bluuebunny/crossref_metadata_2025 huggingface dataset:
Pan-cancer analysis of Krüppel-like factor 3 and its carcinogenesis in pancreatic cancer
Authors: Zhu Jinfeng , Teng Hong , Zhu Xiaojian , Yuan Jingxuan , Zhang Qiong , Zou Yeqing
Published: August 2023

Background

Krüppel-like factor 3 (KLF3) is a key transcriptional repressor, which is involved in various biological functions such as lipogenesis, erythropoiesis, and B cell development, and has become one of the current research hotspots. However, the role of KLF3 in the pan-cancer and tumor microenvironment remains unclear.

Methods

TCGA and GTEx databases were used to evaluate the expression difference of KLF3 in pan-cancer and normal tissues. The cBioPortal database and the GSCALite platform analyzed the genetic variation and methylation modification of KLF3. The prognostic role of KLF3 in pan-cancer was identified using Cox regression and Kaplan-Meier analysis. Correlation analysis was used to explore the relationship between KLF3 expression and tumor mutation burden, microsatellite instability, and immune-related genes. The relationship between KLF3 expression and tumor immune microenvironment was calculated by ESTIMATE, EPIC, and MCPCOUNTER algorithms. TISCH and CancerSEA databases analyzed the expression distribution and function of KLF3 in the tumor microenvironment. TIDE, GDSC, and CTRP databases evaluated KLF3-predicted immunotherapy response and sensitivity to small molecule drugs. Finally, we analyzed the role of KLF3 in pancreatic cancer by in vivo and in vitro experiments.

Results

KLF3 was abnormally expressed in a variety of tumors, which could effectively predict the prognosis of patients, and it was most obvious in pancreatic cancer. Further experiments verified that silencing KLF3 expression inhibited pancreatic cancer progression. Functional analysis and gene set enrichment analysis found that KLF3 was involved in various immune-related pathways and tumor progression-related pathways. In addition, based on single-cell sequencing analysis, it was found that KLF3 was mainly expressed in CD4Tconv, CD8T, monocytes/macrophages, endothelial cells, and malignant cells in most of the tumor microenvironment. Finally, we assessed the value of KLF3 in predicting response to immunotherapy and predicted a series of sensitive drugs targeting KLF3.

Conclusion

The role of KLF3 in the tumor microenvironment of various types of tumors cannot be underestimated, and it has significant potential as a biomarker for predicting the response to immunotherapy. In particular, it plays an important role in the progression of pancreatic cancer.
Deletion of the non-adjacent genes UL148 and UL148D impairs human cytomegalovirus-mediated TNF receptor 2 surface upregulation
Authors: Le-Trilling Vu Thuy Khanh , Maaßen Fabienne , Katschinski Benjamin , Hengel Hartmut , Trilling Mirko
Published: August 2023

Human cytomegalovirus (HCMV) is a prototypical β-herpesvirus which frequently causes morbidity and mortality in individuals with immature, suppressed, or senescent immunity. HCMV is sensed by various pattern recognition receptors, leading to the secretion of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα). TNFα binds to two distinct trimeric receptors: TNF receptor (TNFR) 1 and TNFR2, which differ in regard to their expression profiles, affinities for soluble and membrane-bound TNFα, and down-stream signaling pathways. While both TNF receptors engage NFκB signaling, only the nearly ubiquitously expressed TNFR1 exhibits a death domain that mediates TRADD/FADD-dependent caspase activation. Under steady-state conditions, TNFR2 expression is mainly restricted to immune cells where it predominantly submits pro-survival, proliferation-stimulating, and immune-regulatory signals. Based on the observation that HCMV-infected cells show enhanced binding of TNFα, we explored the interplay between HCMV and TNFR2. As expected, uninfected fibroblasts did not show detectable levels of TNFR2 on the surface. Intriguingly, however, HCMV infection increased TNFR2 surface levels of fibroblasts. Using HCMV variants and BACmid-derived clones either harboring or lacking the ULb’ region, an association between TNFR2 upregulation and the presence of the ULb’ genome region became evident. Applying a comprehensive set of ULb’ gene block and single gene deletion mutants, we observed that HCMV mutants in which the non-adjacent genes UL148 or UL148D had been deleted show an impaired ability to upregulate TNFR2, coinciding with an inverse regulation of TACE/ADAM17.
The IgA of hares (Lepus sp.) and rabbit confirms that the leporids IgA explosion is old and reveals a new case of trans-species polymorphism
Authors: Pinheiro Ana , de Sousa-Pereira Patrícia , Esteves Pedro J.
Published: August 2023

Background

Immunoglobulin A (IgA) is the mammalian mucosal antibody, providing an important line of defense against pathogens. With 15 IgA subclasses, the European rabbit has an extremely complex IgA system, strikingly more complex than most other mammals, which have only one IgA or, in the case of hominoids, two IgA subclasses. Similar to the two hominoid primate IGHA genes, the expansion of the rabbit IGHA genes appears to have begun in an ancestral lagomorph since multiple IgA copies were found by Southern blot analysis for the genera Sylvilagus, Lepus, and Ochotona.

