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Abstract Background Antiretroviral therapy (ART) has significantly improved the prognosis for people living with human immunodeficiency virus (PLWH). However, alterations in the gut microbiota of PLWH affect their metabolic environment and may contribute to chronic inflammation and premature aging, despite effective ART. Given that inflammation in the body have been shown to be risk factors for age-related diseases, elucidating changes in the gut microbiota and metabolic levels over time in individuals would be for understanding the dynamics in the body that lead to disease development. Methods The study assessed changes in blood markers, gut microbiota, and metabolic environment of PLWH on ART for four years, with participants divided into two groups based on median CD4 cell count (580/µL). Results The high-CD4 group was more obese than the low-CD4 group, but there was no significant difference in comorbidities, such as diabetes, hypertension, and dyslipidemia. An investigation of the alterations in gut microbiota over a 4-year period revealed a reduction in specific groups of bacteria that produce short-chain fatty acids (SCFAs) and an increase in the occurrence of Enterobacteriaceae. In addition, a decline in bacterial thiamine synthesis was predicted, and a decreased abundance of the Ruminococcus gauvreauii group, which relies on supplementation with thiamine from symbiotic bacteria, was observed. The abundance of Collinsella and Catenibacterium at baseline was positively correlated with the predicted number of thiamine-synthesizing pathway. The presence of Catenibacterium at follow-up was inversely correlated with the rate of increase in plasma levels of lipopolysaccharide-binding protein, an indicator of a leaky gut. In terms of assessing the diversity of gut microbiota, a trend towards an increase in opportunistic bacteria with different genetic distances was observed in the high-CD4 group at follow-up. Conclusion These observations suggested that, despite effective ART, the thiamine-deficient environment in the gut continues to reduce thiamine-requiring bacteria, such as certain SCFA-producing bacteria. As a result, secondary effects, such as proliferation of opportunistic bacteria and chronic inflammation associated with increased intestinal permeability, proceed in PLWH. Thus, certain essential nutrient deficiencies for gut metabolic environment may disrupt the symbiotic relationship between gut bacteria and increase the risk of developing inflammatory diseases.

Abstract Background Person with human immunodeficiency virus type-1 (PWH) are prone to chronic inflammation due to residual viral production, even with antiretroviral therapy (ART), which increases the risk of age-related diseases. There is also limited information on changes in the intestinal environment of PWH during ART. In this longitudinal study, we investigated changes in the gut microbiota, persistence of chronic inflammation, interactions between the gut environment and inflammation, and metabolic changes in PWH using long-term ART. Results We analyzed changes in clinical parameters and gut microbiota in 46 PWH over a mean period of 4 years to understand the influence of gut dysbiosis on inflammation. Overall, changes in the gut microbiota included a decrease in some bacteria, mainly involved in short-chain fatty acid (SCFA) production, and an increase in certain opportunistic bacteria. Throughout the study period, an increase in bacterial-specific metabolic activity was observed in the intestinal environment. Continued decline in certain bacteria belonging to the Clostridia class and metabolic changes in gut bacteria involved in glucose metabolism. Additionally, patients with a low abundance of Parabacteroides exhibited low bacterial alpha diversity and a significant increase in body mass index (BMI) during the study period. Monocyte chemoattractant protein 1, a marker of macrophage activation in the plasma, continued to increase from baseline (first stool collection timepoint) to follow-up (second stool collection timepoint), demonstrating a mild correlation with BMI. Elevated BMI was mild to moderately correlated with elevated levels of plasma interleukin 16 and chemokine ligand 13, both of which may play a role in intestinal inflammation and bacterial translocation within the gut microbiota. The rate of BMI increase correlated with the rate of decrease in certain SCFA-producing bacteria, such as Anaerostipes and Coprococcus 3. Conclusion Our data suggest that despite effective ART, PWH with chronic inflammation exhibit persistent dysbiosis associated with gut inflammation, resulting in a transition to an intestinal environment with metabolic consequences. Moreover, the loss of certain bacteria such as Parabacteroides in PWH correlates with weight gain and may contribute to the development of metabolic diseases.

Abstract Background Corynebacterium is a rare but important cause of peritoneal dialysis (PD)-associated infection. A previous study reported that continued antibiotic use at the exit site is associated with increased Corynebacterium exit site infection (ESI), although the latest International Society of Peritoneal Dialysis guideline recommends its use. This study aims to verify the prognosis of Corynebacterium-associated PD-related infections, focusing on ESI. Methods We conducted a single-center, retrospective study about ESI, tunnel infection (TI), and PD-associated peritonitis due to Corynebacterium between April 2018 and January 2023. We primarily examined the prognosis and characteristics of Corynebacterium ESI. Results In this study, we included 125 patients with PD (mean age at PD onset: 69.4 ± 13.7 years, 71.2% male, 48% diabetic, mean estimated glomerular filtration rate at the introduction of PD 7.4 ± 2.6 ml/min/1.73 m2, total follow-up 179.6 patient dialysis year). Between April 2018 and January 2023, 191 cases of ESI, 62 cases of Corynebacterium ESI in 24 patients, 10 cases of TI, and 32 cases of PD-associated peritonitis were detected. In total, 16 of 24 patients with Corynebacterium-associated ESI tested positive for Corynebacterium multiple times in cultures against the exit site, with a maximum of eight times. The estimated glomerular filtration rate during PD introduction was relatively lower in patients with Corynebacterium-associated ESI than in patients without ESI (6.4 versus 7.9 mL/min/1.73 m2, respectively; P = 0.052). Although three of the Corynebacterium ESI cases progressed to TI, there were no cases that progressed directly to PD-associated peritonitis. Conclusions Corynebacterium-associated ESI progresses to TI with a certain probability; however, it is thought that it rarely progresses to PD-associated peritonitis directly.

