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Background Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis. Case presentation: This study investigated the role of the gut microbiota during the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvement in enteritis symptoms. Conversely, genera Fusobacterium, Faecalibacterium, Bacteroides, Prevotella, and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations. Conclusions Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs. Keywords: Immune-related adverse events, Enteritis, Microbiota, Immune checkpoint inhibitors, Author(s): Yuki Hirata[sup.1], Yoshiki Tanaka[sup.2], Haruka Yokota[sup.2], Hiroshi Ohno[sup.2], Koji Nishida[sup.1], Hikaru Shimizu[sup.1], Noboru Mizuta[sup.1], Kei Nakazawa[sup.1], Ryoji Koshiba[sup.1], Kazuki Kakimoto[sup.1], Takako Miyazaki[sup.1], Shiro Nakamura[sup.1] and Hiroki Nishikawa[sup.1] Background As [...]

Objective was to compare the accuracy of three formulas (IA; Sanders, Retzlaff, and Kraff/Theoretical (SRK/T); and Barrett Universal II (BUII)), in achieving emmetropia in eyes implanted with TFNT lenses (Alcon). Patients and Methods: A total of 145 eyes of 145 patients were included in the evaluation. Preoperative data were obtained from IOLMaster 700, while intraoperative data were collected from ORA SYSTEMTM. Visual acuity ≥ 0.8 at the 3-month post-surgery mark was confirmed. We assessed refractive prediction error (RPE), which is the difference between predicted refraction (PR) and postoperative subjective refraction. This evaluation aimed to identify the optimal IOL power with the implemented algorithm. Results: Among the 145 eyes evaluated, 55.9%, 78.7%, and 97.2% achieved postoperative subjective refraction within ± 0.13 Diopters (D), ± 0.25 D, and ± 0.50 D, respectively. The percentages of eyes within ± 0.25 D of PR varied by formula type, with values of 57%, 57%, and 54% for IA, BUII, and SRK/T, respectively. For eyes with short to medium axial length (AL< 26.00 mm), the percentages within ± 0.25 D of RPE were 52%, 58%, and 58% for IA, SRK/T, and BUII, respectively. In contrast, for eyes with long axial length (≥ 26.00 mm) the percentages were 68%, 52%, and 45% for IA, BUII, and SRK/T, respectively. Conclusion: The proposed majority decision algorithm incorporating IA and two IOL frequency formulas was effective in reducing postoperative refractive error. IA was particularly beneficial for eyes with long axial length. These findings suggest the algorithm has potential to optimize IOL power selection to improve quality of life of patients and clinical practice outcomes. [ABSTRACT FROM AUTHOR]

Isomeric states of the neutron-rich isotope 18973Ta116 were populated via fragmentation of a primary beam of 208Pb ions at 1 GeV/u impinging on a 9Be target at GSI, Darmstadt, Germany. The isotopes of interest were separated, identified and delivered to the DESPEC setup. Two isomers were deduced in 189Ta116 and their lifetimes were measured based on the γ-ray time distributions.

Uptake of thiosulfate ions as an inorganic sulfur source from the environment is important for bacterial sulfur assimilation. Recently, a selective thiosulfate uptake pathway involving a membrane protein YeeE (TsuA) in Escherichia coli was characterized. YeeE-like proteins are conserved in some bacteria, archaea, and eukaryotes. However, the precise function of YeeE, along with its potential partner protein in the thiosulfate ion uptake pathway, remained unclear. Here, we assessed selective thiosulfate transport via Spirochaeta thermophila YeeE in vitro and characterized E. coli YeeD (TsuB) as an adjacent and essential protein for YeeE-mediated thiosulfate uptake in vivo. We further showed that S. thermophila YeeD possesses thiosulfate decomposition activity and that a conserved cysteine in YeeD was modified to several forms in the presence of thiosulfate. Finally, the crystal structures of S. thermophila YeeE-YeeD fusion proteins at 3.34-Å and 2.60-Å resolutions revealed their interactions. The association was evaluated by a binding assay using purified S. thermophila YeeE and YeeD. Based on these results, a model of the sophisticated uptake of thiosulfate ions by YeeE and YeeD is proposed. YeeE is a bacterial membrane protein that mediates thiosulfate uptake, but whether it acts alone it is unclear. This study identifies YeeD as a necessary partner of YeeE, characterizing the cooperation of the two proteins -which is based on the thiosulfate ion decomposition activity of YeeD- at both structural and functional levels. [ABSTRACT FROM AUTHOR]

