bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation analysis of maternal condition during pregnancy with head circumference and autism spectrum disorder: A propensity score-matched study
Authors: Liu Lei , Zhao Shichun
Published: February 2024

To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study included 41 Han children with ASD who visited the Children’s Health Clinic of the Second Hospital of Shandong University between March 2018 and February 2019, and 264 Han children with typical development (TD) who visited the clinic during the same period. Physical measurements were performed on the children. The questionnaire obtained information on maternal risk factors that may be related to the increased risk of ASD and folic acid (FA) supplementation. We designed an observational case–control study using propensity score matching and multivariate logistic regression analysis. The incidence of macrocephaly in the ASD group was 22.0%, significantly higher than that in the TD group (1.8%). The incidence of microcephaly in the ASD group was 17.1% (n = 7), significantly higher than that in the TD group (1.8%). The differences between the comparisons were statistically significant. Maternal FA supplementation during pregnancy was significantly associated with ASD (P < .05), with an odds ratio (95% confidence interval of 3.69 (1.76, 7.76)). Also was associated with macrocephaly (P < .05), odds ratio (95% confidence interval) were 8.13 (1.63, 40.61) and 4.16 (1.18, 14.60), respectively. The incidence of abnormal HC was higher in the ASD group than that in the TD group. Maternal FA supplementation during pregnancy may be negatively associated with the occurrence of ASD and abnormal HC in the offspring. Further examination of the role of maternal health status in the etiology of ASD is recommended.
Application on perioperative ERAS concept in elderly lung cancer patients undergoing surgery
Authors: Zhang Ming , Cai Ping
Published: February 2024

Investigating the applying effects of the enhanced recovery after surgery (ERAS) in the perioperative period of elderly lung cancer patients undergoing the surgery. We randomly selected 98 elderly patients with lung cancer who were admitted to our hospital and underwent surgery from January 2022 to September 2023 as study subjects. The control group received conventional care during the perioperative period, and the intervention group received ERAS-guided care measures. The differences in perioperative-related indices, pulmonary function, pain level, inflammatory factors, and postoperative complication rates between these 2 groups were compared. The postoperative extubation time, the activity time since getting out of bad and hospital stay were lower in the observation group than those in the control group (P 
< .05). At 3 days postoperatively, the FEV1, forced vital capacity and maximum ventilation volume of these 2 groups were lower than those of their same groups before surgery, and those of the observation group were higher than those of the control group (P 
< .05). At 3 days postoperatively, the numerical rating scale in both groups were lower than those of their same groups at 6 hours postoperatively, and the numerical rating scale of the observation group was lower than that of the control group (P 
< .05). At 3 days postoperatively, tumor necrosis factor-α, IL-6, and CRP in both groups were higher than those in their same groups before surgery, and those of the observation group was lower than those of the control group (P 
< .05). The incidence of postoperative complications in the observation group was lower than that in the control group (P 
< .05). ERAS applied in the perioperative period of elderly lung cancer patients undergoing surgery can shorten the hospital stay, promote the postoperative recovery on pulmonary function, alleviate inflammation, and reduce the risk of postoperative complications.
A systemic lupus erythematosus patient with persistent elevated conjugated bilirubin as the initial symptom: A case report
Authors: Liu Jun , Shen Tingting , Li Long , Li Xingyi , Zhao Fang , Liu Xiaoxia , Zhang Shan , Wu Pengjia , Li Na , Zeng Jiashun
Published: February 2024

Rationale:

While some systemic lupus erythematosus (SLE) patients may experience varying degrees of liver function abnormalities, only a small portion of these cases have clinical significance, and the majority of patients typically exhibit low levels of serum bilirubin. However, in this article, we present a case of a middle-aged female patient with SLE who exhibited persistent skin jaundice as her initial symptom, offering a fresh perspective on diagnosing and treating patients who exhibit unexplained liver dysfunction and SLE combined with liver injury.

Patient concerns:

A 45-year-old woman was initially admitted to the hospital due to yellowing of the skin and sclera, and her symptoms did not improve significantly during treatment. The results were abnormal after relevant immunological tests.

Diagnoses:

Persistent non-conjugated bilirubin elevation due to lupus hepatitis.

Interventions:

The use of methylprednisolone sodium succinate (40 mg/Qd) and mycophenolate mofetil (0.75 g/d) suppressed immunity, polyolefin choline (20 mL/d) and glutathione (0.6 g/Qd) improved liver function, and nutritional support therapy.

Outcomes:

After 2 weeks of treatment, a significant decrease in the yellow skin and sclera of the patient was observed.

Lessons:

Most clinicians overlook that liver function abnormalities are the main manifestation of SLE, resulting in many patients not receiving timely treatment. This study highlights the importance that SLE is also a cause of abnormal liver function.
Successful endotracheal intervention for primary tracheal acinic cell carcinoma: A case report and literature review
Authors: Huang Shuhui , Peng Xinru , Li Hailong , Zhao Jiale , Hou Jia
Published: February 2024

Introduction:

Primary tracheal acinic cell carcinoma (ACC) is an exceptionally rare malignancy, posing challenges in understanding its clinical behavior and optimal management. Surgical resection has traditionally been the primary treatment modality, but we present a compelling case of tracheal ACC managed with endotracheal intervention, challenging conventional approaches.

