bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesenchymal stromal cells ameliorate mitochondrial dysfunction in α cells and hyperglucagonemia in type 2 diabetes via SIRT1/FoxO3a signaling
Authors: Song Jia , Wang Lingshu , Wang Liming , Guo Xinghong , He Qin , Cui Chen , Hu Huiqing , Zang Nan , Yang Mengmeng , Yan Fei , Liang Kai , Wang Chuan , Liu Fuqiang , Sun Yujing , Sun Zheng , Lai Hong , Hou Xinguo , Chen Li 
Published: June 2024

Abstract
Dysregulation of α cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stromal cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α-cell mitochondrial dysfunction remains unclear. Here, human umbilical cord MSCs (hucMSCs) were used to treat 2 kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by Western blotting analysis. In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued the islet structure and decreased α- to β-cell ratio. Glucagon secretion from αTC1-6 cells was consistently inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion. Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.
Success of Resident Research Grants in Orthopaedic Trauma From 2000 to 2022: A Retrospective Review
Authors: Stanley Mackinzie A. , Tseng Joyee , Bird Mackenzie , Marecek Geoffrey S. 
Published: June 2024

OBJECTIVES:
The objective of this study was to determine the publication rate for orthopaedic trauma resident research projects that receive grant funding and the long-term academic involvement of the grant recipients.

METHODS:

Design:
Retrospective.

Setting:
Publically available records for resident research grant recipients.

Patient Selection Criteria:
Resident research grants on orthopaedic trauma topics from Orthopaedic Trauma Association (OTA), AO North America (AONA), and Orthopaedic Research and Education Foundation from 2000 to 2022.

Outcome Measures and Comparisons:
Subsequent related publications, grant size, time to publication, sustained academic involvement of the residents as measured by academic position, total number of publications, and h-index.

RESULTS:
Three hundred ninety-seven orthopaedic trauma grants (OTA 117, AONA 225, and OREF 55) were identified. A total of 38% (151) of grants resulted in a publication with no significant difference between agencies (P = 0.94). The average amount awarded was $9,843, with no correlation to publication (P = 0.63). The mean time to publication was 3.57 ± 2.33 years. The time to publication for AONA was significantly longer than for OTA (4.14 vs. 2.83 years, P = 0.004). There was no difference in total publications, h-index, or NIH grants between grant recipients from different agencies. More OTA grant recipients held an academic position compared with AONA grant recipients (63% vs. 43%, P = 0.003). Grant awardees with initial publication success were 1.7 times as likely to have a future academic appointment (P = 0.014) and had 1.9 times the number of publications than those without (P = 0.001). Awardees with an h-index in the top quartile were significantly more likely to have published than those with an h-index in the bottom quartile (P = 0.007).

CONCLUSIONS:
Fewer than half of orthopaedic trauma-related resident research grants resulted in a publication with comparable rates across agencies. Grant size did not predict publication success. Publication success was a positive predictor of continued academic involvement. Most publications occurred within 5 years, suggesting that these grants may be most helpful in career development if awarded during the first 1–2 years of a 5-year orthopaedic residency program.
Operative Time Associated With Increased Length of Stay After Single-level Cervical Disk Arthroplasty
Authors: Ng Mitchell K. , Tracey Olivia , Vasireddi Nikhil , Emara Ahmed , Lam Aaron , Wellington Ian J. , Ford Brian , Ahn Nicholas U. , Houten John K. , Saleh Ahmed , Razi Afshin E. 
Published: June 2024

Study Design:
Level III evidence—retrospective cohort.

Objective:
The purpose of this study was to (1) determine whether longer CDA operative time increases the risk of 30-day postoperative complications, (2) analyze the association between operative time and subsequent health care utilization, and (3) discharge disposition.

Background:
Cervical disk arthroplasty (CDA) most commonly serves as an alternative to anterior cervical discectomy and fusion (ACDF) to treat cervical spine disease, however, with only 1600 CDAs performed annually relative to 132,000 ACDFs, it is a relatively novel procedure.

