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Abstract Objectives Apples are one of the most frequently consumed fruits and are effective in preventing lifestyle-related and other diseases. However, few studies have been conducted to evaluate health benefits of processed apple products such as juice. In this study, we analyzed the health benefits of consuming apple juice, focusing on changes in the gut microbiota, which plays an important role in maintaining human health. Results Rats were fed apple juice ad libitum, and the relative abundances of various gut microbiota in fecal samples were analyzed. In addition, rats treated apple juice were fed with a high-fat diet, and body weight, plasma triglyceride, glucose, and cholesterol levels were measured. The relative abundance of Clostridium cluster XIV did not change with the treatment of apple juice, but the relative abundance of Clostridium cluster IV was significantly decreased. In contrast, the relative abundances of Lactobacillus and Bifidobacterium, which provide benefits to the human body, were significantly increased by 3-fold and 10-fold, respectively, with apple juice consumption. When apple juice-treated rats were fed a high-fat diet, the increase in body weight, liver fat, and blood lipid parameters were all suppressed compared to high-fat alone group. Conculusion This study suggests that the consumption of apple juice changes the gut microbiota, exerts a prebiotic effect, and is effective in improving lifestyle-related diseases.

Background: The C-reactive protein (CRP)–albumin–lymphocyte (CALLY) index is a novel immuno-nutritional biomarker based on the levels of CRP, serum albumin, and lymphocyte count. This study examined the prognostic value of the CALLY index in patients with colorectal cancer undergoing curative surgery. Methods: Between 2010 and 2017, 578 patients with stage II-III colorectal cancer who underwent curative resection were enrolled. The CALLY index was defined as (albumin × lymphocyte)/(CRP × 104). We investigated the association of the CALLY index with disease-free survival (DFS) and overall survival (OS). Results: The cutoff value of the CALLY index was determined to be 2. Of the 578 patients, 175 (30%) had a preoperative CALLY index

In polyvinyl alcohol (PVA) production plants, the cloud point is controlled as one of the product properties. The cloud point is the temperature at which the water solubility rapidly decreases because hydrogen bonds between PVA and water are broken. If the cloud point falls below a controlled value, the performance of the PVA as a product deteriorates, and thus it is necessary to monitor the cloud point in real time and ensure that it does not deviate from the controlled value. However, the cloud point cannot be analysed frequently in practical operations. In this study, a soft sensor that continuously predicts the cloud point from process variables that can be measured in real time was constructed using machine learning. Furthermore, the prediction accuracy of the model was improved by (1) increasing the number of samples using a data set of similar quality to the cloud point, considering that the number of samples near the control value of the cloud point is small, and (2) selecting the optimum process variable and time-delay range, considering the time delay of the process variable to accommodate the dynamic behaviour of the plant. Analysis was conducted using data measured from an actual PVA manufacturing plant. When comparing the conventional method with the proposed method, the coefficient of determination, used as an indicator to evaluate model performance, improved from 0.288 to 0.729. Furthermore, the root mean squared error decreased from 1.52 to 0.937. These results demonstrate that the proposed method contributes to improved prediction accuracy.

IntroductionImmune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for esophageal cancer (EC). Although ICIs enable long-term survival in some patients, the efficacy of ICIs varies widely among patients. Therefore, predictive biomarkers are necessary for identifying patients who are most likely to benefit from ICIs to improve the efficacy of the treatment. We retrospectively analyzed the outcomes of combination therapy, including nivolumab plus ipilimumab or chemotherapy plus anti-programmed cell death 1 (PD-1) antibodies in our institute to identify biomarkers.MethodsTwenty-seven patients received nivolumab plus ipilimumab, and thirty-six patients received chemotherapy plus anti-PD-1 antibodies were included in this study. We analyzed patient characteristics, efficacy, and safety. Multivariable analysis of biomarkers evaluated the correlation among overall survival (OS), progression-free survival (PFS), and the following variables: body mass index, performance status, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein level, and albumin level before treatment.ResultsIn multivariable analysis, albumin level was significantly correlated with PFS in the cisplatin plus 5-fluorouracil (CF) plus pembrolizumab group. NLR and albumin level were significantly correlated with OS in the nivolumab plus ipilimumab group. Other variables, including PS, BMI, and CRP did not correlate with any of the outcomes.ConclusionsHigh NLR in EC patients prior to treatment was significantly less effective for ICIs. In chemotherapy combined with ICIs, NLR before the treatment was not associated with treatment efficacy, suggesting combination chemotherapy may be beneficial for EC patients with high NLR. NLR may be an indicator of immunocompetence in anti-tumor immunity and a convenient predictive biomarker for selecting appropriate treatments including ICIs.