Abstract Phosphorylated H2AX, known as γH2AX, forms in response to genotoxic insults in somatic cells. Despite the high abundance of H2AX in zygotes, the level of irradiation-induced γH2AX is low at this stage. Another H2A variant, TH2A, is present at a high level in zygotes and can also be phosphorylated at its carboxyl end. We constructed H2AX- or TH2A-deleted mice using CRISPR Cas9 and investigated the role of these H2A variants in the DNA damage response (DDR) of zygotes exposed to γ-ray irradiation at the G2 phase. Our results showed that compared to irradiated wild-type zygotes, irradiation significantly reduced the developmental rates to the blastocyst stage in H2AX-deleted zygotes but not in TH2A-deleted ones. Furthermore, live cell imaging revealed that the G2 checkpoint was activated in H2AX-deleted zygotes, but the duration of arrest was significantly shorter than in wild-type and TH2A-deleted zygotes. The number of micronuclei was significantly higher in H2AX-deleted embryos after the first cleavage, possibly due to the shortened cell cycle arrest of damaged embryos and, consequently, the insufficient time for DNA repair. Notably, FRAP analysis suggested the involvement of H2AX in chromatin relaxation. Moreover, phosphorylated CHK2 foci were found in irradiated wild-type zygotes but not in H2AX-deleted ones, suggesting a critical role of these foci in maintaining cell cycle arrest for DNA repair. In conclusion, H2AX, but not TH2A, is involved in the DDR of zygotes, likely by creating a relaxed chromatin structure with enhanced accessibility for DNA repair proteins and by facilitating the formation of pCHK2 foci to prevent premature cleavage.

Summary: Membrane-less subcellular compartments play important roles in various cellular functions. Although techniques exist to identify components of cellular bodies, a comprehensive method for analyzing both static and dynamic states has not been established. Here, we apply an antibody-based in situ biotinylation proximity-labeling technique to identify components of static and dynamic nuclear bodies. Using this approach, we comprehensively identify DNA, RNA, and protein components of Cajal bodies (CBs) and then clarify their interactome. By inhibiting transcription, we capture dynamic changes in CBs. Our analysis reveals that nascent small nuclear RNAs (snRNAs) transcribed in CBs contribute to CB formation by assembling RNA-binding proteins, including frontotemporal dementia-related proteins, RNA-binding motif proteins, and heterogeneous nuclear ribonucleoproteins.

Summary: Background: Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes. Methods: We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients). Findings: The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169+ macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169+ macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022). Interpretation: We concluded that lymph nodes with breast cancer metastases have fewer CD169+ macrophages, which may be detrimental to the activity of anti-cancer immunity. Funding: JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.

Objectives: Parastomal hernia (PSH) is a common complication of colostomy; however, its risk factors remain poorly investigated. In this study, we examined the associations between sarcopenia, visceral and subcutaneous fat, and PSH in patients who underwent transperitoneal colostomy for colorectal cancer. Methods: This retrospective, single-center, cohort study included 60 patients who underwent laparoscopic or robot-assisted abdominoperineal resection or Hartmann's procedure for colorectal cancer between November 2010 and February 2022. Stoma creation was uniformly performed using the transperitoneal approach, and PSH was diagnosed via abdominal computed tomography (CT) at 1 year postoperatively. Visceral fat areas (VFAs) and subcutaneous fat areas (SFAs) were measured through preoperative CT images using an image analysis system. Risk factors for PSH were retrospectively analyzed. Results: PSH was diagnosed in 13 (21.7%) patients. In the univariate analysis, PSH was significantly associated with body mass index >22.3 kg/m2 (p=0.002), operation time >319 min (p=0.027), estimated blood loss >230 mL (p=0.008), postoperative complications (p=0.028), stoma diameter >18.6 mm (p=0.015), VFA >89.2 cm2 (p=0.005), and SFA >173.2 cm2 (p=0.001). Multivariate analyses confirmed that SFA >173.2 cm2 (odds ratio: 16.7, 95% confidence interval 1.29-217.2, p=0.031) was an independent risk factor for PSH. Conclusions: Subcutaneous fat area is significantly associated with the development of PSH after transperitoneal colostomy. Applying these insights could help to prevent PSH.

Abstract Background The origin of variation is of central interest in evolutionary biology. Maternal mRNAs govern early embryogenesis in many animal species, and we investigated the possibility that heterogeneity in maternal mRNA provisioning of eggs can be modulated by environmental stimuli. Results We employed two sibling species of the ascidian Ciona, called here types A and B, that are adapted to different temperature regimes and can be hybridized. Previous study showed that hybrids using type B eggs had higher susceptibility to thermal stress than hybrids using type A eggs. We conducted transcriptome analyses of multiple single eggs from crosses using eggs of the different species to compare the effects of maternal thermal stress on heterogeneity in egg provisioning, and followed the effects across generations. We found overall decreases of heterogeneity of egg maternal mRNAs associated with maternal thermal stress. When the eggs produced by the F1 AB generation were crossed with type B sperm and the progeny (‘ABB’ generation) reared unstressed until maturation, the overall heterogeneity of the eggs produced was greater in a clutch from an individual with a heat-stressed mother compared to one from a non-heat-stressed mother. By examining individual genes, we found no consistent overall effect of thermal stress on heterogeneity of expression in genes involved in developmental buffering. In contrast, heterogeneity of expression in signaling molecules was directly affected by thermal stress. Conclusions Due to the absence of batch replicates and variation in the number of reads obtained, our conclusions are very limited. However, contrary to the predictions of bet-hedging, the results suggest that maternal thermal stress at the embryo stage is associated with reduced heterogeneity of maternal mRNA provision in the eggs subsequently produced by the stressed individual, but there is then a large increase in heterogeneity in eggs of the next generation, although itself unstressed. Despite its limitations, our study presents a proof of concept, identifying a model system, experimental approach and analytical techniques capable of providing a significant advance in understanding the impact of maternal environment on developmental heterogeneity.

