bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain-wide alterations revealed by spatial transcriptomic and proteomic analyses in COVID-19 infection
Authors: Geschwind Daniel , Zhang Ting , Li Yunfeng , Pan Liuliu , Sha Jihui , Bailey Michael , Faure-Kumar Emmanuelle , Williams Christopher , Wohlschlegel James , Magaki Shino , Niu Chao , Lee YooJin , Su Yu-chyuan , Li Xinmin , Vinters Harry 
Published: October 2023

Abstract

Understanding the pathological basis of the neurological symptoms observed following SARS-CoV2 infection is essential to optimizing outcomes and developing therapeutics. To date, small sample sizes and narrow molecular profiling limit the generalizability of findings. We performed proteomics coupled with bulk and spatial transcriptomics in multiple cortical and subcortical regions in postmortem COVID-19 patient brains and matched controls (total n=42). We observed a multi-regional antiviral response and identified broad dysregulation of synaptic and mitochondrial pathways in deep-layer excitatory neurons and up-regulation of neuroinflammatory pathways in glia at the mRNA and protein levels. These changes overlapped those observed in multiple neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our work, based on multiple experimental and analytical methods, shows that severe COVID-19 has a broad impact across cortical and subcortical regions and shares core neuronal and glial changes with neurodegenerative conditions typically associated with aging.
Transcriptomic Effects of Paternal Cocaine-seeking on the Reward Circuitry of Male Offspring
Authors: Le Qiumin , Huang Nan , Cui Jian , Fan Guangyuan , Pan Tao , Han Kunxiu , Xu Kailiang , Jiang Changyou , Liu Xing , Wang Feifei , Ma Lan 
Published: October 2023

Abstract
In previous research, it has been established that a strong incentive motivation for cocaine, rather than the drug itself, can contribute to the intergenerational inheritance of cocaine addiction susceptibility in descendants. However, the precise impact of paternal cocaine-seeking on the reward circuitry of offspring remains not fully elucidated. To differentiate between cocaine-exposure and cocaine-seeking factors, we employed two distinct paternal cocaine acquisition paradigms: cocaine self-administration and yoked administration. These paradigms were used to generate the F1 generation, along with a control group receiving saline treatment. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naive conditions and after cocaine self-administration. Our study revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine-exposure. Conversely, the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) showed alterations that were more closely linked to the paternal voluntary cocaine-seeking experience. Based on transcriptomic analysis, measurements of dopamine levels (DOPA), and cellular activation analysis, we propose that the VTA-dStr pathway plays a pivotal role in mediating the effects of paternal voluntary cocaine-seeking on offspring. Furthermore, we identified potential transcriptomic regulatory mechanisms mediated by key transcriptional factors. Our findings provide a comprehensive overview of the transcriptional changes resulting from paternal highly-motivated cocaine-seeking. Importantly, our data highlight vulnerable neurocircuitry and novel gene candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.
Depression and risk of infectious diseases: A mendelian randomization study
Authors: Li Jun , Shi Luchen , Ren Junsong , Jin Ke 
Published: October 2023

Abstract

Previous observational inquiries have revealed a correlation between depression and infectious maladies. This study endeavors to scrutinize the causal linkages between depression and infectious diseases. Nonetheless, the causative nature of the association between Major Depressive Disorder (MDD) and infectious diseases remains enigmatic. Two-sample Mendelian Randomization (MR) analysis was executed utilizing single nucleotide polymorphisms (SNPs) significantly connected with MDD and infectious diseases as instrumental variables (IVs). A series of sensitivity analyses were subsequently conducted. Genetic variants linked to MDD were employed as instrumental variables sourced from a genome-wide meta-analysis comprising 500,199 individuals. Summary-level data on five infectious diseases, including candidiasis, pneumonia, skin and soft tissue infections (SSTI), upper respiratory tract infections (URTI), and urinary tract infections (UTI), were acquired from the UK Biobank and FinnGen study. Our findings evinced that genetically predicted MDD exhibited a heightened risk of candidiasis (OR = 1.52, 95% CI 1.06–2.17; P = 2.38E-02), pneumonia (OR = 1.14, 95% CI 1.01–1.29; P = 3.16E-02), URTI (OR = 1.23, 95% CI 1.12–1.36; P = 3.71E-05), and UTI (OR = 1.26, 95% CI 1.12–1.42; P = 8.90E-05). Additionally, we identified bidirectional causal relationships between UTI and MDD. The associations between MDD and the risk of URTI and UTI remained consistent in multivariable MR analysis, accounting for genetically predicted smoking and body mass index. In conclusion, this investigation ascertained a causal connection between MDD and the susceptibility to infectious diseases, particularly URTI and UTI.
Paternal Cocaine-Seeking Motivation Defines Offspring's Vulnerability to Addiction by Down-Regulation of GABAergic GABRG3 in the Ventral Tegmental Area
Authors: Le Qiumin , Cui Jian , Huang Nan , Fan Guangyuan , Pan Tao , Han Kunxiu , Jiang Changyou , Liu Xing , Wang Feifei , Ma Lan 
Published: October 2023