Abstract The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

We present our recent development of the surface-emitting quantum cascade laser with a PC (photonic crystal) resonator and a strain-compensated MQW (multiple quantum well) active layer operating at around 4.3 μm. We describe the laser performance mainly from the viewpoint of the design and analysis of the PC resonators, which include both numerical calculations by FEM (finite element method) and analytical calculations using the k·p perturbation theory and group theory. We analyze the resonance quality factor, overlap factor, extraction efficiency, and far-field pattern, and show how the output power and beam quality have been improved by the appropriate design of the PC resonator.

Chemical modifications of cellular RNAs play key roles in gene expression and host defense. The cap-adjacent N6,2′-O-dimethyladenosine (m6Am) is a prevalent modification of vertebrate and viral mRNAs and is catalyzed by the newly discovered N6 methyltransferase PCIF1. However, its role in gene expression remains unclear due to conflicting reports on its effects on mRNA stability and translation. In this study, we investigated the impact of siRNA-mediated transient suppression of PCIF1 on global mRNA expression in HeLa cells. We identified a subset of differentially expressed genes (DEGs) that exhibited minimal overlap with previously reported DEGs. Subsequent validation revealed that PCIF1 positively and negatively regulates RAB23 and CNOT6 expression, respectively, at both the mRNA and protein levels. Mechanistic analyses demonstrated that PCIF1 regulates the stability of these target mRNAs rather than their transcription, and rescue experiments confirmed the requirement of PCIF1’s methyltransferase activity for these regulations. Furthermore, MeRIP-qPCR analysis showed that PCIF1 suppression significantly reduced the m6A levels of RAB23 and CNOT6 mRNAs. These findings suggest that PCIF1 regulates the stability of specific mRNAs in opposite ways through m6A modification, providing new insights into the role of m6Am in the regulation of gene expression.

A ubiquitous and pink-pigmented facultatively methylotrophic bacterium, designated LRY1–08 (=JCM 33120), was isolated from a lichen in Thailand. Strain LRY1–08 and Methylobacterium durans NBRC 112876T shared 99.92 % similarity based on the 16S rRNA gene sequence. The draft genome of LRY1–08 was 5.26 Mbp with 4,952 protein-coding sequences and an average G + C content of 70.0 mol%. Comparing strain LRY1–08 to M. durans NBRC 112876T, the ANIb, ANIm, AAI, and digital DNA-DNA hybridization values were 96.29 %, 97.10 %, 96.7 %, and 82.29 %, respectively. Based on the phenotypic characteristics and genome analysis, it was identified as M. durans. Its genomic sequence data revealed the PHB and CoQ10 biosynthesis genes. Therefore, the results offer suggestions for further investigation into possible applications of this bacterium in biotechnology. The draft genome was deposited at DDBJ/EMBL/GenBank (DNA Databank of Japan/European Molecular Biology Laboratory/Genbank) (JAYEEX000000000).

Abstract It is generally assumed that all bacteria must have at least one rRNA operon (rrn operon) on the chromosome, but some strains of the genera Aureimonas and Oecophyllibacter carry their sole rrn operon on a plasmid. However, other related strains and species have chromosomal rrn loci, suggesting that the exclusive presence of rrn operons on a plasmid is rare and unlikely to be stably maintained over long evolutionary periods. Here, we report the results of a systematic search for additional bacteria without chromosomal rrn operons. We find that at least four bacterial clades in the phyla Bacteroidota, Spirochaetota, and Pseudomonadota (Proteobacteria) lost chromosomal rrn operons independently. Remarkably, Persicobacteraceae have apparently maintained this peculiar genome organization for hundreds of millions of years. In our study, all the rrn-carrying plasmids in bacteria lacking chromosomal rrn loci possess replication initiator genes of the Rep_3 family. Furthermore, the lack of chromosomal rrn operons is associated with differences in copy numbers of rrn operons, plasmids, and chromosomal tRNA genes. Thus, our findings indicate that the absence of rrn loci in bacterial chromosomes can be stably maintained over long evolutionary periods.