Results

To gain a better insight into the extraordinary lagomorph IgA evolution, we sequenced, for the first time, expressed IgA genes for two Lepus species, L. europaeus and L. granatensis. These were aligned with the 15 rabbit IgA isotypes, and evolutionary analyses were conducted. The obtained phylogenetic tree shows that the Lepus IgA sequences cluster with and among the rabbit IgA isotypes, and the interspecies and intraspecies nucleotide genetic distances are similar. A comparison of the amino acid sequences of the Lepus and rabbit IgA confirms that there are two trans-species polymorphisms and that the rabbit and Lepus sequences share a common genetic pool. In fact, the main differences between the studied leporids IgAs reside in the characteristics of the hinge region.

Conclusion

The Lepus IgA sequences we have obtained strongly suggest that the great expansion of the leporid IGHA genes occurred in a common ancestral species and was then maintained in the descendants. A strong selective pressure caused the extraordinary expansion of the IGHA genes but then subsided, leading to the maintenance of the acquired polymorphisms in the descendants, with little subsequent divergence. This is a unique evolutionary pattern in which an ancient gene expansion has been maintained for approximately 18 million years.
Development of an immunoassay for the simultaneous detection of GADA and ZnT8A in autoimmune diabetes using a ZnT8/GAD65 chimeric molecule
Authors: Trabucchi Aldana , Bombicino Silvina Sonia , Sabljic Adriana Victoria , Marfía Juan Ignacio , Targovnik Alexandra Marisa , Iacono Rubén Francisco , Miranda María Victoria , Valdez Silvina Noemí
Published: August 2023

Introduction

The combined presence of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GADA) and to the islet-specific cation efflux transporter ZnT8 (ZnT8A) in serum is the best predictive sign of the loss of immune tolerance and the clinical manifestation of autoimmune diabetes mellitus (DM). The screening of GADA and ZnT8A could help to reach to a correct diagnosis and to start an early and adequate treatment. The aim of the study was to develop an immunoassay for the simultaneous detection of these autoantibodies using a chimera molecule that includes the immunodominant regions of ZnT8 and GAD65, expressed by baculovirus-insect cells system.

Materials and Methods

ZnT8/GAD65 was expressed using the Bac to Bac™ baculovirus expression system. The recombinant chimera was purified by an His6-tag and identified by SDS-PAGE and western blot analysis, and by an indirect ELISA using specific antibodies against ZnT8 and GAD65. A fraction of ZnT8/GAD65 was biotinylated. A bridge ELISA (b-ELISA) was developed using ZnT8/GAD65 immobilized in polystyrene microplates, human sera samples from healthy individuals (n = 51) and diabetic patients (n = 49) were then incubated, and afterwards ZnT8/GAD65-biotin was added. Immune complexes were revealed with Streptavidin-Horseradish Peroxidase. Results were calculated as specific absorbance and expressed as standard deviation scores: SDs.

Results

ZnT8/GAD65 was efficiently produced, yielding 30 mg/L culture medium, 80% pure. This recombinant chimera retains the immunoreactive conformation of the epitopes that are recognized by their specific antibodies, so it was used for the development of a high sensitivity (75.51%) and specificity (98.04%) b-ELISA for the detection of ZnT8A and/or GADA, in a one-step screening assay. The ROC curves demonstrated that this method had high accuracy to distinguish between samples from healthy individuals and diabetic patients (AUC = 0.9488); the cut-off value was stablished at 2 SDs.

Conclusions

This immunoassay is useful either to confirm autoimmune diabetes or for detection in routine screening of individuals at risk of autoimmune DM. As DM is a slow progress disease, remaining asymptomatic for a long preclinical period, serological testing is of importance to establish a preventive treatment.
Lipid oxidation dysregulation: an emerging player in the pathophysiology of sepsis
Authors: Muniz-Santos Renan , Lucieri-Costa Giovanna , Almeida Matheus Augusto P. de , Moraes-de-Souza Isabelle , Brito Maria Alice Dos Santos Mascarenhas , Silva Adriana Ribeiro , Gonçalves-de-Albuquerque Cassiano Felippe
Published: August 2023

Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development.
Antibodies to leukotoxin A from the periodontal pathogen Aggregatibacter actinomycetemcomitans in patients at an increased risk of rheumatoid arthritis
Authors: Martinsson Klara , Di Matteo Andrea , Öhman Carina , Johansson Anders , Svärd Anna , Mankia Kulveer , Emery Paul , Kastbom Alf
Published: August 2023

Objectives

Periodontitis and underlying bacteria have been linked to the development of rheumatoid arthritis (RA). One suggested pathogen is Aggregatibacter actinomycetemcomitans (A.a.), which expresses leukotoxin A (LtxA) that can citrullinate human proteins, providing a possible trigger for the production of anti-citrullinated protein antibodies (ACPA). In this study, we seek to determine the presence of antibodies toward LtxA in patients at risk of developing RA.

Methods

Two prospective observational patient cohorts (one Swedish and one British) with symptomatic at-risk patients were studied. Anti-LtxA antibodies were analyzed by a cell-based neutralization assay in baseline serum and compared to 100 Swedish blood donors that served as controls.