Patient Concerns:

A 53-year-old woman presented with shortness of breath, cough, and hemoptysis. Enhanced computed tomography revealed an obstructive tracheal lesion, leading to her referral for further assessment.

Diagnosis:

Microscopic evaluation, immunohistochemistry, and clinical assessments confirmed primary tracheal ACC, an exceedingly rare condition with limited clinical insights.

Interventions:

We utilized rigid bronchoscopy to perform endotracheal intervention, successfully resecting the tumor and restoring tracheal patency. Postoperatively, the patient received no radiotherapy or chemotherapy.

Outcomes:

The patient achieved complete recovery, with 24-month follow-up examinations indicating no recurrence or metastatic disease. Only minimal scar tissue remained at the resection site.

Conclusion:

This case demonstrates the potential of endotracheal intervention as a curative approach for primary tracheal ACC, minimizing invasiveness and preserving tracheal function. Collaborative research efforts and extensive case reporting are crucial for advancing our understanding of this rare malignancy and optimizing treatment strategies for improved patient outcomes.
Relationship between hepatic surgical margins of colorectal cancer liver metastases and prognosis: A review
Authors: Ai Xiang-Nan , Zhang Qiang , Jin Chang-Guo , Hu Hao , Zhang Wen-Xuan , Wu Zhen-Yu , Xiu Dian-Rong
Published: February 2024

Colorectal cancer (CRC) remains a significant global health concern, as characterized by its high mortality rate ranking second among all the leading causes of death. The liver serves as the primary site of CRC metastasis, and the occurrence of liver metastasis is a significant contributor to mortality among patients diagnosed with CRC. The survival rate of patients with colorectal liver metastasis has significantly increased with the advancement of comprehensive tumor therapy. However, radical surgery remains the key factor. Since there are frequently multiple liver metastases, which are prone to recurrence after surgery, it is crucial to preserve as much liver parenchyma as possible without affecting the prognosis. The issue of surgical margins plays a crucial role in this regard. In this review, we begin by examining the occurrence of positive surgical margins in liver metastases of patients diagnosed with CRC. We aim to define positive margins in hepatic surgery, examine the relationship between margins and prognosis and establish a foundation for future research in this field.
Invasive cellular blue nevus in the cervical spine: A case report
Authors: Rao Xianfeng , Kang Zhengwen , Chen Jianwei , Wang Tong , Ma Mengyao , Yang Shuwen , Wu Zetao , Wang Bo , Zhang Qiusheng
Published: February 2024

Introduction:

Cellular blue nevus is an uncommon neoplasm in the spine.

Patient concerns:

Here, we present a case of a 24 years old male with a 2 months history of numbness in the right upper limb and shoulder.

Diagnosis:

Cervical spine and subcutaneous tissue invasive cellular blue nevus.

Interventions:

The patient underwent C4 laminectomy and partial C3 and C5 laminectomy for total resection of the lesion. Histopathology revealed a nodular tumor with unclear boundaries, which was composed of heavily pigmented dendritic cells and more pigmented spindle cells.

Outcomes:

There was no recurrence during 3 years follow-up.

Conclusion:

Invasive cellular blue nevus of the spine can be wrongly diagnosed as spinal meningeal melanocytoma and meningeal melanoma due to its special cell behavior and rarity. Therefore, it is important to understand its pathological and clinical characteristics to avoid over-treatment.
Association of serum YKL-40 and DPP4 with T2-high asthma in Chinese adults
Authors: Zhang Li , Li Liang , Zhou Mei , Zhou Qian-Yun , Tang Ji-Hong , Liang Mei , Liu Qin , Fu Xiao-Feng
Published: February 2024

This study aimed to assess the utility of serum YKL-40 and serum dipeptidyl peptidase IV (DPP4) as biomarkers for distinguishing between type 2 (T2)-high and T2-low asthma in the Chinese population. Additionally, we sought to explore the associations of serum YKL-40 and DPP4 levels with asthma characteristics and conventional markers. A real-world observational cross-sectional study was conducted, involving a total of 75 adult asthma patients. We collected general information, including demographics and medical history. Measurements included complete blood count, fractional exhaled nitric oxide (FeNO), post-bronchodilator spirometry, serum YKL-40 and serum DPP4 levels. Asthma endotypes, T2-high and T2-low, were defined through a comprehensive review of existing literature and expert group discussions. Logistic and linear regression models were employed. Our findings indicated no significant association between serum YKL-40 or serum DPP4 levels and T2-high asthma across all models. In the fully adjusted model, their odds ratios (OR) were 0.967 (95% CI: 0.920–1.017) and 0.997 (95% CI: 0.993–1.001), respectively. Notably, serum YKL-40 exhibited a positive correlation with FeNO (β = 0.382, 95% CI: 0.230–0.533) after adjusting for confounding factors. This association, however, diminished in patients under 40 years old (P = .24), males (P = .25), and those with FEV1%pred of 80% or higher (P = .25). Serum DPP4 demonstrated a negative correlation with FEV1/FVC in the fully adjusted model (β: −0.005, 95% CI: −0.009, −0.000). Among Chinese adult asthma patients, a positive correlation was observed between serum YKL-40 levels and FeNO in females aged over 40 with FEV1%pred less than 80%. Additionally, a weak negative correlation was found between serum DPP4 levels and FEV1/FVC. However, neither serum YKL-40 nor serum DPP4 levels exhibited the capability to differentiate between T2-high and T2-low asthma.
A 30-year bibliometric analysis of the literature in the disciplines of orthopedics, surgery, or oncology on chondrosarcoma from 1993 to 2023
Authors: Yilmaz Selçuk , Kurt Mehmet
Published: February 2024

