Marked Increase Research Articles

Influence of Covid-19 disease on hemostasis dynamics during extracorporeal membrane oxygenation (ECMO)1.

COVID-19 causes a considerable degradation of pulmonary function to the point of an acute respiratory distress syndrome (ARDS). Over the course of the disease the gas exchange capability of the lung can get impaired to such an extent that extracorporeal membrane oxygenation (ECMO) is needed as a life-saving intervention. In patients COVID-19 as well as ECMO may cause severe coagulopathies which manifest themselves in micro and macro thrombosis. Previous studies established D-dimers as a marker for critical thrombosis of the ECMO system while on admission increased D-dimers are associated with a higher mortality in COIVD-19 patients. It is therefore crucial to determine if COVID-19 poses an increased risk of early thrombosis of the vital ECMO system. 40 patients who required ECMO support were enrolled in a retrospective analysis and assigned into 2 groups. The COVID group consist of 20 COVID-19 patients who required ECMO support (n = 20), whereas 20 ECMO patients without COVID-19 were assigned to the control group. D-dimers, fibrinogen, antithrombin III (AT III), lactate dehydrogenase (LDH) and platelet count were analysed using locally weighted scatterplot smoothing and MANOVAs. The analysis of both groups shows highly significant differences in the dynamics of hemostasis. The increase in D-dimers that is associated with thrombosis of the ECMO systems occurs in COVID-19 patients around 2 days earlier (p = 2,8115 10-11) while fibrinogen is consumed steadily. In the control group fibrinogen levels increase rapidly after ten days with a plateau phase of around five days (p = 1,407 10-3). Both groups experience a rapid increase in AT III after start of support by ECMO (p = 5,96 10-15). In the COVID group platelet count decreased from 210 giga/l to 130 giga/l within eight days, while in the same time span in the control group platelets decreased from 180 giga/l to 105 giga/l (p = 1,1 10-15). In both groups a marked increase in LDH beyond 5000 U/l occurs (p = 3,0865 10-15). The early increase in D-dimers and decrease in fibrinogen suggests that COVID-19 patients bear an increased risk of early thrombosis of the ECMO system compared to other diseases treated with ECMO. Additionally, the control group shows signs of severe inflammation 10 days after the start of ECMO which were absent in COVID-19 patients.

How socio-political change is associated with the number of individually reported negative life events: a population-based study using the German reunification 1989/1990 as an example

BackgroundSocio-political change often leads to disruptions in employment and social networks, which can exacerbate health issues and increase mortality rates. These consequences are likely observed as an increase in negative...

Biological significance and clinical utility of lactate in sepsis.

Sepsis is a global health problem; progression to septic shock is associated with a marked increase in morbidity and mortality. In this setting, increased plasma lactate levels demonstrated to be an indicator of severity and a predictor of mortality, and are usually interpreted almost exclusively as a marker of low tissue perfusion. However, a recent paradigm shift has occurred in the exegesis of lactate metabolism and its biological properties. Indeed, metabolic adaptation to stress, even with an adequate oxygen supply, may account for high circulating lactate levels. Likewise, other pathophysiological consequences of sepsis, such as mitochondrial dysfunction, are associated with the development of hyperlactatemia, which is not necessarily accompanied by low tissue perfusion. Interpreting the origin and function of lactate may be of great clinical utility in sepsis, especially when circulating lactate levels are the basis for resuscitative measures.