Abstract We evaluated the usefulness of a newly devised tumor marker index (TMI), namely, the geometric mean of normalized carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), in determining colorectal cancer (CRC) prognosis. This retrospective cohort study included 306 patients with stages I–III CRC who underwent elective laparoscopic resection between April 2010 and March 2020. Survival rates and risk factors of relapse-free survival (RFS) and cancer-specific survival (CSS) were analyzed using Kaplan–Meier curves and Cox proportional hazards model. High-TMI group (122 patients) had significantly lower rates (95% confidence interval [95% CI]) for 5-year RFS (89.7%, 83.9–93.5 vs. 65.8%, 56.3–73.8, p

Objective: The human adrenal cortex comprises three functionally and structurally distinct layers that produce layer-specific steroid hormones. With aging, the human adrenal cortex undergoes functional and structural alteration or “adrenal aging”, leading to the unbalanced production of steroid hormones. Given the marked species differences in adrenal biology, the underlying mechanisms of human adrenal aging have not been sufficiently studied. This study was designed to elucidate the mechanisms linking the functional and structural alterations of the human adrenal cortex. Methods: We conducted single-cell RNA sequencing and spatial transcriptomics analysis of the aged human adrenal cortex. Results: The data of this study suggest that the layer-specific alterations of multiple signaling pathways underlie the abnormal layered structure and layer-specific changes in steroidogenic cells. We also highlighted that macrophages mediate age-related adrenocortical cell inflammation and senescence. Conclusions: This study is the first detailed analysis of the aged human adrenal cortex at single-cell resolution and helps to elucidate the mechanism of human adrenal aging, thereby leading to a better understanding of the pathophysiology of age-related disorders associated with adrenal aging.

Abstract Background People living with HIV (PLWH) with chronic inflammation may have an increasing risk for coronavirus disease 2019 (COVID-19) severity; however, the impact of their gut microbiota on COVID-19 is not fully elucidated. Here, we analyzed the temporal changes in the gut microbiota composition of hospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected PLWH (PLWH-CoV) and their correlation with COVID-19 severity. Result The 16S rRNA analysis results using stool samples (along the timeline from disease onset) from 12 hospitalized PLWH-CoV, whose median CD4 + T cell count was 671 cells/µl, were compared to those of 19 healthy people and 25 PLWH. Bacterial diversity in PLWH-CoV is not significantly different from that of healthy people and SARS-CoV-2 non-infected PLWH, but a significant difference in the microbiota diversity was observed in the classification according to the disease severity. Immediately after the disease onset, remarkable changes were observed in the gut microbiota of PLWH-CoV, and the changing with a decrease in some short-chain fatty acid-producing bacteria and an increase in colitis-related pathobiont. In the second week after disease onset, relative amounts of specific bacteria distinguished between disease severity. One month after the disease onset, dysbiosis of the gut microbiota persisted, and the number of Enterobacteriaceae, mainly Escherichia-Shigella, which is potentially pathogenic, increased and were enriched in patients who developed post-acute sequelae of COVID-19 (PASC). Conclusion The changes in the gut microbiota associated with SARS-CoV-2 infection observed in PLWH in this study indicated a persistent decrease in SCFA-producing bacteria and an intestinal environment with an increase in opportunistic pathogens associated with enteritis. This report demonstrates that the intestinal environment in PLWH tends to show delayed improvement even after COVID-19 recovery, and highlights the importance of the dysbiosis associated with SARS-CoV-2 infection as a potential factor in the COVID-19 severity and the PASC in PLWH.

Abstract Tumor tissues consist of heterogeneous cells that originate from stem cells; however, their cell fate determination program remains incompletely understood. Using patient-derived organoids established from patients with advanced colorectal cancer (CRC), we evaluated the potential of olfactomedin 4 (OLFM4)+ stem cells to produce a bifurcated lineage of progenies with absorptive and secretory properties. In the early phases of organoid reconstruction, OLFM4+ cells preferentially gave rise to secretory cells. Additionally, we found that Paneth-like cells, which do not exist in the normal colon, were induced in response to Notch signaling inhibition. Video recordings of single OLFM4+ cells revealed that organoids containing Paneth-like cells were effectively propagated and that their selective ablation led to organoid collapse. In tumor tissues, Paneth-like cells were identified only in the region where tumor cells lost cell adhesion. These findings indicate that Paneth-like cells are directly produced by OLFM4+ stem cells and that their interaction contributes to tumor formation by providing niche factors. This study reveals the importance of the cell fate specification program for building a complete tumor cellular ecosystem, which might be targeted with novel therapeutics.