Abstract
Epidemiological investigations indicate that parental drug abuse experiences significantly influenced addiction vulnerability of offspring. In studies using animal models, paternal cocaine-highly motivated drug-seeking behavior has been found to be an important determinant of offspring addiction susceptibility, but the key molecules contributing to offspring addiction susceptibility are currently unclear. We used the cocaine self-administration model and compared SA rat with paired yoke rat to differentiate paternal cocaine-seeking motivation, and the ventral tegmental area (VTA) transcriptomes of rat offspring in the natural state and after self-administration training were analyzed. Paternal cocaine-seeking experience, but not cocaine exposure, could increase lever-pressing behavior in male F1 offspring, without significantly altering cocaine drug sensitivity. RNA-seq of the ventral tegmental area in male F1 under drug-free state and after cocaine-self administration unveil that paternal cocaine self-administration, but not cocaine exposure alone, induced specific gene expression changes in specific modules. Gabrg3 was at the core position of the drug-seeking motivation related module network and highly correlated with parental drug-seeking motivation score. The downregulation of Gabrg3 expression caused by paternal experience of motivational cocaine-seeking mainly occurred in GABAergic neurons in VTA, potentially regulating synaptic and transmitter transmission in VTA. Paternal experience of motivational cocaine seeking can reshape the transcriptional network in the VTA of male offspring rats, possibly by downregulating Gabrg3 in GABAergic neurons. Gabrg3 perturbation may affect the processes related to synapse formation and transmitter transmission, which may be the possible neurobiological mechanism that enhances cocaine-seeking motivation in male offspring rats.
Targeting osteoclast-derived DPP4 alleviates inflammation-mediated ectopic bone formation in ankylosing spondylitis.
Authors: Lee Seung Hoon , Lee Kyu Hoon , Jeon Chanhyeok , Whangbo Min , Jo Hye-Ryeong , Youn Jeehee , Lee Chang-Hun , Park Ye-Soo , Jo Sungsin , Kim Tae Hwan 
Published: October 2023