Abstract 1948: Resistance to RAS inhibition promotes remodeling of the immunosuppressive microenvironment of pancreatic cancer

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to acquired chemotherapy resistance. MRTX-1133, a promising KRAS-G12D inhibitor, has demonstrated initial efficacy; however, resistance analogous to that seen with KRAS-G12C inhibitors is an emerging challenge. The tumor microenvironment (TME) is increasingly recognized as a contributor to resistance, often fostering tumor survival and immune evasion. Methods: To elucidate the resistance mechanisms to KRAS-G12D inhibition, we established resistant mouse and human PDAC cell lines derived from mouse and human models. These models were analyzed using flow cytometry and single cell RNA sequencing to define TME dynamics as resistant is acquired and after is has been established. We also analyzed cytokines released by resistant tumor cells using protein arrays and RNA sequencing. Results: Our investigation revealed significant TME alterations associated with acquired resistance. Notably, there was a marked increase in the population CD4+ Tregs and neutrophil while activated CD8+ T cells are decreased in the resistant tumors. Concurrently, an increased secretion of chemokines such as CXCL1 and CXCL2 was observed in resistant tumor cells relative to their parental counterparts. Conclusions: The adaptation of PDAC to circumvent KRAS inhibition involves a distinct reprogramming of the TME, attenuating immune surveillance and potentially facilitating tumor progression. Current efforts are directed towards delineating the key pathways implicated in these TME modifications to pioneer new therapeutic approaches for managing KRAS inhibitor resistant PDAC. Citation Format: Herve Tiriac. Resistance to RAS inhibition promotes remodeling of the immunosuppressive microenvironment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1948.

Abstract 4108: Safety and feasibility of personalized neoantigen DC vaccines in postoperative esophagus squamous cell carcinoma: A Phase 1b trial

Abstract Background: Immunotherapy, currently stands at the forefront of esophagus squamous cell carcinoma (ESCC) research. Yet, the landscape of post-surgical adjuvant therapy, particularly for patients resistant or unresponsive to initial immunotherapy, remains unexplored. Addressing this, our prospective study evaluates the efficacy of a personalized neoantigen-loaded dendritic cell vaccine (Neo-DCVac) as a novel adjuvant in ESCC patients after neoadjuvant immunochemotherapy (nICT). Methods: Neo-DCVac, designed for 12 ESCC patients post-radical mastectomy following nICT. The vaccine regimen included five doses at weeks 1, 2, 4, 6, and 8, followed by bi-monthly boosts for a year. The primary endpoints were safety and immune response post-vaccination, with 1- and 2-year overall survival (OS) and progression-free survival as secondary endpoints. The T-cell response to neoantigen peptides was evaluated using ELISPOT, flow cytometry, ELISA, and single-cell sequencing to investigate the vaccine's mechanism of action. Results: From April 2021 to October 2023, a total of 12 ESCC patients were enrolled. The occurrence of all-grade AEs was 38.5% (5/12), all of grade 1-2, with no dose-limiting toxicities. No treatment interruptions or treatment-related deaths were observed. Till October 27 2023, the median follow-up was 31.2 months. Survival analysis revealed 1-year and 2-year disease-free survival (DFS) and overall survival(OS) rates of 88.3%, 66.7%, and 100.0%, 91.7%, respectively. Patients with diver genes had a longer median DFS (not reached) compared with patients without diver genes (10.8 months, P = 0.001). Post-vaccine immunization, all patients showed a marked increase in peripheral blood T cell subtypes (CD3, CD4, CD8), with significant neoantigen peptide response in 75% (9/12) as evidenced by ELISPOT and ELISA tests. Single-cell sequencing coupled with CoNGA analysis revealed a distinct MAIT cell population, displaying 65 clonotypes and 146 cells with consistent GEX profiles and TCR sequences. GLIPH2 analysis on Neo-Vac immunotherapy patients identified shared peptide-MHC specificities, notably in patient ES0-01, and similar patterns in patients ES0-04 and ES0-07, suggesting T cell expansion and neoantigen-specific responses post-vaccination. Conclusions: The neoantigen DC vaccine demonstrated favorable safety and exhibited notable efficacy in ESCC. Clinical trial information: NCT05023928. Research Sponsor: No. Citation Format: Yueyun Chen, Hua-Shan Shi, Yang Hu, Yong Yuan, Yu-Shang Yang, Heng Xu, Li Yang, Zhen-Yu Ding. Safety and feasibility of personalized neoantigen DC vaccines in postoperative esophagus squamous cell carcinoma: A Phase 1b trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4108.

