Abstract Objective To analyze the regularities and clinical features of sintilimab-related autoimmune myocarditis, and to summarize the differential diagnosis key points between sintilimab-related autoimmune myocarditis and acute myocardial infarction. Methods The case reports about sintilimab-related autoimmune myocarditis were searched on databases from the establishment of the database to April 1st 2024. The relevant medical records were searched on the hospital information system of Beijing Hospital of Traditional Chinese Medicine in the past 3 years. The case reports and medical records were collected for statistical analysis. Result Twenty three cases were collected including 22 case reports and 1 case record. Most of the sintilimab-related autoimmune myocarditis were in elderly men aged 60–75 years old and occurred between the end of the first dose of treatment to the beginning of the second dose. The symptom was nonspecific such as chest tightness and palpitation, sometimes with symptom of myasthenia as muscle weakness or myositisand as muscle soreness. Elevated cardiac biomarkers and changes in electrocardiogram were common, and decreased left ventricular ejection fraction was rarely seen in echocardiography. 9 cases underwent coronary angiography or computed coronary tomography angiography, and 3 cases underwent cardiovascular magnetic resonance. Conclusion The manifestations of sintilimab-related autoimmune myocarditis are not specific. The medication history and concomitant symptoms are of warning value. Coronary angiography or coronary computed coronary tomography angiography can be helpful when ruling out acute myocardial infarction. Cardiovascular magnetic resonance and myocardial biopsy can confirm the diagnosis. Cardiac biomarkers and the electrocardiogram can assist in diagnosis and prognosis assessment.
Introduction: Heavy metal pollution including lead (Pb) has become one of the serious global issues threatening food security, human health, and the ecosystem. Exogenous application of astaxanthin (ATX), a potent natural antioxidant, has been shown to enhance plant tolerance to various abiotic stresses. However, the role of endogenous ATX in alleviating Pb stress and the underlying molecular mechanisms remain poorly understood. Objectives: This study aimed to systematically investigate the effects and mechanism of endogenous ATX in biofortified tobacco (T-ATX) in promoting plant growth, particularly enhancing plant tolerance to Pb toxicity and blocking Pb pollution. Methods: Pot experiments were employed to investigate plant growth and Pb tolerance as well as Pb absorption and translocation in T-ATX and wild-type (SNN) tobacco seedlings subjected to various doses of Pb stress. Multiple physiological and cellular examinations were conducted, followed by integrated omics approaches in this study. Results: T-ATX plants exhibited an increased plant height, root length, leaf area, and biomass compared to SNN under Pb stress. T-ATX displayed higher levels of chlorophyll, photosynthetic efficiency, antioxidant enzyme activities, and non-enzymatic antioxidants, with improved integrity of subcellular structures. Remarkably, Pb content in various organs and Pb translocation coefficient were significantly reduced in T-ATX. Multiple genes and metabolites associated with antioxidant defense mechanisms, detoxification pathways, carotenoid metabolism, Pb ion transport, and plant hormone signal transduction were significantly upregulated in T-ATX tobacco plants. Conclusion: Endogenous ATX enriched in the T-ATX genotype significantly confers plant healthy performance and high tolerance to Pb stress by enhancing the antioxidant defense system, maintaining cellular structural integrity, reducing Pb absorption and translocation, upregulating detoxification and the related signaling pathways. These findings provide new insights into the endogenous ATX-mediated molecular mechanisms to promote plant growth and mitigate Pb toxicity, establishing a foundation for using ATX-fortified crops for green control technology of heavy metal pollution.