Background:

A thorough bibliometric analysis of publications published in the field of chondrosarcoma research has not yet been performed using the Web of Science database, especially for publications published between 1993 and 2023. This study, with a focus on the fields of orthopedics, surgery, and oncology, aims to fill this knowledge gap by providing a thorough analysis of current knowledge in the field of chondrosarcoma.

Methods:

In this bibliometric study, a literature search was performed using the Web of Science database to find all publications on chondrosarcoma. A bibliometric software program was used for data visualization and analysis (opensource visualization application, Vosviewer). The Web of Science Core Collection data used for this retrospective bibliometric study, which covers the period from January 1993 to September 2023, revealed interesting trends in chondrosarcoma research.

Results:

As the most popular fields of study, orthopedics, surgery, and oncology account for a sizable portion of publications. A noteworthy increase in research output from 2014 to 2023, accounting for 41.74% of the papers, reflects the thriving research environment. The leading countries for publication were China, Japan, and the United States, demonstrating cross-border cooperation in chondrosarcoma research. Their contributions were highlighted by their important affiliations with institutions such as Harvard University, Leiden University, and China Medical University Taiwan. A thorough keyword mapping analysis also highlighted research priorities and encouraged interdisciplinary cooperation. The field’s scholarly importance and ongoing relevance are highlighted by the study’s high citation count (30,076) and highly cited articles.

Conclusion:

Overall, this study offers crucial insights into the development and collaborative nature of the chondrosarcoma research landscape and its long-lasting influence on academic research and clinical practice.
Selection of the appropriate treatment for the combination of interstitial lung disease and lung cancer: A retrospective observational study
Authors: Karapinar Kemal , Yurt Sibel , Toptaş Mehmet , Bahadir Ayşe , Erdoğu Volkan , Akçil Ali Murat , Onur Seda Tural
Published: February 2024

Interstitial lung disease (ILD) independently heightens the risk of lung cancer (LC), often necessitating chemoradiotherapy (CRT) due to advanced disease stages. However, CRT may compromise survival through complications such as ILD exacerbation or radiation pneumonitis. The aim of this study was to determine the optimal surgical or nonsurgical treatment approaches for patients with concurrent ILD and LC. Over a 10-year period, a retrospective evaluation was conducted on 647 patients with confirmed diagnoses of LC and ILD from a total of 4541 patients examined in the polyclinic. This assessment included a comprehensive review of demographic, treatment, and survival records. Study groups included those treated for both ILD and LC with surgical treatment (ST), chemotherapy (CT), radiotherapy (RT), or CRT. A control group comprised ILD-only cases. In the whole sample of 647 patients with complete data, the length of stay in hospital and respiratory intensive care unit was significantly shorter in the ST group and longer in the CT group. Significant differences in discharge status (P < .001) were observed, with higher recovery rates in the ST and RT groups. The CT group showed an increased rate of transfer to other centers, in-hospital mortality was determined to be higher in the CRT group, and the control group exhibited no change in discharge. No statistically significant difference was determined between the groups with respect to the 24- and 48-month survival rates (P = .100). Although no disparity was found in 2- and 4-year survival rates, there were seen to be advantages in survival and quality of life with the addition of radiotherapy to regions aligning with surgical margins for LC patients with ILD, evaluated as radiological N0, undergoing wedge resection. This underscores the need for personalized treatment strategies to balance effective cancer control and to minimize ILD-related complications.
Comparison of therapeutic effects of endoscopic assisted different surgical approaches in hypertensive intracerebral hemorrhage: A retrospective cohort study
Authors: Wang Song , Su Fei , Zhou Xiguang , Liu Long , Zhang Ruishan , Xue Zhensheng
Published: February 2024

We aimed to explore the therapeutic effects of endoscopically assisted surgical approaches for HICH. In this retrospective cohort study, we retrospectively analyzed the treatment status of 118 patients with HICH who underwent surgery for hematoma removal. Among them, 61 patients underwent endoscopically assisted hematoma removal surgery through the frontal lobe approach (frontal lobe group); 57 patients underwent endoscopic hematoma assisted via the temporal lobe approach (temporal lobe group). Treatment effects, cerebral hemodynamic status before and after treatment, postoperative prognosis at one month, and incidence of complications were compared between the 2 groups. We found that the total effective treatment rate in the frontal lobe group was higher than that in the temporal lobe group (P < .05). After surgery, the R during the contraction period of the common cerebral artery in both groups decreased compared to that before surgery, and the frontal lobe group was significantly lower than the temporal lobe group; the V and Q were higher than those before surgery, and the frontal lobe group was significantly higher than the temporal lobe group (P < .05). The prognosis of the frontal lobe group was better than that of the temporal lobe group (P < .05). Compared to the endoscopic-assisted temporal approach, the endoscopic-assisted frontal lobe approach for the treatment of HICH can improve cerebral hemodynamic status, enhance treatment efficacy, and improve prognosis.
Treatment of lung cancer by acupuncture combined with medicine based on pathophysiological mechanism: A review
Authors: Guan Chenguang , Chen Hong , Chen Haipeng , Li Shuhua , Chen Yuhan , Chen Jingyu , Dong Yushan , Zheng Zhitao , Wang Kaiwen , Pan Chuqiao
Published: February 2024