Abstract 2874: Cancer metabolism in radiation resistance: Complementary roles of O-GlcNAc transferase and PARP1

Abstract The efficacy of image-guided radiotherapy (RT) has been linked to directing increased chromosomal double strand breaks (DSBs) to tumor cells while sparing surrounding normal tissue. DSBs can block cell cycle progression and promote mitotic catastrophe, cell death and senescence. End processing of persistent DSBs releases single strand DNA (ssDNA), driving cGAS/STING signaling and anti-tumor immune response. DSB repair, whether by non-homologous end-joining (NHEJ) or homologous recombination (HR), is a resistance mechanism, supporting cell survival, repopulation and immune evasion. Decades of effort to block DSB repair to enhance benefits of RT has yet to produce approved agents. Toxicity due to lack of cancer specificity may prevent the current generation of targeted agents from reaching the clinic. An answer may come from examining cancer metabolic reprogramming as a determinant of intrinsic radiation resistance. Along with other glucose metabolites, the Warburg effect increases N-acetyl glucosamine (GlcNAc) biosynthesis, which not only supports N-glycosylation but also modification of nucleocytoplasmic proteins by O-GlcNAc transferase (OGT). OGT-dependent O-GlcNAcylation confers radiation resistance, in part by accelerating DSB repair. OGT regulates γH2AX, 53BP1 and BRCA1 foci kinetics and suppresses ssDNA formation at DSB ends, limiting HR but favoring NHEJ for S/G2 DSB repair. Blocking OGT induces radiation sensitization in vitro and in vivo. In cells, OGT inhibition results in hyperresection, persistent RPA and RAD51 foci and accumulation of cytosolic DNA. One mediator may be the histone methyltransferase EZH2, which is rapidly recruited to deposit H3K27me3 at DSBs, promoting NHEJ repair. Irradiation of EZH2 KO cells results in hyperresection that cannot be suppressed by O-GlcNAcylation. Cancer cells may also accumulate NAD+, a substrate for PARP1 incorporated into poly-ADP-ribose to initiate DSB repair. Much like OGT inhibition, blocking PARP1 induces hyperresection and shifts repair toward HR and away from NHEJ. Importantly, increasing O-GlcNAcylation can suppress ssDNA formation even in PARP1 KO cells. In turn, inhibiting PARP1 enhances hyperesection in EZH2 KO cells, leading to a marked increase in cytosolic ssDNA. Our data assign complementary roles for EZH2 and PARP1 in DSB repair pathway choice by independently limiting 5' end resection. This directs DSBs to rapid, imprecise repair by NHEJ over slow and precise repair by HR. An implication is that PARP inhibitor resistance due to the Warburg effect may be mediated by EZH2. Driving hyperresection by targeting O-GlcNAcylation or H3K27 trimethylation along with PARP inhibition may saturate the capacity of HR and produce irreversible damage in cancer cells. Targeting impacts of metabolic reprogramming on DSB repair may not only enhance the therapeutic index of radiation but also sharpen synthetic lethality with HR deficiency. Citation Format: Elena E. Efimova, Sera Averbek, Donald J. Wolfgeher, Ding Wu, Yue Liu, Stephen J. Kron. Cancer metabolism in radiation resistance: Complementary roles of O-GlcNAc transferase and PARP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2874.

Overexpression of the FBA and TPI genes promotes high production of HDMF in Zygosaccharomyces rouxii.

