bluuebunny/crossref_metadata_2025_split huggingface dataset:
High incidence of imperforate vagina in ADGRA3-deficient mice
Authors: Kvam Jone Marita , Nybo Maja Lind , Torz Lola , Sustarsic Riia Karolina , Jensen Kristian Høj Reveles , Nielsen John Erik , Frederiksen Hanne , Gadgaard Sarina , Spiess Katja , Poulsen Steen Seier , Thomsen Jesper Skovhus , Cowin Pamela , Blomberg Jensen Martin , Kurita Takeshi , Rosenkilde Mette Marie 
Published: April 2024

Abstract
Background
Ten percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development. Although ADGRA3 is a well-established spermatogonial stem cell marker, its role within the female urogenital system remains unclear.

Results
In this study, we found Adgra3 to be expressed throughout the murine female urogenital system, with higher expression pre-puberty than after sexual maturation. We generated a global Adgra3−/− mouse line and observed imperforate vagina in 44% of Adgra3−/− females, resulting in distension of the reproductive tract and infertility. Ovarian morphology, plasma estradiol, ovarian Cyp19a1, and vaginal estrogen receptor α (Esr1) expression were unaffected. However, compared to controls, a significantly lower bone mineral density was found in Adgra3−/− mice. Whereas vaginal opening in mice is an estrogen-dependent process, 17β-estradiol treatment failed to induce vaginal canalization in Adgra3−/− mice. Furthermore, a marked reduction in vaginal and ovarian progesterone receptor expression was observed concomitant with an upregulation of apoptotic regulators Bcl2, Bid, and Bmf in adult Adgra3−/− females with a closed vagina.

Conclusions
Our collective results shed new insights into the complex mechanisms by which the adhesion receptor ADGRA3 regulates distal vaginal tissue remodeling during vaginal canalization via altered sex hormone responsiveness and balance in apoptotic regulators. This highlights the potential of ADGRA3 as a target in diagnostic screening and/or therapy for obstructive vaginal malformations in humans.
Impact of microglia isolation and culture methodology on transcriptional profile and function
Authors: Mizrachi Mark , Diamond Betty 
Published: April 2024

Abstract
Background
Microglial isolation and culturing methods continue to be explored to maximize cellular yield, purity, responsiveness to stimulation and similarity to in vivo microglia. This study aims to evaluate five different microglia isolation methods—three variants of microglia isolation from neonatal mice and two variants of microglia isolation from adult mice—on transcriptional profile and response to HMGB1.

Methods
Microglia from neonatal mice, age 0–3 days (P0–P3) were isolated from mixed glial cultures (MGC). We included three variations of this protocol that differed by use of GM-CSF in culture (No GM-CSF or 500 pg/mL GM-CSF), and days of culture in MGC before microglial separation (10 or 21). Protocols for studying microglia from adult mice age 6–8 weeks included isolation by adherence properties followed by 7 days of culture with 100 ng/mL GM-CSF and 100 ng/mL M-CSF (Vijaya et al. in Front Cell Neurosci 17:1082180, 2023), or acute isolation using CD11b beads (Bordt et al. in STAR Protoc 1:100035, 2020. https://doi.org/10.1016/j.xpro.2020.100035). Purity, yield, and RNA quality of the isolated microglia were assessed by flow cytometry, hemocytometer counting, and Bioanalyzer, respectively. Microglial responsiveness to an inflammatory stimulus, HMGB1, was evaluated by measuring TNFα, IL1β, and IFNβ concentration in supernatant by ELISA and assessing gene expression patterns using bulk mRNA sequencing.

Results
All five methods demonstrated greater than 90% purity. Microglia from all cultures increased transcription and secretion of TNFα, IL1β, and IFNβ in response to HMGB1. RNA sequencing showed a larger number of differentially expressed genes in response to HMGB1 treatment in microglia cultured from neonates than from adult mice, with sparse changes among the three MGC culturing conditions. Additionally, cultured microglia derived from adult and microglia derived from MGCs from neonates display transcriptional signatures corresponding to an earlier developmental stage.

