bluuebunny/crossref_metadata_2025 huggingface dataset:
Education, intelligence, and 20 gastrointestinal disorders: A Mendelian randomization study
Authors: He Jun , Lin Yunzhi , Ding Zhen
Published: December 2024

Previous observational studies have suggested that higher levels of education attainment and intelligence (IQ) are associated with better health outcomes in humans. However, the causal link between education attainment and IQ and their association with health outcomes remains unclear. This study aims to investigate the distinct impacts of intelligence and educational attainment on gastrointestinal symptoms. From the genome-wide association between educational attainment and the IQ study database, results were obtained from the FinnGen summary database. We used univariate and multivariate Mendelian randomization (MR) techniques to explore the relationship between exposures and outcomes. To assess the validity of inverse-variance-weighted-based results, we used several supplementary analytical techniques and performed sensitivity analysis. Our multivariate MR study confirmed the findings from univariable analyses and showed a genetically predicted causal association between educational attainment and 8 gastrointestinal disorders, including gastroesophageal reflux disease, chronic gastritis, gastroduodenal ulcer, cirrhosis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and irritable bowel syndrome. Our univariate MR study found an association between IQ and 6 gastrointestinal conditions: gastroesophageal reflux disease, cirrhosis, cholelithiasis, acute pancreatitis, pancreatic malignancy, and irritable bowel syndrome. However, the connection was much weaker in multivariate MR analysis. Our study revealed causal relationships between gastrointestinal disorders and educational attainment. Educational attainment may mediate between intelligence and the impacts on the gastrointestinal system. However, further research is required to understand the underlying pathogenic processes completely.
Bibliometric analysis of autophagy in NAFLD from 2004 to 2023
Authors: Xu Sumei , Zhang Yating , Huang Qi , Xie Yiwen , Tong Xiaojuan , Liu Haoge
Published: December 2024

Background:

Autophagy is a cellular process in which damaged organelles or unnecessary proteins are encapsulated into double-membrane structures and transported to lysosomes for degradation. Autophagy plays a crucial role in various liver diseases, including nonalcoholic fatty liver disease. This study aims to elucidate the role of autophagy in nonalcoholic fatty liver disease through bibliometric analysis.

Methods:

Literature was retrieved from Web of Science CoreCollection database, and the search time was from January 01, 2004 to December 31, 2023. Data retrieval was performed using the Bibliometrix package in R software. VOSviewer and CiteSpace were utilized to visualize the research hotspots and trends related to the effect of autophagy on nonalcoholic fatty liver disease.

Results:

A total of 966 papers were obtained, published in 343 journals from 1385 institutions across 57 countries. The journals with the most publications were the “International Journal of Molecular Sciences” and “Scientific Reports.” China had the highest number of published papers. The most productive authors were Yen Paul M and Jung Tae Woo, while Singh R was the most frequently co-cited author. Emerging research hotspots were associated with keywords such as insulin resistance, ferroptosis, endoplasmic reticulum stress, and mitochondrial function.

Conclusion:

Research on autophagy in nonalcoholic fatty liver disease is still in its early stages, with a growing body of literature. This study is the first to provide a comprehensive bibliometric analysis, synthesizing research trends and advancements. It identifies current development trends, global cooperation models, foundational knowledge, research hotspots, and emerging frontiers in the field.
Lymphocyte infiltration in breast cancer: A promising prognostic indicator
Authors: Obeagu Emmanuel Ifeanyi , Obeagu Getrude Uzoma
Published: December 2024

Breast cancer is a leading cause of cancer-related mortality among women worldwide, necessitating the identification of reliable prognostic markers to guide treatment and improve patient outcomes. Recent research has highlighted the prognostic significance of tumor-infiltrating lymphocytes (TILs) in breast cancer, with high levels of TILs being associated with improved survival rates and better responses to therapy. This review delves into the mechanisms driving lymphocyte infiltration, its clinical implications, and the potential for TILs to serve as predictive biomarkers in breast cancer management. The presence of TILs within the tumor microenvironment reflects a dynamic interplay between tumor cells and the host immune system. Chemokine signaling, antigen presentation, and immune checkpoint interactions are key mechanisms that facilitate the recruitment and activity of lymphocytes at the tumor site. Clinically, the density of TILs varies across breast cancer subtypes, with the most significant prognostic value observed in triple-negative and HER2-positive breast cancers. High TIL levels correlate with improved overall survival and disease-free survival, underscoring their potential as a valuable prognostic indicator. Therapeutically, the role of TILs has opened new avenues in breast cancer treatment, particularly in the realm of immunotherapy. Immune checkpoint inhibitors, adoptive cell therapy, and combination therapies leveraging TILs are being explored to enhance antitumor responses. As research progresses, the integration of TIL assessment into routine clinical practice could revolutionize personalized treatment strategies, ultimately improving prognostic accuracy and patient outcomes in breast cancer care.
Optimal duration of progesterone before cryopreserved embryo transfer in hormone replacement therapy cycles: A prospective pilot study
Authors: Zhao Lijuan , Liu Liu , Dai Yongdong , Zhou Feng , Li Chao , Hu Xiaoxiao , Li Jing , Zhang Yanling , Zhang Songying
Published: December 2024