Lung cancer is one of the most frequently diagnosed cancers in the world. There are an estimated 2.2 million new cases and 1.79 million deaths each year. Over the past 2 decades, our understanding of disease biology, the use of predictive biomarkers, and improvements in therapeutic approaches have made significant progress and transformed the outcomes of many patients. Treatment is determined by the subtype and stage of the cancer; however, the effect of personalized treatment remains unsatisfactory. The use of Chinese medicines has attracted increasing attention worldwide. Chinese medicine treatment of lung cancer has few side effects, which can effectively prolong the survival expectation of patients and improve their quality of life, and has attracted increasing attention. Based on the pathophysiological mechanism of lung cancer reported in modern medical research, this article explores the efficacy and safety of acupuncture combined with medicine in the treatment of lung cancer.
Signaling networks guiding erythropoiesis
Authors: Kuttikrishnan Shilpa , Prabhu Kirti S. , Khan Abdul Q. , Uddin Shahab
Published: February 2024

Purpose of review

Cytokine-mediated signaling pathways, including JAK/STAT, PI3K/AKT, and Ras/MAPK pathways, play an important role in the process of erythropoiesis. These pathways are involved in the survival, proliferation, and differentiation function of erythropoiesis.

Recent findings

The JAK/STAT pathway controls erythroid progenitor differentiation, proliferation, and survival. The PI3K/AKT signaling cascade facilitates erythroid progenitor survival, proliferation, and final differentiation. During erythroid maturation, MAPK, triggered by EPO, suppresses myeloid genes, while PI3K is essential for differentiation. Pro-inflammatory cytokines activate signaling pathways that can alter erythropoiesis like EPOR-triggered signaling, including survival, differentiation, and proliferation.

A comprehensive understanding of signaling networks is crucial for the formulation of treatment approaches for hematologic disorders. Further investigation is required to fully understand the mechanisms and interactions of these signaling pathways in erythropoiesis.
Detection and significance of anti-Mycobacterium tuberculosis specific IgG antibody response for the diagnosis of pulmonary tuberculosis using enzyme-linked immunosorbent assay.
Authors: Chaudhary Pooja , Mohanty Keshar K. , Kumar Santosh , Sikarwar Arun P. , Patil Shripad A
Published: February 2024

Objective: For rapid serodiagnosis of pulmonary tuberculosis (PTB), the clinical usefulness of IgG antibody response against the in-house prepared Mycobacterium tuberculosis soluble extract (MTSE) antigen using the ELISA test was evaluated.
Methods: In this study, a total of 758 pulmonary TB patients (652 AFB-positive and 106 AFB-negative), 276 healthy controls, and 43 pulmonary infectious disease controls other than TB were recruited. IgG antibody level against MTB soluble extract was measured in sera samples of all study groups using an ELISA test. The level of IgG antibody responses was compared among groups by the Kruskal-Wallis test. The pairwise comparison was made by the Mann-Whitney test, A positive score was represented by optical density above the cut–off value which was calculated from OD values of healthy controls. The evaluation of diagnostic value was considered based on sensitivity and specificity.   
Results: Significantly higher levels of IgG antibody response were observed in PTB patients compared to healthy control and non-TB other pulmonary infectious disease control groups (p value<0.0001). The percent positivity for the IgG antibody response was higher in AFB-positive 574/652 (88.04%) and 79/106 (74.53%) AFB-negative PTB patients as compared to healthy control 9/276 (3.26%) and non-TB other pulmonary infectious disease control 3/43 (6.97%). The sensitivity of the test in PTB patients (AFB-positive and AFB-negative) was 86.15% (95% CI; 83.48-88.53), and the specificity was 96.74% (95% CI; 93.90-98.50).
 
Conclusion: This developed immunological test could be much more efficient in detecting IgG antibody response in PTB patients. Further, this test could be useful for diagnosing AFB-negative presumptive TB cases.
Considerations for reporting variants in novel candidate genes identified during clinical genomic testing
Authors: Chong Jessica Xiao-Ling , Berger Seth , Baxter Samantha , Smith Erica , Xiao Changrui , Calame Daniel , Hawley Megan , Rivera-Munoz E. Andres , DiTroia Stephanie ,   Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium, Bamshad Michael , Rehm Heidi
Published: February 2024

Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
PRMT5 deficiency disturbs Nur77 methylation to inhibit endometrial stromal cell differentiation in recurrent implantation failure
Authors: Cao Zhiwen , Wang Xiaoying , Liu Yang , Tang Xinyi , Wu Min , Zhen Xin , Kang Nannan , Ding Lijun , Sun Jianxin , Cai Xinyu , Sun Haixiang , Yan Guijun , Jiang Ruiwei
Published: February 2024