Abstract Background Today we experience “Super-aged society”, and a drastic increase in the number of older people needing assistance is an urgent matter for everyone from medical and socio-economical standpoints. Locomotive organ dysfunction due to musculoskeletal disorders is one of the main problems in these patients. Although the concepts of frailty and sarcopenia have been proposed for functional decline, pain remains the main and non-negligible complaint in these of such disorders. This prospective cohort study aimed to observe the changes of reduced mobility in patients with locomotive disorders and to determine the risk factors for functional deterioration of those patients using statistical modeling. Methods A cohort of older adults with locomotive disorders who were followed up every 6 months for up to 18 months was organized. Pain, physical findings related to the lower extremities, locomotive function in performing daily tasks, and Geriatric Locomotive Function Scale-25 (GLFS-25) score were collected to predict the progress of deterioration. Group-based trajectory analysis was used to identify subgroups of changes of GLFS-25 scores, and multinomial logistic regression analysis was performed to investigate potential predictors of the GLFS-25 trajectories. Results Overall, 314 participants aged between 65 and 93 years were included. The participants were treated with various combinations of orthopedic conservative treatments on an outpatient basis. The in-group trajectory model analysis revealed a clear differentiation between the four groups. The mild and severe groups generally maintained their GLFD-25 scores, while the moderate group included a fluctuating group and a no change group. This study showed that comorbidity of osteoporosis was related to GLFS-25 score over 18 months. Age was a weak factor to be moderate or severe group, but gender was not. In addition, the number of pain locations, number of weak muscles, one-leg standing time, grip strength and BMI significantly contributed to the change in GLFS-25 score. Conclusions This study proposes an effective statistical model to monitor locomotive functions and related findings. Pain and comorbid osteoporosis are significant factors that related to functional deterioration of activities. In addition, the study shows a patient group recovers from the progression and their possible contributing factors.

ABSTRACT Aim To investigate the impact of the COVID‐19 pandemic and its preventive measures on the glycemic and lipid control in people with diabetes mellitus (DM). Materials and methods We conducted this retrospective cohort study from April 2019 to March 2021; we termed the period from April 2019 to March 2020 as the pre‐COVID‐19 period, and the period from April 2020 to March 2021 as the COVID‐19 period, and divided each of these two periods into four quarters. Results In the 1st quarter of the COVID period, when the Japanese government declared the first public health emergency, 3,465 people with diabetes mellitus were receiving treatment, which was 10.4% lower than that in the pre‐COVID period. The annual mean HbA1c level was significantly elevated in the COVID‐19 period. The annual mean total cholesterol (TC) and triglyceride (TG) levels were also significantly higher in the COVID‐19 period. Although there were no significant differences in the glycemic control or annual medication between the two periods in people with type 1 diabetes mellitus, the annual mean HbA1c, TC, and TG levels were significantly higher in the COVID‐19 period in people with type 2 diabetes mellitus. Furthermore, a significant increase in the percentage of prescriptions for glinides, biguanides, sodium‐glucose cotransporter 2 inhibitors, and glucagon‐like peptide‐1 receptor agonists for people with type 2 diabetes mellitus was observed in the COVID period. Conclusions It appears from our study that COVID‐19 and its preventive measures had a negative impact on the glycemic and lipid control in people with diabetes mellitus.

Summary: Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.

Archaeal cells are typically enveloped by glycosylated S-layer proteins. Archaeal protein glycosylation provides valuable insights not only into their adaptation to their niches but also into their evolutionary trajectory. Notably, thermophilic Thermoproteota modify proteins with N-glycans that include two GlcNAc units at the reducing end, resembling the ''core structure'' preserved across eukaryotes. Recently, Asgard archaea, now classified as members of the phylum Promethearchaeota, have offered unprecedented opportunities for understanding the role of archaea in eukaryogenesis. Despite the presence of genes indicative of protein N-glycosylation in this archaeal group, these have not been experimentally investigated. Here we performed a glycoproteome analysis of the firstly isolated Asgard archaeon Promethearchaeum syntrophicum. Over 700 different proteins were identified through high-resolution LC-MS/MS analysis, however, there was no evidence of either the presence or glycosylation of putative S-layer proteins. Instead, N-glycosylation in this archaeon was primarily observed in an extracellular solute-binding protein, possibly related to chemoreception or transmembrane transport of oligopeptides. The glycan modification occurred on an asparagine residue located within the conserved N-X-S/T sequon, consistent with the pattern found in other archaea, bacteria, and eukaryotes. Unexpectedly, three structurally different N-glycans lacking the conventional core structure were identified in this archaeon, presenting unique compositions that included atypical sugars. Notably, one of these sugars was likely HexNAc modified with a threonine residue, similar to modifications previously observed in mesophilic methanogens within the Methanobacteriati. Our findings advance our understanding of Asgard archaea physiology and evolutionary dynamics.

AimsShorter and longer sleep durations are associated with adverse health consequences. However, available evidence on the association of sleep duration with constipation is limited, especially in patients with diabetes, who are at a high risk of both conditions. This study aimed to examine the association between sleep duration and constipation in patients with type 2 diabetes.MethodsA total of 4,826 patients with type 2 diabetes were classified into six groups according to sleep duration: ResultsShorter and longer sleep durations were associated with a higher likelihood of constipation than an intermediate duration (6.5-7.4 hours/day). This U-shaped association persisted after adjusting for confounding factors, including lifestyle behavior, measures of obesity and glycemic control, and comorbidities. Broadly identical findings were observed when decreased defecation frequency and laxative use were individually assessed.ConclusionsThis study shows a U-shaped association between sleep duration and constipation in patients with type 2 diabetes, and highlights the importance of assessing sleep duration in daily clinical practice.