This prospective pilot cohort study aimed to ascertain the optimal duration of progesterone supplementation prior to frozen embryo transfer (FET) in women undergoing hormone replacement therapy (HRT) cycles. A total of 127 participants were enrolled and divided into 2 cohorts. The first cohort, comprising of 39 women, was used to determine the peak period of endometrial receptivity. These participants underwent serial assessments of integrin alphavbeta3, homeobox gene A10, and leukemia inhibitory expression levels from days 3 to 7 (P + 3 to P + 7) during the mock HRT cycles. The second cohort included 88 women who embarked on their inaugural HRT-FET cycle and were monitored for pregnancy outcomes after the transfer of D3 embryos after 3 or 4 days of progesterone administration. The results indicated a significant enhancement in biochemical pregnancy and embryo implantation rates in the P + 3 group (87.18% and 74.36%, respectively) compared to those in the P + 4 group (68.42% and 65.79%; P = .047 and P = .044, respectively). These data suggest that a 3-day progesterone regimen prior to D3 embryo transfer may be more beneficial. Notably, the maximal expression of endometrial receptivity markers was observed on day P + 6 within the HRT cycles, which is consistent with previous research that correlated day 6 embryos with peak endometrial receptivity. Therefore, a 3-day progesterone lead-in may enhance synchrony between D3 embryos and the endometrium. Our findings suggest that initiating D3 embryo transfer after 3 days of progesterone administration may optimize embryo-endometrial synchronization, thereby potentially enhancing clinical outcomes in FET cycles.
New systemic inflammatory indices as predictors of ascending aortic dilation in children with bicuspid aortic valve: A retrospective cross-sectional study
Authors: Yükcü Bekir , Arslan Hilmi Furkan
Published: December 2024

Systemic inflammatory indices, originally developed to predict the prognosis of cancer patients, have found increasing application in various medical areas, including cardiovascular research. This study aimed to investigate the relationship between ascending aortic dilatation in bicuspid aortic valve patients and systemic inflammatory indices. This retrospective cross-sectional study included 122 patients with bicuspid aortic valves. These patients were divided into 2 groups based on the presence or absence of dilatation according to ascending aorta z-scores. Complete blood counts were analyzed, focusing on leukocyte, neutrophil, lymphocyte, monocyte, and platelet counts. Additionally, systemic inflammatory indices including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), Systemic Immune-Inflammation Index (SII), Systemic Inflammatory Response Index (SIRI), and monocyte-to-lymphocyte ratio (MLR) and pan-immune-inflammation value (PIV) were calculated from these parameters. MLR, SIRI, and PIV demonstrated acceptable diagnostic power in detecting ascending aortic dilatation in bicuspid aortic valve patients, with area under the curve (AUC) values of 0.709, 0.741, and 0.779, respectively. PLR and SII exhibited fair diagnostic power, with AUC values of 0.673 and 0.688, respectively. According to the receiver operating characteristic analysis, PIV had the highest AUC value of 0.779 (95% confidence interval [CI] = 0.69–0.86), with a sensitivity of 70.9% and specificity of 70.8% at a cutoff value of 224.93. A relationship exists between PLR, MLR, SII, SIRI, PIV, and ascending aorta dilatation in pediatric patients with bicuspid aortic valves. These findings suggest that inflammation may play a role in the dilatation of the ascending aorta in bicuspid aortic valve patients.
Clinical and genetic characteristics of a case of Koolen-De Vries syndrome caused by KANSL1 gene mutation and literature review: A case report
Authors: Zhang Haozheng , Yuan Limei , Fan Meili , Liu Zhaotian , Yan Yuxi , Liu Qinghua , Zhang Kaihui , Li Chunmiao , Liu Deyao
Published: December 2024

Rationale:

Koolen-De Vries syndrome (KdVS, OMIM: 612452), also known as 17q21.31 microdeletion syndrome, is an autosomal dominant genetic disease. In the study, we analyze of clinical phenotype and gene variation of a child with Koolen-De Vries syndrome, review the literature to improve the understanding of the disease.

Patient concerns:

The patient is a male, aged 1 month and 3 days. The patient has poor airway development, difficulty weaning from respiratory support, seizures, and recurrent low granulocyte counts.

Diagnoses:

High-throughput sequencing showed a heterozygous mutation NM_001193466.1: c.1574_1578del (P.525HFS *24) in the KANSL1 gene of the proband, which was considered a new mutation since neither of his parents carried this mutation based on Sanger sequencing results. Combining clinical features and genetic results, the proband was diagnosed as KdVS.

Interventions and outcomes:

The patient was in good condition after receiving bronchoscopy and laser interventional therapy, meeting the criteria for discharge. Follow-up for 1 year and 6 months indicated that the patient’s physical signs were normal and there was no recurrence.

Lessons:

According to literature review, KdVS is a multi-organ disease characterized by feeding difficulties, seizures, characteristic facial features, dysplasia of the respiratory system and cardiac abnormalities. In this study, laryngeal malacia accounted for 23.2% of the clinical manifestations of KdVS patients, limb convulsions/seizures accounted for 62.5%, and cardiac development defects accounted for 23.5%. The disease was rare in China and had a variety of clinical manifestations. The summary of reported cases can enable doctors to have more understanding of the disease. The new mutations enrich the KANSL1 gene mutation spectrum.
Ethnicity as a Risk Factor for Early Neurological Deterioration
Authors: Goldstein Eric D. , Liew Sabrina Q.R. , Shu Liqi , Rocha Alicia , Yaghi Shadi
Published: December 2024

Objectives:

Nearly 25% of those with a small vessel stroke will develop early neurological deterioration (END). The objectives of this study were to identify clinical risk factors for small vessel stroke-related END and its associated impact on functional outcomes in an ethnically diverse data set.