4-Hydroxy-2,5-dimethyl-3 (2H)-furanone (HDMF) is widely used in the food industry as a spice and flavoring agent with high market demand. In this study, fructose-1,6-bisphosphate aldolase (FBA) and triose phosphate isomerase (TPI) were overexpressed in Zygosaccharomyces rouxii in the form of single and double genes, respectively, via electroporation. High-yield HDMF-engineered yeast strains were constructed by combining the analysis of gene expression levels obtained by real-time fluorescence quantitative PCR technology and HDMF production measured by HPLC. The results showed that there was a significant positive correlation between the production of HDMF and the expression levels of the FBA and TPI genes in yeast; the expression levels of the FBA and TPI genes were also positively correlated (p < 0.05). Compared with the wild type (WT), the engineered strains F10-D, T17-D, and TF15-A showed marked increases in HDMF production and FBA and TPI gene expression (p < 0.05) and exhibited great genetic stability with no obvious differences in biomass or colony morphology. In addition, the exogenous addition of d-fructose promoted the growth of Z. rouxii. Among the engineered strains, when fermented in YPD media supplemented with d-fructose for 5 days, TF15-A (overexpressing the FBA and TPI genes) generated the highest HDMF production of 13.39 mg/L, which is 1.91 times greater than that of the wild-type strain. The results above indicated that FBA and TPI, which are key enzymes involved in the process of HDMF biosynthesis by Z. rouxii, positively regulate the synthesis of HDMF at the transcriptional level. d-fructose can be used as a precursor for the biosynthesis of HDMF by engineered yeast in industrial production.

Navigating the vestibular maze: text-mining analysis of publication trends over five decades.

The field of vestibular science, encompassing the study of the vestibular system and associated disorders, has experienced notable growth and evolving trends over the past five decades. Here, we explore the changing landscape in vestibular science, focusing on epidemiology, peripheral pathologies, diagnosis methods, treatment, and technological advancements. Publication data was obtained from the US National Center for Biotechnology Information (NCBI) PubMed database. The analysis included epidemiological, etiological, diagnostic, and treatment-focused studies on peripheral vestibular disorders, with a particular emphasis on changes in topics and trends of publications over time. Our dataset of 39,238 publications revealed a rising trend in research across all age groups. Etiologically, benign paroxysmal positional vertigo (BPPV) and Meniere's disease were the most researched conditions, but the prevalence of studies on vestibular migraine showed a marked increase in recent years. Electronystagmography (ENG)/ Videonystagmography (VNG) and Vestibular Evoked Myogenic Potential (VEMP) were the most commonly discussed diagnostic tools, while physiotherapy stood out as the primary treatment modality. Our study presents a unique opportunity and point of view, exploring the evolving landscape of vestibular science publications over the past five decades. The analysis underscored the dynamic nature of the field, highlighting shifts in focus and emerging publication trends in diagnosis and treatment over time.

ACKR3 in olfactory glia cells shapes the immune defense of the olfactory mucosa.

Barrier-forming olfactory glia cells, termed sustentacular cells, play important roles for immune defense of the olfactory mucosa, for example as entry sites for SARS-CoV-2 and subsequent development of inflammation-induced smell loss. Here we demonstrate that sustentacular cells express ACKR3, a chemokine receptor that functions both as a scavenger of the chemokine CXCL12 and as an activator of alternative signaling pathways. Differential gene expression analysis of bulk RNA sequencing data obtained from WT and ACKR3 conditional knockout mice revealed upregulation of genes involved in immune defense. To map the regulated genes to the different cell types of the olfactory mucosa, we employed biocomputational methods utilizing a single-cell reference atlas. Transcriptome analysis, PCR and immunofluorescence identified up-regulation of NF-κB-related genes, known to amplify inflammatory signaling and to facilitate leukocyte transmigration, in the gliogenic lineage. Accordingly, we found a marked increase in leukocyte-expressed genes and confirmed leukocyte infiltration into the olfactory mucosa. In addition, lack of ACKR3 led to enhanced expression and secretion of early mediators of immune defense by Bowman's glands. As a result, the number of apoptotic cells in the epithelium was decreased. In conclusion, our research underlines the importance of sustentacular cells in immune defense of the olfactory mucosa. Moreover, it identifies ACKR3, a druggable G protein-coupled receptor, as a promising target for modulation of inflammation-associated anosmia.