Abstract Human urine-derived cells (UDCs) are primary cultured cells originating from the upper urinary tract and are known to be multipotent. We previously developed MYOD1-transduced UDCs (MYOD1-UDCs) as a model recapitulating the pathogenesis of Duchenne muscular dystrophy (DMD) caused by a lack of dystrophin. MYOD1-UDCs also allow evaluation of the efficacy of exon skipping with antisense oligonucleotides. However, despite the introduction of MYOD1, some MYOD1-UDCs failed to form myotubes, possibly because of heterogeneity among UDCs. Here, we carried out single-cell RNA-sequencing analyses and revealed that CD90/Thy-1 was highly expressed in a limited subpopulation of UDCs with high myogenic potency. Furthermore, CD90-positive MYOD1-UDCs, but not CD90-negative cells, could form myotubes expressing high levels of myosin heavy chain and dystrophin. Notably, overexpression of CD90 in CD90-negative MYOD1-UDCs did not enhance myogenic differentiation, whereas CD90 suppression in CD90-positive UDCs led to decreased myotube formation and decreased myosin heavy chain expression. CD90 may thus contribute to the fusion of single-nucleated MYOD1-UDCs into myotubes but is not crucial for promoting the expression of late muscle regulatory factors. Finally, we confirmed that CD90-positive MYOD1-UDCs derived from patients with DMD were a valuable tool for obtaining a highly reproducible and stable evaluation of exon skipping using antisense oligonucleotide.

Abstract The mechanism underlying the development of tumors, particularly at early stages, still remains mostly elusive. Here, we report whole-genome long and short read sequencing analysis of 76 lung cancers, focusing on very early-stage lung adenocarcinomas such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. The obtained data is further integrated with bulk and spatial transcriptomic data and epigenomic data. These analyses reveal key events in lung carcinogenesis. Minimal somatic mutations in pivotal driver mutations and essential proliferative factors are the only detectable somatic mutations in the very early-stage of AIS. These initial events are followed by copy number changes and global DNA hypomethylation. Particularly, drastic changes are initiated at the later AIS stage, i.e., in Noguchi type B tumors, wherein cancer cells are exposed to the surrounding microenvironment. This study sheds light on the pathogenesis of lung adenocarcinoma from integrated pathological and molecular viewpoints.

Abstract Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic agents. However, most TNBCs acquire resistance to chemotherapy, thereby lowering the therapeutic outcome. In addition to oncogenic mutations in TNBC, microenvironment-induced mechanisms render chemoresistance more complex and robust in vivo. Here, we aimed to analyze whether depletion of Munc18-1 interacting protein 3 (Mint3), which activates hypoxia-inducible factor 1 (HIF-1) during normoxia, sensitizes TNBC to chemotherapy. We found that Mint3 promotes the chemoresistance of TNBC in vivo. Mint3 depletion did not affect the sensitivity of human TNBC cell lines to doxorubicin and paclitaxel in vitro but sensitized tumors of these cells to chemotherapy in vivo. Transcriptome analyses revealed that the Mint3–HIF-1 axis enhanced heat shock protein 70 (HSP70) expression in tumors of TNBC cells. Administering an HSP70 inhibitor enhanced the antitumor activity of doxorubicin in TNBC tumors, similar to Mint3 depletion. Mint3 expression was also correlated with HSP70 expression in human TNBC specimens. Mechanistically, Mint3 depletion induces glycolytic maladaptation to the tumor microenvironment in TNBC tumors, resulting in energy stress. This energy stress by Mint3 depletion inactivated heat shock factor 1 (HSF-1), the master regulator of HSP expression, via the AMP-activated protein kinase/mechanistic target of the rapamycin pathway following attenuated HSP70 expression. In conclusion, Mint3 is a unique regulator of TNBC chemoresistance in vivo via metabolic adaptation to the tumor microenvironment, and a combination of Mint3 inhibition and chemotherapy may be a good strategy for TNBC treatment.

Abstract Each tissue has a dominant set of functional proteins required to mediate tissue-specific functions. Epigenetic modifications, transcription, and translational efficiency control tissue-dominant protein production. However, the coordination of these regulatory mechanisms to achieve such tissue-specific protein production remains unclear. Here, we analyzed the DNA methylome, transcriptome, and proteome in mouse liver and skeletal muscle. We found that DNA hypomethylation at promoter regions is globally associated with liver-dominant or skeletal muscle-dominant functional protein production within each tissue, as well as with genes encoding proteins involved in ubiquitous functions in both tissues. Thus, genes encoding liver-dominant proteins, such as those involved in glycolysis or gluconeogenesis, the urea cycle, complement and coagulation systems, enzymes of tryptophan metabolism, and cytochrome P450-related metabolism, were hypomethylated in the liver, whereas those encoding-skeletal muscle-dominant proteins, such as those involved in sarcomere organization, were hypomethylated in the skeletal muscle. Thus, DNA hypomethylation characterizes genes encoding tissue-dominant functional proteins.

Abstract Metastasis from small‐cell lung cancer to the colon is very rare. A 74‐year‐old man without respiratory or abdominal symptoms underwent a follow‐up lower gastrointestinal endoscopy after a polypectomy. He was diagnosed with a 5 mm IIa non‐hyperplastic polyp in the cecum and underwent a cold snare polypectomy. The histopathological findings confirmed the diagnosis of small cell carcinoma. The tumor was positive in the deep margins of the submucosal layer. Subsequent systemic examination revealed a mass in the lower lobe of the left lung. Thus, the tumor in the cecum was determined to be a colorectal metastasis from primary small‐cell carcinoma of the lung. Metastasis to the colon was diagnosed as small‐cell lung cancer based on local positivity for thyroid transcription factor‐1 and morphologic and immunochemical features. To our best knowledge, this is the first report of colon metastasis from small cell carcinoma identified by endoscopic treatment.

Summary: Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.