Methods:
A retrospective query was performed identifying patients who underwent single-level CDA between January 2012 and December 2018 using a nationwide database. Differences in baseline patient demographics were identified through univariate analysis. Multivariate logistic regression was performed to identify associations between operative time (reference: 81–100 min), medical/surgical complications, and health care utilization.

Results:
A total of 3681 cases were performed, with a mean patient age of 45.52 years and operative time of 107.72±49.6 minutes. Higher odds of length of stay were demonstrated starting with operative time category 101–120 minutes (odds ratio: 2.164, 95% CI: 1.247–3.754, P=0.006); however, not among discharge destination, 30-day unplanned readmission, or reoperation. Operative time <40 minutes was associated with 10.7x odds of nonhome discharge, while >240 minutes was associated with 4.4 times higher odds of LOS>2 days (P<0.01). Increased operative time was not associated with higher odds of wound complication/infection, pulmonary embolism, deep venous thrombosis, or urinary tract infections.

Conclusions:
Prolonged CDA operative time above the reference 81–100 minutes is independently associated with increased length of stay, but not other significant health care utilization parameters, including discharge disposition, readmission, or reoperation. There was no association between prolonged operative time and 30-day medical/surgical complications, including wound complications, infections, pulmonary embolism, or urinary tract infection.
Multimodal learning system integrating electronic medical records and hysteroscopic images for reproductive outcome prediction and risk stratification of endometrial injury: a multicenter diagnostic study
Authors: Li Bohan , Chen Hui , Lin Xiaona , Duan Hua 
Published: June 2024

Objective:
To develop a multimodal learning application system that integrates electronic medical records (EMR) and hysteroscopic images for reproductive outcome prediction and risk stratification of patients with intrauterine adhesions (IUAs) resulting from endometrial injuries.

Materials and methods:
EMR and 5014 revisited hysteroscopic images of 753 post hysteroscopic adhesiolysis patients from the multicenter IUA database we established were randomly allocated to training, validation, and test datasets. The respective datasets were used for model development, tuning, and testing of the multimodal learning application. MobilenetV3 was employed for image feature extraction, and XGBoost for EMR and image feature ensemble learning. The performance of the application was compared against the single-modal approaches (EMR or hysteroscopic images), DeepSurv and ElasticNet models, along with the clinical scoring systems. The primary outcome was the 1-year conception prediction accuracy, and the secondary outcome was the assisted reproductive technology (ART) benefit ratio after risk stratification.

Results:
The multimodal learning system exhibited superior performance in predicting conception within 1-year, achieving areas under the curves of 0.967 (95% CI: 0.950–0.985), 0.936 (95% CI: 0.883–0.989), and 0.965 (95% CI: 0.935–0.994) in the training, validation, and test datasets, respectively, surpassing single-modal approaches, other models and clinical scoring systems (all P<0.05). The application of the model operated seamlessly on the hysteroscopic platform, with an average analysis time of 3.7±0.8 s per patient. By employing the application’s conception probability-based risk stratification, mid-high-risk patients demonstrated a significant ART benefit (odds ratio=6, 95% CI: 1.27−27.8, P=0.02), while low-risk patients exhibited good natural conception potential, with no significant increase in conception rates from ART treatment (P=1).

Conclusions:
The multimodal learning system using hysteroscopic images and EMR demonstrates promise in accurately predicting the natural conception of patients with IUAs and providing effective postoperative stratification, potentially contributing to ART triage after IUA procedures.
Correlation between fetal ventricular echogenic foci in pregnancy and fetus chromosomal anomaly: a case-control study in Bandar Abbas city
Authors: Rastegar Mazyar , Rajaei Shahrokh , Yazdian Anari Negin , Hashemi Seyyed Mohammad , Entezar Baghiatallah Amir , Ghazalgoo Arezoo , Namazi Sholes , Soltani Moghadam Saman , Aleali Maryam Sadat , Keivanlou Mohammad-Hossein , Amini-Salehi Ehsan 
Published: June 2024

Background:
Ventricular echogenic foci are small structures within the hearts of some fetuses. These small areas result from increased echogenicity in the ventricles of fetuses located near the papillary muscles. An association between these foci and chromosomal abnormalities in fetuses has been reported. Considering that chromosomal abnormalities are a major cause of prenatal death, this study aimed to determine the value of fetal echogenic foci as markers for chromosomal abnormalities.