AbstractBackground: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by ectopic bone formation. The anti-inflammatory function of dipeptidyl peptidase-4 (DPP4) inhibitor has been reported in bone metabolism, but its utility in AS has not previously been investigated.Methods: We assessed DPP4 level in serum, synovial fluid, and facet joint tissue of AS patients. Additionally, we investigated the effect of a DPP4 inhibitor in an experimental AS mouse model induced by intraperitoneal injection with 3 mg curdlan. Following curdlan injection, SKG mice were orally administered a DPP4 inhibitor three times per week for 5 weeks, and ankles of mice were scored for thickness and given clinical arthritis scores. At the end of 5 weeks, mice were sacrificed, and micro-CT and histological analyses were performed. Furthermore, osteoclast precursor cells (OPCs) from curdlan-injected SKG mice were treated with DPP4 inhibitor, and the effects of this treatment on osteoclastogenesis and differentiation markers were evaluated.Results: Soluble DPP4 level was elevated in the serum and synovial fluid of patients with AS compared to those in the control group. Expression of DPP4 increased gradually during human osteoclastogenesis and was high in mature osteoclasts. Histological analysis revealed that oral administration of a DPP4 inhibitor resulted in a decrease in thickness of the hind paw, clinical arthritis scores, and enthesitis at the ankle in curdlan-injected SKG mice compared to the control group. Micro-CT data showed a significant reduction in inflammation-induced low bone density and ectopic bone formation in the DPP4 inhibitor group compared to those in the control group. Intriguingly, DPP4 co-expressed in TRAP-positive osteoclasts was detected in ectopic bone in the tibia of curdlan-injected SKG mice as well as spinal bone tissue of AS patients. Moreover, treatment with a DPP4 inhibitor significantly reduced osteoclastogenesis in the bone marrow of curdlan-injected SKG mice in addition to decreasing expression of osteoclast differentiation markers.Conclusion: Our findings suggest that inhibiting DPP4 may have a therapeutic effect on excessive bone formation in AS patients.
Plasma arachidonic acid levels are associated with both bipolar disorder and the effects of FADS gene variants
Authors: Saito Takeo , Ashizawa Takuma , Okochi Tomo , Ninomiya Kohei , Ito Kenta , Aoki Rei , Ikeda Masashi , Iwata Nakao 
Published: October 2023

Abstract

Recent genome-wide association studies (GWASs) have identified fatty acid desaturase (FADS) genes, which code key enzymes involved in polyunsaturated fatty acid (PUFA) desaturation as susceptibility genes for bipolar disorder (BD). Several quantitative changes in PUFAs suggest their involvement in BD pathogenesis. Therefore, this study aimed to clarify the relationship between BD and PUFAs by conducting lipidomics covariating with the FADS gene variant (rs174550), which is associated with PUFA levels and BD susceptibility. The Concentrations of 23 fatty acids were measured using plasma samples from the BD group (n = 535) and the control group (n = 107). Differences in each PUFA concentration ratio were compared between the two groups. Also, differences in each PUFA concentration ratio were compared for each genotype in rs174550. Our results showed that the BD group had significantly lower concentrations of linoleic acid (LA) (β = −0.3615, p = 0.0233) and arachidonic acid (AA) (β = –0.1789, p = 0.0123) than the control group. Concerning the effect of FADS on the PUFA concentration ratio, carriers of C-allele at rs174550 had significantly decreased γ-linolenic acid and AA concentration ratios. A previous GWAS reported that the presence of a C-allele at rs174550 increased the BD risk. This direction is consistent with the lipidomic results of the present study. In conclusion, both the FADSand BD were considered to regulate the AA concentration. Thus, as the FADS gene variant is crucial for conductinglipidomics of BD we believe that the allele frequency of FADS must be analyzed.
Genome-wide analyses reveals an association between invasive urothelial carcinoma in the Shetland sheepdog, NIPAL1, and the MAPK signaling pathway
Authors: Ostrander Elaine , Parker Heidi , Harris Alexander , Plassais Jocelyn , Dhawan Deepika , Knapp Deborah , Kim Erika 
Published: October 2023

Abstract

Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy and, low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans, however most are of small effect. There exists a need for new and accurate animal models of invasive bladder cancer. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. In the association study presented here, inclusive of 100 Shetland sheepdogs and 58 dogs of other breeds, we identify a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12–22.71), accounting for nearly 30% of iUC risk in the Shetland sheepdog. Inclusion of six additional loci accounts for the majority of disease risk in the breed and explains nearly 75% of the phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs.
The Effects of Podcasts on Medical Education: A Systematic Review
Authors: Wang Shaoyuan , Meckling Gray , Hanafi Sarah , Kasbia Gurnaam Singh , Singhal Nikhita , Zhou Carrol , Raben Alex 
Published: October 2023

