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Abstract Background Alzheimer’s disease (AD) is the most common form of dementia. Although drugs focusing on reducing amyloid β slow progression, they fail to improve cognitive function. Deficits in glucose metabolism are reflected in FDG-PET and parallel the neurodegeneration and synaptic marker loss closely preceding cognitive decline, but the role of metabolic deficits as a cause or consequence of neurodegeneration is unclear. Pyruvate dehydrogenase (PDH) is lost in AD and an important enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle by converting pyruvate into acetyl-CoA. It is negatively regulated by pyruvate dehydrogenase kinase (PDHK) through phosphorylation. Methods In the present study, we assessed the in vitro/ in vivo pharmacological profile of the novel PDHK inhibitor that we discovered, Compound A. We also assessed the effects of Compound A on AD-related phenotypes including neuron loss and cognitive impairment using 5xFAD model mice. Results Compound A inhibited human PDHK1, 2 and 3 but had no inhibitory activity on PDHK4. In primary neurons, Compound A enhanced pyruvate and lactate utilization, but did not change glucose levels. In contrast, in primary astrocytes, Compound A enhanced pyruvate and glucose utilization and enhanced lactate production. In an efficacy study using 5xFAD mice, Compound A ameliorated the cognitive dysfunction in the novel object recognition test and Morris water maze. Moreover, Compound A prevented neuron loss in the hippocampus and cerebral cortex of 5xFAD without affecting amyloid β deposits. Conclusions These results suggest ameliorating metabolic deficits by activating PDH by Compound A can limit neurodegeneration and is a promising therapeutic strategy for treating AD.

Elucidating the mechanisms of action of steroid hormones will contribute to the development of therapeutic strategies for hormone-dependent tumors. Recent advances in genetic engineering have revealed the complex and diverse mechanisms of steroid hormone signaling; however, these techniques are limited to in vitro or animal experiments. It is believed that verifying hormone signals elucidated using human pathological tissue specimens will directly aid in treatment and diagnosis. However, pathological tissue specimens are generally formalin-fixed paraffin-embedded (FFPE), and protein/gene analyses of FFPE tissues are limited. Protein detection using immunohistochemistry with specific antibodies in FFPE tissues is a classical technique essential for diagnosis and treatment decisions in various types of cancer. In steroid hormone signaling, the expression and localization of receptors, hormone-related enzymes, and proteins encoded by response genes can be clarified using immunohistochemistry. Although protein-protein interactions such as receptor dimers and DNA-binding proteins are mainly detected in vitro, they can be examined in FFPE tissues using in situ proximity ligation assays and southwestern histochemistry, respectively. Using these detection methods, including immunohistochemistry, it is possible to analyze each hormone signaling pathway in hormone-related tumors histopathologically. Although FFPE tissues still suffer from gene and protein denaturation, their advantages include the ability to retrospectively study target factors/signals and obtain spatial information through microscopy. This review describes a visualization method for elucidating steroid hormone signaling in hormone-dependent tumors using FFPE tissues.

The transcriptional coactivator Yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) induces cell proliferation through nuclear localization at low cell density. Conversely, at extremely high cell density, the Hippo pathway, which regulates YAP/TAZ, is activated. This activation leads to the translocation of YAP/TAZ into the cytoplasm, resulting in cell cycle arrest. Various cancer cells have several times more YAP/TAZ than normal cells. However, it is not entirely clear whether this several-fold increase in YAP/TAZ alone is sufficient to overcome proliferation inhibition (contact inhibition) under high-density conditions, thereby allowing continuous proliferation. In this study, we construct a three-dimensional (3D) mathematical model of cell proliferation incorporating the Hippo-YAP/TAZ pathway. Herein, a significant innovation in our approach is the introduction of a novel modeling component that inputs cell density, which reflects cell dynamics, into the Hippo pathway and enables the simulation of cell proliferation as the output response. We assume such 3D model with cell-cell interactions by solving reaction and molecular dynamics (MD) equations by applying adhesion and repulsive forces that act between cells and frictional forces acting on each cell. We assume Lennard-Jones (12-6) potential with a softcore character so that each cell secures its exclusive domain. We set cell cycles composed of mitotic and cell growth phases in which cells divide and grow under the influence of cell kinetics. We perform mathematical simulations at various YAP/TAZ levels to investigate the extent of YAP/TAZ increase required for sustained proliferation at high density. The results show that a twofold increase in YAP/TAZ levels of cancer cells was sufficient to evade cell cycle arrest compared to normal cells, enabling cells to continue proliferating even under high-density conditions. Finally, this mathematical model, which incorporates cell-cell interactions and the Hippo-YAP/TAZ pathway, may be applicable for evaluating cancer malignancy based on YAP/TAZ levels, developing drugs to suppress the abnormal proliferation of cancer cells, and determining appropriate drug dosages. The source codes are freely available.

Due to the problem of carbon dioxide (CO2) emissions, alternative fuels such as ammonia (NH3) have garnered a lot of attention lately. This is due to its carbon-free molecular structure, ease of transport, and high energy density. Unfortunately, ammonia is not without flaws since it is considered a difficult fuel to burn in conventional internal combustion engines. To further investigate the burning characteristics of ammonia, this study is conducted for ammonia/gasoline co-combustion using a modified engine equipped with a sub-chamber. The engine ran at 1000 RPM and had a 17.7 compression ratio with two injection timings of -55 and 10 crank angle degrees (°CA) after the top dead center (ATDC), while the ammonia energy ratios were adjusted across a range from 40% to 70%. The results show that the earlier injection timing allowed better premixing between the air and fuel mixture, thus enhancing the overall combustion characteristics. For the later injection timing, the nitrogen oxide (NOx) emissions decrease at the higher ammonia energy ratio due to the denitrification of the nitrogen oxides (DeNOX) process. Overall, the earlier injection timing appears optimal for the 40% to 70% ammonia energy ratio under the present condition.