IntroductionSchistosomiasis japonica, a zoonotic parasitic disease, induces complex immune regulation during infection. The inflammatory responses and immunosuppressive mechanisms co-exist to maintain immune homeostasis in schistosomiasis. B7-H4 is a critical immune checkpoint molecule that modulates T cell activation and exerts immunosuppressive effects. Our previous investigations revealed that B7-H4 mRNA expression was elevated in mice infected with Schistosoma japonicum, with interleukin-10 (IL-10) demonstrating regulatory capacity to enhance B7-H4 expression in RAW264.7 macrophages. In this study, we further explore the mechanism underlying IL-10-mediated B7-H4 upregulation.MethodsWestern blot was performed to detect B7-H4 expression levels, both in mice infected with Schistosoma japonicum and in RAW264.7 cells stimulated with IL-10. RT-qPCR was performed to screen microRNAs (miR-140 et al.) in RAW264.7 cells stimulated with IL-10. Then dual-luciferase reporter assay was performed to confirm that miR-140 can directly bind to the 3’UTR of B7-H4. miR-140 promoter activity in RAW264.7 cells was also detected via dual-luciferase reporter assays. In addition, ChIP was performed to confirm the binding of transcription factors and miR-140 promoter.ResultsNotably, miR-140 was decreased in IL-10-treated microphages, accompanied by B7-H4 expression was upregulated. miR-140 can directly bind to the 3’UTR of B7-H4 and then inhibit the expression of B7-H4 in RAW264.7 cells. Meanwhile, miR-140 mimics can also attenuate IL-10-induced B7-H4 expression in RAW264.7 cells. Then we found that IL-10 may inhibit miR-140 promoter activity in RAW264.7 cells through transcription factors that binding to the - 576/- 94 bp region of the miR-140 promoter. Results by Western blot and ChIP further indicated that IL-10 could downregulate miR-140 promoter activity in a STAT5 dependence manner. After the sequence of STAT5 binding site within the - 456/- 446 bp region of the miR-140 promoter was mutated, IL-10 failed to suppress the activity produced by mutant miR-140 promoter.DiscussionIn summary, IL-10 can inhibit miR-140 through STAT5, thereby upregulating the expression of B7-H4 in RAW264.7 cells. This study may suggest a new mechanism underlying IL-10-mediated B7-H4 upregulation in macrophages.
Epilepsy is one of the most common neurological disorders in both children and adults, characterized by significant clinical heterogeneity and dynamic natural course. The pathophysiological roles of astrocytes in epilepsy have been increasingly recognized. Fluid biomarkers derived from astrocytes are actively studied in epileptic disorders, although their use remains limited in clinical practice. This review aims to compile and analyze clinical and experimental findings concerning astrocytic biomarkers in epilepsy and related conditions, with a focus on glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B). Herein we examine their roles in assessing seizure burden and temporal dynamics, explore their potential in distinguishing epileptic from psychogenic non-epileptic seizures, and discuss their therapeutic, prognostic, and mechanistic implications in the context of epileptic disorders.
Sjoerd J.D. Tjalsma, Niels J. Rinzema, Marjon J.A.M. Verstegen
et al.
Summary: Cell-type-specific gene activation is regulated by enhancers, sometimes located at large genomic distances from target gene promoters. Whether distal enhancers require specific factors to orchestrate gene regulation remains unclear. Here, we used enhancer distance-controlled reporter screens to find candidate factors. We depleted them and employed activity-by-contact predictions to genome-wide classify genes based on enhancer distance. Predicted distal enhancers typically control tissue-restricted genes and often are strong enhancers. We find cohesin, but also mediator, most specifically required for long-range activation, with cohesin repressing short-range gene activation and prioritizing distal over proximal HBB genes competing for shared enhancers. Long-range controlled genes are also most sensitive to perturbations of other regulatory proteins and to BET inhibitor JQ1, this being more a consequence of their distinct enhancer features than distance. Our work predicts that lengthening of intervening sequences can help limit the expression of target genes to specialized cells with optimal trans-factor environments.
Nobumitsu Hirai, Yuhei Miwa, Shunta Hattori
et al.
Biofilms cause a variety of problems, such as food spoilage, food poisoning, infection, tooth decay, periodontal disease, and metal corrosion, so knowledge on biofilm prevention and removal is important. A detailed observation of the three-dimensional structure of biofilms on the nanoscale is expected to provide insight into this. In this study, we report on the successful in situ nanoscale observations of a marine bacterial biofilm on glass in phosphate buffer solution (PBS) using both scanning ion conductance microscopy (SICM) and confocal laser scanning microscopy (CLSM) over the same area. By observing the same area by SICM and CLSM, we were able to clarify the three-dimensional morphology of the biofilm, the arrangement of bacteria within the biofilm, and the difference in local ion conductivity within the biofilm simultaneously, which could not be achieved by observation using a microscope alone.