The development of near‐infrared (NIR) fluorophores that have both excellent chemical stability and photostability, as well as efficient cell permeability, is highly demanded. In this study, we present phospha‐rhodamine (POR) dyes which display significantly improved performance for protein labeling. This is achieved by incorporating a 2‐carboxy‐3‐benzothiophenyl group at the 9‐position of the xanthene scaffold. The resulting cis and trans isomers were successfully isolated and structurally characterized using X‐ray diffraction. The HaloTag ligand conjugates of the two isomers exhibited different staining abilities in live cells. While the cis isomer showed non‐specific accumulation on the organelle membranes, the trans isomer selectively labeled the HaloTag‐fused proteins, enabling the long‐term imaging of cell division and the 5‐color imaging of cell organelles. Molecular dynamics simulations of the HaloTag ligand conjugates within the lipid membrane suggested that the cis isomer is more prone to forming oligomers in the membrane. In contrast, the oligomerization of the trans isomer is effectively suppressed by its interaction with the lipid molecules. By taking advantage of the superior labeling performance of the trans isomer and its NIR‐emissive properties, multi‐color time‐lapse super‐resolution 3D imaging, namely super‐resolution 5D‐imaging, of the interconnected network between the endoplasmic reticulum and microtubules was achieved in living cells. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have attracted a great deal of interest as a therapeutic tool for renal fibrosis. Although both adipose-derived and bone marrow-derived MSCs (ADSCs and BMSCs, respectively) suppress renal fibrosis, which of these two has a stronger therapeutic effect remains unclear. This study aimed to compare the antifibrotic effects of ADSCs and BMSCs extracted from adipose tissue and bone marrow derived from the same rats. When cultured in serum-containing medium, ADSCs had a more potent inhibitory effect than BMSCs on renal fibrosis induced by ischemia-reperfusion injury in rats. ADSCs and BMSCs cultured in serum-free medium were equally effective in suppressing renal fibrosis. Mice infused with ADSCs (serum-containing or serum-free cultivation) had a higher death rate from pulmonary embolism than those infused with BMSCs. In vitro, mRNA levels of tissue factor, tumor necrosis factor-α-induced protein 6 and prostaglandin E synthase were higher in ADSCs than in BMSCs, while that of vascular endothelial growth factor was higher in BMSCs than in ADSCs. Although ADSCs had a stronger antifibrotic effect, these findings support the consideration of thromboembolism risk in clinical applications. Our results emphasize the importance of deciding between ADSCs and BMSCs based upon the target disease and culture method. [ABSTRACT FROM AUTHOR]

Hypertriton is the lightest hypernucleus and a benchmark in hypernuclear physics. However, it has recently been suggested that its lifetime and binding energy values may differ from the established values. To solve this puzzle, it is necessary to measure both values with a higher precision. For the precise measurement of the binding energy, we are aiming at developing a novel technique to measure the hypertriton binding energy with unprecedented accuracy by combining nuclear emulsion data and machine learning techniques. The analysis will be based on the J-PARC E07 nuclear emulsion data. Furthermore, a machine-learning model is being developed to identify other single and double-strangeness hypernuclei.