Abstract Diabetes mellitus is recognized as a major predisposing factor for Moraxella keratitis. However, how diabetes mellitus contributes to Moraxella keratitis remains unclear. In this study, we examined Moraxella keratitis; based on the findings, we investigated the impact of advanced glycation end products (AGEs) deposition in the cornea of individuals with diabetic mellitus on the adhesion of Moraxella isolates to the cornea. A retrospective analysis of 27 culture-proven cases of Moraxella keratitis at Ehime University Hospital (March 2006 to February 2022) was performed. Moraxella isolates were identified using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Among the patients, 30.4% had diabetes mellitus and 22.2% had the predominant ocular condition of using steroid eye drops. The species identified were Moraxella nonliquefaciens in 59.3% and Moraxella lacunata in 40.7% of patients. To investigate the underlying mechanisms, we assessed the effects of M. nonliquefaciens adherence to simian virus 40-immortalized human corneal epithelial cells (HCECs) with or without AGEs. The results demonstrated the number of M. nonliquefaciens adhering to HCECs was significantly increased by adding AGEs compared with that in controls (p

The use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is well-established for the treatment of advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. In this study, we report the long-term efficacy of EGFR-TKI therapy in a patient with postoperative recurrent NSCLC. A 58-year-old Japanese woman experienced recurrence after surgery, and an EGFR L858R mutation was identified. The patient continued gefitinib therapy for over 13 years, achieving a long-term survival of 21 years after postoperative recurrence, and 24 years after the initial diagnosis. This is the first report of a long-term response to EGFR-TKI therapy in an NSCLC patient with an L858R mutation. This case suggests the potential effectiveness of combining local therapy with EGFR-TKI treatment for metachronous oligometastatic disease.

Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynamin like GTPase (OPA1) gene. OPA1 encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant-negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of the dOPA1 gene in Drosophila can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human OPA1 (hOPA1) gene, indicating that hOPA1 is functionally interchangeable with dOPA1 in the fly system. However, mutations previously identified did not ameliorate the dOPA1 deficiency phenotype. By expressing both WT and DOA plus mutant hOPA1 forms in the optic nerve of dOPA1 mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant-negative mutations in hOPA1. This fly model aids in distinguishing DOA from DOA plus and guides initial hOPA1 mutation treatment strategies.

Severe hypertriglyceridemia is a pathological condition caused by genetic factors alone or in combination with environmental factors, sometimes leading to acute pancreatitis (AP). In this study, exome sequencing and biochemical analyses were performed in 4 patients with hypertriglyceridemia complicated by obesity or diabetes with a history of AP or decreased post-heparin LPL mass. In a patient with a history of AP, SNP rs199953320 resulting in LMF1 nonsense mutation and APOE rs7412 causing apolipoprotein E2 were both found in heterozygous form. Three patients were homozygous for APOA5 rs2075291, and one was heterozygous. ELISA and Western blot analysis of the serum revealed the existence of apolipoprotein A-V in the lipoprotein-free fraction regardless of the presence or absence of rs2075291; furthermore, the molecular weight of apolipoprotein A-V was different depending on the class of lipoprotein or lipoprotein-free fraction. Lipidomics analysis showed increased serum levels of sphingomyelin and many classes of glycerophospholipid; however, when individual patients were compared, the degree of increase in each class of phospholipid among cases did not coincide with the increases seen in total cholesterol and triglycerides. Moreover, phosphatidylcholine, lysophosphatidylinositol, and sphingomyelin levels tended to be higher in patients who experienced AP than those who did not, suggesting that these phospholipids may contribute to the onset of AP. In summary, this study revealed a new disease-causing gene mutation in LMF1, confirmed an association between overlapping of multiple gene mutations and severe hypertriglyceridemia, and suggested that some classes of phospholipid may be involved in the pathogenesis of AP.

We introduce $ d-\delta $ systems on differential forms in Eucliean spaces and show the interface vanishing of the solution. This result generalizes previous theorems on stationary and non-stationary Maxwell's equation. Other applications are also given.

Introduction: RRAS2, a member of the R-Ras subfamily of Ras-like low-molecular-weight GTPases, is considered to regulate cell proliferation and differentiation via the RAS/MAPK signaling pathway. Seven RRAS2 pathogenic variants have been reported in patients with Noonan syndrome; however, few functional analyses have been conducted. Herein, we report two patients who presented with a Noonan-like phenotype with recurrent and novel RRAS2 pathogenic variants (p.Gly23Val and p.Gly24Glu, respectively) and the results of their functional analysis.Materials and methods: Wild-type (WT) and mutant RRAS2 genes were transiently expressed in Human Embryonic Kidney293 cells. Expression of RRAS2 and phosphorylation of ERK1/2 were confirmed by Western blotting, and the RAS signaling pathway activity was measured using a reporter assay system with the serum response element-luciferase construct. WT and p.Gly23Val RRAS2 were expressed in Drosophila eye using the glass multiple reporter-Gal4 driver. Mutant mRNA microinjection into zebrafish embryos was performed, and the embryo jaws were observed.Results: No obvious differences in the expression of proteins WT, p.Gly23Val, and p.Gly24Glu were observed. The luciferase reporter assay showed that the activity of p.Gly23Val was 2.45 ± 0.95-fold higher than WT, and p.Gly24Glu was 3.06 ± 1.35-fold higher than WT. For transgenic flies, the p.Gly23Val expression resulted in no adults flies emerging, indicating lethality. For mutant mRNA-injected zebrafish embryos, an oval shape and delayed jaw development were observed compared with WT mRNA-injected embryos. These indicated hyperactivity of the RAS signaling pathway.Discussion: Recurrent and novel RRAS2 variants that we reported showed increased in vitro or in vivo RAS signaling pathway activity because of gain-of-function RRAS2 variants. Clinical features are similar to those previously reported, suggesting that RRAS2 gain-of-function variants cause this disease in patients.