Abstract Identification of factors that regulate chromatin condensation is important for understanding of gene regulation. High-mobility group AT-hook (HMGA) proteins 1 and 2 are abundant nonhistone chromatin proteins that play a role in many biological processes including tissue stem-progenitor cell regulation, but the nature of their protein function remains unclear. Here we show that HMGA2 mediates direct condensation of polynucleosomes and forms droplets with nucleosomes. Consistently, most endogenous HMGA2 localized to transposase 5– and DNase I–inaccessible chromatin regions, and its binding was mostly associated with gene repression, in mouse embryonic neocortical cells. The AT-hook 1 domain was necessary for chromatin condensation by HMGA2 in vitro and in cellulo, and an HMGA2 mutant lacking this domain was defective in the ability to maintain neuronal progenitors in vivo. Intrinsically disordered regions of other proteins could substitute for the AT-hook 1 domain in promoting this biological function of HMGA2. Taken together, HMGA2 may regulate neural cell fate by its chromatin condensation activity.

Abstract Aim Cachexia is associated with the morbidity and mortality of cancer patients. The cachexia index (CXI) is a novel biomarker of cachexia associated with the prognosis for certain cancers. This study analyzed the relationship between CXI with long‐term outcomes of gastric cancer patients. Methods We included 175 gastric cancer patients who underwent curative gastrectomy at our hospital between January 2011 and October 2019. The CXI was calculated using skeletal muscle index, serum albumin level, and neutrophil‐to‐lymphocyte ratio. The prognostic value of CXI was investigated by univariate and multivariate Cox hazard regression models adjusting for potential confounders. Results In the multivariate analyses, tumor location (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11–0.49; p

Abstract Radiotherapy (RT) plus immunotherapy is a promising modality; however, the therapeutic effects are insufficient, and the molecular mechanism requires clarification to further develop combination therapies. Here, we found that the RNA virus sensor pathway dominantly regulates the cellular immune response in NSCLC and ESCC cell lines. Notably, transposable elements (TEs), especially long terminal repeats (LTRs), functioned as key ligands for the RNA virus sensor RIG-I, and the mTOR–LTR–RIG-I axis induced the cellular immune response and dendritic cell and macrophage infiltration after irradiation. Moreover, RIG-I-dependent immune activation was observed in ESCC patient tissue. scRNA sequencing and spatial transcriptome analysis revealed that radiotherapy induced the expression of LTRs, and the RNA virus sensor pathway in immune and cancer cells; this pathway was also found to mediate tumour conversion to an immunological hot state. Here, we report the upstream and ligand of the RNA virus sensor pathway functions in irradiated cancer tissues.

Abstract The unremitting emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitates ongoing control measures. Given its rapid spread, the new Omicron subvariant BA.5 requires urgent characterization. Here, we comprehensively analyzed BA.5 with the other Omicron variants BA.1, BA.2, and ancestral B.1.1. Although in vitro growth kinetics of BA.5 was comparable among the Omicron subvariants, BA.5 was much more fusogenic than BA.1 and BA.2. Airway-on-a-chip analysis showed that, among Omicron subvariants, BA.5 had enhanced ability to disrupt the respiratory epithelial and endothelial barriers. Furthermore, in our hamster model, in vivo pathogenicity of BA.5 was slightly higher than that of the other Omicron variants and less than that of ancestral B.1.1. Notably, BA.5 gains efficient virus spread compared with BA.1 and BA.2, leading to prompt immune responses. Our findings suggest that BA.5 has low pathogenicity compared with the ancestral strain but enhanced virus spread /inflammation compared with earlier Omicron subvariants.

Abstract Background The mucosa serves as the first defence against pathogens and facilitates the surveillance and elimination of symbiotic bacteria by mucosal immunity. Recently, the mRNA vaccine against SARS-CoV-2 has been demonstrated to induce secretory antibodies in the oral and nasal cavities in addition to a systemic immune response. However, the mechanism of induced immune stimulation effect on mucosal immunity and commensal bacteria profile remains unclear. Methods Here, we longitudinally analysed the changing nasal microbiota and both systemic and nasal immune response upon SARS-CoV-2 mRNA vaccination, and evaluated how mRNA vaccination influenced nasal microbiota in 18 healthy participants who had received the third BNT162b. Results The nasal S-RBD IgG level correlated significantly with plasma IgG levels until 1 month and the levels were sustained for 3 months post-vaccination. In contrast, nasal S-RBD IgA induction peaked at 1 month, albeit slightly, and correlated only with plasma IgA, but the induction level decreased markedly at 3 months post-vaccination. 16 S rRNA sequencing of the nasal microbiota post-vaccination revealed not an overall change, but a decrease in certain opportunistic bacteria, mainly Fusobacterium. The decrease in these bacteria was more pronounced in those who exhibited nasal S-RBD IgA induction, and those with higher S-RBD IgA induction had lower relative amounts of potentially pathogenic bacteria such as Pseudomonas pre-vaccination. In addition, plasma and mucosal S-RBD IgG levels correlated with decreased commensal pathogens such as Finegoldia. Conclusions These findings suggest that the third dose of SARS-CoV-2 mRNA vaccination induced S-RBD antibodies in the nasal mucosa and may have stimulated mucosal immunity against opportunistic bacterial pathogens. This effect, albeit probably secondary, may be considered one of the benefits of mRNA vaccination. Furthermore, our data suggest that a cooperative function of mucosal and systemic immunity in the reduction of bacteria and provides a better understanding of the symbiotic relationship between the host and bacteria in the nasal mucosa.