Conclusion
These findings suggest that while all methods provided high purity, the choice of protocol may significantly influence yield, RNA quality, baseline transcriptional profile and response to stimulation. This comparative study provides valuable insights to inform the choice of microglial isolation and culture method.
Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation
Authors: Chasseigneaux Stéphanie , Cochois-Guégan Véronique , Lecorgne Lucas , Lochus Murielle , Nicolic Sophie , Blugeon Corinne , Jourdren Laurent , Gomez-Zepeda David , Tenzer Stefan , Sanquer Sylvia , Nivet-Antoine Valérie , Menet Marie-Claude , Laplanche Jean-Louis , Declèves Xavier , Cisternino Salvatore , Saubaméa Bruno 
Published: April 2024

Abstract
Background
The blood-brain barrier (BBB) is pivotal for the maintenance of brain homeostasis and it strictly regulates the cerebral transport of a wide range of endogenous compounds and drugs. While fasting is increasingly recognized as a potential therapeutic intervention in neurology and psychiatry, its impact upon the BBB has not been studied. This study was designed to assess the global impact of fasting upon the repertoire of BBB transporters.

Methods
We used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in male rats that were fed ad libitum or fasted for one to three days. Brain endothelial cells were acutely purified and transcriptionaly profiled using RNA-Seq. Isolated brain microvessels were used to assess the protein expression of selected BBB transporters through western blot. The molecular mechanisms involved in the adaptation to fasting were investigated in primary cultured rat brain endothelial cells. MCT1 activity was probed by in situ brain perfusion.

Results
Fasting did not change the expression of the main drug efflux ATP-binding cassette transporters or P-glycoprotein activity at the BBB but modulated a restrictive set of solute carrier transporters. These included the ketone bodies transporter MCT1, which is pivotal for the brain adaptation to fasting. Our findings in vivo suggested that PPAR δ, a major lipid sensor, was selectively activated in brain endothelial cells in response to fasting. This was confirmed in vitro where pharmacological agonists and free fatty acids selectively activated PPAR δ, resulting in the upregulation of MCT1 expression. Moreover, dosing rats with a specific PPAR δ antagonist blocked the upregulation of MCT1 expression and activity induced by fasting.

Conclusions
Altogether, our study shows that fasting affects a selected set of BBB transporters which does not include the main drug efflux transporters. Moreover, we describe a previously unknown selective adaptive response of the brain vasculature to fasting which involves PPAR δ and is responsible for the up-regulation of MCT1 expression and activity. Our study opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain.
A visceral organ function-focused therapeutic strategy using a 6-hour time window for patients with acute type a aortic dissection complicated by mesenteric malperfusion
Authors: Huang Ling-chen , Chen Shuang-kun , Peng Hua , Wu Xi-jie 
Published: April 2024

Abstract
Background
Acute type A aortic dissection (ATAAD) complicated by mesenteric malperfusion is a critical and complicated condition. The optimal treatment strategy remains controversial, debate exists as to whether aortic dissection or mesenteric malperfusion should be addressed first, and the exact time window for mesenteric ischemia intervention is still unclear. To solve this problem, we developed a new concept based on the pathophysiological mechanism of mesenteric ischemia, using a 6-hour time window to divide newly admitted patients by the time from onset to admission, applying different treatment protocols to improve the clinical outcomes of patients with ATAAD complicated by mesenteric malperfusion.

Methods
This was a retrospective study that covered a five-year period. From July 2018 to December 2020(phase I), all patients underwent emergency open surgery. From January 2021 to June 2023(phase II), patients with an onset within 6 h all underwent open surgical repair, followed by immediately postoperative examination if the malperfusion is suspected, while the restoration of mesenteric perfusion and visceral organ function was performed first, followed by open repair, in patients with an onset beyond 6 h.

Results
There were no significant differences in baseline and surgical data. In phase I, eleven patients with mesenteric malperfusion underwent open surgery, while in phase II, our novel strategy was applied, with sixteen patients with an onset greater than 6 h and eleven patients with an onset less than 6 h. During the waiting period, none died of aortic rupture, but four patients died of organ failure, twelve patients had organ function improvement and underwent surgery successfully survived. The overall mortality rate decreased with the use of this novel strategy (54.55% vs. 18.52%, p = 0.047). Furthermore, the surgical mortality rate between the two periods showed even stronger statistical significance (54.55% vs. 4.35%, p = 0.022). Moreover, the proportions of patients with sepsis and multiorgan failure also showed differences.