Resilience-based management strategies are gaining attention as tools to improve coral survival and recovery under increasingly stressful conditions. Prioritizing locations to implement these strategies depends on knowing where corals already show potential signs of resilience and how environmental conditions may shift with climate change. We synthesized environmental conditions and coral cover trends in Guam and American Samoa using present-day climate conditions and 2 future climate scenarios: Representative Concentration Pathways 4.5 and 8.5. We examined the spatial overlap between favorable and unfavorable environmental conditions and locations where coral reefs have maintained or increased coral cover over the past decade. Locations representing 4 combinations of the aforementioned characteristics may be subject to different management strategies: (1) conservation and restoration of robust corals, (2) restoration of declining corals, (3) conservation of genetic material of robust corals and stressor mitigation, and (4) no clear strategy for declining corals. We estimated areas in which multiple management actions could be performed based on these combinations. Under present-day climate conditions, the conservation of genetic material and stressor mitigation were overrepresented in Guam, comprising 23% of the study area; this declined to 15% in future climate scenarios. Coral restoration was at first underrepresented (0%). In American Samoa, the proportional area for each strategy remained consistent regardless of climate. Coral restoration was overrepresented, comprising 54% to 56% of the study area, whereas the conservation of genetic material and stressor mitigation were underrepresented (9% to 11%, respectively). Our approach offers a rapid way to assess where potential management actions could be applied based on data aggregated over large spatial extents, which can complement more detailed, labor-intensive assessments of reef community dynamics, particularly if distinct coral communities inform the boundaries of aggregation units. These results may guide managers in selecting ecologically suitable locations for implementing resilience-based management strategies for coral reefs.
Abstract Background Epithelial mesenchymal transformation (EMT) in alveolar type 2 epithelial cells (AT2) is closely associated with pulmonary fibrosis (PF). Histone deacetylase 3 (HDAC3) is an important enzyme that regulates protein stability by modulating the acetylation level of non-histones. Here, we aimed to explore the potential role and regulatory mechanisms associated with HDAC3 in PF. Methods We quantified HDAC3 expression both in lung tissues from patients with PF and from bleomycin (BLM)-treated mice. HDAC3 was also detected in TGF-β1-treated AT2. The mechanistic activity of HDAC3 in pulmonary fibrosis and EMT was also explored. Results HDAC3 was highly expressed in lung tissues from patients with PF and bleomycin (BLM)-treated mice, especially in AT2. Lung tissues from AT2-specific HDAC3-deficient mice stimulated with BLM showed alleviative fibrosis and EMT. Upstream of HDAC3, TGF-β1/SMAD3 directly promoted HDAC3 transcription. Downstream of HDAC3, we also found that genetic or pharmacologic inhibition of HDAC3 inhibited GATA3 expression at the protein level rather than mRNA. Finally, we found that intraperitoneal administration of RGFP966, a selective inhibitor of HDAC3, could prevent mice from BLM-induced pulmonary fibrosis and EMT. Conclusion TGF-β1/SMAD3 directly promoted the transcription of HDAC3, which aggravated EMT in AT2 and pulmonary fibrosis in mice via deacetylation of GATA3 and inhibition of its degradation. Our results suggest that targeting HDAC3 in AT2 may provide a new therapeutic target for the prevention of PF.
Christian G. Ziegler, Carina Riediger, Matthias Gruber
et al.
Pheochromocytomas (PCCs) are rare but potentially lethal tumors that arise from the adrenal medulla. The clinical suspicion and diagnosis of PCC can be challenging due to the non-specific nature of signs and symptoms. In many patients, infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could lead to long-term symptoms including fatigue, headaches, and cognitive dysfunction. Here, we present the case of a patient incidentally diagnosed with an adrenal mass that proved to be a PCC after imaging was performed due to persisting complaints after coronavirus disease 2019 (COVID-19) infection. A 37-year-old male patient was referred to our center because of a right-sided inhomogeneous adrenal mass, incidentally found during a computed tomographic scan of the thorax performed due to cough and dyspnea that persisted after COVID-19 infection. Other complaints that were present prior to COVID-19 infection included profuse sweating, dizziness, exhaustion with chronic fatigue, and concentration difficulties. The patient had no history of hypertension, his blood pressure was normal, and the 24-h ambulatory blood pressure monitoring confirmed normotension but with the absence of nocturnal dipping. Plasma normetanephrine was 5.7-fold above the upper limit (UL) of reference intervals (738 pg/ml, UL = 129 pg/ml), whereas plasma metanephrine and methoxytyramine were normal at 30 pg/ml (UL = 84 pg/ml) and <4 pg/ml (UL = 16 pg/ml), respectively. Preoperative preparation with phenoxybenzamine was initiated, and a 4-cm tumor was surgically resected. Profuse sweating as well as dizziness was resolved after adrenalectomy pointing toward PCC and not COVID-19-associated patient concerns. Altogether, this case illustrates the difficulties in recognizing the possibility of PCC due to the non-specific nature of signs and symptoms of the tumor, which in this case did not include hypertension and coincided with some of the symptoms of long COVID-19.