Abstract
Objective
Podcasts have been growing in popularity among medical learners, mostly due to their accessibility and convenience. There is a gap in the literature, however, on the impact of podcasts on objective changes in knowledge, behaviours, skills, attitudes, and patient outcomes. This study reviewed existing literature on the effectiveness of podcasts in changing knowledge and practice outcomes for medical students and residents.
Methods
The authors searched Embase, ERIC, MEDLINE, and Scopus for studies that examined the effects of audio-only podcasts on medical learners. Subsequently, two independent authors screened all abstracts, then full-texts for inclusion. Data on learning and behavioral outcomes were extracted from all included studies. Finally, the authors summarized findings using qualitative analysis.
Results
The authors found 6372 studies from our initial search, of which 2501 remained after removing duplicates. 181 articles remained after abstract screening and only 2 remained after full-text screening. Both studies found a statistically significant effect of podcast use on immediate knowledge retention.
Conclusions
The reviewed studies showed that podcasts are effective in generating immediate knowledge retention. Beyond that, there remains little evidence on their effectiveness in the real world. In the face of their increased usage, more research is required to better characterize the impact of podcasts on medical learners.
Evaluation of in vitro antibacterial, DNA binding, DNA damage, DFT and antioxidant studies of aminobenzaldehyde based heterocyclic Schiff base derivatives
Authors: Arif Rizwan , . Akrema , Pulaganti Madhusudana , Rubab Umme , Ali Ahmad , Khan Md Shahzad , UDDIN RAHIS 
Published: October 2023

Abstract
Heterocyclic Schiff base derivatives have been synthesized by condensation of dimethylaminobenzaldehyde and substituted amines in 1:1 molar ratio. Synthesized heterocyclic Schiff base derivatives (3a-3h) were structurally characterized by UV-visible, IR, 1H and 13C NMR spectroscopy, elemental analysis and mass spectrometry. Antibacterial property of heterocyclic Schiff base derivatives has been explored against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus using disc diffusion method. Results revealed that Schiff base derivatives 3c, 3f and 3h have significant antibacterial activity against tested bacterial strains. Heterocyclic Schiff base derivatives also explored for DNA binding interactions study with calf thymus-DNA (Ct-DNA) by absorption spectroscopy, fluorescence measurements, circular dichroism, viscosity measurement and molecular docking study. Heterocyclic Schiff base derivatives 3c, 3f and 3h bind with Ct-DNA through groove binding mode with (Kb) 1.62 × 104, 1.58 × 104 M-1 and 2.3 × 104 M-1 respectively. Molecular docking the target compounds was also studied against B-DNA dodecamer d(CGCGAATTCGCG)2. Agarose gel electrophoresis study revealed that after the addition of compounds 3c, 3f and 3h, DNA damage induced by free radical has been inhibited. Antioxidant potential of heterocyclic Schiff base derivatives was also estimated by Diphenyl-1-picryl-hydrazyl (DPPH) free radical and hydrogen peroxide assay. The experimental results of the spectral properties of the synthesized derivatives 3c, 3f and 3h in solution were interpreted at the molecular level with aid of the DFT and TD-DFT/CAM-B3LYP/6-31+G(d) computational methods with Becke-3-Lee-Yang-Parr(B3LYP) exchange-correlation functional approach.
Microcrystalline induced physical-crosslinking towards high performance branched anion exchange membrane
Authors: Wei Zidong , Lu Xiaoli , Ma Xiaoqin , Yuan Wei , Yuan Caili , Zeng Lingping , Wang Jianchuan , Liao Qiang 
Published: October 2023

Abstract
Anion exchange membrane (AEM) is the core component of low-cost anion exchange membrane fuel cell (AEMFC). To realize the commercial application of AEMFC, extremely low swelling of AEM is vital for the membrane electrode assembly preparation and cell integrity, except for high hydroxide conductivity, strength and chemical stability. However, it is hard to achieve extremely low swelling ratio while maintain high conductivity, especially for homogenous membrane. Herein, a series of quaternized poly(trans-1,2-diphenylethylene-co-terphenyl-N,N′-dimethyl piperidinium) with sophisticated structure are synthesized for AEM to address such dilemma. The physical-crosslinking induced by microcrystalline, effectively restricts the swelling of AEM (< 5.8%@80°C). Moreover, branched structure is also introduced to increase the free volume in the polymer membrane, leading to high conductivity up to 275.6 mS cm-1@80°C simultaneously. Accordingly, excellent fuel cell performance with peak power density of 1.13 W cm-2 for H2-O2 at 80°C is attained.
Comprehensive Single-Cell Transcriptomic Profiling Identifies Molecular Subtypes and Prognostic Biomarkers in Esophageal Squamous Cell Carcinoma: Implications for Targeted Therapy
Authors: Zhang Dengfeng , Zhao Fangchao , Guo Pengfei , Li Zhirong , Li Shujun 
Published: October 2023