This study analyzed the non-canonical NF-κB pathway, which controls functions distinct from those of the canonical pathway. Although oscillations of NF-κB have been observed in the non-canonical pathway, a detailed mechanism explaining the observed behavior remains elusive, owing to the different behaviors observed across cell types. This study demonstrated that oscillations cannot be produced by the experimentally observed pathway alone, thereby suggesting the existence of an unknown reaction pathway. Assuming this pathway, it became evident that the oscillatory structure of the non-canonical pathway was caused by stable periodic orbits. In addition, we demonstrated that altering the expression levels of specific proteins reproduced various behaviors. By fitting 14 parameters, excluding those measured in previous studies, this study successfully reproduce nuclear retention (saturation), oscillation, and singular events that had been experimentally confirmed. The analysis also provided a comprehensive understanding of the dynamics of the RelB protein and suggested a potential inhibitory role for the unknown factor. These findings indicate that the unknown factor may be an isoform of IκB, contributing to the regulation of NF-κB signaling. Based on these models, we gained invaluable understanding of biological systems, paving the way for the development of new strategies to manipulate specific biological processes.

Abstract Recently, ammonia (NH3), which has a higher energy density than hydrogen, has gained attention for zero-carbon emission goals in the transportation sector. However, in a conventional internal combustion engine (ICE), NH3 combustion mechanism is still under investigation. In this paper, to further expand the knowledge on the adoption of NH3 in ICEs, authors conducted NH3/gasoline co-combustion experiments in a modified, 17.7:1 compression ratio, naturally aspirated spark-assisted CI engine with sub-chamber. The sub-chamber was chosen in order to enhance the combustion speed of NH3. In addition, the sub-chamber was equipped with glow and spark plugs to overcome the high auto-ignition temperature of NH3. Engine performance and NOX emissions were studied under three different intake air temperatures. During the experiments, NH3 content was increased gradually where the engine was run under lean conditions. Although higher NH3 content was achieved compared to our previous work, increasing the intake air temperature resulted in decreased charging efficiency. In addition, corrosion was found on the piston ring after 120 h of operation, negatively affecting the engine performance. Furthermore, NH3/gasoline co-combustion duration was shortened drastically with the influence of the sub-chamber, where the longest combustion duration under the present conditions was found to be 17°CA.

Summary: Neurons establish specific synapses based on the adhesive properties of cell-surface proteins while also retaining the ability to form synapses in a relatively non-selective manner. However, comprehensive understanding of the underlying mechanism reconciling these opposing characteristics remains incomplete. Here, we have identified Side-IV/Beat-IIb, members of the Drosophila immunoglobulin superfamily, as a combination of cell-surface recognition molecules inducing synapse formation. The Side-IV/Beat-IIb combination transduces bifurcated signaling with Side-IV’s co-receptor, Kirre, and a synaptic scaffold protein, Dsyd-1. Genetic experiments and subcellular protein localization analyses showed the Side-IV/Beat-IIb/Kirre/Dsyd-1 complex to have two essential functions. First, it narrows neuronal binding specificity through Side-IV/Beat-IIb extracellular interactions. Second, it recruits synapse formation factors, Kirre and Dsyd-1, to restrict synaptic loci and inhibit miswiring. This dual function explains how the combinations of cell-surface molecules enable the ranking of preferred interactions among neuronal pairs to achieve synaptic specificity in complex circuits in vivo.

Key Clinical Message Extrapulmonary lymphangioleiomyomatosis (LAM) can present as incidental nodal LAM in gynecological surgery specimens, that warrants systemic investigation and follow‐up of concurrent and subsequent development of pulmonary and extrapulmonary LAM.

Abstract Postoperative surgical site infection (SSI) is common in open long bone fractures, so early administration of prophylactic antibiotics is critical to prevent SSI. However, the necessity of initial broad-spectrum coverage for Gram-positive and -negative pathogens remains unclear. The purpose of this study was to clarify the effectiveness of prophylactic broad-spectrum antibiotics in a large, national-wide sample. We reviewed an open fracture database of prospectively collected data from 111 institutions managed by our society. A retrospective cohort study was designed to compare the rates of deep SSI between narrow- and broad-spectrum antibiotics, which were initiated within three hours after injury. A total of 1041 type III fractures were evaluated at three months after injury. Overall deep SSI rates did not differ significantly between the narrow-spectrum group (43/538, 8.0%) and broad-spectrum group (49/503, 9.8%) (p = 0.320). During propensity score-matched analysis, 425 pairs were analyzed. After matching, no significant difference in the SSI rate was seen between the narrow- and broad-spectrum groups, with 42 SSIs (9.9%) and 40 SSIs (9.4%), respectively (p = 0.816). The probability of deep SSI was not reduced by broad-spectrum antibiotics compared with narrow-spectrum antibiotics in type III open long bone fractures.