Results

Serum anti-LtxA levels or positivity did not differ between patients and blood donors. In the British cohort, anti-LtxA was more prevalent among ACPA-positive arthralgia patients compared with ACPA-negative arthralgia cases (24% vs. 13%, p < 0.0001). In the Swedish at-risk cohort, anti-LtxA positive patients were at increased risk of progression to arthritis (hazard ratio (HR) 2.10, 95% CI 1.04–4.20), but this was not confirmed in the UK at-risk cohort (HR 0.99, CI 0.60–1.65).

Conclusion

Serum anti-LtxA is not elevated before RA diagnosis, and associations with disease progression and ACPA levels differ between populations. Other features of the oral microbiome should be explored in upcoming periodontitis-related RA research.
Use of social media for the improvement of safety knowledge and awareness among Saudi Arabian phlebotomists
Authors: Attar Razaz , Almohanna Asmaa , Almusharraf Ahlam , Alhazmi Amal , Alanzi Nouf , Al-Anezi Fahad , Alanzi Turki , Sroor Raghad , Albishri Ahmed , Alzahrani Amwaj , Alsabilah Taif , Alkenani Ali , Alghamdi Raghad , AlGethami Fai , AlGethami Arub
Published: August 2023

Purpose

The purpose of this study is to investigate the use of social media for the improvement of safety knowledge and awareness among phlebotomists.

Methods

As this study was intended to arrive at specific conclusions using empirical evidence, a deductive quantitative cross-sectional online survey design was adopted. A total of 521 phlebotomists participated in the survey, and 86 incomplete responders were removed, resulting in a final sample of 435 considered in this study. T-tests and ANOVA were used to analyze the data.

Results

A total of 41.6% stated that social media was very effective, and 31.5% stated that it was somewhat effective in improving safety knowledge and awareness. in addition, this study revealed no major differences between male and female participants (p > 0.05) with respect to the effectiveness of social media. However, statistically significant differences (p < 0.05) among the age groups were identified in relation to the effectiveness of social media and the intention to use it in the future.

Conclusion

Social media applications are effective for knowledge dissemination among healthcare professionals.
Drug-eluting beads bronchial arterial chemoembolization vs. conventional bronchial arterial chemoembolization in the treatment of advanced non-small cell lung cancer
Authors: Yu Guocan , Shen Yanqin , Chen Liangliang , Xu Xudong , Yang Jun
Published: August 2023

Purpose

To compare the effectiveness and safety of drug-eluting bead bronchial artery chemoembolization (DEB-BACE) with conventional bronchial artery chemoembolization (cBACE) and provide a novel treatment option for advanced non-small cell lung cancer (NSCLC).

Methods

Patients with advanced NSCLC underwent DEB-BACE or cBACE and were screened retrospectively. Progression-free survival (PFS) and overall survival (OS) were the primary outcome indicators, while technical success rate, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were the secondary ones.

Results

A total of 41 patients were enrolled in the study, 12 in the DEB-BACE group and 29 in the cBACE group, according to the treatment regimen. No patient achieved complete response. Eighteen patients achieved partial response (9 in each group), 15 patients achieved stable disease (3 in the DEB-BACE group and 12 in the cBACE group), and eight patients achieved progressive disease (all in the cBACE group) when treated for 2 months. The overall ORR and DCR were 43.9% (18/41) and 80.5% (33/41), respectively. ORR and DCR in the DEB-BACE group were 50.0% (9/12) and 100.0% (12/12), respectively, while ORR and DCR in the cBACE group were 31.0% (9/29) and 72.4% (21/29), respectively. Compared to cBACE, the ORR and DCR of DEB-BACE were significantly improved (p < 0.05). The median PFS was better in the DEB-BACE group than in the cBACE group (6.95 months vs. 3.20 months, respectively, Hazard Ratio [HR] = 0.416; p = 0.005). Furthermore, the median OS was significantly better in the DEB-BACE group than in the cBACE group (28.5 months vs. 22.5 months, respectively, HR = 0.316; p = 0.020).

Conclusion

DEB-BACE has a good safety and therapeutic profile in advanced NSCLC and is superior to cBACE. DEB-BACE can be used as an alternative treatment option for advanced NSCLC, even in elderly patients.
Case report: Continuous infusions of ceftazidime-avibactam and aztreonam in combination through elastomeric infusors for 12 weeks for the treatment of bone and joint infections due to metallo-β-lactamase producing Enterobacterales
Authors: Merad Yanis , Conrad Anne , Brosset Sophie , Schmidt Axel , Hanriat Camille , Lustig Sebastien , Laurent Frederic , Kolenda Camille , Roussel-Gaillard Tiphaine , Batailler Cecile , Ferry Tristan ,   Lyon BJI Study group
Published: August 2023

Among carbapenem-resistant Enterobacterales, metallo-beta-lactamase producing strains represent a growing therapeutic challenge. While the association of aztreonam and ceftazidime-avibactam has been investigated in recent years for the treatment of infections involving these strains, little to no clinical data support the use of this association for the treatment of bone and joint infections. We report two cases of complex bone and joint infections involving metallo-beta-lactamase-producing Enterobacterales, successfully treated at our referral center with aztreonam and ceftazidime-avibactam for 12 weeks in continuous infusions through elastomeric infusors.
Genetic and environmental factors in interstitial lung diseases: current and future perspectives on early diagnosis of high-risk cohorts
Authors: Stanel Stefan Cristian , Callum Jack , Rivera-Ortega Pilar
Published: August 2023