Methods:

We performed a post hoc analysis of the “Secondary Prevention of Small Subcortical Strokes” trial. The primary outcome was END defined as progressive or stuttering stroke-related neurological symptoms. Standard descriptive and inferential statistical methods were used for analysis. Functional outcomes are reported by modified Rankin Scale score and analyzed by the Wilcoxon signed-rank test.

Results:

In all, 69 participants met the inclusion criteria; 21 (30%) had END. Of the cohort, Spanish, Hispanic, or Latino ethnicity (grouping per trial definition) most frequently developed END [11 (52.4%) vs 4 (8.3%), P < 0.001] with a higher adjusted likelihood of END (odds ratio: 14.1, 95% CI: 2.57-76.7, P = 0.002). Black or African-American race less commonly had END [3 (14.3%) vs 21 (43.8%), P = 0.03] but lost significance after adjustment (odds ratio: 1.46, 95% CI: 0.26-8.17, P = 0.67) due to powering. END was associated with a higher mean modified Rankin Scale (2.06 ± 0.94 vs 1.17 ± 0.79, P = 0.006) but did not differ in the shift analysis.

Conclusions:

We found that Spanish, Hispanic, or Latino ethnicity was the most consistent risk factor for END though it was without meaningful functional outcome differences.
Notable Programs in Neurotology Series: The University of Miami Ear Institute
Authors: Oliva Allison D. , Angeli Simon I.
Published: December 2024

The University of Miami Ear Institute (UMEI) was conceived and founded by Dr. W. Jarrard (Jerry) Goodwin in 1990, then Chairman of the University of Miami Department of Otolaryngology–Head and Neck Surgery. Dr. Goodwin’s goal was to establish a state-of-the-art institution featuring world-renowned experts in otology, audiology, cochlear implants, balance disorders, skull base surgery, and research. With the support of many within and outside the University, he succeeded in this endeavor and appointed Thomas J. Balkany the first director of the Ear Institute. Under Dr. Balkany’s leadership, the institute continued to evolve alongside the growing University of Miami Department of Otolaryngology, pioneering developments in pediatric cochlear implant surgery and postoperative care and basic science research. Dr. Balkany transitioned from UMEI Director in 2010, succeeded by Dr. Fred F. Telischi, and subsequently Dr. Simon I. Angeli who is the current Ear Institute Director. The Ear Institute experienced exponential growth in clinical services, research, education, and advocacy throughout the 2nd decade of the 21st century. Renamed the UHealth Ear Institute, its organizational structure evolved to meet new challenges. In its 34-year history, the UHealth Ear Institute has transformed from an idea into a nationally and internationally recognized center of excellence. It remains dedicated to advocating for universal hearing health, ensuring access to hearing health services, providing exceptional patient care, advancing innovative research, and training future specialists.
Childhood Familial Mediterranean Fever in the United States
Authors: Fathalla Basil M. , Thomas Ronald
Published: December 2024

Objectives

The aim of this study was to report the spectrum of Familial Mediterranean Fever (FMF) in children living in Southeast Michigan.

Methods

We reviewed prerecorded data in medical records of FMF patients. Statistical analysis of the data included Fisher exact test, Pearson χ2 procedure, parametric independent samples t test, and parametric analysis of variance using SPSS Version 29.0, IBM Inc.

Results

The study included 29 males and 21 females. The mean age at presentation was 4.63 ± 3.66 years, and the mean time to diagnosis was 2.1 ± 2.18 years. A slight majority presented in the first 3 years of age (54%). Family history of FMF was reported in only 58% of patients. Clinical manifestations included fever (84%), gastrointestinal (84%), musculoskeletal (64%; including chronic arthritis, sacroiliitis, and nonbacterial osteomyelitis), chest (28%), cutaneous (14%), and other manifestations (16%). Fever without other manifestations was reported only in patients presenting at ≤3 years of age (p = 0.016), whereas older patients reported more gastrointestinal manifestations (p = 0.04). Reported MEFV variants included p.M694V (n = 26), p.V726A (n = 23), p.M694I (n = 13), and others (n = 10). Homozygote and compound heterozygote patients had more gastrointestinal manifestations (p < 0.001), whereas fever was more common in the heterozygote patients (p = 0.04). The mean follow-up period was 5.34 ± 4.13 years with no renal disease.

Conclusions

We report the largest childhood FMF cohort in the United States. A negative family history should not preclude consideration of FMF as a cause of periodic fever. Recurrent fever can be the only manifestation, particularly in young patients with FMF. The absence of fever and chronic progressive musculoskeletal manifestations can uncommonly occur.
Chronic digoxin exposure causes hyperactivity, anxiolysis, and alters brain monoamine content in zebrafish (Danio rerio)
Authors: Kazanskaya Rogneda B. , Ilyin Nikita P. , Abaimov Denis A. , Derzhavina Ksenia A. , Demin Konstantin A. , Kalueff Allan V. , Gainetdinov Raul R. , Lopachev Alexander V.
Published: December 2024