Various posttranslational modifications (PTMs) have been implicated in endometrial stromal cell (EnSC) differentiation, but the potential role of PTM crosstalk has not been identified. Here, we report that protein arginine methyltransferase 5 (PRMT5) is indispensable for human endometrial decidualization, functioning as a key regulator of decidualization defect in recurrent implantation failure (RIF) patients. Uterine-selective deletion ofPrmt5led to defective embryo implantation in mice due to impaired EnSC decidualization. Mechanistically, we find that PRMT5 catalyzes symmetric dimethylation of orphan nuclear receptor Nur77 at arginine 346, which in turn promotes Nur77 nuclear localization and increases its transcriptional activity in EnSC. Moreover, we demonstrate that PRMT5-mediated Nur77 methylation antagonizes AKT-induced phosphorylation of Nur77 at serine 351 in the transition from proliferation to differentiation of EnSC and disruption of the balance between methylation and phosphorylation of Nur77 is essentially involved in the endometrium of RIF patients. Furthermore, by modulating the methylation-phosphorylation of Nur77 and its transcriptional activity, we rescued impaired decidualization in RIF, further highlighting the critical role of the PRMT5/AKT/Nur77 complex in uterine receptivity to embryo implantation.
Longitudinal Fragility Phenotyping Predicts Lifespan and Age-Associated Morbidity in C57BL/6 and Diversity Outbred Mice
Authors: Luciano Alison , Robinson Laura , Garland Gaven , Lyons Bonnie , Korstanje Ron , Di Francesco Andrea , Churchill Gary A.
Published: February 2024

Aging studies in mammalian models often depend on natural lifespan data as a primary outcome. Tools for lifespan prediction could accelerate these studies and reduce the need for veterinary intervention. Here, we leveraged large-scale longitudinal frailty and lifespan data on two genetically distinct mouse cohorts to evaluate noninvasive strategies to predict life expectancy in mice. We applied a modified frailty assessment, the Fragility Index, derived from existing frailty indices with additional deficits selected by veterinarians. We developed an ensemble machine learning classifier to predict imminent mortality (95% proportion of life lived [95PLL]). Our algorithm represented improvement over previous predictive criteria but fell short of the level of reliability that would be needed to make advanced prediction of lifespan and thus accelerate lifespan studies. Highly sensitive and specific frailty-based predictive endpoint criteria for aged mice remain elusive. While frailty-based prediction falls short as a surrogate for lifespan, it did demonstrate significant predictive power and as such must contain information that could be used to inform the conclusion of aging experiments. We propose a frailty-based measure of healthspan as an alternative target for aging research and demonstrate that lifespan and healthspan criteria reveal distinct aspects of aging in mice.
Morroniside promotes skin wound re-epithelialization by facilitating epidermal stem cell proliferation through GLP-1R-mediated upregulation of β-catenin expression
Authors: Yu Chenghao , Yu Siyuan , Liu Zuohua , Xu Lei , Zhang Zhiqiang , Wan Jiaming , Ji Pengxiang , Zhang Ping , Fu Yi , Le Yingying , Hou Ruixing
Published: February 2024

Epidermal stem cells (EpSCs) play a vital role in skin wound healing through re-epithelialization. Identifying chemicals that can promote EpSC proliferation is helpful for treating skin wounds. This study investigates the effect of morroniside on cutaneous wound healing in mice and explores the underlying mechanisms. Application of 10-50 μg/mL of morroniside to the skin wound promotes wound healing in mice. In vitro studies demonstrate that morroniside stimulates the proliferation of mouse and human EpSCs in a time- and dose-dependent manner. Mechanistic studies reveal that morroniside promotes the proliferation of EpSCs by facilitating the cell cycle transition from the G1 to S phase. Morroniside increases the expression of β-catenin via the glucagon-like peptide-1 receptor (GLP-1R)-mediated PKA, PKA/PI3K/AKT and PKA/ERK signalling pathways, resulting in the increase of cyclin D1 and cyclin E1 expression, either directly or by upregulating c-Myc expression. This process ultimately leads to EpSC proliferation. Administration of morroniside to mouse skin wounds increases the phosphorylation of AKT and ERK, the expression of β-catenin, c-Myc, cyclin D1, and cyclin E1, as well as the proliferation of EpSCs, in periwound skin tissue, and accelerates wound re-epithelialization. These effects of morroniside are mediated by the GLP-1R. Overall, these results indicate that morroniside promotes skin wound healing by stimulating the proliferation of EpSCs via increasing β-catenin expression and subsequent upregulation of c-Myc, cyclin D1, and cyclin E1 expression through GLP-1R signalling pathways. Morroniside has clinical potential for treating skin wounds.
Recognition ofChlamydia trachomatisby Toll-Like Receptor 9 is altered during persistence
Authors: Diallo Aissata , Overman Grace , Sah Prakash , Liechti George W.
Published: February 2024