Within the wide scope of interstitial lung diseases (ILDs), familial pulmonary fibrosis (FPF) is being increasingly recognized as a specific entity, with earlier onset, faster progression, and suboptimal responses to immunosuppression. FPF is linked to heritable pathogenic variants in telomere-related genes (TRGs), surfactant-related genes (SRGs), telomere shortening (TS), and early cellular senescence. Telomere abnormalities have also been identified in some sporadic cases of fibrotic ILD. Air pollution and other environmental exposures carry additive risk to genetic predisposition in pulmonary fibrosis. We provide a perspective on how these features impact on screening strategies for relatives of FPF patients, interstitial lung abnormalities, ILD multi-disciplinary team (MDT) discussion, and disparities and barriers to genomic testing. We also describe our experience with establishing a familial interstitial pneumonia (FIP) clinic and provide guidance on how to identify patients with telomere dysfunction who would benefit most from genomic testing.
Differential expression analysis of miRNAs in macrophage-derived exosomes in the tuberculosis-infected bone microenvironment
Authors: Sun Zhicheng , Pang Xiaoyang , Wang Xiyang , Zeng Hao
Published: August 2023

Background

Macrophages play an important role in regulating the course of spinal tuberculosis within the bone microenvironment. This study aimed to investigate the differential expression of miRNA in macrophage-derived exosomes within the tuberculosis-infected bone microenvironment, to identify miRNAs that hold potential as diagnostic markers and therapeutic targets.

Methods

We established study cohorts for spinal tuberculosis, collected bone marrow blood samples, isolated macrophage exosomes, and performed exosome miRNA sequencing. A miRNA-mRNA co-expression network was constructed using WGCNA analysis. Gene GO analysis and KEGG pathway enrichment analysis were performed using KOBAS software. Target miRNAs were selected based on fold change, P-value, and false discovery rate, and their validation was carried out using qRT-PCR and ROC curve studies. Subsequently, we constructed a target gene network for these miRNAs and performed KEGG pathway enrichment analysis to explore the potential signaling mechanisms involved in regulating the disease course of spinal tuberculosis.

Results

Our findings revealed that macrophages from the tuberculosis-infected bone microenvironment exhibited an M1 phenotype. The successful extraction of exosomes from macrophage supernatants was confirmed through electron microscopy, particle size analysis, and protein blot analysis. Exosome miRNA-seq demonstrated that 28 miRNAs were up-regulated, while 34 miRNAs were down-regulated in individuals with spinal tuberculosis. GO analysis and KEGG pathway enrichment analysis indicated that the differentially expressed miRNAs were involved in various biological processes, cell components, molecular functions, and signaling pathways, which collectively contribute to the regulation of the disease course of spinal tuberculosis. Notably, miRNA-125b-5p was successfully selected based on fold change, p-value, and false discovery rate. qRT-PCR validation further confirmed the significant up-regulation of miRNA-125b-5p in spinal tuberculosis. The ROC curve revealed that miR-125b-5p is a potential diagnostic biomarker for spinal tuberculosis. Moreover, construction of the miRNA-125b-5p target gene network and subsequent KEGG enrichment analysis highlighted the importance of MAPK, TNF, Ras, Rap1, and the PI3K-Akt signaling pathways in the regulation of the disease course of spinal tuberculosis.

Conclusion

Our study demonstrates differential expression of miRNAs in macrophage-derived exosomes in the tuberculosis-infected bone microenvironment. Specifically, MiRNA-125b-5p is significantly up-regulated in spinal tuberculosis and shows potential as a diagnostic biomarker for spinal tuberculosis.
Genomic traits of multidrug resistant enterotoxigenic Escherichia coli isolates from diarrheic pigs
Authors: Hu Jiameng , Li Junlin , Huang Xiaobo , Xia Jing , Cui Min , Huang Yong , Wen Yiping , Xie Yue , Zhao Qin , Cao Sanjie , Zou Likou , Han Xinfeng
Published: August 2023