To investigate the effects of chronic exposure to the cardiotonic steroid digoxin on locomotor activity, anxiety, and brain tissue monoamine content in Zebrafish. In total 24 adult (3–5 months) wild-type experimentally naïve zebrafish (50 : 50 ratio of females to males) were housed in 4-L tanks, in groups of six animals per tank. Two μM Digoxin was maintained in half of the tanks for 7 days. The ‘Novel tank test’ was performed on day 7 and the animals were euthanized. Concentrations of dopamine, serotonin, and their metabolites were then quantified in brain tissue using HPLC-ED. Seven-day exposure to 2 μM water solution of digoxin caused robust hyperlocomotion and reduced anxiety-like behavior in adult zebrafish in the ‘Novel tank test’. The treatment also evoked pronounced neurochemical responses in zebrafish, including increased whole-brain 3-methoxytyramine, reduced norepinephrine and serotonin, and unaltered dopamine, homovanillic acid or 5-hydroxyindoleacetic acid levels. Deficits in monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission are a key pathogenetic factor for multiple neuropsychiatric and neurodegenerative diseases. Commonly used clinically to treat cardiac conditions, cardiotonic steroids can affect dopaminergic neurotransmission. Chronic exposure to digoxin evokes hyperactivity-like behavior accompanied by altered monoamine neurotransmission in zebrafish, which may be relevant to understanding the central nervous system side effects of cardiotonic steroids.
Protein Kinase C-β Inhibition and Survival Signaling after Simulated Cardioplegic Ischemia/Reperfusion in Non-Diabetic and Diabetic Human Coronary Arterial Endothelial Cells
Authors: Nho Ju-Woo , Banerjee Debolina , Harris Dwight D , Stone Christopher , Xing Hang , Kanuparthy Meghamsh , Li Janelle , Sellke Frank W , Feng Jun
Published: December 2024

Background:

Cardioplegic ischemia/reperfusion (I/R) injury poses substantial challenges during postoperative recovery, with diabetic patients particularly susceptible to adverse events. Using a model entailing the subjection of human coronary artery endothelial cells (HCAECs) to simulated cardioplegic I/R, we investigated the potential of protein kinase c β (PKC-β) inhibition to augment cellular survival in this context.

Study Design:

HCAECs were isolated from harvested coronary arteries of diabetic (D) and nondiabetic (C) patients (N = 4 per group). HCAECs were either cultured in normoxic conditions without drug (D and C), subjected to hypoxia/reoxygenation alone (DH and CH), or subjected to hypoxia/reoxygenation and the PKC-β inhibitor LY333531 (DHT and CHT). Molecular signaling was assessed using immunoblotting.

Results:

Simulated I/R decreased anti-apoptotic phosphorylated protein kinase b (p-Akt, p = 0.04) and p-Akt:Akt ratio (p = 0.004) in CH versus C, with PKC-β inhibition restoring expression in CHT (p ≤ 0.04). Treatment also increased p-Akt:Akt ratio in DHT versus D (p = 0.03). Anti-apoptotic inducible nitric oxide synthase increased in CHT versus CH (p = 0.003), and pro-apoptotic phosphor-FOXO:FOXO ratio decreased in CHT versus CH (p = 0.001). I/R elevated Bcl-2-associated agonist of cell death (BAD) in CH versus C (p = 0.01), but PKC-β inhibition increased anti-apoptotic p-BAD (p = 0.001) and p-BAD:BAD ratio (p = 0.03) in CHT. I/R also increased cleaved PARP (p < 0.001) and cleaved caspase 3 (p < 0.001) in DH versus D, both of which were reversed by treatment (p < 0.001 for DHT versus DH).

Conclusion:

PKC-β inhibitor treatment increased pro-survival signaling and decreased pro-apoptotic signaling in nondiabetic and diabetic HCAECs subjected to simulated I/R, with mechanistic differences observed between these cohorts.
Dexmedetomidine and Nitrous Oxide as Anesthetic Agents for Electroconvulsive Therapy
Authors: Chung In Won , Kim Heung Sik , Lee Junhee , Kim Jee Hee , Kim Sang Ha , Kim Yong Sik
Published: December 2024

Electroconvulsive therapy (ECT) is a therapeutic intervention that induces generalized seizures under general anesthesia. This case report compares the efficacy of dexmedetomidine (DEX) and nitrous oxide (N2O) to that of propofol during ECT procedures. A 33-year-old woman with a 15-year history of schizophrenia and recurrent psychotic episodes underwent ECT. During a previous hospitalization, she underwent 14 ECT sessions using propofol and succinylcholine. The mean electrical stimulation dose was 598.9 ± 237.6 mC, with mean motor and electroencephalogram seizure durations of 23.8 ± 8.0 and 34.9 ± 8.3 seconds, respectively. During her current hospitalization, she underwent an additional 14 ECT sessions using DEX and N2O. The mean electrical stimulation dose was significantly lower, at 239.4 ± 54.7 mC, with comparable motor and electroencephalogram seizure durations of 34.6 ± 11.6 and 36.3 ± 12.5 seconds, respectively. Our case report emphasizes the effectiveness of using DEX and N2O for ECT anesthesia compared to propofol. Despite a significantly lower mean electrical stimulation dose requirement with DEX and N2O (t = 5.5155, P < 0.00001), no significant differences were observed in electroencephalogram seizure duration between the groups.
Translation and Critical Evaluation of the Columbia University Autobiographical Memory Interview—Short Form for use in the Dutch Language
Authors: Nwatarali Chioma , Verwijk Esmée , Blokland Dominique , Bergfeld Isidoor O.
Published: December 2024

Introduction

Assessment of autobiographical memory following electroconvulsive therapy is lacking multilingual options. We therefore developed the Dutch translation of the Columbia University Autobiographical Memory Interview—Short Form (CUAMI-SF). We aimed to assess its practical use and identify segments for potential revision to improve the interview’s applicability.