Conclusions
Our novel strategy for patients with ATAAD complicated by mesenteric malperfusion not only improves the surgical success rate but also reduces the overall mortality rate.
Efficacy and safety of intracoronary pro-urokinase combined with low-pressure balloon pre-dilatation during percutaneous coronary intervention in patients with anterior ST-segment elevation myocardial infarction
Authors: Yu Shicheng , Jia Haoxuan , Ding Shengkai , Zhang Mengda , Li Fengyun , Xu Pan , Tian Yuan , Ma Lingling , Gong Lijie , Feng Jun , Sun Zhaojin , Qian Fudong , Li Hui 
Published: April 2024

Abstract
Background
The efficacy and safety of low-pressure balloon pre-dilatation before intracoronary pro-urokinase (pro-UK) in preventing no-reflow during percutaneous coronary intervention (PCI) remains unknown. This study aimed to evaluate the clinical outcomes of intracoronary pro-UK combined with low-pressure balloon pre-dilatation in patients with anterior ST-segment-elevation myocardial infarction (STEMI).

Methods
This was a randomized, single-blind, investigator-initiated trial that included 179 patients diagnosed with acute anterior STEMI. All patients were eligible for PCI and were randomized into two groups: intracoronary pro-UK combined with (ICPpD group, n = 90) or without (ICP group, n = 89) low-pressure balloon pre-dilatation. The main efficacy endpoint was complete epicardial and myocardial reperfusion. The safety endpoints were major adverse cardiovascular events (MACEs), which were analyzed at 12 months follow-up.

Results
Patients in the ICPpD group presented significantly higher TIMI myocardial perfusion grade 3 (TMPG3) compared to those in the ICP group (77.78% versus 68.54%, P = 0.013), and STR ≥ 70% after PCI 30 min (34.44% versus 26.97%, P = 0.047) or after PCI 90 min (40.0% versus 31.46%, P = 0.044). MACEs occurred in 23 patients (25.56%) in the ICPpD group and in 32 patients (35.96%) in the ICP group. There was no difference in hemorrhagic complications during hospitalization between the groups.

Conclusion
Patients with acute anterior STEMI presented more complete epicardial and myocardial reperfusion with adjunctive low-pressure balloon pre-dilatation before intracoronary pro-UK during PCI.

Trial registration
2019xkj213.
In a porcine model of implantable pacemakers for pediatric unilateral diaphragm paralysis, the phrenic nerve is the best target
Authors: Kratz Tobias , Dauvergne Jan , Ruff Roman , Koch Timo , Breuer Johannes , Asfour Boulos , Herberg Ulrike , Bierbach Benjamin 
Published: April 2024

Abstract
Background
A frequent complication of Fontan operations is unilateral diaphragmatic paresis, which leads to hemodynamic deterioration of the Fontan circulation. A potential new therapeutic option is the unilateral diaphragmatic pacemaker. In this study, we investigated the most effective stimulation location for a potential fully implantable system in a porcine model.

Methods
Five pigs (20.8 ± 0.95 kg) underwent implantation of a customized cuff electrode placed around the right phrenic nerve. A bipolar myocardial pacing electrode was sutured adjacent to the motor point and peripherally at the costophrenic angle (peripheral diaphragmatic muscle). The electrodes were stimulated 30 times per minute with a pulse duration of 200 µs and a stimulation time of 300 ms. Current intensity was the only variable changed during the experiment.

Results
Effective stimulation occurred at 0.26 ± 0.024 mA at the phrenic nerve and 7 ± 1.22 mA at the motor point, a significant difference in amperage (p = 0.005). Even with a maximum stimulation of 10 mA at the peripheral diaphragm muscle, however, no effective stimulation was observed.

Conclusion
The phrenic nerve seems to be the best location for direct stimulation by a unilateral thoracic diaphragm pacemaker in terms of the required amperage level in a porcine model.
Acute gastric dilatation with segmented abdominal paresis as a rare manifestation of herpes zoster: a case report and review of the literature
Authors: Yagyu Toshihiko , Yakami Yoshikazu , Bando Tomoki 
Published: April 2024

Abstract
Background
Herpes zoster is a common disease that can affect men and women at any age. Sensory neuropathy is the most common complication while motor neuropathy of the abdominal muscles is rare complication appearing in ~ 0.7% of patients. Furthermore, visceral nerve involvement causing gastroparesis is an extremely rare postherpetic complication. We present an extremely rare case of acute gastric dilatation with segmented abdominal paresis as a rare manifestation of herpes zoster infection.