Diarrhea caused by enterotoxigenicEscherichia coli(ETEC) infections poses a significant challenge in global pig farming. To address this issue, the study was conducted to identify and characterize 19 ETEC isolates from fecal samples of diarrheic pigs sourced from large-scale farms in Sichuan Province, China. Whole-genome sequencing and bioinformatic analysis were utilized for identification and characterization. The isolates exhibited substantial resistance to cefotaxime, ceftriaxone, chloramphenicol, ciprofloxacin, gentamicin, ampicillin, tetracycline, florfenicol, and sulfadiazine, but were highly susceptible to amikacin, imipenem, and cefoxitin. Genetic diversity among the isolates was observed, with serotypes O22:H10, O163orOX21:H4, and O105:H8 being dominant. Further analysis revealed 53 resistance genes and 13 categories of 195 virulence factors. Of concern was the presence oftet(X4) in some isolates, indicating potential public health risks. The ETEC isolates demonstrated the ability to produce either heat-stable enterotoxin (ST) alone or both heat-labile enterotoxin (LT) and ST simultaneously, involving various virulence genes. Notably, STa were linked to human disease. Additionally, the presence of 4 hybrid ETEC/STEC isolates harboring Shiga-like toxin-related virulence factors, namelystx2a,stx2b, andstx2e-ONT-2771, was identified. IncF plasmids carrying multiple antimicrobial resistance genes were prevalent, and a hybrid ETEC/STEC plasmid was detected, highlighting the role of plasmids in hybrid pathotype emergence. These findings emphasized the multidrug resistance and pathogenicity of porcine-origin ETEC strains and the potential risk of epidemics through horizontal transmission of drug resistance, which is crucial for effective control strategies and interventions to mitigate the impact on animal and human health.
Targeting mitochondrial dynamics proteins for the treatment of doxorubicin-induced cardiotoxicity
Authors: Chen Rui , Niu Mengwen , Hu Xin , He Yuquan
Published: August 2023

Doxorubicin (DOX) is an extensively used chemotherapeutic agent that can cause severe and frequent cardiotoxicity, which limits its clinical application. Although there have been extensive researches on the cardiotoxicity caused by DOX, there is still a lack of effective treatment. It is necessary to understand the molecular mechanism of DOX-induced cardiotoxicity and search for new therapeutic targets which do not sacrifice their anticancer effects. Mitochondria are considered to be the main target of cardiotoxicity caused by DOX. The imbalance of mitochondrial dynamics characterized by increased mitochondrial fission and inhibited mitochondrial fusion is often reported in DOX-induced cardiotoxicity, which can result in excessive ROS production, energy metabolism disorders, cell apoptosis, and various other problems. Also, mitochondrial dynamics disorder is related to tumorigenesis. Surprisingly, recent studies show that targeting mitochondrial dynamics proteins such as DRP1 and MFN2 can not only defend against DOX-induced cardiotoxicity but also enhance or not impair the anticancer effect. Herein, we summarize mitochondrial dynamics disorder in DOX-induced cardiac injury. Furthermore, we provide an overview of current pharmacological and non-pharmacological interventions targeting proteins involved in mitochondrial dynamics to alleviate cardiac damage caused by DOX.
Research progress of mitophagy in chronic cerebral ischemia
Authors: Yu Mayue , Zhang Manqing , Fu Peijie , Wu Moxin , Yin Xiaoping , Chen Zhiying
Published: August 2023

Chronic cerebral ischemia (CCI), a condition that can result in headaches, dizziness, cognitive decline, and stroke, is caused by a sustained decrease in cerebral blood flow. Statistics show that 70% of patients with CCI are aged > 80 years and approximately 30% are 45–50 years. The incidence of CCI tends to be lower, and treatment for CCI is urgent. Studies have confirmed that CCI can activate the corresponding mechanisms that lead to mitochondrial dysfunction, which, in turn, can induce mitophagy to maintain mitochondrial homeostasis. Simultaneously, mitochondrial dysfunction can aggravate the insufficient energy supply to cells and various diseases caused by CCI. Regulation of mitophagy has become a promising therapeutic target for the treatment of CCI. This article reviews the latest progress in the important role of mitophagy in CCI and discusses the induction pathways of mitophagy in CCI, including ATP synthesis disorder, oxidative stress injury, induction of reactive oxygen species, and Ca2+ homeostasis disorder, as well as the role of drugs in CCI by regulating mitophagy.
Wildtype peers rescue social play and 50-kHz ultrasonic vocalization deficits in juvenile female Cacna1c heterozygous rats
Authors: Bogdan Rebecca , Kayumova Rukhshona , Schwarting Rainer K. W. , Wöhr Markus , Kisko Theresa M.
Published: August 2023

Background

Healthy brain development depends on early social practices and experiences. The risk gene CACNA1C is implicated in numerous neuropsychiatric disorders, in which key characteristics include deficits in social functioning and communication. Recently, we reported sex-dependent impairments in social behavior and ultrasonic vocalizations (USV) in juvenile heterozygous Cacna1c+/− (HET) rats. Specifically, HET females displayed increases in rough-and-tumble play that eliminated the typically observed sex difference between male and female rats. Interestingly, female wild-type Cacna1c+/+ (WT) pairs also showed a similar increase in social play when housed with HET females, suggesting their behavior may be influenced by HET cage mates. This indicates that the genetic makeup of the social environment related to Cacna1c can influence social play, yet systematic studies are lacking.

Methods

In the present study, we housed juvenile females in MIXED- or SAME-genotype cages and tested them in a social play paradigm with a same- and opposite-genotype partner.

Results

The results show that the early social environment and the genotype of the play partner influence social play and 50-kHz USV emission. Experience with a WT play partner appears necessary for HET females to show comparable levels of play and 50-kHz USV emission. Same-genotype HET pairs played less and emitted fewer 50-kHz USV than same-genotype WT or opposite-genotype pairs; however, we found that the decrease in social play and 50-kHz USV in HET pairs can be rescued by playing with a WT partner. The effect was particularly prominent when the first play partner was WT, as we found it increased play and 50-kHz USV emission in all subsequent interactions with ensuing partners.