Methods

The CUAMI-SF comprises 30 questions asking details about 6 segments (eg, last trip, last birthday) and 7 question categories (eg, dates, list of persons present). The interview was translated to Dutch using blind back-translation principles. We evaluated practicality and potential redundancy, through surveying a focus group and quantitative analyses of 60 participants, including depressed patients treated with electroconvulsive therapy (n = 14) or deep brain stimulation (n = 25) and healthy controls (n = 21). For the quantitative analyses, we compared the average percentage of nonanswered questions at baseline between groups. The average consistency scores after a follow-up of approximately 6 weeks were also calculated and compared for each segment between the groups.

Results

The focus group mostly found the CUAMI-SF easy to use and to score, but argued redundancy in specific questions asking for dates, numbers, and addresses. The largest differences in consistency scores between the groups were present for the segments “travel,” “birthdays,” “New Year’s Eve,” and “doctor’s visits,” indicating higher sensitivity compared with “family member” and “job.”

Discussion

The CUAMI-SF was found easy to use by administrators. The segments “family member” and “job” emerged as less sensitive. Therefore, removal might maintain sensitivity while reducing administration time, which could prove beneficial in clinical and research settings.
Parallel and converging multisensory cascades in theDrosophilaconnectome
Authors: Betzel Richard , Puxeddu Maria Grazia , Seguin Caio , Misic Bratislav
Published: December 2024

Connectomes are network maps of synaptic connectivity. A key functional role of any connectome is to constrain inter-neuronal signaling and to sculpt the flow of activity across the nervous system. Connectomes therefore play a central role in the rapid tranmission of information about an organism’s environment from sensory neurons to higher-order neurons for action planning and ultimately to effectors. Here, we use a parsimonious model of activity spread to investigate the connectome’s role in shaping putative sensory cascades. Our model allows us to simulate the signaling pathways from sensors to the rest of brain, mapping the similarity of these pathways between different sensory modalities and identifying convergence zones–neurons that are activated simultaneously by different sensory modalities. Further, we considered two multisensory integration scenarios – a cooperative case where different sensory modalities interacted to “speed up” (reduce) neurons’ activation times and a competitive “winner take all” case, where different sensory streams vied for the same neural territory. Finally, we use a data-driven algorithm to partition neurons into different classes based on their behavior during the cascade simulations. Our work helps underscore the role of “simple” models for enriching connectome data, while offering a data-driven classification of neurons based on their joint connectional/dynamical properties.
Microfiber-Templated Porogel Bioinks Enable Tubular Interfaces and Microvascularization Down to the Building Blocks for 3D Bioprinting
Authors: Guo Yuzhi , Wang Ziyu , Zhang Xuening , Li Jinghang , Ouyang Liliang
Published: December 2024

Vascularization is key to the biofabrication of large-scale tissues. Despite the progress, there remain some outstanding challenges, such as limited vessel density, difficulty in fabricating microvasculatures, and inhomogeneity of post-seeding cells. Here, we introduce a new form of bioink called microfiber-templated porogel (μFTP) bioink to engineer vasculatures down to the filament building blocks of 3D bioprinted hydrogels. The cell-laden sacrificial microfibers (diameter ranges from 50-150 μm) are embedded in the bioink to template tubular voids and deliver endothelial cells forin-situendothelialization. The inclusion of softening hydrogel microfibers retains the desirable rheological properties of the bioink for extrusion-based bioprinting. Such bioinks can be printed into a well-defined 3D structure with tunable tubular porosities up to 55%. Compared to the conventional bulk bioink counterpart, the μFTP bioink supports the significant growth and spread of endothelial cells either embedded in the matrix or sacrificial fibers, free of the post-cell seeding procedure. Furthermore, the bioprinted scaffolds based on μFTP bioink are seen to significantly promote the in-growth of blood vessels and native tissuesin vivo. The μFTP bioink approach enables the engineering of tubular bio-interfaces within the building blocks and contributes to thein-situendothelialization of microvasculatures, providing a versatile tool for the construction of customized vascularized tissue models.
Microvascular preservation and cardiomyocyte hyperplasia underlie adaptive right ventricular development in congenital heart disease-associated pulmonary arterial hypertension
Authors: Smith Michael A. , Guardado Eleana Stephanie , Boehme Jason , Datar Sanjeev A. , Maltepe Emin , Swami Naveen , Raff Gary W. , Bodansky Aaron , Moreno Joseph , Prince Annelise , Powers Nevan , Huang Guo N. , de Jesus Perez Vinicio , Fineman Jeffrey R.
Published: December 2024

Abstract

Background

Right ventricular (RV) failure is the primary cause of death among patients with pulmonary arterial hypertension (PAH). Patients with congenital heart disease- associated PAH (CHD-PAH) demonstrate improved outcomes compared to patients with other forms of PAH, which is related to the maintenance of an adaptively hypertrophied RV. In an ovine model of CHD-PAH, we aimed to elucidate the cellular, microvascular, and transcriptional adaptations to congenital pressure overload that support RV function in CHD-PAH.

Methods

Fetal surgery was performed on late gestation lambs to insert a large aortopulmonary graft, leading to a persistent congenital left-right shunt and RV pressure load. At 3 days and 4-6 weeks of life, shunt RV microvasculature, cardiomyocyte structure, and myocardial growth mechanisms were compared to age-matched controls and unoperated fetal RV. RNA sequencing was performed to assess differences in the RV transcriptomes.