Genetic characterisation of canine adenovirus type 1 in an 18‐month‐old mixed breed male dog and its effect on clinico‐pathology, hemato‐biochemistry and serum oxidant–antioxidant status

AbstractAn 18‐month‐old, mixed breed male dog was presented with hypothermia, recumbency, hematemesis, melena, and moribund condition, and screened by rapid antigen detection kit followed by polymerase chain reaction confirmation for canine adenovirus type 1 infection. The phylogenetic analysis of the sequence revealed clustering with Indian, Spanish, Italian, Portuguese, Chinese, and Australian sequences with amino acid homology of 98.81%–100%. There was a mutation (N127D) in the E3 protein encoding sequence, which was hitherto reported only in one Indian (GQ340423) sequence. Haemogram revealed anaemia, neutropenic leukopenia, and thrombocytopenia. Serum biochemistry revealed marked hyperglycaemia, hypoproteinemia, hypoalbuminemia, and an increase in the activities of hepatic enzymes. Serum oxidant antioxidant parameters revealed a marked increase in the level of oxidant and a decreased level of antioxidants. Postmortem examination revealed multifocal necrotic patches in the liver, marked haemorrhage in the stomach and intestines, emphysematous lungs, splenomegaly, and congested kidney. Histopathology revealed necrohaemorrhagic hepatitis and intranuclear inclusion bodies in the hepatocytes and glomerular degeneration.

A Systematic Analysis of Statewide Reports on Missing and Murdered Indigenous Peoples in the U.S.: What We Know and Where to Go from Here☆

AbstractFor generations, Indigenous communities have been calling attention to a widespread form of victimization known as Missing and Murdered Indigenous Peoples (MMIP). In response to grassroots efforts across rural communities, there has been a marked increase in legislation at the federal and state levels to address MMIP from 2018 to the present. Federal legislation has provided the most comprehensive and coordinated model of response to MMIP. This study analyzes how the scope and themes of federal legislation addressing MMIP are mirrored in the bills recently enacted by 14 states addressing MMIP. One goal of this study is to identify strengths and limitations within state legislation and provide insight into critical areas of focus for improving state legislative responses to MMIP. Next, we analyze reports from federal MMIP legislation and the 10 states (among the 14 with legislation) that have currently published MMIP reports to date. Our analysis of MMIP reports expands knowledge on (1) how data were collected and interpreted across jurisdictions, and (2) whether states experience MMIP in similar or different ways. Drawing on our comparative analysis of legislation and reports across jurisdictions, we offer data‐driven recommendations for states to consider when addressing MMIP.

Functionality of Pizza Cheese as Affected Using Saccharomyces boulardii Adjunct Culture During Refrigerated Storage

Background: Mozzarella/Pizza cheese remains the preferred choice for topping pizza. There is currently no information available on the production of Pizza cheese employing Saccharomyces boulardii as an adjunct culture. The research was conducted to study the influence of S. boulardii adjunct culture on the functional properties of Pizza cheese during refrigerated storage. Methods: Experimental Pizza cheese was manufactured using a blend of homogenized and unhomogenized milks (1:1; cheese designated as CBHM). Control cheese was prepared from unhomogenized milk involving stretching of curd, post whey draining. Result: The baking properties viz., meltability as well as melting time were markedly affected by T, P and the interaction T´P. The fat leakage and stretch length of cheeses were markedly affected by T and P only. The melt and fat leakage values exhibited marked increase with the advancement of the storage period. It is recommended to consume such cheese before 21 days since CBHM cheese elicits the desirable baking characteristics up to 21 days.