Conclusion

These findings suggest that the genetic makeup related to the social environment and/or social peers influences social play in Cacna1c+/− haploinsufficient rats. Specifically, our results show that WT peers can rescue behavior and communication alterations in Cacna1c female rats. Our findings have important implications because they show that the genetic makeup of the social environment can divulge phenotypic changes in genetic rat models of neuropsychiatric disorders.
Lipidation states orchestrate CLICK-III/CaMKIγ's stepwise association with Golgi and rafts-enriched membranes and specify its functional coupling to STEF-Rac1-dependent neurite extension
Authors: Ageta-Ishihara Natsumi , Takemoto-Kimura Sayaka , Kondo Yayoi , Okamura Michiko , Bito Haruhiko
Published: August 2023

CLICK-III/CaMKIγ is a lipid-anchored neuronal isoform of multifunctional Ca2+/calmodulin-dependent protein kinases, which mediates BDNF-dependent dendritogenesis in cultured cortical neurons. We found that two distinct lipidation states of CaMKIγ, namely, prenylation and palmitoylation, controlled its association with detergent-resistant microdomains in the dendrites and were essential for its dendritogenic activity. However, the impact of each lipid modification on membrane targeting/trafficking and how it specifies functional coupling leading to polarized changes in neuronal morphology are not clear. Here, we show that prenylation induces membrane anchoring of CaMKIγ, permitting access to the Golgi apparatus, and a subsequent palmitoylation facilitates association with cholesterol-enriched lipid microdomains or lipid rafts, in particular at the Golgi. To specifically test the role of palmitoylated CaMKγ in neurite extension, we identified and took advantage of a cell system, PC12, which, unlike neurons, conveniently lacked CaMKIγ and was deficient in the activity-dependent release of a neuritogenic growth factor while possessing the ability to activate polarized rafts signaling for morphogenesis. This system allowed us to rigorously demonstrate that an activity-dependent, lipid rafts-restricted Rac activation leading to neuritogenesis could be functionally rescued by dually lipidated CaMKIγ expression, revealing that not only prenylation but also palmitoylation is essential for CaMKIγ to activate a compartmentalized STEF-Rac1 pathway. These results shed light on the significance of recruiting prenylated and palmitoylated CaMKIγ into the coalescing signalosomes at lipid rafts together with Rac1 and its specific GEF and STEF and forming a compartmentalized Ca2+ signaling pathway that underlies activity-dependent neuritogenesis and morphogenesis during axodendritic polarization critical for brain development and circuitogenesis.
Triglyceride-glucose index predicts death in patients with stroke younger than 65
Authors: Liu Ruishan , Li Lijuan , Wang Lu , Zhang Shihong
Published: August 2023

Background

The triglyceride-glucose index (TGI), a reliable surrogate indicator of insulin resistance (IR), has been proven to be a predictor of the incidence of ischemic stroke. The role of TGI in predicting the outcomes of stroke patients remains controversial. Susceptibility to IR-related diseases varies among patients of different ages. The study aims to evaluate the predictive value of TGI levels on clinical outcomes of patients with ischemic stroke of different ages.

Method

This was a retrospective cohort study including patients with ischemic stroke in the Department of Neurology at West China Hospital. TGI was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The patients were subdivided into 3 tertiles according to TGI levels. Multivariate logistic regression analyses were conducted to estimate the association between TGI levels and post-stroke outcomes among the whole patients, younger patients (<65), and older patients (>=65). The outcomes included death and unfavorable functional outcome (modified Rankin scale score 3–6) at 3 and 12 months after stroke.

Results

A total of 3,704 patients (men, 65.08%, mean age, 61.44 ± 14.15; women 34.92%, mean age, 65.70 ± 13.69) were enrolled in this study. TGI levels were not associated with 3 month or 12 month death in the whole patients. Patients with higher TGI levels (T2 and T3) had a higher risk of 3 month death than those had lower TGI levels (T1) in the younger group (T2 vs. T1: OR 2.64, 95% CI 1.03–6.79, p = 0.043; T3 vs. T1: OR 2.69, 95% CI 1.00–7.10, p = 0.049) but not in the older group. Additionally, Kaplan–Meier estimate analysis illustrated that the 12 month death risk was significantly higher in the group with the highest TGI among younger patients (p for log-rank test = 0.028) but not among older patients. There was an interactive effect between TGI and age on 3 month death (p for interaction = 0.013) and 12 month death (p for interaction = 0.027). However, TGI was not associated with unfavorable functional outcome at 3 month or 12 month after stroke.

Conclusion

Elevated TGI independently predicts death at 3 months and 12 months in patients under 65 with ischemic stroke. Regulating TGI is expected to be an approach to enhance prognosis in young individuals affected by ischemic stroke.
C-NODDI: a constrained NODDI model for axonal density and orientation determinations in cerebral white matter
Authors: Alsameen Maryam H. , Gong Zhaoyuan , Qian Wenshu , Kiely Matthew , Triebswetter Curtis , Bergeron Christopher M. , Cortina Luis E. , Faulkner Mary E. , Laporte John P. , Bouhrara Mustapha
Published: August 2023

Purpose

Neurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo-time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM.