Materials and methods:
Fetal echocardiography was performed by an experienced cardiologist on 149 pregnant women in the second trimester. Of these, 75 were reported to have positive echogenic foci, and 74 were reported to have no echogenic foci. Subsequently, the three chromosomal anomalies including trisomies 21, 18, and 13 were examined. The information of the individuals, including gestational age and echogenic foci, was recorded.

Results:
Based on the findings of the present study, seven infants (4.7%) had trisomy 21, four infants (2.7%) had trisomy 13, and six infants (4.1%) had trisomy 18. The mean gestational age of pregnant women with positive and negative echogenic foci was 21.07±3.23 and 21.03±3.09, respectively. No significant relationship was found between ventricular echogenic foci and trisomy 21, 18, or 13.

Conclusion:
The present study suggests no significant relation between the presence of echogenic foci and chromosomal trisomies. This finding indicates that additional tests are required to confirm chromosomal abnormalities when echogenic intracardiac foci are present, especially in high-risk fetuses. Moreover, the absence of echogenic focus does not rule out chromosomal disorders.
VCAb: A web-tool for structure-guided antibody engineering
Authors: Guo Dongjun , Ng Joseph Chi-Fung , Dunn-Walters Deborah K. , Fraternali Franca 
Published: June 2024

AbstractEffective responses against different immune challenges require secretion of antibodies with various isotypes performing specific effector functions. Structural information on these isotypes is essential to engineer antibodies with desired physico-chemical features of their antigen-binding properties, and optimal stability and developability as potential therapeutic antibodies.In silicomutational scanning profiles on antibody structures would further pinpoint candidate mutations for enhancing antibody stability and function. Although a number of antibody structure databases exist, a public data resource which provides clear, consistent annotation of isotypes, species coverage of 3D antibody structures and their deep mutation profiles is currently lacking. TheVandCregion bearingantibody (VCAb) web tool is established with the purpose to clarify these annotations and provide an accessible and easily consultable resource to facilitate antibody engineering. VCAb currently provides data on 6,948 experimentally determined antibody structures including both V and C regions from different species. Additionally, VCAb provides annotations of species and isotypes with both V and C region numbering schemes applied, which can be interactively queried or downloaded in batch. Multiplein silicomutational scanning methods are applied on VCAb structures to provide an easily accessible interface for querying the impact of mutations on antibody stability. These features are implemented in a R shiny application to enable interactive data interrogation. VCAb is freely accessible athttps://fraternalilab.cs.ucl.ac.uk/VCAb/. The source code to generate the VCAb database and the online R shiny application is available athttps://github.com/Fraternalilab/VCAb, enabling users to set up local VCAb instances.
Pathway activation model for personalized prediction of drug synergy
Authors: Trac Quang Thinh , Huang Yue , Erkers Tom , Östling Päivi , Bohlin Anna , Österroos Albin , Vesterlund Mattias , Jafari Rozbeh , Siavelis Ioannis , Bäckvall Helena , Kiviluoto Santeri , Orre Lukas M. , Rantalainen Mattias , Lehtiö Janne , Lehmann Sören , Kallioniemi Olli , Pawitan Yudi , Vu Trung Nghia 
Published: June 2024