Background: Due to advanced maternal age, conception rate is affected by the quality of fertilized eggs. However, the conception rate after transplanting good-quality embryos is not high. Therefore, it is necessary to examine the interaction between the endometrium and the embryo to improve the conception rate. Methods: Cell sheet engineering is a technique used for cell transplantation into target tissues. In this study, rat endometrial epithelial and stromal cell sheets were harvested, and layering was performed for these two types of cells to create three-dimensional (3D) endometrial tissues. A piece of 3D endometrial tissue was prepared by layering one endometrial epithelial cell sheet with two endometrial stromal cell sheets. A thawed blastocyst was implanted into the 3D endometrial tissue, and the embryo was analyzed histologically using a confocal microscope at 6, 12, and 24 hours after embryo implantation. Results: After embryo transplantation, invasion of the transplanted embryo into the 3D endometrial tissue was confirmed in vitro over time, similar to the embryo implantation process in the living body. Conclusion: We believe that these results can help reveal the interaction between the endometrium and embryo during embryo implantation and will contribute to better conception outcomes for women with infertility.

Abstract The global coronavirus disease-2019 (COVID-19) pandemic is associated with reduced rate of percutaneous coronary intervention (PCI). However, there were a few data showing how emergency medical system (EMS) and management strategies for acute coronary syndrome (ACS) changed during the pandemic. We sought to clarify changes on characteristics, treatments, and in-hospital mortality of patients with ACS transported via EMS between pre- and post-pandemic. We examined consecutive 656 patients with ACS admitted to Sapporo City ACS Network Hospitals between June 2018 and November 2021. The patients were divided into pre- and post-pandemic groups. The number of ACS hospitalizations declined significantly during the pandemic (proportional reduction 66%, coefficient −0.34, 95% CI −0.50 to −0.18, p

Abstract Background Indium lung is characterized by interstitial pneumonia and/or emphysema which occurs in indium-tin oxide (ITO) workers. Indium lung is now known to progress after stopping exposure to ITO, but the long-term influences of ITO remain unclear. Case presentation Forty seven years old, a never-smoker, who had been engaged in an ITO manufacturing process for 8 years. Emphysema was indicated by the medical check-up for ex-ITO workers, and he was diagnosed with indium lung. He underwent partial lung resections for pneumothorax two times, and obstructive pulmonary dysfunction had progressed through the years. He underwent right single lung transplant 20 years after ITO exposure. Pathologically, his lung showed severe distal acinar emphysema and honeycomb change. Fibrosis and destruction of the lung tissue significantly progressed compared to the previous partial resections. Scanning electron microscopy combined with energy dispersive spectroscopy revealed that the deposited particles contained indium and tin. After the transplantation, his respiratory function was improved. Conclusions In this case, ITO resided in the lung tissue for 20 years, and lung tissue destruction kept progressing. Careful medical follow-up is recommended for ITO-workers even if they are asymptomatic.

Abstract To determine the risk of mask-associated dry eye (MADE), we investigated the fluorescein tear break-up time (FBUT), ocular surface temperature and blood flow, along with corneal sensitivity, in mask wearers. We enrolled 60 mask wearers (mean age, 27.1 ± 5.2 years) and then measured FBUT, corneal temperature and conjunctival blood flow without wearing masks (no mask), with masks, and with taped masks. We defined MADE as the condition in which dry eye symptoms appeared and the FBUT with mask was less than 5 s. The FBUT with a mask was significantly shorter compared to the no mask and taped mask groups (P

Abstract The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C > G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms.

Background and Aims: Corticotropin-releasing hormone (CRH) is a major regulator of the stress response to internal and external factors. CRH and its receptors (CRHR1 and CRHR2) are expressed in the central nervous system and some cancer cells, suggesting the importance of CRH signaling in pancreatic cancers. However, the clinicopathological significance of CRH remains unknown because the immunolocalization of CRH, CRHR1, and CRHR2 has not been examined in pancreatic carcinoma tissues. We clarified the correlation of the expression of CRH and its receptors with overall survival in pancreatic cancer. Methods: This study evaluated 96 patients with pancreatic cancer who underwent microscopic complete resection (R0) but not neoadjuvant chemotherapy from 1988 to 2007 at Tohoku University Hospital, Japan. CRH, CRHR1, and CRHR2 immunoreactivity were detected in the pancreatic carcinoma cells. Overall survival curves were generated according to the Kaplan–Meier method. Results: CRHR1 immunoreactivity was significantly associated with an increased risk of poorer prognosis in all patients (P = .038) and the adjuvant therapy group (P = .022). Overall survival was worse in the CRHR1-positive group than in the CRHR1-negative group among the 62 patients treated with gemcitabine hydrochloride (P = .046) and the 22 patients treated with other drugs (P = .047). CRHR1 expression was correlated with survival in univariate analysis but not in multivariate analysis. Conclusion: This study is the first to immunolocalize CRH, CRHR1, and CRHR2 in pancreatic carcinoma tissues and to examine the biological prognosis. This study revealed that survival in patients with pancreatic cancer was significantly associated with expression of CRHR1 by assessing biological progression according to CRH and the expression of its receptors. However, CRHR1 expression was correlated with survival in univariate analysis but not in multivariate analysis.

We study quasilinear reaction diffusion systems relative to the Shigesada-Kawasaki-Teramoto model. Nonlinearity standing for the external force is provided with mass dissipation. Estimate in several norms of the solution is provided under the restriction of diffusion coefficients, growth rate of reaction, and space dimension.

Abstract The stimulation of photosynthesis is a strategy for achieving sustainable plant production. Red light is useful for plant growth because it is absorbed by chlorophyll pigments, which initiate natural photosynthetic processes. Ultraviolet (UV)-to-red wavelength-converting materials are promising candidates for eco-friendly plant cultures that do not require electric power. In this study, transparent films equipped with a UV-to-red wavelength-converting luminophore, the Eu3+ complex, were prepared on commercially available plastic films for plant growth experiments. The present Eu3+-based films absorb UV light and exhibit strong red luminescence under sunlight. Eu3+-painted films provide significant growth acceleration with size increment and biomass production for vegetal crops and trees in a northern region. The plants cultured with Eu3+-painted films had a 1.2-fold height and 1.4-fold total body biomass than those cultures without the Eu3+ luminophores. The present film can promote the plant production in fields of agriculture and forestry.