Toll-like receptor 9 (TLR9) is an innate immune receptor that localizes to endosomes in antigen presenting cells and recognizes single stranded unmethylated CpG sites on bacterial genomic DNA. Previous bioinformatic studies have indicated that the genome of the human pathogenChlamydia trachomatiscontains TLR9 stimulatory motifs, and correlative studies have implied a link between human TLR9 (hTLR9) genotype variants and susceptibility to infection. Here we present our evaluation of the stimulatory potential ofC. trachomatisgDNA and its recognition by hTLR9– and murine TLR9 (mTLR9)-expressing cells. We confirm that hTLR9 colocalizes with chlamydial inclusions in the pro-monocytic cell line, U937. Utilizing HEK293 reporter cell lines, we demonstrate that purified genomic DNA fromC. trachomatiscan stimulate hTLR9 signaling, albeit at lower levels than gDNA prepared from other Gram-negative bacteria. Interestingly, we found that whileC. trachomatisis capable of signaling through hTLR9 and mTLR9 during live infections in non-phagocytic HEK293 reporter cell lines, signaling only occurs at later developmental time points. Chlamydia-specific induction of hTLR9 is blocked when protein synthesis is inhibited prior to the RB-to-EB conversion and exacerbated by the inhibition of lipooligosaccharide biosynthesis. The induction of aberrance / persistence also significantly alters Chlamydia-specific TLR9 signaling. Our observations support the hypothesis that chlamydial gDNA is released at appreciable levels by the bacterium during the conversion between its replicative and infectious forms and during treatment with antibiotics targeting peptidoglycan assembly.
Dominant suppressor genes of p53-induced apoptosis inDrosophila melanogaster
Authors: Lukacsovich Tamás , Szlanka Tamás , Bálint Éva , Szabó Kornélia , Hajdu Ildikó , Molnár Enikő , Virágh Erika , Lin Yu-Hsien , Méhi Orsolya , Zvara Ágnes , Török István , Hegedűs Zoltán , Kiss Brigitta , Ramasz Beáta , Magdalena Laura M. , Puskás László , Mechler Bernard M. , Fónagy Adrien , Asztalos Zoltán , Žurovec Michal , Boros Imre , Kiss István
Published: February 2024

Apoptosis, the programmed cell death, is responsible for the removal of cells seriously damaged or unwanted in development. A major function of apoptosis is the removal of cells which suffered oncogenic mutations, thereby preventing cancerous transformation.

By making use of theDEPtransposon, aPelement derivative made in our laboratory, we made an insertional mutagenesis screen inDrosophila melanogasterto identify genes which, when overexpressed, suppress thep53-activated apoptosis. TheDEPelement has Gal4-activatable, outward-directedUAS-promoters at both ends which can be deleted separatelyin vivo. In theDEPinsertion mutants, we used theGMR-Gal4driver to induce transcription from bothUAS-promoters and tested the suppression effect on the apoptotic rough eye phenotype generated by an activatedUAS-p53transgene.

ByDEPinsertions, seven genes were identified which suppressed thep53-induced apoptosis. In four mutants, the suppression effect was resulted by single genes activated by oneUAS-promoter (Pka-R2, Rga, crol, Spt5). In the other three (Orct2, Polr2M, stg), deleting eitherUAS-promoter eliminated the suppression effect. In qPCR experiments we found that the genes in the vicinity of theDEPinsertion also showed an elevated expression level. This suggested an additive effect of the nearby genes on suppressing apoptosis.

In the eucaryotic genomes there are co-expressed gene clusters. Three of theDEPinsertion mutants are included and two are in close vicinity of separate co-expressed gene clusters. This raises the possibility that the activity of some of the genes in these clusters may help the suppression of the apoptotic cell death.
Optimizing genomics pipeline execution with integer linear programming
Authors: Melnichenko Olesya , Malladi Venkat S.
Published: February 2024

Abstract

In the field of genomics, bioinformatics pipelines play a crucial role in processing and analyzing vast biological datasets. These pipelines, consisting of interconnected tasks, can be optimized for efficiency and scalability by leveraging cloud platforms such as Microsoft Azure. The choice of compute resources introduces a trade-off between cost and time. This paper introduces an approach that uses Linear Programming (LP) to optimize pipeline execution. We consider optimizing two competing cases: minimizing cost with a run duration restriction and minimizing duration with a cost restriction. Our results showcase the utility of using LP in guiding researchers to make informed compute decisions based on specific data sets, cost and time requirements, and resource constraints.
Interplay Between FoxM1 and Dab2 Promotes Endothelial Cell Responses in Diabetic Wound Healing
Authors: Bhattacharjee Sudarshan , Gao Jianing , Lu Yao Wei , Eisa-Beygi Shahram , Wu Hao , Li Kathryn , Birsner Amy E. , Wong Scott , Song Yudong , Shyy John Y-J. , Cowan Douglas B. , Wei Wenyi , Aikawa Masanori , Shi Jinjun , Chen Hong
Published: February 2024