Abstract Heterosis contributes greatly to the worldwide agricultural yield. However, the molecular mechanism underlying heterosis remains unclear. This study took advantage of Arabidopsis intraspecific hybrids to identify heterosis-related metabolites. Forty-six intraspecific hybrids were used to examine parental effects on seed area and germination time. The degree of heterosis was evaluated based on biomass: combinations showing high heterosis of F1 hybrids exhibited a biomass increase from 6.1 to 44% over the better parent value (BPV), whereas that of the low- and no-heterosis hybrids ranged from − 19.8 to 9.8% over the BPV. Metabolomics analyses of F1 hybrids with high heterosis and those with low one suggested that changes in TCA cycle intermediates are key factors that control growth. Notably, higher fumarate/malate ratios were observed in the high heterosis F1 hybrids, suggesting they provide metabolic support associated with the increased biomass. These hybrids may produce more energy-intensive biomass by speeding up the efficiency of TCA fluxes. However, the expression levels of TCA-process-related genes in F1 hybrids were not associated with the intensity of heterosis, suggesting that the post-transcriptional or post-translational regulation of these genes may affect the productivity of the intermediates in the TCA cycle.

This paper builds a model of dynamic tournaments under incomplete contract situations to analyze how the government, as a national development strategy, induces incentives or forms of competition between multiple companies (between state-owned enterprises (SOEs), between private-owned enterprises (POEs), or between SOEs and POEs) in the long-run. This paper can be considered as a model analysis of “controlled competition” under “State Capitalism”, in which the government participates in the market as an active player, such as in China, Singapore, and in a broad sense, in Japanese Industrial Policy in the past. In addition to clarifying the incentive mechanism embedded in this model, we also examine the problems and areas for improvement from the perspective of incentive design. In particular, in the long-term competition between two heterogeneous companies, it would be a beneficial policy for the government if the feedback effect could be mitigated by handicapping the winner and favoring the loser, thereby restoring the competitive pressure that had decreased. At the same time, as excessive competition-inhibiting discriminatory prizes (“Cronyism”) greatly impede investment incentives for both companies, these can be viewed as a ''government failure'', and thus the institution should be redesigned to correct such obstacles, thereby maintaining appropriate competitive pressures.

[This corrects the article DOI: 10.1371/journal.pone.0187703.].

Although spinach is predominantly dioecious, monoecious plants with varying proportions of female and male flowers are also present. Recently, monoecious inbred lines with highly female and male conditions have been preferentially used as parents for F1-hybrids, rather than dioecious lines. Accordingly, identifying the loci for monoecism is an important issue for spinach breeding. We here used long-read sequencing and Hi-C technology to construct SOL_r2.0_pseudomolecule, a set of six pseudomolecules of spinach chromosomes (total length: 879.2 Mb; BUSCO complete 97.0%) that are longer and more genetically complete than our previous version of pseudomolecules (688.0 Mb; 81.5%). Three QTLs, qFem2.1, qFem3.1, and qFem6.1, responsible for monoecism were mapped to SOL_r2.0_pseudomolecule. qFem3.1 had the highest LOD score and corresponded to the M locus, which was previously identified as a determinant of monoecious expression, by genetic analysis of progeny from female and monoecious plants. The other QTLs were shown to modulate the ratio of female to male flowers in monoecious plants harboring a dominant allele of the M gene. Our findings will enable breeders to efficiently produce highly female- and male-monoecious parental lines for F1-hybrids by pyramiding the three QTLs. Through fine-mapping, we narrowed the candidate region for the M locus to a 19.5 kb interval containing three protein-coding genes and one long non-coding RNA gene. Among them, only RADIALIS-like-2a showed a higher expression in the reproductive organs, suggesting that it might play a role in reproductive organogenesis. However, there is no evidence that it is involved in the regulation of stamen and pistil initiation, which are directly related to the floral sex differentiation system in spinach. Given that auxin is involved in reproductive organ formation in many plant species, genes related to auxin transport/response, in addition to floral organ formation, were identified as candidates for regulators of floral sex-differentiation from qFem2.1 and qFem6.1.

Summary: EG.5.1 is a subvariant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB variant that is rapidly increasing in prevalence worldwide. However, the pathogenicity, transmissibility, and immune evasion properties of isolates of EG.5.1 are largely unknown. Here, we show that there are no obvious differences in growth ability and pathogenicity between EG.5.1 and XBB.1.5 in hamsters. We also demonstrate that, like XBB.1.5, EG.5.1 is transmitted more efficiently between hamsters compared to its predecessor, BA.2. In contrast, unlike XBB.1.5, we detect EG.5.1 in the lungs of four of six exposed hamsters, suggesting that the virus properties of EG.5.1 are different from those of XBB.1.5. Finally, we find that the neutralizing activity of plasma from convalescent individuals against EG.5.1 was slightly, but significantly, lower than that against XBB.1.5 or XBB.1.9.2. Our data suggest that the different virus properties after transmission and the altered antigenicity of EG.5.1 may be driving its increasing prevalence over XBB.1.5 in humans.

Abscisic acid (ABA)-mediated abiotic stress tolerance causes plant growth inhibition. Under such stress conditions, some mosses generate de novo stress-resistant stem cells, also called brood cells or brachycytes, that do not exist under normal conditions. However, the cell physiological basis of the growth inhibition and the stem cell formation is not well understood. Here, we show that the ABA-induced growth inhibition of the moss Physcomitrium patens apical protonemal cells (protonemal stem cells) is mediated through a shift from asymmetric to symmetric cell division. This change of the cell division mode, and consequently change of stem cell activity, is substantiated by dampening cell polarity and cell proliferative activity through the altered distribution of cytoskeletal elements, the mitotic spindle and the vacuole, which results in the production of stress-resistant stem cells. Alteration of the cell physiological data is supported by the results of RNAseq analysis indicating rapid changes in both cell polarity and cell cycle regulation, while long-term treatments with ABA for 5 to 10 days impact mainly the transcriptional and translational regulation. The regulation of cell polarity and cell cycle genes suggests growth arrest mediated by small GTPases (ROPs) and their guanine exchange factors (ROPGEFs) and by cyclin and cyclin-dependent-kinase complex, respectively. Our data suggest that a tradeoff relationship between growth ability and abiotic stress response in the moss is substantiated by ABA signaling to suppress cell polarity and asymmetric cell growth and may play a pivotal role in stem cell fate conversion to newly produced stress-resistant stem cells.