Road vehicles, particularly cars, are one of the primary sources of CO2 emissions in the transport sector. Shifting to unconventional energy sources such as solar and wind power may reduce their carbon footprints considerably. Consequently, using ammonia as a fuel due to its potential benefits, such as its high energy density, being a carbon-free fuel, and its versatility during storage and transportation, has now grabbed the attention of researchers. However, its slow combustion speed, larger combustion chamber requirements, ignition difficulties, and limited combustion stability are still major challenges. Therefore, authors tried to analyze the combustion pressure of ammonia in a constant-volume combustion chamber across different equivalence ratios by adopting a machine learning approach. While conducting the analysis, the experimental values were assessed and subsequently utilized to predict the induced combustion pressure in a constant-volume combustion chamber across various equivalence ratios. In this research, a two-step prediction process was employed. In the initial step, the Random Forest algorithm was applied to assess the combustion pressure. Subsequently, in the second step, artificial neural network machine learning algorithms were employed to pinpoint the most effective algorithm with a lower root-mean-square error and R2. Finally, Linear Regression illustrated the lowest error in both steps with a value of 1.0, followed by Random Forest.

The push for decarbonization of internal combustion engines (ICEs) has spurred interest in alternative fuels, such as hydrogen and ammonia. To optimize combustion efficiency and reduce emissions, a closer look at the intake system and in-cylinder flows is crucial, especially when a hard-to-burn fuel, such as ammonia is utilized. In port fuel injection ICEs, airflow within cylinders profoundly affects combustion and emissions by influencing the air–fuel mixing phenomenon. Adjusting intake port openings is an important factor in controlling the in-cylinder airflow. In previous experiments with a transparent cylinder, tangential and helical ports demonstrated that varying the helical port’s opening significantly impacts flow velocities, swirl ratios, and swirl center positions (SCPs). In this study, we used a particle image velocimetry technique to investigate how the tangential port’s opening affects intake and in-cylinder flows. Flow velocities were assessed at different planes near the cylinder head, evaluating streamline maps, turbulent kinetic energy (TKE), and SCPs. Under the given experimental conditions, swirl flows were successfully generated early in the compression stroke when the tangential port opening exceeded 25%. Our findings emphasize the importance of minimizing TKE and SCP variation for successful swirl flow generation in engine cylinders equipped with both tangential and helical ports.

Invadopodia are finger-like protrusions that are commonly spotted at the membrane of the invasive cancer cell. These structures are a major cause of death among cancer patients through metastasis process. Signal transduction stimulated upon contact between ligand and membrane receptors is identified as one of key factors in invadopodia formation. In this study, a time-dependent mathematical model of signal and ligand is investigated numerically. The moving boundary of plasma membrane is taken as a zero-level set function and is moved by the velocity that accounted as the difference of gradient between intra-cellular signal and extra-cellular ligand. The model is solved using a combination of ghost with linear extrapolation and finite difference methods. The results showed that the stimulation of signal from membrane associated ligand consequently moved the plasma membrane outward as time increases. The highest densities of signal and ligand are recorded on the membrane and slowly diffused into intra-cellular and extra-cellular regions, respectively.

Abstract Embryoid cells and induced pluripotent stem cells (iPSCs) are pluripotent stem cells (PSCs). They retain differentiation and self-renewal potential. However, the differentiation potential of PSCs can be changed by the culture medium. PSCs retain their differentiation potential when cultured with medium that supports the glycolytic pathway, showing high expression of chromodomain-helicase-DNA-binding protein 7 (CHD7), but lose their differentiation potential with medium that supports mitochondrial function, showing reduced levels of CHD7. Labeling cells by their copy number variant profile revealed that genetically different PSC populations can be cultured by medium selection. Another factor that defines the self-renewal potential of PSCs is culture condition. PSCs form colonies as they grow, and spontaneous differentiation inevitably occurs along the rim of these colonies in areas that lack cell-to-cell contact; because of this, undifferentiated cell populations would diminish if differentiated cells are not removed properly. Seeding cells on a less potent cell-binding material may minimize the inclusion of differentiated cells, exploiting the reduced adhesive properties of differentiated cells. Culturing cells with medium that supports the glycolytic pathway, using CHD7 as a biomarker for differentiation potential, and culturing cells on less sticky material can improve the differentiation potential of already established PSC clones.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a multifactorial disease, the molecular profile of which remains unclear. This study aimed at unveiling the disease-related protein networks associated with different outcomes of resectable, node-positive PDAC cases. We assessed laser-microdissected cancerous cells from PDAC tissues of a poor outcome group (POG; n = 4) and a better outcome group (BOG; n = 4). Noncancerous pancreatic duct tissues (n = 5) were used as the reference. We identified four representative network modules by applying a weighted network correlation analysis to the obtained quantitative PDAC proteome datasets. Two network modules that were significant for POG were associated with the heat shock response to hypoxia-related stress; in the latter, a large involvement of the non-canonical Hedgehog pathway (regulated by GLI1), the internal ribosome entry site-mediated cap-independent translation, the inositol requiring enzyme 1-alpha (IRE1α)/X-box binding protein 1 pathway of the unfolding protein response (UPR), and the aerobic glycolysis was observed. By contrast, the BOG characteristic module was involved in the inactivation of the UPR pathway via the synoviolin 1-dependent proteasomal degradation of IRE1α, the activation of SOX2, and the loss of PALB2 (partner and localizer of BRCA2) function, all potentially suppressing malignant tumor development. Our findings might facilitate future therapeutic strategies for PDAC.