Results

At 4-6 weeks of age, shunt lambs demonstrate significant RV enlargement (shunt 37.1 ± 2.9g vs control 15.9 ± 1.0g, p<0.001) but maintain stable microvascular density (fetal 3.0 ± 0.6 vs shunt 2.9 ± 0.3 vs control 3.1 ± 0.6 capillaries per 1000 µm3, p>0.05). Shunt RV cardiomyocytes are significantly smaller by cross-sectional area and more numerous than age-matched controls (shunt 73.3 ± 5.5 µm2vs control 99.2 ± 4.9 µm2, p=0.013). At 3 days, shunt RV cardiomyocytes show evidence of increased proliferative capacity and ongoing hyperplasia compared to controls. RNA sequencing analyses reveal a distinct gene expression profile in shunt RV consistent with a delay in terminal differentiation and metabolic adaptations to support adaptive function.

Conclusions

This study provides novel insights into the development of adaptive RV hypertrophy in CHD-PAH, demonstrating roles for preserved microvascular density and increased postnatal cardiomyocyte hyperplasia in supporting RV performance. Future investigations into the mechanisms underlying these changes could have significant implications for the development of novel therapeutic strategies for supporting RV function.
Essential strategies for the detection of constitutive and ligand-dependent Gi-directed activity of 7TM receptors using bioluminescence resonance energy transfer
Authors: Endzhievskaya Sofia , Chahal Kirti , Resnick Julie , Khare Ekta , Roy Suchismita , Handel Tracy M. , Kufareva Irina
Published: December 2024

The constitutive (ligand-independent) signaling of G protein-coupled receptors (GPCRs) is being increasingly appreciated as an integral aspect of their function; however, it can be technically hard to detect for poorly characterized, e.g. orphan, receptors of the cAMP-inhibitory Gi-coupled (GiPCR) family. In this study, we delineate the optimal strategies for the detection of such activity across several GiPCRs in two cell lines. As our study examples, we chose two canonical GiPCRs - the constitutively active Smoothened and the ligand-activated CXCR4,-and one atypical GPCRs, the chemokine receptor ACKR3. We verified the applicability of three Bioluminescence Resonance Energy Transfer (BRET)-based assays - one measuring changes in intracellular cAMP, another in Gβγ/GRK3ct association and third in Gαi-Gβγ dissociation, - for assessing both constitutive and ligand-modulated activity of these receptors. We also revealed the possible caveats and sources of false positives, and proposed optimization strategies. All three types of assays confirmed the ligand-dependent activity of CXCR4, the controversial G protein incompetence of ACKR3, the constitutive Gi-directed activity of SMO, and its modulation by PTCH1. We also demonstrated that PTCH1 promotes SMO localization to the cell surface, thus enhancing its responsiveness not only to agonists but also to antagonists, which is a novel mechanism of regulation of a Class F GiPCR Smoothened.
Regulation of B cell migration to the Bursa of Fabricius by CCR7 and cell adhesion molecules in chicken embryonic development
Authors: Brunner Milena , Cavaleiro Catarina L. C. T. , Berghof Tom V. L. , Wurmser Christine , Elleder Daniel , von Heyl Theresa , Schusser Benjamin
Published: December 2024

The development of functional B lymphocytes during chicken embryogenesis relies on a series of tightly regulated processes. Precursor B cells migrate from the spleen via the blood to the bursa of Fabricius, where they colonize the bursal follicles to undergo further maturation and differentiation. To better understand the molecular mechanisms underlying early B cell migration in the chicken embryo, transcriptome analysis of B cells isolated from the spleen, blood, and bursa at embryonic days (ED) 12, ED14, and ED16 was performed. These findings suggest that sphingosine-1-phosphate (S1P) and its receptors regulate B cell presence in the bloodstream, while CCR7 and CXCR4 guide B cells to the bursa. Additionally, integrins and cell adhesion molecules, such as PECAM1, appear to facilitate transendothelial migration into the bursal mesenchyme. This study highlights a coordinated interplay between chemokines, integrins and cell adhesion molecules involved in B cell recruitment and colonization of the bursa microenvironment. These findings enhance our understanding of early B cell migration and shed light on the mechanisms governing B cell trafficking during chicken embryonic development.
Modeling and predicting single-cell multi-gene perturbation responses with scLAMBDA
Authors: Wang Gefei , Liu Tianyu , Zhao Jia , Cheng Youshu , Zhao Hongyu
Published: December 2024

Understanding cellular responses to genetic perturbations is essential for understanding gene regulation and phenotype formation. While high-throughput single-cell RNA-sequencing has facilitated detailed profiling of heterogeneous transcriptional responses to perturbations at the single-cell level, there remains a pressing need for computational models that can decode the mechanisms driving these responses and accurately predict outcomes to prioritize target genes for experimental design. Here, we present scLAMBDA, a deep generative learning framework designed to model and predict single-cell transcriptional responses to genetic perturbations, including single-gene and combinatorial multi-gene perturbations. By leveraging gene embeddings derived from large language models, scLAMBDA effectively integrates prior biological knowledge and disentangles basal cell states from perturbation-specific salient representations. Through comprehensive evaluations on multiple single-cell CRISPR Perturb-seq datasets, scLAMBDA consistently outperformed state-of-the-art methods in predicting perturbation outcomes, achieving higher prediction accuracy. Notably, scLAMBDA demonstrated robust generalization to unseen target genes and perturbations, and its predictions captured both average expression changes and the heterogeneity of single-cell responses. Furthermore, its predictions enable diverse downstream analyses, including the identification of differentially expressed genes and the exploration of genetic interactions, demonstrating its utility and versatility.
SpatioMark: Quantifying the impact of spatial proximity on cell phenotype
Authors: Iyengar Sourish S , Qin Alex R , Robertson Nicholas , Harman Andrew N , Patrick Ellis
Published: December 2024