Background and Aim: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. Methods: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. Results: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. Conclusion: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs. [ABSTRACT FROM AUTHOR]

Phacoemulsification has emerged as the global standard for cataract surgery, and various novel methods, tools, and agents have promoted surgical efficiency and reduced complications. Conventionally, the phaco tip, which cleaves and aspirates the cataractous lens, has been mainly constructed of metal. In this study, the risk of anterior capsule rupture was evaluated under conditions of different power modes, longitudinal (Mode-L), torsional (Mode-T), or both (Mode-LT), and different aspiration powers (0 or 200 mmHg), using a traditional metal phaco tip (Group-M) or a new phaco tip with a high-strength polymer overmold on the needle edge (Group-P), which was developed to reduce the risk of capsule rupture. One hundred twenty porcine eyes were used for experiments within a setting of typical human physiological intraocular pressure. We found that Group-M showed capsule rupture with a smaller ultrasound power than did Group-P, regardless of power mode or aspiration power. In Group-M, there was no significant difference in risk of capsule rupture among power modes, however in Group-P, capsule rupture was least likely to occur with Mode-T. These results provide useful information for inexperienced ophthalmologists to improve surgical safety. [ABSTRACT FROM AUTHOR]

In the Japanese hagfish, Eptatretus burgeri, approximately 21% of the genomic DNA in germ cells (2n = 52) consists of 16 chromosomes (eliminated [E]-chromosomes) that are eliminated from presumptive somatic cells (2n = 36). To uncover the eliminated genome (E-genome), we have identified 16 eliminated repetitive DNA families from eight hagfish species, with 11 of these repeats being selectively amplified in the germline genome of E. burgeri. Furthermore, we have demonstrated that six of these sequences, namely EEEb1–6, are exclusively localized on all 16 E-chromosomes. This has led to the hypothesis that the eight pairs of E-chromosomes are derived from one pair of ancestral chromosomes via multiple duplication events over a prolonged evolutionary period. NGS analysis has recently facilitated the re-assembly of two distinct draft genomes of E. burgeri, derived from the testis and liver. This advancement allows for the prediction of not only nonrepetitive eliminated sequences but also over 100 repetitive and eliminated sequences, accomplished through K-mer-based analysis. In this study, we report four novel eliminated repetitive DNA sequences (designated as EEEb7–10) and confirm the relative chromosomal localization of all eliminated repeats (EEEb1–10) by fluorescence in situ hybridization (FISH). With the exception of EEEb10, all sequences were exclusively detected on EEEb1-positive chromosomes. Surprisingly, EEEb10 was detected as an intense signal on EEEb1-positive chromosomes and as a scattered signal on other chromosomes in germ cells. The study further divided the eight pairs of E-chromosomes into six groups based on the signal distribution of each DNA family, and fiber-FISH experiments showed that the EEEb2–10 family was dispersed in the EEEb1-positive extended chromatin fiber. These findings provide new insights into the mechanisms underlying chromosome elimination and the evolution of E-chromosomes, supporting our previous hypothesis. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to investigate and compare the effects of manual acupuncture (MA) and electroacupuncture (EA) on current perception thresholds (CPTs) using quantitative methods. Methods: Twenty-nine healthy volunteers participated in this prospective crossover trial, in which three acupuncture methods were compared: control, MA, and EA. Acupuncture needles were inserted to a depth of 15 mm at LI4 and LI11 on the left side and retained for 30 min with or without electrical stimulation at a frequency of 2 Hz (EA and MA, respectively). The needles were removed and participants rested for 30 min. CPT in the left mental region was measured at 2000, 250, and 5 Hz, corresponding to the activation of Aβ, Aδ, and C-fibers, respectively, at four time points: baseline, T0; 15 min after needle application, T1; immediately after needle removal, T2; and 30 min after needle removal, T3. In the control session, only a sensory test was performed (without acupuncture). Results: Significant effects of time course on CPT were observed (p < 0.001). CPT values increased significantly at T1, T2, and T3, compared with those at T0, at all stimulation frequencies during MA and EA. Changes in CPT values with EA were not significantly greater than those with MA. Conclusions: Both MA and EA increased the sensory thresholds of Aβ, Aδ, and C-fibers in the mental region for ⩾30 min after needle removal. Additional of electrical stimulation may not confer additional benefits over needling alone. Trial registration number: UMIN000017983 (University Hospital Medical Information Network Clinical Trials Registry). [ABSTRACT FROM AUTHOR]