Diabetes mellitus can cause impaired and delayed wound healing, leading to lower extremity amputations; however, the mechanisms underlying the regulation of vascular endothelial growth factor (VEGF)-dependent angiogenesis remain uncertain and could reveal new therapeutic targets. In our study, the molecular underpinnings of endothelial dysfunction in diabetes were investigated, focusing on the roles of Disabled-2 (Dab2) and Forkhead Box M1 (FoxM1) in VEGF receptor 2 (VEGFR2) signaling and endothelial cell (EC) function. Bulk RNA-sequencing analysis identified significant downregulation of Dab2 in high concentrations glucose treated primary mouse skin ECs, simulating hyperglycemic conditions in diabetes mellitus. In diabetic mice with a genetic EC deficiency of Dab2 angiogenesis was reducedin vivoandin vitrowhen compared with wild-type mice. Restoration of Dab2 expression by injected mRNA-containing lipid nanoparticles rescued impaired angiogenesis and wound healing in diabetic mice. At the same time, FoxM1 was downregulated in skin ECs subjected to high glucose conditions as determined by RNA-sequencing analysis. FoxM1 was found to bind to the Dab2 promoter, regulating its expression and influencing VEGFR2 signaling. The FoxM1 inhibitor FDI-6 reduced Dab2 expression and phosphorylation of VEGFR2. These findings indicate that restoring Dab2 expression through targeted therapies can enhance angiogenesis and wound repair in diabetes. To explore this therapeutic potential, we tested LyP-1-conjugated lipid nanoparticles (LNPs) containing Dab2 or control mRNAs to target ECs and found the former significantly improved wound healing and angiogenesis in diabetic mice. This study provides evidence of the crucial roles of Dab2 and FoxM1 in diabetic endothelial dysfunction and establishes targeted delivery as a promising treatment for diabetic vascular complications.
Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability
Authors: LaCoursiere Christopher Mark , Ullmann Jeremy F.P. , Koh Hyun Yong , Turner Laura , Baker Cristina M. , Robens Barbara , Shao Wanqing , Rotenberg Alexander , McGraw Christopher M. , Poduri Annapurna
Published: February 2024

Hundreds of novel candidate human epilepsy-associated genes have been identified thanks to advancements in next-generation sequencing and large genome-wide association studies, but establishing genetic etiology requires functional validation. We generated a list of >2200 candidate epilepsy-associated genes, of which 81 were determined suitable for the generation of loss-of-function zebrafish models via CRISPR/Cas9 gene editing. Of those 81 crispants, 48 were successfully established as stable mutant lines and assessed for seizure-like swim patterns in a primary F2screen. Evidence of seizure-like behavior was present in 5 (arfgef1, kcnd2, kcnv1, ubr5, wnt8b) of the 48 mutant lines assessed. Further characterization of those 5 lines provided evidence for epileptiform activity via electrophysiology inkcnd2andwnt8bmutants. Additionally,arfgef1andwnt8bmutants showed a decrease in the number of inhibitory interneurons in the optic tectum of larval animals. Furthermore, RNAseq revealed convergent transcriptional abnormalities between mutant lines, consistent with their developmental defects and hyperexcitable phenotypes. These zebrafish models provide strongest experimental evidence supporting the role ofARFGEF1, KCND2, andWNT8Bin human epilepsy and further demonstrate the utility of this model system for evaluating candidate human epilepsy genes.

Highlights

Zebrafish models generated by CRISPR/Cas9 gene editing display seizure-like swim patterns in five candidate human epilepsy genes:arfgef1, kcnd2, kcnv1, ubr5, wnt8b.

Local field potential abnormalities recorded fromkcnd2andwnt8bcrispants provide additional evidence of hyperexcitability.

Arfgef1andwnt8bmutant larvae have fewer inhibitory interneurons than wild type in the optic tectum.

CRISPR-generated mutants of epilepsy genes displayed convergent transcriptional dysregulation, consistent with developmental abnormalities and their hyperexcitability phenotype.
A meta-analysis of the gut microbiome in inflammatory bowel disease patients identifies disease-associated small molecules
Authors: Elmassry Moamen M. , Sugihara Kohei , Chankhamjon Pranatchareeya , Camacho Francine R. , Wang Shuo , Sugimoto Yuki , Chatterjee Seema , Chen Lea Ann , Kamada Nobuhiko , Donia Mohamed S.
Published: February 2024

Changes in the gut microbiome have been associated with several human diseases, but the molecular and functional details underlying these associations remain largely unknown. Here, we performed a multi-cohort analysis of small molecule biosynthetic gene clusters (BGCs) in 5,306 metagenomic samples of the gut microbiome from 2,033 Inflammatory Bowel Disease (IBD) patients and 833 matched healthy subjects and identified a group of Clostridia-derived BGCs that are significantly associated with IBD. Using synthetic biology, we discovered and solved the structures of six fatty acid amides as the products of the IBD-enriched BGCs. Using two mouse models of colitis, we show that the discovered small molecules disrupt gut permeability and exacerbate inflammation in chemically and genetically susceptible mice. These findings suggest that microbiome-derived small molecules may play a role in the etiology of IBD and represent a generalizable approach for discovering molecular mediators of microbiome-host interactions in the context of microbiome-associated diseases.
Novel 3D Approach to Model Non-Alcoholic Fatty Liver Disease using human Pluripotent Stem Cells
Authors: Morell Carola Maria , Tilson Samantha Grace , Tomaz Rute Alexandra , Shahsavari Arash , Munteanu Andi , Canu Giovanni , Wesley Brandon Tyler , Perrin Marion , Geti Imbisaat , Mukhopadhyay Subhankar , Mazzacuva Francesca , Gissen Paul , Garcia-Bernardo Jose , Bachman Martin , Rimland Casey Allison , Sampaziotis Fotios , Mohorianu Irina , Vallier Ludovic
Published: February 2024

Background and aims

Non-alcoholic fatty liver disease (NAFLD) is a major health care challenge and new therapies are urgently needed. However, the mechanisms underlying disease remain to be understood. Indeed, studying NAFLD remains challenging due to the lack of model systems recapitulating the different aspects of the human pathology. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity to address this limitation since they can be differentiated into large quantity of liver cells. Here, we took advantage of hiPSCs to develop a multi-cellular platform mimicking the complex interplays involved in NAFLD progression.