AbstractTargeted monotherapies for cancer often fail due to inherent or acquired drug resistance. By aiming at multiple targets simultaneously, drug combinations can produce synergistic interactions that increase drug effectiveness and reduce resistance. Computational models based on the integration of omics data have been used to identify synergistic combinations, but predicting drug synergy remains a challenge. Here, we introduce DIPx, an algorithm for personalized prediction of drug synergy based on biologically motivated tumor- and drug-specific pathway activation scores (PASs). We trained and validated DIPx in the AstraZeneca-Sanger (AZS) DREAM Challenge dataset using two separate test sets: Test Set 1 comprised the combinations already present in the training set, while Test Set 2 contained combinations absent from the training set, thus indicating the model”s ability to handle novel combinations. The Spearman correlation coefficients between predicted and observed drug synergy were 0.50 (95% CI: 0.47–0.53) in Test Set 1 and 0.26 (95% CI: 0.22–0.30) in Test Set 2, compared to 0.38 (95% CI: 0.34–0.42) and 0.18 (95% CI: 0.16–0.20), respectively, for the best performing method in the Challenge. We show evidence that higher synergy is associated with higher functional interaction between the drug targets, and this functional interaction information is captured by PAS. We illustrate the use of PAS to provide a potential biological explanation in terms of activated pathways that mediate the synergistic effects of combined drugs. In summary, DIPx can be a useful tool for personalized prediction of drug synergy and exploration of activated pathways related to the effects of combined drugs.
Rac1 and Nectin3 are essential for PCP-directed axon guidance in the peripheral auditory system
Authors: Clancy Shaylyn , Xie Nicholas , Eluvathingal Muttikkal Tess , Wang Jasmine , Fateh Esha , Smith Margaret , Wilson Phillip , Smith Matthew , Hogan Arielle , Sutherland Ann , Lu Xiaowei 
Published: June 2024

AbstractOur sense of hearing is critically dependent on the spiral ganglion neurons (SGNs) that connect the sound receptors in the organ of Corti (OC) to the cochlear nuclei of the hindbrain. Type I SGNs innervate inner hair cells (IHCs) to transmit sound signals, while type II SGNs (SGNIIs) innervate outer hair cells (OHCs) to detect moderate-to-intense sound. During development, SGNII afferents make a characteristic 90-degree turn toward the base of the cochlea and innervate multiple OHCs. It has been shown that the Planar Cell Polarity (PCP) pathway acts non-autonomously to mediate environmental cues in the cochlear epithelium for SGNII afferent turning towards the base. However, the underlying mechanisms are unknown. Here, we present evidence that PCP signaling regulates multiple downstream effectors to influence cell adhesion and the cytoskeleton in cochlear supporting cells (SCs), which serve as intermediate targets of SGNII afferents. We show that the core PCP gene Vangl2 regulates the localization of the small GTPase Rac1 and the cell adhesion molecule Nectin3 at SC-SC junctions through which SGNII afferents travel. Throughin vivogenetic analysis, we also show that loss of Rac1 or Nectin3 partially phenocopied SGNII peripheral afferent turning defects inVangl2mutants, and that Rac1 plays a non-autonomous role in this process in part by regulating PCP protein localization at the SC-SC junctions. Additionally, epistasis analysis indicates that Nectin3 and Rac1 likely act in the same genetic pathway to control SGNII afferent turning. Together, these experiments identify Nectin3 and Rac1 as novel regulators of PCP-directed SGNII axon guidance in the cochlea.Significance statementPlanar Cell Polarity (PCP) signaling plays a non-autonomous role in the guidance of type II spiral ganglion neuron (SGNII) afferent projections that innervate cochlear hair cells. However, little is known about the underlying mechanisms. Here, we identify the small GTPase Rac1 and the cell adhesion molecule Nectin3 as two downstream effectors of PCP signaling in SGNII afferent guidance. We show that PCP signaling regulates Rac1 and Nectin3 localization in cochlear supporting cells that serve as intermediate targets for SGNII afferents and that Rac1 and Nectin3 likely act in the same genetic pathway to non-autonomously regulate SGNII afferent guidance. These findings significantly advance our understanding of auditory circuit assembly and shed light on PCP-directed axon guidance mechanisms.
The polyadenylation landscape afterin vivolong-term potentiation in the rat brain
Authors: Gumińska Natalia , Pauzin Francois P , Kuźniewska Bożena , Miłek Jacek , Wardaszka Patrycja , Krawczyk Paweł S. , Mroczek Seweryn , Jeleń Sebastian , Pagenhart Patrick U. , Bramham Clive R. , Dziembowski Andrzej , Dziembowska Magdalena 
Published: June 2024

