISPR/Cas9 nucleases. Collectively, these tools will facilitate modern developmental genetics in this fascinating fish, leading to future insights into the regulation of plasticity.
Correcting 4sU induced quantification bias in nucleotide conversion RNA-seq data
Authors: Berg Kevin , Lodha Manivel , Garcia Yilliam Cruz , Hennig Thomas , Wolf Elmar , Prusty Bhupesh K , Erhard Florian
Published: April 2023

Nucleoside analogues like 4-thiouridine (4sU) are used to metabolically label newly synthesized RNA. Chemical conversion of 4sU before sequencing induces T-to-C mismatches in reads sequenced from labelled RNA, allowing to obtain total and labelled RNA expression profiles from a single sequencing library. Cytotoxicity due to extended periods of labelling or high 4sU concentrations has been described, but the effects of extensive 4sU labelling on expression estimates from nucleotide conversion RNA-seq have not been studied. Here, we performed nucleotide conversion RNA-seq with escalating doses of 4sU with short-term labelling (1h) and over a progressive time course (up to 2h) in different cell lines. With high concentrations or at later time points, expression estimates were biased in an RNA half-life dependent manner. We show that bias arose by a combination of reduced mappability of reads carrying multiple conversions, and a global, unspecific underrepresentation of labelled RNA due to impaired reverse transcription efficiency and potentially global reduction of RNA synthesis. We developed a computational tool to rescue unmappable reads, which performed favourably compared to previous read mappers, and a statistical method, which could fully remove remaining bias. All methods developed here are freely available as part of our GRAND-SLAM pipeline and grandR package.
LDO proteins and Vac8 form a vacuole-lipid droplet contact site required for lipophagy in response to starvation
Authors: Álvarez-Guerra Irene , Block Emma , Broeskamp Filomena , Gabrijelčič Sonja , de Ory Ana , Habernig Lukas , Andréasson Claes , Levine Tim P. , Höög Johanna L. , Büttner Sabrina
Published: April 2023

Lipid droplets (LDs) are fat storage organelles critical for energy and lipid metabolism. Upon nutrient exhaustion, cells consume LDs via gradual lipolysis or via lipophagy, theen blocuptake of LDs into the vacuole. Here, we show that LDs dock to the vacuolar membrane via a contact site that is required for lipophagy in yeast. The LD-localized LDO proteins carry an intrinsically disordered region that associates with vacuolar Vac8 to form vCLIP, the vacuolar-LD contact site. Nutrient limitation drives vCLIP formation, and its inactivation blocks lipophagy. Vac8 is sufficient to recruit LDs to cellular membranes. We establish a functional link between lipophagy and microautophagy of the nucleus, both requiring Vac8 to form respective contact sites upon metabolic stress. In sum, we unravel the molecular architecture of vCLIP, a contact site required for lipophagy, and find that Vac8 provides a platform for multiple and competing contact sites associated with autophagy.
Neuroticism and emotion regulation: An effective connectivity analysis of large-scale resting-state brain networks
Authors: Sultana Tajwar , Hasan Muhammad Abul , Razi Adeel
Published: April 2023