Abstract
Background: Esophageal squamous cell carcinoma (ESCC) is a genetically heterogeneous disease with poor clinical outcomes. Identification of biomarkers linked to DNA replication stress may enable improved prognostic risk stratification and guide therapeutic decision making. We performed integrated single-cell RNA sequencing and computational analyses to define the molecular determinants and subtypes underlying ESCC heterogeneity.
Methods: Single-cell RNA sequencing was performed on ESCC samples and analyzed using Seurat. Differential gene expression analysis was used to identify esophageal cell phenotypes. DNA replication stress-related genes were intersected with single-cell differential expression data to identify potential prognostic genes, which were used to generate a DNA replication stress (DRS) score. This score and associated genes were evaluated in survival analysis. Putative prognostic biomarkers were evaluated by Cox regression and consensus clustering. Mendelian randomization analyses assessed the causal role of PRKCB.
Results: High DRS score associated with poor survival. Four genes (CDKN2A, NUP155, PPP2R2A, PRKCB) displayed prognostic utility. Three molecular subtypes were identified with discrete survival and immune properties. A 12-gene signature displayed robust prognostic performance. PRKCB was overexpressed in ESCC, while PRKCB knockdown reduced ESCC cell migration.
Conclusions: This integrated single-cell sequencing analysis provides new insights into the molecular heterogeneity and prognostic determinants underlying ESCC. The findings identify potential prognostic biomarkers and a gene expression signature that may enable improved patient risk stratification in ESCC. Experimental validation of the role of PRKCB substantiates the potential clinical utility of our results.
Barriers to Transanal Endoscopic Surgery Referral in Canada
Authors: Raskin Robert , Neumann Katerina , Jones Jennifer 
Published: October 2023

Abstract
Backgroud:
Transanal endoscopic surgery (TES) is a minimally invasive procedure that allows for full thickness local excision of adenomas and select early rectal adenocarcinomas. Despite its advantages, TES is not uniformly utilized across Canada.
Methods
Potential barriers to TES referral were explored via a survey distributed to endoscopists across Canada, using a stratified sampling method.
Results
In total, 199/501 endoscopists completed our survey, including 62 (31%) gastroenterologists and 136 (69%) surgeons, consistent with a 39% response rate. For patients with clear and unclear indications for TES, 30/146 (27%) and 64/146 (44%) of referring endoscopists have a low referral rate, respectively. On univariable analysis, factors associated with low referral rate include lack of confidence with indications for TES [OR 9.9 (CI 3.15–31.4) p < 0.001], poor understanding regarding the advantages of TES [OR 11.3 (CI 3.83–33.1) p < 0.001], low comfort with referring [OR 183.7 (CI 21.9-1537.5) p < 0.001], distance greater than one hour from a TES surgeon [OR 5.786 (CI 2.63–12.8) p < 0.001] and lack of access to TES [OR 7.8 (CI 3.34-18.0) p < 0.001]. Gastroenterologists are more likely to have a low referral rate than surgeons [OR 2.76 (CI 1.30–5.8) p < 0.01]. On multivariable analysis, low comfort with referring [OR 67.4 (CI 5.8-779.8) p < 0.001] and greater distance to a TES surgeon [OR 4.5 (CI 1.17–16.9 p < 0.001)] remained independently associated with low referral rate. Provinces with a population of > 1 million [OR 3.66 (CI 1.49-9.0) p < 0.01], academic practice settings [OR 3.05 (CI 1.29–7.3) p < 0.05], and surgeon endoscopists [OR 4.5 (CI 1.68, 12.1) p < 0.01] were all independently associated with greater TES accessibility.
Conclusions
Many patients who are potentially eligible for TES are not being referred for consideration. An educational gap regarding indications, lack of comfort among referring physicians and geographic inaccessibility are among the greatest barriers to referral.