AbstractLocal protein synthesis in neurons is vital for synaptic plasticity, yet the regulatory mechanisms, particularly cytoplasmic polyadenylation, are not fully understood. This study employed nanopore sequencing to examine transcriptomic responses in rat hippocampi duringin vivolong-term potentiation (LTP) and in synaptoneurosomes afterin vitrostimulation. Our long-read transcriptomic dataset allows for detailed analysis of mRNA 3′-ends, poly(A) tail lengths, and composition. We observed dynamic shifts in polyadenylation site preference post-LTP induction, with significant poly(A) tail lengthening restricted to transcriptionally induced mRNAs. Poly(A) tails of these genes showed increased non-adenosine abundance. In synaptoneurosomes, chemical stimulation led to shortening of poly(A) tails on preexisting mRNAs, indicating translation-induced deadenylation. Additionally, we discovered a group of neuronal transcripts with poly(A) tails abundant in non-adenosine residues. These tails are semi-templated and derived from extremely adenosine-rich 3′UTRs. This study provides a comprehensive overview of mRNA 3′-end dynamics during LTP, offering insights into post-transcriptional regulation in neuronal activation.
Noise induces intercellular Ca2+signaling waves and the unfolded protein response in the hearing cochlea
Authors: Park Yesai , Li Jiang , Ismail Mohamad Noura , Matthews Ian R. , Santra Peu , Sherr Elliott H. , Chan Dylan K. 
Published: June 2024

AbstractExposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response, have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways has been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GcAMP is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db SPL) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure and was noise dose-dependent, with the pro-apoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae, but re-activated upon noise exposure. 106 dB noise exposure was associated with more persistent and expansive ICS wave activity. These findings demonstrate a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.
Amygdala Self-Neuromodulation Capacity as a Window for Process-Related Network Recruitment
Authors: Gurevitch Guy , Lubianiker Nitzan , Markovits Taly , Or-Borichev Ayelet , Fine Naomi B. , Fruchtman-Steinbok Tom , Keynan Jacob N. , Friedman Alon , Singer Neomi , Hendler Talma 
Published: June 2024

AbstractNeurofeedback (NF) has emerged as a promising avenue for demonstrating process-related neuroplasticity, enabling self-regulation of brain function. NF targeting the amygdala has drawn attention for therapeutic potential in psychiatry, by potentially harnessing emotion-regulation processes. However, not all individuals respond equally to NF training, possibly due to varying self-regulation abilities. This underscores the importance of understanding the mechanisms behind successful neuromodulation (i.e. capacity). This study aimed to investigate the establishment and neural correlates of neuromodulation capacity by using data from repeated sessions of Amygdala Electrical Finger Print (EFP)-NF and post-training fMRI-NF session.Results from 97 psychiatric patients and healthy participants revealed increased amygdala-EFP neuromodulation capacity over training, associated with post-training amygdala fMRI modulation-capacity and improvements in alexithymia. Individual differences in this capacity were associated with pre-training amygdala reactivity and initial neuromodulation success. Additionally, amygdala down-regulation during fMRI-NF co-modulated with other regions such as the posterior-insula and parahippocampal gyrus. This combined modulation better explained EFP-modulation capacity and improvement in alexithymia than the amygdala modulation alone, suggesting the relevance of this broader network to the gained capacity. These findings support a network-based approach for NF and highlight the need to consider individual differences in brain function and modulation capacity to optimize NF interventions.