Engine properties such as engine speed and fuel injection quantity may affect the swirl flow of diesel engines. In this paper, experiments are conducted at two engine rpm and various operation conditions. For instance, motoring with no fuel injected, pre-ignition firing conditions, in addition to different fuel quantities. In this experimental analysis, PIV technique is performed to observe the flow patterns of the charging gas. The obtained results indicate that the swirls behavior is similar under all operation conditions during the intake and compression strokes regardless of the engine speed. In comparison to pre-ignition firing process, generation of more swirl centers has been observed for both engine speeds i.e., 1000 rpm and 1500 rpm under motoring conditions. Additionally, at CA of 610 deg., the swirls centers were maintained for all configurations except for motoring conditions and lowest fuel quantity of 2 mg. Moreover, during expansion strokes for both engine speeds the least magnitude of velocity-vectors was observed under motoring condition. Nevertheless, the higher mean velocity-vectors among that of expansion stroke was observed under pre-ignition firing configuration. The obtained results suggest that, the movement of the induced swirl centers across the piston cavity during expansion to exhaust strokes and increasing the engine speed corresponded to an increase in the mean-velocity, swirl ratios, and TKE.

Abstract Breast cancer is the most common cancer type among women worldwide. The majority of breast cancer expresses estrogen receptor (ER) and endocrine therapy is a standard treatment of ER-positive breast cancer. However, development of the therapy resistance is still a major challenge and thus new therapeutic approaches are needed. Here we show that an RNA-binding protein, PSPC1, play a crucial role in ER-positive breast cancer growth through post-transcriptional gene regulation. We showed that siRNA-mediated PSPC1 silencing suppressed the proliferation of ER-positive breast cancer cells. Strong immunoreactivity (IR) of PSPC1 was correlated with poor prognosis for ER-positive breast cancer patients. Using immunoprecipitation, RNA-immunoprecipitation (RIP) and quantitative PCR (qPCR) experiments, we showed that PSPC1 interacted with PSF and was involved in post-transcriptional regulation of PSF target genes, ESR1 and SCFD2. Strong SCFD2 IR was correlated with poor prognosis for ER-positive breast cancer patients and combinations of PSPC1, PSF, and SCFD2 IRs were potent prognostic factors. Moreover, we identified DDIAS and MYBL1 as SCFD2 downstream target genes using microarray analysis, and finally showed that SCFD2 silencing suppressed tamoxifen-resistant breast tumor growth in vivo. These results indicated that PSPC1 and SCFD2 axis could be a promising target in the clinical management of the disease.

Abstract The oral cavity is an entrance for respiratory viruses, such as influenza. Recently, saliva has been shown to exert both antimicrobial and antiviral activities. Thus, saliva may be a biological factor that contributes to the prevention of influenza infection. However, the actual salivary anti-influenza A virus (IAV) activity in individuals and its determinant factors are unknown. By assessing individual variations in salivary anti-IAV activity in 92 people using an established new high-throughput system in this study, we found that the anti-IAV activity varied widely between individuals and showed a significant positive correlation with protein-bound sialic acid (BSA) level (ρ = 0.473; p

Ammonia is a kind of energy carrier of hydrogen, and its use as engine fuel has been studied. However, it requires overcoming shortcomings of low combustion speed. We focus that the laminar combustion velocity of gasoline mixture with an excess air ratio at 2.0 is the same as that of ammonia. The combustion of ammonia was simulated by using gasoline experiments under lean-burn conditions and the experimental engine with the sub-chamber and the glow plug. Through experiments, data such as the optimal ignition angle and NOx emissions during lean combustion are obtained. Based on the above experimental data, authors did the co-combustion experiment of gasoline/ammonia/air. Under the conditions of excess air ratio of 1.1, 1.2, 1.3, maximum ammonia content is 33%NH3, the engine could be operated with less than 10% variation in IMEP.

This paper presents a mathematical model governing the dynamics of a morphogenetic vascular endothelial cell (EC) during angiogenesis, and vascular growth formed by EC. Especially, we adopt a multiparticle system for modeling these cells. This model does not distinguish a tip cell from a stalk cell. A formed vessel is modeled using phase-field equation to prevent capillary expansion with time stepping in particular. Numerical simulation reveals that all cells are moving in the direction of high concentration of vascular endothelial growth factor (VEGF), and that they are mutually repellent in cases in which they are closer than some threshold.

Efficient management of fragility fractures of the pelvis (FFPs) is established during the acute phase of injury. However, a small number of FFPs exhibit fracture progression with increased instability over time. Fracture progression is typically seen in sacral fractures and rare in iliac fractures. Herein, we present the case of a 72-year-old woman with Rommens type IIIa FFP, following an isolated iliac fracture. It was successfully treated four months after the initial injury with retrograde suprapubic screw fixation via the anterior intra-pelvic approach and percutaneous lateral compression type-2 screw fixation using an interdigitating technique.

Breast cancer is a hormone-dependent cancer, and sex steroids play a pivotal role in breast cancer progression. Estrogens are strongly associated with breast cancers, and the estrogen receptor (estrogen receptor α; ERα) is expressed in 70–80% of human breast carcinoma tissues. Although antiestrogen therapies (endocrine therapies) have significantly improved clinical outcomes in ERα-positive breast cancer patients, some patients experience recurrence after treatment. In addition, patients with breast carcinoma lacking ERα expression do not benefit from endocrine therapy. The androgen receptor (AR) is also expressed in >70% of breast carcinoma tissues. Growing evidence supports this novel therapeutic target for the treatment of triple-negative breast cancers that lack ERα, progesterone receptor, and human EGF receptor 2, and ERα-positive breast cancers, which are resistant to conventional endocrine therapy. However, the clinical significance of AR expression is still controversial and the biological function of androgens in breast cancers is unclear. In this review, we focus on the recent findings concerning androgen action in breast cancers and the contributions of androgens to improved breast cancer therapy.