Fine Pitch Micro Indium Bump Interconnect Flip Chip Bonding

Quantum computing processors, micro LED displays and Focal Plane Array (FPA) imaging and detector devices such as infrared (IR) thermal imaging sensors are seeing higher demand as more practical applications requiring these components are coming into research and development, industrial, military and consumer markets. This paired with higher pixel and Qubit count and interconnect density, on larger and larger chips is driving hybridization and monolithic integration in these technologies. This is showing a marked increase in demand for fine pitch micro bump interconnection flip chip die bonding. However, some critical challenges facing these technologies are; larger component sizes mean higher density interconnections over increasing surface area. Submicron accuracy required to align fine pitch micro interconnect arrays. This together with the challenges facing the materials that are becoming the industry standard for these applications, such as the requirement for the assembled components to remain stable in extreme conditions such as cryogenic application environments. Combined with low loss high strength mechanical/ electrical interconnect requirements on components containing sensitive materials, structures and unmatched coefficient of thermal expansion (CTE) means that processing gases such as formic acid or high temperature reflow bonding can no longer be used to bond these devices. These challenges mean that the industry is fast approaching the limitations of even state-of-the-art die bonders and die bonding methods on the market today. This paper is going to highlight these challenges and the methods used to address them to produce large format, high density IR thermal imaging FPA devices, Quantum processors and micro LED displays using fine pitch micro Indium bump array interconnections that meet today’s industry requirements.

Platycodon D protects human nasal epithelial cells from pyroptosis through the Nrf2/HO-1/ROS signaling cascade in chronic rhinosinusitis

BackgroundPyroptosis has been demonstrated being closely associated with the inflammatory progression in chronic rhinosinusitis (CRS). However, platycodon D (PLD) has emerged as a key anti-inflammatory mediator in the inflammatory progression of various respiratory diseases. This study aims at investigating whether PLD could reduce inflammatory progression of CRS by inhibiting pyroptosis.MethodsNasal mucosal tissues from patients with CRS and the control group (simple nasal septal deviation) were analyzed for morphological difference using hematoxylin & eosin staining and for the expression of pyroptosis-related makers by immunofluorescence (IF). Human nasal epithelial cells (HNEpCs) were cultured and co-stimulated with lipopolysaccharide (LPS)/adenosine triphosphate (ATP) to construct an in vitro cellular model simulating CRS. After pretreatment with PLD, EthD-I staining, TUNEL staining, transmission electron microscopy (TEM), and GSDMD-NT detection were performed to evaluate pyroptosis markers. The NLRP3 inflammasome was detected by IF and western blotting (WB). Reactive oxygen species (ROS) were detected by H2DCFDA staining, and mitochondrial membrane potential was evaluated by JC-1 staining. Mitochondrial morphology and structure were observed using TEM. The Nrf2/HO-1 antioxidant signaling pathway was detected using WB.ResultsThe nasal mucosa structure of patients with CRS exhibited significant damage, with a marked increase in the expression of pyroptosis-related proteins compared with the control group. LPS/ATP co-stimulation resulted in an increased expression of IL-18 and IL-1β in HNEpCs, causing significant damage to nuclear and cell membranes, GSDMD-NT accumulation around the cell membrane, and intracellular NLRP3 inflammasome activation. Furthermore, it led to increased ROS expression, significantly decreased mitochondrial membrane potential, and damaged mitochondrial structure. However, pretreatment with PLD significantly reversed the aforementioned trends and activated the Nrf2/HO-1 antioxidant signaling pathway.ConclusionsThe results of this study confirm that NLRP3-mediated pyroptosis plays a crucial role in the pathological process of nasal mucosal impairment in patients with CRS. PLD inhibits NLRP3-mediated pyroptosis, preventing inflammatory damage in HNEpCs of patients with CRS by activating the Nrf2/HO-1 antioxidant signaling pathway, which in turn reduces ROS production and ameliorates mitochondrial damage.

Surviving the serenade: how conflicting selection pressures shape the early stages of sexual signal diversification.

Understanding how the early stages of sexual signal diversification proceed is critically important because these microevolutionary dynamics directly shape species trajectories and impact macroevolutionary patterns. Unfortunately, studying this is challenging because signals involve complex interactions between behavior, morphology, and physiology, much of which can only be measured in real-time. In Hawaii, male Pacific field cricket song attracts both females and a deadly parasitoid fly. Over the past two decades, there has been a marked increase in signal variation in Hawaiian populations of these crickets, including novel male morphs with distinct mating songs. We capitalize on this rare opportunity to track changes in morph composition over time in a population with three novel morphs, investigating how mate and parasitoid attraction (components of sexual and natural selection) may shape signal evolution. We find dramatic fluctuation in morph proportions over the three years of the study, including the arrival and rapid increase of one novel morph. Natural and sexual selection pressures act differently among morphs, with some more attractive to mates and others more protected from parasitism. Collectively, our results suggest that differential protection from parasitism among morphs, rather than mate attraction, aligns with recent patterns of phenotypic change in the wild.