Diseases of the endocrine glands. Clinical endocrinology
The abundant homohexameric AAA + ATPase p97 (also known as valosin-containing protein, VCP) is highly conserved from Dictyostelium discoideum to human and a pivotal factor of cellular protein homeostasis as it catalyzes the unfolding of proteins. Owing to its fundamental function in protein quality control pathways, it is regulated by more than 30 cofactors, including the UBXD protein family, whose members all carry an Ubiquitin Regulatory X (UBX) domain that enables binding to p97. One member of this latter protein family is the largely uncharacterized UBX domain containing protein 9 (UBXD9). Here, we analyzed protein-protein interactions of D. discoideum UBXD9 with p97 using a series of N- and C-terminal truncation constructs and probed the UBXD9 interactome in D. discoideum. Pull-down assays revealed that the UBX domain (amino acids 384–466) is necessary and sufficient for p97 interactions and that the N-terminal extension of the UBX domain, which folds into a β0-α–1-α0 lariat structure, is required for the dissociation of p97 hexamers. Functionally, this finding is reflected by strongly reduced ATPase activity of p97 upon addition of full length UBXD9 or UBXD9261–573. Results from Blue Native PAGE as well as structural model prediction suggest that hexamers of UBXD9 or UBXD9261–573 interact with p97 hexamers and disrupt the p97 subunit interactions via insertion of a helical lariat structure, presumably by destabilizing the p97 D1:D1’ intermolecular interface. We thus propose that UBXD9 regulates p97 activity in vivo by shifting the quaternary structure equilibrium from hexamers to monomers. Using three independent approaches, we further identified novel interaction partners of UBXD9, including glutamine synthetase type III as well as several actin-binding proteins. These findings suggest a role of UBXD9 in the organization of the actin cytoskeleton, and are in line with the hypothesized oligomerization-dependent mechanism of p97 regulation.
Abstract Cavefishes represent one of the most bizarre and intriguing life forms inhabiting groundwater environments. One‐third of the known cavefishes worldwide is endemic to China, and almost half of those belongs to a single genus, Sinocyclocheilus (Cypriniformes: Cyprinidae). Analyzing the morphometrics of three Sinocyclocheilus species, we aimed to assess whether variability among conspecific populations exists. We predict that populations inhabiting different subterranean habitats (shallow vs. deep) show divergences in specific morphological traits to better cope with the local ecological conditions. Our results showed that the populations showing bigger eyes and reduced humpback were those occurring close to the cave entrance (habitats with light and high food availability), while specimens with smaller eyes and increased humpback were collected from deeper groundwater areas (habitats laying in darkness with food scarcity). This explorative study paves the way for further researches aiming to collect novel data on Chinese cavefishes and highlights the usefulness of these species in evolutionary studies.
Jannigje G. Kers, Egil A.J. Fischer, J. Arjan Stegeman
et al.
In the short life of broiler chickens, their intestinal microbiota undergoes many changes. To study underlying biological mechanisms and factors that influence the intestinal microbiota development, longitudinal data from flocks and individual birds is needed. However, post-mortem collection of samples hampers longitudinal data collection. In this study, invasively collected cecal and ileal content, cloacal swabs collected from the same bird, and boot sock samples and cecal droppings from the litter of the broilers’ poultry house, were collected on days 0, 2, 7, 14 and 35 post-hatch. The different sample types were evaluated on their applicability and reliability to characterize the broiler intestinal microbiota. The microbiota of 247 samples was assessed by 16S ribosomal RNA gene amplicon sequencing. Analyses of α and β measures showed a similar development of microbiota composition of cecal droppings compared to cecal content. Furthermore, the composition of cecal content samples was comparable to that of the boot socks until day 14 post-hatch. This study shows that the value of non-invasive sample types varies at different ages and depends on the goal of the microbiota characterization. Specifically, cecal droppings and boot socks may be useful alternatives for cecal samples to determine intestinal microbiota composition longitudinally.
Tritium is an important nuclide that must be monitored for radiation safety management. In this study, HTO was orally administered to rats at the level of 37 kBq (1 μCi) or 370 kBq (10 μCi) to examine tissue distribution and excretion levels. After sacrifice, wet and dry tissue samples were weighed and analyzed for tissue free-water tritium (TFWT) and organically bound tritium (OBT). The mean tissue concentrations of TFWT (OBT) were 30.9 (17.8) and 4.4 (8.1) Bq/g on days 7 and 13 at the 37 kBq level and 30.8 (64.6) Bq/g on day 17 at the 370 kBq level. To assess the cytogenetic damage due to tritium exposure, a cytokinesis-blocked micronucleus (MN) assay was performed in blood samples from rats exposed to HTO for 14 and 21 days after oral administration. There was no significant difference in the MN frequencies between the control and exposed rats. Keywords: Tritium, Organically bound tritium (OBT), Tissue free-water tritium (TFWT)
Fatemeh Atabaki pasdar, Alireza Khooei, Alireza Fazel
et al.