In hormone-dependent cancers, the activation of hormone receptors promotes the progression of cancer cells. Many proteins exert their functions through protein– protein interactions (PPIs). Moreover, in such cancers, hormone–hormone receptor binding, receptor dimerization, and cofactor mobilization PPIs occur primarily in hormone receptors, including estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptors. The visualization of hormone signaling has been primarily reported by immunohistochemistry using specific antibodies; however, the visualization of PPIs is expected to improve our understanding of hormone signaling and disease pathogenesis. Visualization techniques for PPIs include Förster resonance energy transfer (FRET) and bimolecular fluorescence complementation analysis; however, these techniques require the insertion of probes in the cells for PPI detection. Proximity ligation assay (PLA) is a method that could be used for both fo rmalin-fixed paraffin-embedded (FFPE) tissue as well as immunostaining. It can also v isualize hormone receptor localization and post-translational modifications of hormone receptors. This review summarizes the results of recent studies on visualization techniques for PPIs with hormone receptors; these techniques include FRET and PLA. In addition, super-resolution microscopy has been recently reported to be applicable to their visualization in both FFPE tissues and living cells. Super-resolution microscopy in conjunction with PLA and FRET could also contribute to the visualization of PPIs and subsequently provide a better understanding of the pathogenesis of hormone-dependent cancers in the future.

Abstract Cesarean section via a transverse uterine fundal incision is performed in patients with placenta previa to reduce blood loss. We describe a case of uterine rupture in a pregnant woman who previously underwent a cesarean section and recovered from cardiac arrest by multidisciplinary management.

Fucosylation is involved in cancer and inflammation, and several fucosylated proteins, such as AFP-L3 for hepatocellular carcinoma, are used as cancer biomarkers. We previously reported an increase in serum fucosylated haptoglobin (Fuc-Hp) as a biomarker for several cancers, including pancreatic and colon cancer and hepatocellular carcinoma. The regulation of fucosylated protein production is a complex cellular process involving various fucosylation regulatory genes. In this report, we investigated the molecular mechanisms regulating Fuc-Hp production in cytokine-treated hepatoma cells using a partial least squares (PLS) regression model. We found that SLC35C1, which encodes GDP-fucose transporter 1 (GFT1), is the most responsible factor for Fuc-Hp production among various fucosylation regulatory genes. Furthermore, the transcription factor SP1 was essential in regulating SLC35C1 expression. We also found that an SP1 inhibitor was able to suppress Fuc-Hp production without affecting total Hp levels. Taken together, Fuc-Hp production was regulated by SP1 via induction of GFT1 in the hepatoma cell line HepG2.

To improve internal combustion engine cooling systems, it is required to utilize the nucleate boiling heat transfer. Previous studies revealed it is affected by surface roughness, flow velocity, and degree of subcooling. This study investigated the heat transfer mechanisms (latent heat transport mechanism, sensible heat transport mechanism, and bubble agitation mechanism) when changing the above parameters. It was found that the increase in flow velocity and degree of subcooling increased the heat transfer due to the latent and sensible heat transport, while the increase in surface roughness increased the heat transfer due to the sensible heat transport and bubble agitation.

We present a mathematical model of an individual cell to expand the simulation of invadopodia formation to a three-dimensional (3D) domain for a more realistic complexity. Simulating invadopodia replication in order for it to be biologically relevant is important since it helps us to understand cancer invasion and metastasis better as well as giving some insight into investigating ways to stop the spread of this fatal disease. Invadopodia formation is formulated using the Stefan problem approach, where the free boundary is characterised by the Stefan free boundary condition, in which the boundary membrane is not known in advance. Level set method is proposed to indicate the behaviour of the cell interface and the motion of the plasma membrane. An enthalpy method (phase-transition problem) is used to describe the cell membrane diffusion. In addition to this, we were able to improve the simulation outcome, giving it a more realistic complexity by using a different simulation technique and domain as well as a different data set. Singularities and instabilities were eliminated. The results that were achieved have the potential to be helpful for novel approaches or to be extended to other methods in the development of a more accurate numerical simulation.

To improve the cooling system of internal combustion engines, the utilization of the nucleate boiling heat transfer is desired. Our previous study revealed the relationship between the water nucleate boiling heat flux and dimensionless numbers. By using 50% ethylene glycol aqueous solution (EG50%) as coolant, the nucleate boiling heat flux was measured on the corroded heating surface and compared with the experimental data of water as coolant. Subsequently, dimensional analyses were done to investigate the necessary dimensionless numbers affecting the forced flow nucleate boiling. Two new models are proposed for water and EG50% as coolants, and predicted heat flux results were found to be in an average error of 9.7% and 10.1%, respectively.