Simple Summary: In this retrospective study of 198 HCC patients receiving ablation therapy, participants were divided into two groups based on body mass index (BMI): overweight patients (BMI ≥ 25) and non-overweight patients (BMI < 25). The technical success rate (TSR) in the first session was significantly higher in non-overweight patients than in overweight patients (90.3% vs. 78.4%, p = 0.03). Fifteen (20.3%) overweight and eleven (8.9%) non-overweight patients required additional ablation therapy for residual tumors, resulting in almost similar TSRs at the final session (95.9% vs. 99.2%, p = 0.3). Local tumor progression and distant recurrence rates were not significantly different between the two groups, but overall survival was better in overweight patients than in non-overweight patients (p < 0.001). Despite the potential adverse impact of being overweight on public health problems, the present findings showed the relationship between being overweight and improved survival. The negative aspects of being overweight might remain as minor technical issues in HCC patients receiving ablation therapy. This study aimed to investigate the effect of being overweight on the outcome of ablation therapy for patients with early-stage hepatocellular carcinoma (HCC). This retrospective study included 198 patients with HCC who underwent radiofrequency ablation or microwave ablation at Gunma Saiseikai Maebashi Hospital between April 2017 and December 2021. We divided the patients into two groups based on their body mass index (BMI): overweight (BMI ≥ 25 kg/m2, n = 74 (37.4%)) and non-overweight (BMI < 25 kg/m2, n = 124 (62.6%)). The technical success rates (TSRs) in the first session were 78.4% and 90.3% in overweight and non-overweight patients, respectively, with a significant difference (p = 0.03). Additional ablation therapy for residual tumors was required in 15 (20.3%) overweight and 11 (8.9%) non-overweight patients (p = 0.03), resulting in 95.9% and 99.2% TSRs at the final session, respectively, without a significant difference (p = 0.3). While local tumor progression and distant recurrence rates were not significantly different between the two groups, overall survival was better in overweight patients than in non-overweight patients (p < 0.001). Despite the potential adverse impact of being overweight on public health problems, the present findings showed the relationship between being overweight and improved survival. The negative aspects of being overweight might remain as minor technical issues in HCC patients receiving ablation therapy. [ABSTRACT FROM AUTHOR]

Measurement of root-mean-square radii of proton distributions of 17–22N from charge-changing cross section shows the emergence of thick neutron skin towards the neutron-drip line. Signature of N = 14 shell gap has been found in nitrogen isotopes along with the emergence of neutron halo in 22N. The measured radii are in good agreement with the shell model calculations.

In this study, we developed a one-step method for fabricating hydrophobic surfaces on copper (Cu) substrates. Cuprous oxide (Cu2O) with low free energy was successfully formed after low-fluence laser direct irradiation. The formation of Cu2O enhanced the hydrophobicity of the Cu substrate surface, and the contact angle linearly increased with the proportion of Cu2O. The Cu2O fabricated by low-fluence laser treatment showed the same crystal plane orientation as the pristine Cu substrate, implying an epitaxial growth of Cu2O on a Cu substrate. [ABSTRACT FROM AUTHOR]

We discovered that the aluminosilicate-stabilized silyl cations, which were created from a solid-acid catalyst, the proton-exchanged montmorillonite, and Et3 SiH, efficiently promoted the reductive benzylation of benzenes with aromatic carboxylic acid chlorides and Et3 SiH in one pot. [ABSTRACT FROM AUTHOR]