As research advances in spatially resolving the biological archetype of various diseases, technologies that capture the spatial relationships between cells are demonstrating increasing value. Whilst there are an increasing number of analytical methods being developed to identify the complex web of interactions between cells, the downstream impacts of these cell-cell relationships are under explored. Here, we present SpatioMark, a statistical framework that simplifies the assessment of gene or protein expression in relation to the spatial proximity of different cell types. We demonstrate its performance across spatial proteomics and transcriptomics datasets and link identified relationships with differences in patient survival. We highlight key challenges in identifying changes in molecular markers associated with the localisation of cells and propose corrections which reduce artefact induced relationships. SpatioMark is implemented in the Statial R package hosted on the Bioconductor Project, ensuring interoperability with existing spatial analysis tools. Ultimately, this work highlights strategies for identifying and interpreting changes in cell phenotype associated with cellular relationships in spatial omics data, with broad applicability across various multiplexed imaging platforms.
Neural Circuit Mechanisms Underlying Dominance Traits and Social Competition
Authors: Yan Han , Wang Jin
Published: December 2024

The survival of animals often hinges on their dominance status, established through repeated social competitions. The dorsomedial prefrontal cortex (dmPFC) plays a pivotal role in regulating these competitions, yet the formation of intrinsic traits like grit and aggressiveness, crucial for competitive outcomes, remains poorly understood. In this study, we constructed a dmPFC circuit model based on experimental recordings to replicate the characteristic activities of dmPFC neurons during various behavioral patterns observed in the dominance tube test. Our findings reveal that the dmPFC circuit supports bistable behavior states—effortful and passive—depending on external conditions. This bistability is essential for understanding how animals adapt their behaviors in social competitions, thereby influencing the establishment of social hierarchies. Our results indicate that increased self-excitation in pyramidal neurons within the dmPFC enhances the robustness of effortful behaviors, akin to perseverance, but reduces flexibility in responding to rapid external changes. This suggests that dominance status benefits more from perseverance than from increased aggression. Additionally, our study shows that when rapid responses to external signals are necessary, the basal activity in dmPFC neurons can be reconfigured to enhance flexibility, albeit at higher energy costs. This research advances our understanding of the neural basis of social behavior and provides a framework for further exploration into how neural circuits contribute to complex behavioral traits, offering insights into the neural dynamics underlying social dominance. This research also opens avenues for investigating psychiatric and neurological disorders where these mechanisms may be disrupted.
Transcriptomic Landscape and Immune Microenvironment Around Wound Bed Define Regenerative versus Non-regenerative Outcomes in Mouse Digit Amputation
Authors: Prabahar Archana , Chamberlain Connie S. , Vanderby Ray , Murphy William L. , Dangelo William , Mangesh Kulkarni , Brown Bryan , Mazumder Barsanjit , Badylak Stephen , Jiang Peng
Published: December 2024

In the mouse distal terminal phalanx (P3), it remains unclear why amputation at less than 33% of the digit results in regeneration, while amputation exceeding 67% leads to non-regeneration. Unraveling the molecular mechanisms underlying this disparity could provide crucial insights for regenerative medicine. In this study, we aim to investigate the tissues within the wound bed to understand the tissue microenvironment associated with regenerative versus non-regenerative outcomes. We employed a P3-specific amputation model in mice, integrated with time-series RNA-seq and a macrophage assay challenged with pro- and anti-inflammatory cytokines, to explore these mechanisms. Our findings revealed that non-regenerative digits exhibit a greater intense early transcriptional response in the wound bed compared to regenerative ones. Furthermore, early macrophage phenotypes differ distinctly between regenerative and non-regenerative outcomes. Regenerative digits also display unique co-expression modules related to Bone Morphogenetic Protein 2 (BMP2). The differentially expressed genes (DEGs) between regenerative and non-regenerative digits are enriched in targets of several transcription factors, such as HOXA11 and HOXD11 from the HOX gene family, showing a time-dependent pattern of enrichment. These transcription factors, known for their roles in bone regeneration, skeletal patterning, osteoblast activity, fracture healing, angiogenesis, and key signaling pathways, may act as master regulators of the regenerative gene signatures. Additionally, we developed a deep learning AI model capable of predicting post-amputation time and level from RNA-seq data, with potential applications in personalized treatment strategies and assessing the impact of interventions on regenerative outcomes.
Motivators and Barriers to Mouthguard Compliance by Adult Gaelic Football Athletes
Authors: Burke Aoife , O’Connor Niall , Duffy Niall , Holohan Katie , Whyte Enda F , O’Connor Siobhán
Published: December 2024

Introduction

Dental injuries contribute to 57% of reported maxillofacial injuries in Gaelic Football, with associated psychological and economic impacts on the affected athletes. Mouthguards have been developed in efforts to mitigate the incidence and severity of dental injuries, and use is mandatory in Gaelic Football. Dental claims have reduced by over 50% since mouthguards became mandatory, but costs of dental injuries are still prevalent. The aim of this study was to determine the mouthguard compliance rates in adult Gaelic Football players, as well as the motivations and barriers to compliance.