Abstract Interactions between various molecular species in biological phenomena give rise to numerous networks. The investigation of these networks, including their statistical and biochemical interactions, supports a deeper understanding of biological phenomena. The clustering of nodes associated with molecular species and enrichment analysis is frequently applied to examine the biological significance of such network structures. However, these methods focus on delineating the function of a node. As such, in-depth investigations of the edges, which are the connections between the nodes, are rarely explored. In the current study, we aimed to investigate the functions of the edges rather than the nodes. To accomplish this, for each network, we categorized the edges and defined the edge type based on their biological annotations. Subsequently, we used the edge type to compare the network structures of the metabolome and transcriptome in the livers of healthy (wild-type) and obese (ob/ob) mice following oral glucose administration (OGTT). The findings demonstrate that the edge type can facilitate the characterization of the state of a network structure, thereby reducing the information available through datasets containing the OGTT response in the metabolome and transcriptome.

The most common site of traditional serrated adenomas (TSA) is the area from the left colon to the rectum; however, there are few reports on TSA in the small intestine. Herein, we report a case of TSA of the ileum with intussusception that was diagnosed and successfully treated with laparoscopic bowel resection. The patient was a 29-year-old female with the chief complaint of recurrent abdominal pain and vomiting. Contrast-enhanced computed tomography showed a mass in the ileum and intussusception with the mass as the lead point. The patient was diagnosed with intussusception secondary to a small intestinal tumor. Due to the difficulty in endoscopic treatment resulting from the localization of the lesion, elective laparoscopic surgery was planned. Intra-abdominal examination revealed intussusception of the small intestine in the pelvic ileum, and an elastic soft mass 400 cm from the ligament of Treitz was identified at the lead point of intussusception. Partial laparoscopic resection of the small intestine was performed, with an operation time of 81 min, and a small amount of bleeding. The pathological diagnosis was TSA of the ileum, and the patient’s postoperative course was good, with no complications. Seven months after the surgery, no recurrence of symptoms was observed. Therefore, from our case of TSA of the ileum with intussusception that was successfully treated with laparoscopic bowel resection, we conclude that when intussusception of the small intestine occurs, TSA of the ileum with malignant potential is possible, and early diagnosis by resection should be considered.

Abstract SARS-CoV-2 continues to spread worldwide. Patients with COVID-19 show distinct clinical symptoms. Although many studies have reported various causes for the diversity of symptoms, the underlying mechanisms are not fully understood. Peripheral blood mononuclear cells from COVID-19 patients were collected longitudinally, and single-cell transcriptome and T cell receptor repertoire analysis was performed. Comparison of molecular features and patients’ clinical information revealed that the proportions of cells present, and gene expression profiles differed significantly between mild and severe cases; although even among severe cases, substantial differences were observed among the patients. In one severely-infected elderly patient, an effective antibody response seemed to have failed, which may have caused prolonged viral clearance. Naïve T cell depletion, low T cell receptor repertoire diversity, and aberrant hyperactivation of most immune cell subsets were observed during the acute phase in this patient. Through this study, we provided a better understanding of the diversity of immune landscapes and responses. The information obtained from this study can help medical professionals develop personalized optimal clinical treatment strategies for COVID-19.

A meta-analysis suggested that marine n-3 polyunsaturated fatty acids (PUFAs), e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), might reduce cancer mortality. However, a randomized clinical trial of marine n-3 PUFA and vitamin D supplementation failed to verify this benefit. This study aimed to investigate the potential interaction between vitamin D supplementation and serum EPA and DHA levels. This post hoc analysis of the AMATERASU trial (UMIN000001977), a randomized controlled trial (RCT), included 302 patients with digestive tract cancers divided into two subgroups stratified by median serum levels of EPA + DHA into higher and lower halves. The 5-year relapse-free survival (RFS) rate was significantly higher in the higher half (80.9%) than the lower half (67.8%; hazard ratio (HR), 2.15; 95% CI, 1.29–3.59). In the patients in the lower EPA + DHA group, the 5-year RFS was significantly higher in the vitamin D (74.9%) than the placebo group (49.9%; HR, 0.43; 95% CI, 0.24–0.78). Conversely, vitamin D had no effect in the higher half, suggesting that vitamin D supplementation only had a significant interactive effect on RFS in the lower half (p for interaction = 0.03). These results suggest that vitamin D supplementation may reduce the risk of relapse or death by interacting with marine n-3 PUFAs.

Nearly all cervical cancer cases are caused by infection with high-risk human papillomavirus (HR-HPV) types. The mechanism of cervical cell transformation is related to the powerful action of viral oncoproteins and cellular gene alterations. Transcriptomic data from cervical cancer and normal cervical cells were utilized to identify upregulated genes and their associated pathways. The laminin subunit beta-3 (LAMB3) mRNAwas overexpressed in cervical cancer and was chosen for functional analysis. The LAMB3 was predominantly expressed in the extracellular region and the plasma membrane, which play a role in protein binding and cell adhesion molecule binding, leading to cell migration and tissue development. LAMB3 was found to be implicated in the pathway in cancer and the PI3K-AKT signaling pathway. LAMB3 knockdown decreased cell migration, invasion, anchorage-dependent and anchorage-independent cell growth and increased the number of apoptotic cells. These effects were linked to a decrease in protein levels involved in the PI3K-AKT signaling pathway and an increase in p53 protein. This study demonstrated that LAMB3 could promote cervical cancer cell migration, invasion and survival.