The crystal structure of the bacterial protein YidC is reported, together with a structure-based functional analysis, providing insight into the role of YidC in inserting single-spanning membrane proteins into the membrane. Structure of YidC from Bacillus halodurans The bacterial protein YidC, a homologue of mitochondrial Oxa1 and chloroplast Alb3, is not just a chaperone that facilitates proper folding and membrane topology of its membrane-protein substrates, in cooperation with the Sec machinery. It also inserts several single- or double-spanning membrane proteins into the membrane independently of Sec. Osamu Nureki and colleagues present the long-awaited structure of YidC, which provides insights into the second role of this membrane protein. The structure suggests that YidC does not adopt a polypeptide-conducting channel-like architecture. Instead, a novel fold within the protein forms a positively charged hydrophilic groove. The authors, using structure-based functional analysis, reveal that electrostatic interactions between a conserved Arg residue in the groove and the acidic residues at the N-terminal region of a substrate protein are essential for the YidC-mediated insertion of the substrate into the membrane. Newly synthesized membrane proteins must be accurately inserted into the membrane, folded and assembled for proper functioning. The protein YidC inserts its substrates into the membrane, thereby facilitating membrane protein assembly in bacteria; the homologous proteins Oxa1 and Alb3 have the same function in mitochondria and chloroplasts, respectively.sup.1,2. In the bacterial cytoplasmic membrane, YidC functions as an independent insertase and a membrane chaperone in cooperation with the translocon SecYEG.sup.3,4,5. Here we present the crystal structure of YidC from Bacillus halodurans, at 2.4 Å resolution. The structure reveals a novel fold, in which five conserved transmembrane helices form a positively charged hydrophilic groove that is open towards both the lipid bilayer and the cytoplasm but closed on the extracellular side. Structure-based in vivo analyses reveal that a conserved arginine residue in the groove is important for the insertion of membrane proteins by YidC. We propose an insertion mechanism for single-spanning membrane proteins, in which the hydrophilic environment generated by the groove recruits the extracellular regions of substrates into the low-dielectric environment of the membrane., Author(s): Kaoru Kumazaki [sup.1] [sup.2] , Shinobu Chiba [sup.3] , Mizuki Takemoto [sup.1] [sup.2] , Arata Furukawa [sup.4] , Ken-ichi Nishiyama [sup.5] , Yasunori Sugano [sup.4] , Takaharu Mori [sup.6] [...]

Author(s): Reiya Taniguchi [1, 2]; Asuka Inoue [3, 4]; Misa Sayama [5]; Akiharu Uwamizu [3]; Keitaro Yamashita [6]; Kunio Hirata [4, 6]; Masahito Yoshida [7]; Yoshiki Tanaka [8]; Hideaki E. [...]

An 81‐year‐old man initially underwent right hepatic lobectomy for liver cancer and was pathologically diagnosed with combined hepatocellular and cholangiocarcinoma (CHC). At 13 months after resection, multiple lymph node metastases were observed. We started atezolizumab plus bevacizumab (Atez/Bev), achieving a 7.5‐month progression‐free survival. Atez/Bev might exhibit efficacy for CHC patients. [ABSTRACT FROM AUTHOR]

Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of [H.sup.+] [...]

Dicopper complexes [Cu2(μ-OH)(Ln)](ClO4)2 [n = 1 (1) and 2 (2)] with a novel phenanthrene amide-tether ligand conjugate (HL1) and the original p-cresol-2,6-bis(amidecyclen) (HL2) were synthesized. A phenanthrene unit of 1 enhances the DNA-binding by 9-fold, enabling 1 to convert supercoiled plasmid DNA with H2O2 to a linear one in a 9.3-fold higher yield than 2. 1 reacts with H2O2 to form the μ-1,1-hydroperoxodicopper(II) complex 3 as the active species. The IC50 values of 1 against cancer cells of the lung and pancreas are 23.8 and 18.4 μM, respectively, 12-fold more toxic than the 284 and 241 μM of 2. Confocal microscopy, fluorescence-activated cell sorting, and caspase activity assays using HeLa cells revealed that 1 induces mitochondrial apoptosis. A DNA-targeting phenanthrene unit of 1 enhances the cancer-cell-selective toxicity via mitochondrial apoptosis. [ABSTRACT FROM AUTHOR]

We performed a missing-mass spectroscopy experiment of the 12C(p, d) reaction at 2.5 GeV proton energy in order to search for η′ mesic nuclei. An excitation-energy spectrum of 11C was obtained around the η′ production threshold. As no significant peak structure was observed in the spectrum, upper limits of the formation cross section of η′ mesic nuclei have been determined. Preliminary results of the experiment as well as future prospects are given.