Methods

Using NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration. Finally, we investigated the TE dependence of NODDI or C-NODDI derived NDI and ODI.

Results

ODI derived values using both approaches were virtually identical, exhibiting constant trends with age. Further, our results indicated a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. Further, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared to NODDI-NDI, with lower NDI values corresponding to higher levels of NfL. Finally, we confirmed the previous finding that NDI estimation using NODDI was dependent on TE, while NDI derived values using C-NODDI exhibited lower sensitivity to TE in WM.

Conclusion

C-NODDI provides a complementary method to NODDI for determination of NDI in white matter.
When fixing problems kills personal development: fMRI reveals conflict between Real and Ideal selves
Authors: Jack Anthony Ian , Passarelli Angela M. , Boyatzis Richard Eleftherios
Published: August 2023

Many coaching approaches aim to change behavior by increasing self-knowledge. However, self-knowledge can be difficult to achieve. One hypothesis (e.g., Jung, Rogers) is that self-knowledge is challenging because there is inherent conflict between different aspects of the self. This hypothesis is foundational to Boyatzis’ intentional change theory (ICT). ICT holds that effective coaching requires deliberate sequencing of the client’s exploration of different aspects of their self. Coaches initially encourage clients to focus exclusively on their Ideal self. The ICT approach differs from that advocated by most coaching organizations that suggest collaborative goal setting at the start of the coaching engagement, encouraging clients to focus on fixing performance deficits and problematic behaviors–aspects of the Real self. If there is conflict between thinking about Ideal and Real selves, then this strategy will be suboptimal. The hypothesis of attentional conflict therefore has significant implications for coaching practice. Previous findings establish a link between attention to Ideal vs. Real selves and global vs. local visual processing, respectively. This association alone does not imply conflict because, in naturalistic settings, global and local perceptual processes usually work in concert. However, certain stimuli such as Navon figures (letters made from many smaller letters, e.g., a large E made of small R’s) create conflict due to incongruence between the global and local features. Does thinking about the self inherently generate conflict, like a Navon figure, or is it more akin to everyday perception? To answer this question the current study uses functional magnetic resonance imaging to examine the overlap in brain activity in young adults between two pairs of otherwise very dissimilar tasks: coaching interactions focused on Ideal vs. Real self; and attention to global vs. local features of Navon figures. Despite the ostensible absence of overlap in the psychological processes involved in these pairs of tasks, we find a remarkable degree of overlap in brain activity. This overlap was pronounced in higher (parietal and temporal) areas known to be involved in resolving attentional conflict. These findings provide compelling biological evidence for inherent conflict between thinking about Ideal and Real selves.
Similarities and differences between intermittent and continuous resting-state fMRI
Authors: Beresniewicz Justyna , Riemer Frank , Kazimierczak Katarzyna , Ersland Lars , Craven Alexander R. , Hugdahl Kenneth , Grüner Renate
Published: August 2023

Introduction

Functional Magnetic Resonance Imaging (fMRI) block-design experiments typically include active ON-blocks with presentation of cognitive tasks which are contrasted with OFF- blocks with no tasks presented. OFF-blocks in between ON-blocks can however, also be seen as a proxy for intermittent periods of resting, inducing temporary resting-states. We still do not know if brain activity during such intermittent periods reflects the same kind of resting-state activity as that obtained during a continuous period, as is typically the case in studies of the classic Default Mode Network (DMN). The purpose of the current study was therefore to investigate both similarities and differences in brain activity between intermittent and continuous resting conditions.

Methods

There were 47 healthy participants in the 3T fMRI experiment. Data for the intermittent resting-state condition were acquired from resting-periods in between active task-processing periods in a standard ON-OFF block design, with three different cognitive tasks presented during ON-blocks. Data for the continuous resting-state condition were acquired during a 5 min resting period after the task-design had been presented.

Results and discussion

The results showed that activity was overall similar in the two conditions, but with some differences. These differences were within the DMN network, and for the interaction of DMN with other brain networks. DMN maps showed weak overlap between conditions in the medial prefrontal cortex (MPFC), and in particular for the intermittent compared to the continuous resting-state condition. Moreover, DMN showed strong connectivity with the salience network (SN) in the intermittent resting-state condition, particularly in the anterior insula and the supramarginal gyrus. The observed differences may reflect a “carry-over” effect from task-processing to the next resting-state period, not present in the continuous resting-state condition, causing interference from the ON-blocks. Further research is needed to fully understand the extent of differences between intermittent and continuous resting-state conditions.
Environmental carcinogens disproportionally mutate genes implicated in neurodevelopmental disorders
Authors: Baker Brennan H. , Zhang Shaoyi , Simon Jeremy M. , McLarnan Sarah M. , Chung Wendy K. , Pearson Brandon L.
Published: August 2023

Introduction

De novo mutations contribute to a large proportion of sporadic psychiatric and developmental disorders, yet the potential role of environmental carcinogens as drivers of causal de novo mutations in neurodevelopmental disorders is poorly studied.