Case presentation
A 91-year-old Asian man was admitted to hospital with 2-day history of vomiting and left abdominal protrusion. He was previously treated for a rash on the left abdominal wall as herpes zoster infection with oral valaciclovir 2 weeks prior. On physical examination, characteristic herpes zoster rash scars and an ipsilateral abdominal bulge were observed on the left side. Computed tomography revealed no abdominal wall defect, mass, or stenosis. Remarkable distension of the stomach, asymmetrical left flank wall bulge, and a thinner abdominal wall on the left compared with the right side were shown. He was diagnosed as acute gastric dilatation owing to gastroparesis and segmental paresis of the abdominal musculature associated with herpes zoster infection. The patient showed significant improvement in symptoms and abdominal paresis within a month of conservative treatment, including nasogastric tube decompression and mosapride administration.

Conclusion
Acute gastric dilatation with abdominal paresis is an extremely rare complication of herpes zoster infection, and to date there have been no reports in the literature. It alerts us that, when examining patients with abdominal bulge, we should be conscious of this rare pathology for the optical diagnosis, avoiding unnecessary invasive examination or surgical exploration.
Oral ulcer treatment using human tonsil-derived mesenchymal stem cells encapsulated in trimethyl chitosan hydrogel: an animal model study
Authors: Ryu Hyun Seok , Abueva Celine , Padalhin Andrew , Park So Young , Yoo Seung Hyeon , Seo Hwee Hyon , Chung Phil-Sang , Woo Seung Hoon 
Published: April 2024

Abstract
Background
Oral ulcers are a common side effect of chemotherapy and affect patients’ quality of life. While stem cell transplantation is a potential treatment for oral ulcers, its efficacy is limited as the stem cells tend to remain in the affected area for a short time. This study aims to develop a treatment for oral ulcers by using trimethyl chitosan (TMC) hydrogel with human tonsil-derived stem cells (hTMSCs) to increase the therapeutic effect of stem cells and investigate their effectiveness.

Methods
Animals were divided into four experimental groups: Control, TMC hydrogel, hTMSCs, and hTMSCs loaded in TMC hydrogel (Hydrogel + hTMSCs) (each n = 8). Oral ulcers were chemically induced by anesthetizing the rats followed by injection of dilute acetic acid in the right buccal mucosa. After confirming the presence of oral ulcers in the animals, a single subcutaneous injection of 100 µL of each treatment was applied to the ulcer area. Histological analyses were performed to measure inflammatory cells, oral mucosal thickness, and fibrosis levels. The expression level of inflammatory cytokines was also measured using RT-PCR to gauge therapeutic the effect.

Results
The ulcer size was significantly reduced in the TMC hydrogel + hTMSCs group compared to the control group. The stem cells in the tissue were only observed until Day 3 in the hTMSCs treated group, while the injected stem cells in the TMC Hydrogel + hTMSCs group were still present until day 7. Cytokine analysis related to the inflammatory response in the tissue confirmed that the TMC Hydrogel + hTMSCs treated group demonstrated superior wound healing compared to other experimental groups.

Conclusion
This study has shown that the adhesion and viability of current stem cell therapies can be resolved by utilizing a hydrogel prepared with TMC and combining it with hTMSCs. The combined treatment can promote rapid healing of oral cavity wounds by enhancing anti-inflammatory effects and expediting wound healing. Therefore, hTMSC loaded in TMC hydrogel was the most effective wound-healing approach among all four treatment groups prolonging stem cell survival. However, further research is necessary to minimize the initial inflammatory response of biomaterials and assess the safety and long-term effects for potential clinical applications.
Combination of bone marrow mesenchymal stem cells and moxibustion restores cyclophosphamide-induced premature ovarian insufficiency by improving mitochondrial function and regulating mitophagy
Authors: Lu Ge , Li Hong-xiao , Song Zi-wei , Luo Jia , Fan Yan-liang , Yin Yao-li , Shen Jie , Shen Mei-hong 
Published: April 2024

Abstract
Background
Premature ovarian insufficiency (POI) is a major cause of infertility. In this study, we aimed to investigate the effects of the combination of bone marrow mesenchymal stem cells (BMSCs) and moxibustion (BMSCs-MOX) on POI and evaluate the underlying mechanisms.