Methods

hiPSCs-derived hepatocyte like cells (HLCs), cholangiocytes, stellate cells, and macrophages were co-cultured in a collagen-based 3D system to reproduce the liver microenvironment. Fatty acid treatments led to a NAFLD phenotype involving cell-cell interactions which were investigated by transcriptomic and functional analyses.

Results

Hepatic cells were grown up to 4weeks in 3D, retaining key functions and markers. Importantly, co-cultured cells spontaneously reorganised into physiologically relevant connections: HLCs arranged around biliary structures, which established contacts with stellate cells, while macrophages organised around HLCs. Fatty acid treatments induced steatosis and lipotoxicity in HLCs. Furthermore, fat-laden HLCs prompted a non-parenchymal cells response altering tissue architecture.

Conclusions

Our multicellular platform provides a new approach to model interactions between human hepatic cells during NAFLD progression. Such approach has the potential to investigate the sequential events driving chronic liver diseases, including hepatocellular injury, inflammation and fibrosis. Furthermore, our system provides a unique and urgently needed tool to investigate the molecular mechanisms associated with NAFLD and ultimately to validate new targets for therapeutics development.

List of abbreviations

COs, cholangiocytes organoids; FFA, free fatty acids; hiPSCs, human induced pluripotent stem cells; HLCs, hepatocyte like cells; HSCs, hepatic stellate cells; M0, hiPSCs-derived macrophages; NAFLD, non-alcoholic fatty liver disease; NPCs, non-parenchymal cells; OA, oleic acid; PA, palmitic acid.
Parental effects of pathogenic bacterial infections inDrosophila melanogaster: trans-generational immune priming without apparent costs
Authors: Basu Aabeer Kumar , Prasad Nagaraj Guru
Published: February 2024

Parental experience with pathogens and parasites can shape offspring susceptibility to infections, a phenomenon commonly referred to as trans-generational immune priming (TgIP) in insects. TgIP can influence the evolution of both host immune traits and pathogen virulence. The host ecology and its environmental pathogen load can in turn shape the evolution of TgIP. Therefore, the functional limits of TgIP and the conditions under which it is observed need to be explored in a variety of species. Majority of empirical studies addressing this phenomenon focus on non-pathogenic infections of parents, implemented via either the use of pathogen substitutes (viz., liposaccharide molecules), or the use of sub-lethal infection doses, by using inactivated pathogens to infect the parents. We tested if exposing parents to pathogenic bacterial infections affects offspring susceptibility to homologous (same pathogen as the one used to infect the parents) and heterologous (different pathogen than the one used to infect the parents) infection challenges inDrosophila melanogaster. We found that parental infection increases offspring survival following a homologous challenge. Similar effects were seen in the case of heterologous challenges too, with the breadth of cross-reactivity being dependent on the pathogen used to infect the parents. Parental infection also improves offspring capacity to restrict systemic pathogen proliferation following a homologous challenge, suggesting increased disease resistance. Parental infection has no effect on offspring reproduction, either in presence or absence of infection, suggesting an absence of associated costs and limited benefit of trans-generational immune priming. Overall, we have demonstrated that parental infection helps offspring better counter infection challenges inD. melanogasterwithout incurring any measurable costs.
Potent AMA1-specific human monoclonal antibody against P. vivax Pre-erythrocytic and Blood Stages
Authors: Winnicki Anna C , King Christopher L , Bosch Jurgen , Malachin Alyssa N , Carias Lenore L , Skomorovska-Prokvolit Yelenna , Tham Wai-Hong , Dietrich Melanie H , Popovici Jean , Roobsoong Wanlapa , Beeson James G , Sattabongkot Jetsumon , Yeoh Lee M , Opi D. Herbert , Feufack-Donfack Lionel Brice , Orban Agnes , Drago Chiara L , McLaine Olivia S , Redinger Karli R , Jung Nicolai C , Baldor Lea , Kirtley Payton , Neilsen Kiersey , Aleshnick Maya , Zanghi Gigliola , Rezakhani Nastaran , Vaughan Ashley M. , Wilder Brandon K
Published: February 2024

New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. We isolated 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. HumAb 826827 blocked the invasion of human erythrocytes using Pv clinical isolates and inhibited sporozoite invasion of human hepatocytes in vitro (IC50 of 0.3 to 3.7 ug/mL). It also significantly reduced liver infection of chimeric FRG humHep mice in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate transcendent, blocks both pre erythrocytic and blood stage infection, and could be a new therapy for Pv.