InR and Pi3K maintain intestinal homeostasis through STAT/EGFR and Notch signaling in enteroblasts.

To maintain the integrity of the adult gut, the proliferation and differentiation of stem cells must be strictly controlled. Several signaling pathways control the proliferation and differentiation of Drosophila intestinal epithelial cells. Although the modulatory effects of insulin pathway components on cell proliferation have been characterized, their specific role in which cell type and how these components interact with other regulatory signaling pathways remain largely unclear. In this study, we found that InR/Pi3K has major functions in enteroblasts (EBs) that were not previously described. The absence of InR/Pi3K in progenitors leads to a decrease in the number of EBs, while it has no significant effect on intestinal stem cells (ISCs). In addition, we found that InR/Pi3K regulates Notch activity in ISCs and EBs in an opposite way. This is also the reason for the decrease in EB. On the one hand, aberrantly low levels of Notch signaling in ISCs inhibit their proper differentiation into EBs; on the other hand, the higher Notch levels in EBs promote their excessive differentiation into enterocytes (ECs), leading to marked increases in abnormal ECs and decreased proliferation. Moreover, we found that Upd/JAK/STAT signaling acts as an effector or modifier of InR/Pi3K function in the midgut and cooperates with EGFR signaling to regulate cell proliferation. Altogether, our results demonstrate that InR and Pi3K are essential for coordinating stem cell differentiation and proliferation to maintain intestinal homeostasis.

C5b-9 promotes ferritinophagy leading to ferroptosis in renal tubular epithelial cells of trichloroethylene-sensitized mice

Trichloroethylene (TCE) is a common environmental contaminant that can cause a severe allergic reaction called TCE hypersensitivity syndrome, which often implicates the patient's kidneys. Our previous study revealed that C5b-9-induced tubular ferroptosis is involved in TCE-caused kidney damage. However, the study did not explain how tubule-specific C5b-9 causes free iron overload, a key event in ferroptosis. Here, we aimed to explore the role of NCOA4-mediated ferritinophagy in C5b-9-induced iron overload and ferroptosis in TCE-sensitized mice. Our results showed that TCE sensitization does not affect iron import or export, but does affect iron storage, causing ferritin degradation and free iron overload. In addition, mitochondrial ROS was upregulated, and these changes were blocked by C5b-9 inhibition. Interestingly, TCE-induced ferritin degradation and ferroptosis were significantly antagonized by the application of the mitochondrial ROS inhibitor, Mito-TEMPO. Moreover, all of these modes of action were further verified in C5b-9-attack signalling HK-2 cells. Further investigation demonstrated that C5b-9-upregulated mitochondrial ROS induced a marked increase in nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy. In addition, the application of NCOA4 small interfering RNA not only significantly reversed ferritinophagy caused by C5b-9 but also reduced C5b-9-induced ferroptosis in HK-2 cells. Taken together, these results suggest that tubule-specific C5b-9 deposition activates NCOA4 through the upregulation of mitochondrial ROS, causing ferritin degradation and elevated free iron, which ultimately leads to tubular epithelial cell ferroptosis and kidney injury in TCE-sensitized mice.