Methods

To explore environmental mutation vulnerability of disease-associated gene sets, we analyzed publicly available whole genome sequencing datasets of mutations in human induced pluripotent stem cell clonal lines exposed to 12 classes of environmental carcinogens, and human lung cancers from individuals living in highly polluted regions. We compared observed rates of exposure-induced mutations in disease-related gene sets with the expected rates of mutations based on control genes randomly sampled from the genome using exact binomial tests. To explore the role of sequence characteristics in mutation vulnerability, we modeled the effects of sequence length, gene expression, and percent GC content on mutation rates of entire genes and gene coding sequences using multivariate Quasi-Poisson regressions.

Results

We demonstrate that several mutagens, including radiation and polycyclic aromatic hydrocarbons, disproportionately mutate genes related to neurodevelopmental disorders including autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder. Other disease genes including amyotrophic lateral sclerosis, Alzheimer’s disease, congenital heart disease, orofacial clefts, and coronary artery disease were generally not mutated more than expected. Longer sequence length was more strongly associated with elevated mutations in entire genes compared with mutations in coding sequences. Increased expression was associated with decreased coding sequence mutation rate, but not with the mutability of entire genes. Increased GC content was associated with increased coding sequence mutation rates but decreased mutation rates in entire genes.

Discussion

Our findings support the possibility that neurodevelopmental disorder genetic etiology is partially driven by a contribution of environment-induced germ line and somatic mutations.
Clinical applications of electrical stimulation for peripheral nerve injury: a systematic review
Authors: Costello Meredith C. , Errante Emily L. , Smartz Taylor , Ray Wilson Z. , Levi Allan D. , Burks Stephen Shelby
Published: August 2023

Introduction

Peripheral nerve injuries are common neurologic injuries that are challenging to treat with current therapies. Electrical stimulation has been shown to accelerate reinnervation and enhance functional recovery. This study aims to review the literature on clinical application of electrical stimulation for peripheral nerve injury.

Methods

PubMed and Embase were sourced from 1995 to August 2022. Selection was based on predetermined inclusion/exclusion criteria. Eight hundred and thirty-five articles were screened with seven being included in this review.

Results

Two hundred and twenty-nine patients with peripheral nerve injuries were represented. Six of the studies were randomized controlled trials. A variety of nerve injuries were represented with all being in the upper extremity and supraclavicular region. Electrical stimulation protocols and evaluation varied. Electrodes were implanted in four studies with one also implanting the stimulator. Length of stimulation per session was either 20 mins or 1 h. Median stimulation frequency was 20 Hz. Stimulation intensity varied from 3 to 30V; pulse width ranged from 0.1 to 1.007 ms. Three protocols were conducted immediately after surgery. Patients were followed for an average of 13.5 months and were evaluated using electrophysiology and combinations of motor, sensory, and functional criteria.

Discussion

Patients who received electrical stimulation consistently demonstrated better recovery compared to their respective controls. Electrical stimulation for peripheral nerve injury is a novel treatment that has not been well-studied in humans. Our review illustrates the potential benefit in implementing this approach into everyday practice. Future research should aim to optimize protocol for clinical use.
Differential CRH expression level determines efficiency of Cre- and Flp-dependent recombination
Authors: Zhao Chen , Ries Clemens , Du Ying , Zhang Jingwei , Sakimura Kenji , Itoi Keiichi , Deussing Jan M.
Published: August 2023

Corticotropin-releasing hormone expressing (CRH+) neurons are distributed throughout the brain and play a crucial role in shaping the stress responses. Mouse models expressing site-specific recombinases (SSRs) or reporter genes are important tools providing genetic access to defined cell types and have been widely used to address CRH+ neurons and connected brain circuits. Here, we investigated a recently generated CRH-FlpO driver line expanding the CRH system-related tool box. We directly compared it to a previously established and widely used CRH-Cre line with respect to the FlpO expression pattern and recombination efficiency. In the brain, FlpO mRNA distribution fully recapitulates the expression pattern of endogenous Crh. Combining both Crh locus driven SSRs driver lines with appropriate reporters revealed an overall coherence of respective spatial patterns of reporter gene activation validating CRH-FlpO mice as a valuable tool complementing existing CRH-Cre and reporter lines. However, a substantially lower number of reporter-expressing neurons was discerned in CRH-FlpO mice. Using an additional CRH reporter mouse line (CRH-Venus) and a mouse line allowing for conversion of Cre into FlpO activity (CAG-LSL-FlpO) in combination with intersectional and subtractive mouse genetic approaches, we were able to demonstrate that the reduced number of tdTomato reporter expressing CRH+ neurons can be ascribed to the lower recombination efficiency of FlpO compared to Cre recombinase. This discrepancy particularly manifests under conditions of low CRH expression and can be overcome by utilizing homozygous CRH-FlpO mice. These findings have direct experimental implications which have to be carefully considered when targeting CRH+ neurons using CRH-FlpO mice. However, the lower FlpO-dependent recombination efficiency also entails advantages as it provides a broader dynamic range of expression allowing for the visualization of cells showing stress-induced CRH expression which is not detectable in highly sensitive CRH-Cre mice as Cre-mediated recombination has largely been completed in all cells generally possessing the capacity to express CRH. These findings underscore the importance of a comprehensive evaluation of novel SSR driver lines prior to their application.