Background: Differential diagnosis between complete hydatidiform mole, partial hydatidiform mole and hydropic abortion, known as hydropic placentas is still a challenge for pathologists but it is very important for patient management.
Objective: We analyzed the nuclear DNA content of various types of hydropic placentas by flowcytometry.
Materials and Methods: DNA ploidy analysis was performed in 20 non-molar (hydropic and non-hydropic spontaneous abortions) and 20 molar (complete and partial moles), formalin-fixed, paraffin-embedded tissue samples by flow cytometry. The criteria for selection were based on the histopathologic diagnosis.
Results: Of 10 cases histologically diagnosed as complete hydatiform mole, 9 cases yielded diploid histograms, and 1 case was tetraploid. Of 10 partial hydatidiform moles, 8 were triploid and 2 were diploid. All of 20 cases diagnosed as spontaneous abortions (hydropic and non-hydropic) yielded diploid histograms.
Conclusion: These findings signify the importance of the combined use of conventional histology and ploidy analysis in the differential diagnosis of complete hydatidiform mole, partial hydatidiform mole and hydropic abortion.
Sujarot Dwi Sasmito, Adilah Ulfiati, Ardhian Wardana
et al.
Malaria infection during pregnancy can cause accumulation of infected red blood cells in placental intervillous space and induces placental tissue inflammation and hypoxia. This condition triggers endoglin expressionand release of soluble endoglin that can interfere TGF-β binding with the receptor. The aim of this study was to investigate the correlation between placental endoglin expression and TGF-β level with low fetal weight (LFW) in
malaria-infected mice. Nine pregnant mice infected with
Plasmodium berghei on the day ninth post mating (malaria-infected group) and eight normal pregnant mice (non-infected group) were used in this study. The mice were sacrificed on the day 18th post mating, and all fetal body weights were measured by analytical scale. Enzyme Link Immunosorbent Assay (ELISA) was done to determine the level of placental TGF-β while immunohistochemical staining was performed to examine endoglin expression in placental tissue. The mean of fetal body weights of malaria-infected group was significantly lower than non-infected group (p= 0,002), while the expression of placental endoglin in malaria- infected group was substantially higher than non-infected group (p= 0.003). The level of placental TGF-β in malaria-infected group was also considerably higher than non-infected group, but the difference was not significant (p= 0.064). Pearson correlation test showed that there were significant negative correlations between fetal body weights with the level of placental TGF-β (p= 0.017, r= -0.568) and the expression of placental endoglin (p= 0.002, r= -0.694). Malaria infection in pregnant mice will increase both TGF-β and endoglin in placenta tissue and correlate with low fetal weight.
David H. Keating, Yaoping Zhang, Irene M. Ong
et al.
Efficient microbial conversion of lignocellulosic hydrolysates to biofuels is a key barrier to the economically viable deployment of lignocellulosic biofuels. A chief contributor to this barrier is the impact on microbial processes and energy metabolism of lignocellulose-derived inhibitors, including phenolic carboxylates, phenolic amides (for ammonia-pretreated biomass), phenolic aldehydes, and furfurals. To understand the bacterial pathways induced by inhibitors present in ammonia-pretreated biomass hydrolysates, which are less well studied than acid-pretreated biomass hydrolysates, we developed and exploited synthetic mimics of ammonia-pretreated corn stover hydrolysate (ACSH). To determine regulatory responses to the inhibitors normally present in ACSH, we measured transcript and protein levels in an Escherichia coli ethanologen using RNA-seq and quantitative proteomics during fermentation to ethanol of synthetic hydrolysates containing or lacking the inhibitors. Our study identified four major regulators mediating these responses, the MarA/SoxS/Rob network, AaeR, FrmR, and YqhC. Induction of these regulons was correlated with a reduced rate of ethanol production, buildup of pyruvate, depletion of ATP and NAD(P)H, and an inhibition of xylose conversion. The aromatic aldehyde inhibitor 5-hydroxymethylfurfural appeared to be reduced to its alcohol form by the ethanologen during fermentation, whereas phenolic acid and amide inhibitors were not metabolized. Together, our findings establish that the major regulatory responses to lignocellulose-derived inhibitors are mediated by transcriptional rather than translational regulators, suggest that energy consumed for inhibitor efflux and detoxification may limit biofuel production, and identify a network of regulators for future synthetic biology efforts.