Exploring the entrepreneurial landscape of university-industry collaboration on public university spin-off creation: A systematic literature review

Research into the factors influencing university-industry collaboration on public university spin-offs creation has focused on management, entrepreneurship, technology and innovation. This research began with a careful systematic literature review of 4427 scientific papers published in the last ten years (2014–2023) and accessible in the prestigious Web of Science core collection. A quantitative methodology was used, complemented by the use of the visual analysis tool Posit PBC™, formerly known as R Cloud Studio. This comprehensive approach facilitated the seamless ingestion of raw data into Biblioshyni, which is a web-based platform specialised in bibliometric analysis. This review has revealed compelling trends, particularly in terms of increasing diversity, the emergence of United Kingdom as a major player, and the central role of university-industry collaboration. Our systematic review identified influential authors in the field, including the prolific contributions of scholars such as D. Radicid, S. Ropers, Y. Li and R. Owen. We also identified important research institutions, such as Utrecht University in Netherlands, Lund University in Sweden and The University of Manchester in the UK. In addition, we have shown that countries such as the United Kingdom, China and USA have made a significant contribution to the volume of publications. The results highlighted a marked increase in the phenomenon of univeristy spin-offs over the past decade, as evidenced by the exponential growth in both publication output and citation rates. This empirical revelation was underpinned by a rigorous exploration of the Web of Science database, using a carefully crafted set of keywords. Thirty-seven pivotal studies were selected for in-depth review through a sophisticated selection process that adhered to the rigorous standards of the PRISMA methodology. The aim of this review is to improve understanding and encourage deeper exploration of spin-off-based public universities through collaboration between academia and industry.

Crater radius analysis after dual droplets successive oblique impact on liquid film

Droplet impact is a common occurrence in nature, agriculture, and industry. The research on the multi‐droplet impact is fundamental to understanding the tangled nature of reality. This paper numerically studies the successive oblique impact of dual droplets on the liquid film by building an effective three‐dimensional model. The leading and trailing droplets are set to pass a certain impact point with the same velocity. The main contribution of this paper is the investigation of the effects of Weber number, liquid film thickness, impact angle, and impact time interval on the interface morphology evolution after the droplet impact. Results show that splash pattern conversion of the primary or secondary crown occurs with the change of these factors. Besides, the variations of the maximum crater radius in upstream, lateral, and downstream directions with time are quantitatively analyzed. The crater radius analysis is carried out from three perspectives, the variation during the single droplet impact, the change during the dual droplets impact, and the comparison between them. It is found that the crater of dual droplets impact exhibits shape distortion in the deformation period and appears a marked dimensional increase in the secondary expansion period.

The impact of isolated obesity compared with obesity and other risk factors on risk of stillbirth: a retrospective cohort study.

Maternal obesity is associated with stillbirth, but uncertainty persists around the effects of higher obesity classes. We sought to compare the risk of stillbirth associated with maternal obesity alone versus maternal obesity and additional or undiagnosed factors contributing to high-risk pregnancy. We conducted a retrospective cohort study using the Better Outcomes Registry and Network (BORN) for singleton hospital births in Ontario between 2012 and 2018. We used multivariable Cox proportional hazard regression and logistic regression to evaluate the relationship between prepregnancy maternal body mass index (BMI) class and stillbirth (reference was normal BMI). We treated maternal characteristics and obstetrical complications as independent covariates. We performed mediator analyses to measure the direct and indirect effects of BMI on stillbirth through major common-pathway complications. We used fully adjusted and partially adjusted models, representing the impact of maternal obesity alone and maternal obesity with other risk factors on stillbirth, respectively. We analyzed data on 681 178 births between 2012 and 2018, of which 1956 were stillbirths. Class I obesity was associated with an increased incidence of stillbirth (adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.35-1.78). This association was stronger for class III obesity (adjusted HR 1.80, 95% CI 1.44-2.24), and strongest for class II obesity (adjusted HR 2.17, 95% CI 1.83-2.57). Plotting point estimates for odds ratios, stratified by gestational age, showed a marked increase in the relative odds for stillbirth beyond 37 weeks' gestation for those with obesity with and without other risk factors, compared with those with normal BMI. The impact of potential mediators was minimal. Maternal obesity alone and obesity with other risk factors are associated with an increased risk of stillbirth. This risk increases with gestational age, especially at term.