Methods

This cross-sectional study utilised an online survey to determine the self-reported compliance of adult Gaelic Footballers with mouthguard use, the perceived peer compliance, and the motivations and barriers to compliance. Chi-square tests were used to examine differences between sex and between elite and sub-elite players.

Results

A total of 545 Gaelic Footballers completed the survey. During training, 22% of players reported to always wear a mouthguard, with 48% never wearing it, and 30% occasionally wearing it. For games, 48% of players reported to wear a mouthguard, with 11% never wearing it and 41% occasionally wearing it. Motivating factors included teeth protection, gum protection and the rules of the game. The main barriers were discomfort, difficulty breathing and difficulty speaking. Females had significantly poorer compliance in training, but had significantly better compliance in games when compared to males.

Conclusion

Mouthguard compliance is relatively poor amongst adult Gaelic Football players. Although compliance improves for games compared to training, there are still 1 in 2 players not wearing a mouthguard for games. Discomfort and challenges with breathing and speaking suggest that players may benefit from having a custom-fit mouthguard. Coaches, refereeing officials and governing bodies should strive to implement the rules more often and improve education around the benefits of mouthguard use within the sport.
Associations Between Menstrual Cycle Phases and Heart Rate, Well-Being, and Perceived Exertion in Female Football Players
Authors: Lipková Lucie , Beníčková Michaela , Wagner Adam , Kumstát Michal
Published: December 2024

This study aimed to investigate potential associations between menstrual cycle (MC) phases and heart rate (HR), perceived exertion (RPE), and subjective well-being in female football players. Data were collected from 11 players (aged 17–29 years) across 10 competitive matches. HR metrics, subjective well-being, and RPE were monitored in the pre-match, during-match, and post-match periods, as was the menstrual cycle in detail. Key findings revealed that during the early luteal (EL) phase, players spent significantly more time in moderate-intensity HR zones (Zone 4) in both the first (p = 0.046) and second halves (p = 0.051), while spending less time in high-intensity zones (Zone 5) during the first half (p = 0.012). Subjective measures highlighted elevated energy levels in the EL phase compared to the late luteal phase (p = 0.001), underscoring the influence of different menstrual cycle phases on well-being. However, RPE and maximum HR were predominantly shaped by external factors such as opponent strength (p < 0.001) and match outcome (p = 0.035). These results underscore the importance of exploring individual and contextual factors in understanding performance and well-being in female football players.
High resolution kinematic approach for quantifying impaired mobility of dystrophic zebrafish larvae
Authors: Widrick Jeffrey J. , Lambert Matthias R. , de Souza Leite Felipe , Jung Youngsook Lucy , Park Junseok , Conner James R. , Lee Eunjung Alice , Beggs Alan H. , Kunkel Louis M.
Published: December 2024

Dystrophin-deficient zebrafish larvae are a small, genetically tractable vertebrate model of Duchenne muscular dystrophy well suited for early stage therapeutic development. However, current approaches for evaluating their impaired mobility, a physiologically relevant therapeutic target, are characterized by low resolution and high variability. To address this, we used high speed videography and deep learning-based markerless motion capture to develop linked-segment models of larval escape response (ER) swimming. Kinematic models provided repeatable, high precision estimates of larval ER performance. Effect sizes for ER peak instantaneous acceleration and speed, final displacement, and ER distance were 2 to 3.5 standard deviations less for dystrophin-deficient mutants vs. wild-types. Further analysis revealed that mutants swam slower because of a reduction in their tail stroke frequency with little change in tail stroke amplitude. Kinematic variables were highly predictive of the dystrophic phenotype with ≤ 3% of larvae misclassified by random forest and support vector machine models. Tail kinematics also performed as well asin vitroassessments of tail muscle contractility in classifying larvae as mutants or wild-type, suggesting that ER kinematics could serve as a non-lethal proxy for direct measurements of muscle function. In summary, ER kinematics can be used as precise, physiologically relevant, non-lethal biomarkers of the dystrophic phenotype. The open-source approach described here may have applications not only for studies of skeletal muscle disease but for other disciplines that use larval mobility as an experimental outcome.
Gaze Following in Pigeons Increases with the Number of Demonstrators
Authors: Delacoux Mathilde , Itahara Akihiro , Kano Fumihiro
Published: December 2024

Gaze following, orienting one’s gaze in the same direction as another individual, is widespread across species and well-studied in terms of cognitive mechanisms. However, the role of collective context on this behavior is less understood. This study tested whether the number of conspecifics looking in a particular direction facilitates gaze following in pigeons (Columba livia). We presented attention-getting stimuli to subsets of pigeons (demonstrators), while other pigeons (observers) could not see the stimuli directly. We used a motion-capture system to track fine-scale movements of head and body orientations. Observer pigeons followed the gaze of demonstrators, specifically toward the target object rather than a perceptually similar distractor. Critically, the likelihood and frequency of gaze following increased with the number of demonstrators looking at the target. We observed no nonlinear effects, such as saturation or quorum thresholds, in this increasing trend, at least under our experimental conditions. In group-living species like pigeons, multiple individuals looking in the same direction may serve as a more reliable social signal. To our knowledge, this is the first study to demonstrate that the number of demonstrators influences gaze following in non- human animals, highlighting the critical role of collective context in animal social cognition.