Methods
A POI rat model was established by injecting different doses of cyclophosphamide (Cy). The modeling of POI and the effects of the treatments were assessed by evaluating estrous cycle, serum hormone levels, ovarian weight, ovarian index, and ovarian histopathological analysis. The effects of moxibustion on BMSCs migration were evaluated by tracking DiR-labeled BMSCs and analyzing the expression of chemokines stromal cell-derived factor 1 (Sdf1) and chemokine receptor type 4 (Cxcr4). Mitochondrial function and mitophagy were assessed by measuring the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, and the mitophagy markers (Drp1, Pink1, and Parkin). Furthermore, the mitophagy inhibitor Mdivi-1 and the mitophagy activator CCCP were used to confirm the role of mitophagy in Cy-induced ovarian injury and the underlying mechanism of combination therapy.

Results
A suitable rat model of POI was established using Cy injection. Compared to moxibustion or BMSCs transplantation alone, BMSCs-MOX showed improved outcomes, such as reduced estrous cycle disorders, improved ovarian weight and index, normalized serum hormone levels, increased ovarian reserve, and reduced follicle atresia. Moxibustion enhanced Sdf1 and Cxcr4 expression, promoting BMSCs migration. BMSCs-MOX reduced ROS levels; upregulated MMP and ATP levels in ovarian granulosa cells (GCs); and downregulated Drp1, Pink1, and Parkin expression in ovarian tissues. Mdivi-1 significantly mitigated mitochondrial dysfunction in ovarian GCs and improved ovarian function. CCCP inhibited the ability of BMSCs-MOX treatment to regulate mitophagy and ameliorate Cy-induced ovarian injury.

Conclusions
Moxibustion enhanced the migration and homing of BMSCs following transplantation and improves their ability to repair ovarian damage. The combination of BMSCs and moxibustion effectively reduced the excessive activation of mitophagy, which helped prevent mitochondrial damage, ultimately improving ovarian function. These findings provide a novel approach for the treatment of pathological ovarian aging and offer new insights into enhancing the efficacy of stem cell therapy for POI patients.

Graphical abstract
A cloud-edge collaborative task scheduling method based on model segmentation
Authors: Zhang Chuanfu , Chen Jing , Li Wen , Sun Hao , Geng Yudong , Zhang Tianxiang , Ji Mingchao , Fu Tonglin 
Published: April 2024

AbstractWith the continuous development and combined application of cloud computing and artificial intelligence, some new methods have emerged to reduce task execution time for training neural network models in a cloud-edge collaborative environment. The most attractive method is neural network model segmentation. However, many factors affect the segmentation point, such as resource allocation, system energy consumption, load balancing, and network Bandwidth allocation. Some segmentation methods consider the shortest task execution time, which ignores the utilization of resources at the edge and can result in resource waste. Additionally, these factors are difficult to measure, which presents a challenge in calculating the best segmentation point to achieve the goal of maximum resource utilization and minimum task execution time. To solve this problem, this paper proposes a cloud-edge collaborative task scheduling method based on model segmentation (CECMS). This method first analyzes the factors affecting the segmentation point of the model and then obtains accurate factors that affect the segmentation point calculation through the pre-execution method. Furthermore, a multi-objective solution algorithm is improved to calculate the optimal model segmentation point. And tasks are separately offloaded to the edge and cloud based on the optimal model segmentation point. Finally, the experiments are conducted to verify the effectiveness of this method. Finally, the effectiveness of the CECMS method was verified through simulation experiments. Compared with the Dynamic Adaptive DNN Surgery (DADS) method and an adaptive DNN inference acceleration framework algorithm with end–edge–cloud collaborative computing algorithm (ADC), CECMS achieves the same effectiveness as DADS and ADC in optimizing task execution time by comprehensively considering the utilization of edge resources and minimizing task execution time, while also effectively ensuring resource utilization.