The neurotic personality has an impact on the regulation of basic negative emotions such as anger, fear, and sadness. There has been extensive research in search of functional connectivity biomarkers of neuroticism and basic negative emotions but there is a lack of research based on effective connectivity. In the current research, we intended to determine the significance of causal interaction of three large-scale resting-state networks – default mode, salience, and executive networks – to predict neuroticism and basic negative emotions. In this study, a large-scale human connectome project dataset comprising functional MRI scans and self-reported scores of neuroticism and negative emotions of 1079 subjects, was utilized. Spectral dynamic causal modelling and parametric empirical Bayes was used to estimate the subject-level effective connectivity parameters and their group-level associations with the neuroticism and emotional scores. Leave-one-out cross-validation using parametric empirical Bayes was employed for prediction analysis. Our results for heightened emotions showed that the self-connection of right hippocampus can predict individuals with high fear, self-connections of dorsal anterior cingulate cortex, posterior cingulate cortex and left dorsolateral prefrontal cortex can predict individuals with high sadness. High anger, low sadness, and neuroticism scores of any emotion category except low fear, could not be predicted using triple network effective connectivity. Our findings revealed that the causal (directed) connections of the resting-state triple network can potentially serve as a connectomic signature for people with high and low fear, high sadness, low anger, and neuroticism with low fear.
DNA damage-induced interaction between a lineage addiction oncogenic transcription factor and the MRN complex shapes a tissue-specific DNA Damage Response and cancer predisposition
Authors: Binet Romuald , Lambert Jean-Philippe , Tomkova Marketa , Tischfield Samuel , Baggiolini Arianna , Picaud Sarah , Sarkar Sovan , Louphrasitthiphol Pakavarin , Dias Diogo , Carreira Suzanne , Humphrey Timothy , Fillipakopoulos Panagis , White Richard , Goding Colin R
Published: April 2023

Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA Damage Response (DDR) programs. However, some cells, in skin for example, are normally exposed to high levels of DNA damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Here we show, using melanoma as a model, that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a non-transcriptional role in shaping the DDR. On exposure to DNA damaging agents, MITF is phosphorylated by ATM/DNA-PKcs, and unexpectedly its interactome is dramatically remodelled; most transcription (co)factors dissociate, and instead MITF interacts with the MRE11-RAD50-NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks, and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement, high MITF levels are associated with increased SNV burden in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of ATM/DNA-PKcs-phosphorylated MITF. Our data suggest that a non-transcriptional function of a lineage-restricted transcription factor contributes to a tissue-specialised modulation of the DDR that can impact cancer initiation.
Renal Cl-/H+ antiporter ClC-5 regulates collagen production and release in Dent Disease models
Authors: Duran M. , Ariceta G. , Semidey ME , Castells-Esteve C , Lu B. , Meseguer A. , Cantero-Recasens G.
Published: April 2023

Mutations in the Cl-/H+antiporter ClC-5 cause Dent’s Disease 1 (DD1), a rare primary tubulopathy that eventually progresses to renal failure. In fact, even with normal kidney function, DD1 patients present renal tubulointerstitial fibrosis. However, the link between ClC-5 loss-of-function and renal fibrosis remains unclear. Here, we have shown that DD1 mice models lacking ClC-5 present higher renal collagen deposition and fibrosis. Accordingly, deletion of ClC-5 in human renal proximal tubule epithelial cells (CLCN5KD) recapitulates this effect. We have demonstrated thatCLCN5KD causes an increase of collagen I (Col I) and IV (Col IV) intracellular levels by promoting their transcription through β-catenin pathway and impairing their lysosomal-mediated degradation. In addition,CLCN5KD cells release more Col I and IV at the extracellular space that form fibres with altered properties and resistance to removal compared to control cells. Altogether, we describe a new regulatory mechanism for collagens’ production and release by ClC-5, which is altered in DD1 and provides a better understanding of disease progression to renal fibrosis.

SIGNIFICANCE STATEMENT

Renal fibrosis is a common pathologic process occurring as consequence of chronic kidney injury and leading to renal dysfunction. Dent’s Disease is a rare renal pathology that progresses to chronic kidney disease and tubulointerstitial fibrosis. Interestingly, it is caused by mutations in a single gene calledCLCN5, therefore it can help understanding the cellular mechanisms of renal fibrosis. Using cellular and mice models of the disease, we describe a mechanism linkingCLCN5function, cell differentiation and regulation of collagen levels, major component of extracellular matrix and important player for renal fibrosis development. In conclusion, our results provide a link betweenCLCN5and altered collagen deposition, which could be relevant for other renal Fanconi syndrome related diseases also progressing to fibrosis.