Lacrimal canaliculitis is a rare infection of the lacrimal canaliculi with canalicular concretions formed by aggregation of organisms. Metagenomic shotgun sequencing analysis using next-generation sequencing has been used to detect pathogens directly from clinical samples. Using this technology, we report cases of successful pathogen detection of canalicular concretions in lacrimal canaliculitis cases. We investigated patients with primary lacrimal canaliculitis examined in the eye clinics of four hospitals from February 2015 to July 2017. Eighteen canalicular concretion specimens collected from 18 eyes of 17 patients were analyzed by shotgun metagenomics sequencing using the MiSeq platform (Illumina). Taxonomic classification was performed using the GenBank NT database. The canalicular concretion diversity was characterized using the Shannon diversity index. This study included 18 eyes (17 patients, 77.1 ± 6.1 years): 82.4% were women with lacrimal canaliculitis; canalicular concretions were obtained from 12 eyes using lacrimal endoscopy and six eyes using canaliculotomy with curettage. Sequencing analysis detected bacteria in all samples (Shannon diversity index, 0.05–1.47). The following genera of anaerobic bacteria (>1% abundance) were identified: Actinomyces spp. in 15 eyes, Propionibacterium spp., Parvimonas spp. in 11 eyes, Prevotella spp. in 9 eyes, Fusobacterium spp. in 6 eyes, Selenomonas spp. in 5 eyes, Aggregatibacter spp. in 3 eyes, facultative and aerobic bacteria such as Streptococcus spp. in 13 eyes, Campylobacter spp. in 6 eyes, and Haemophilus spp. in 3 eyes. The most common combinations were Actinomyces spp. and Streptococcus spp. and Parvinomonas spp. and Streptococcus spp., found in 10 cases. Pathogens were identified successfully using metagenomic shotgun sequencing analysis in patients with canalicular concretions. Canalicular concretions are polymicrobial with anaerobic and facultative, aerobic bacteria.

Transcription factors (TFs) often form distinct networks to regulate transcriptional program during cancer progression. Here the authors show that OCT4 is a common transcriptional factor in two types of advanced PC and as such, OCT4 accelerates a TF complex formation with the FOXA1/AR in castration-resistant PC and NRF1 in neuroendocrine PC.

Abstract Background Tibial rotational alignment in total knee arthroplasty (TKA) is generally determined based on intra-articular structure, and can be difficult to ascertain in some cases. The aim of this study was to investigate whether the medial tangent angle of the tibia (MTAT) could be useful in determining the anteroposterior axis of the tibia. Methods This study was performed on 103 lower limbs in 53 patients who underwent primary total hip arthroplasty. The selection criteria for our study were based on the assumption that knees in patients undergoing THA exhibit fewer degenerative changes than knees in patients undergoing TKA. Using computed tomography images, the MTAT, comprising the medial tangent of the proximal tibia and the anteroposterior (AP) axis of the tibia, was measured on three horizontal planes: at the distal edge of the tibial tubercle (A), at 5 cm distally (B), and at 10 cm further distally (C). The tibial medial surface was grouped into three classes according to shape: valley type, flat type, and hill type. The percentage at which these shapes were observed in each group was also calculated. Measurement reliability was calculated using the intraclass correlation coefficient. Results The angles were 45.2° (interquartile range: IR 43.0–47.7) at A, 42.7° (IR 38.7–45.9) at B, and 42.4° (IR 38.2–45.9) at C. Intra-rater reliability and inter-rater reliability was 0.982 and 0.974 at A, 0.810 and 0.411 at B, and 0.940 and 0.811 at C, respectively. Regarding the tibial medial surface, the valley type was observed in all cases at A, and the hill type was observed in the highest percentage of cases at B and C. Conclusions The MTAT was approximately 45° at level A, and reproducibility was the highest among the three groups. The two points forming the valley on the tibial medial surface were bony ridges. Therefore, the medial tangent of the tibia at level A could be easily determined. Because the distal edge of the tibial tubercle exists at the surgical area and the extra-articular area, it can be a suitable intraoperative, extra-articular landmark in determining the tibial AP axis, even for revision TKA.

Abstract Reduction of elastin in the skin causes various skin diseases as well as wrinkles and sagging with aging. Sialidase is a hydrolase that cleaves a sialic acid residue from sialoglycoconjugate. Cleavage of sialic acid from microfibrils by the sialidase isozyme Neu1 facilitates elastic fiber assembly. In the present study, we showed that a lower layer of the dermis and muscle showed relatively intense sialidase activity. The sialidase activity in the skin decreased with aging. Choline and geranate (CAGE), one of the ionic liquids, can deliver the sialidase subcutaneously while maintaining the enzymatic activity. The elastin level in the dermis was increased by applying sialidase from Arthrobacter ureafaciens (AUSA) with CAGE on the skin for 5 days in rats and senescence-accelerated mice prone 1 and 8. Sialidase activity in the dermis was considered to be mainly due to Neu2 based on the expression level of sialidase isozyme mRNA. Transdermal administration of Neu2 with CAGE also increased the level of elastin in the dermis. Therefore, not only Neu1 but also Neu2 would be involved in elastic fiber assembly. Transdermal administration of sialidase is expected to be useful for improvement of wrinkles and skin disorders due to the loss of elastic fibers.

Injection characteristics play an important role in the emission and overall thermal efficiency of an engine. Several methods have been proposed for analyzing different fuel injection characteristics. This study focused on the interferometric laser imaging for droplet sizing (ILIDS) technique to investigate the effects of droplet size and velocity under different conditions of water-glycerin mixtures. These effects were evaluated using intermittent spray flows in both ambient and pressurized constant volume spray chamber conditions. The initial results were compared to those reported by previous studies and used to determine the Sauter mean diameter (SMD), arithmetic mean diameter (AMD), droplet velocity, and probability density function of the spray droplet size. SMD and AMD tended to decrease as the plate temperature, injection pressure, and viscosity were increased at specific observation areas. The average velocity of the droplet increased with higher plate temperature and injection pressure at specific observation areas. The distribution of the smaller droplet increased with higher plate temperature and injection pressure. For the water-glycerin mixture, as the glycerin ratio increased, more viscous droplets were created. This was followed in higher nozzle shear force at the outlet of the fuel injector, which decreased the particle size and generated more atomized fuel sprays. This result can enable the reduction in hydrocarbon and carbon monoxide emissions from internal combustion engines.