Abstract The detection and sequencing of the mutated ctDNA is one of the irreplaceable clinical measures in the postoperative management of colorectal cancer (CRC) cases. However, we are curious to comprehend the essential traits of mutated genes comprising metastatic sites out of whole mutated genes in primary sites. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes on the panel showed abundant expression but no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors.

Spatial transcriptomics reveal how distant cancer affect gene expression and zonation in mouse liver in a manner that differs between biological pathways.

Introduction: Activation of skeletal progenitors upon tissue injury and the subsequent cell fate specification are tightly coordinated in the bone repair process. Although known osteoimmunological signaling networks play important roles in the microenvironment of the bone defect sites, the molecular mechanism underlying the bone repair process has not been fully understood. Methods: To better understand the behavior of the skeletal progenitors and the heterogeneity of the cells during bone repair at the microenvironmental level, we performed a combinatorial analysis consisting of lineage tracing for skeletal progenitors using the Sox9-CreERT2;R26RtdTomato mouse line followed by single-cell RNA sequencing (scRNA-seq) analysis using a mouse model of calvarial bone repair. To identify a therapeutic target for bone regeneration, further computational analysis was performed focusing on the identification of the cell–cell interactions, followed by pharmacological assessments with a critical-size calvarial bone defect mouse model. Results: Lineage tracing analysis showed that skeletal progenitors marked by Sox9 were activated upon bone injury and contributed to bone repair by differentiating into osteoblasts. The scRNA-seq analysis characterized heterogeneous cell populations at the bone defect sites; the computational analysis predicted a bifurcated lineage from skeletal progenitors toward osteogenic and adipogenic lineages. Chemokine C–C motif ligand 9 (Ccl9) was identified as a signaling molecule that regulates bone regeneration in the mouse model, possibly through the regulation of adipogenic differentiation at the bone defect site. Conclusion: Multipotential skeletal progenitors and the direction of the cell differentiation were characterized at single cell resolution in a mouse bone repair model. The Ccl9 signaling pathway may be a key factor directing osteogenesis from the progenitors in the model and may be a therapeutic target for bone regeneration.

Abstract Background Enterocutaneous fistula after removal of the jejunostomy tube leads to multiple problems, such as cosmetic problems, decreased quality of life, electrolyte imbalances, infectious complications, and increased medical costs. However, the risk factors for refractory enterocutaneous fistula (REF) after button jejunostomy removal remain unclear. Therefore, in this study, we assessed the risk factors for REF after button jejunostomy removal in patients with oesophageal cancer and reported the surgical outcomes of the novel extraperitoneal approach (EPA) for REF closure. Methods This retrospective cohort study included 47 patients who underwent button jejunostomy removal after oesophagectomy for oesophageal cancer. We assessed the risk factors for REF in these patients and reported the surgical outcomes of the novel EPA for REF closure at the International University of Health and Welfare Hospital between March 2013 and October 2021. The primary endpoint was defined as the occurrence of REF after removal of the button jejunostomy, which was assessed using a maintained database. The risk factors and outcomes of the EPA for REF closure were retrospectively analysed. Results REFs occurred in 15 (31.9%) patients. In the univariate analysis, REF was significantly more common in patients with albumin level 12 months for button jejunostomy removal (p = 0.003), and with a fistula 12 months for button jejunostomy removal (odds ratio [OR]: 7.15; 95% confidence interval [CI]: 1.38–36.8; p = 0.019) and fistula 12 months for button jejunostomy removal and fistula

In this work, Yoshinaga et al. use functional CRISPR screens and in vivo analyses to show that an RNA methyltransferase METTL16 and MTR4-nuclear exosome play an essential role in maintaining erythropoiesis and regulating DNA repair in erythroblasts.

Abstract When biologically interpretation of the data obtained from the single-cell RNA sequencing (scRNA-seq) analysis is attempted, additional information on the location of the single cells, behavior of the surrounding cells, and the microenvironment they generate, would be very important. We developed an inexpensive, high throughput application while preserving spatial organization, named “semibulk RNA-seq” (sbRNA-seq). We utilized a microfluidic device specifically designed for the experiments to encapsulate both a barcoded bead and a cell aggregate (a semibulk) into a single droplet. Using sbRNA-seq, we firstly analyzed mouse kidney specimens. In the mouse model, we could associate the pathological information with the gene expression information. We validated the results using spatial transcriptome analysis and found them highly consistent. When we applied the sbRNA-seq analysis to the human breast cancer specimens, we identified spatial interactions between a particular population of immune cells and that of cancer-associated fibroblast cells, which were not precisely represented solely by the single-cell analysis. Semibulk analysis may provide a convenient and versatile method, compared to a standard spatial transcriptome sequencing platform, to associate spatial information with transcriptome information.

Abstract Sarcopenia affects the swallowing and chewing muscles, such as the masseter muscle. However, the significance of masseter muscle loss in pneumonia remains unclear. We investigated the effects of masseter muscle sarcopenia (MMS) on postoperative pneumonia in patients with esophageal cancer. In this retrospective cohort study, we analyzed the data of 86 patients who underwent esophagectomy for stage I–III esophageal cancer at our hospital between March 2013 and October 2021. The primary endpoint was postoperative pneumonia within 3 months of surgery. MMS was defined as a (1) masseter muscle index (MMI) that was less than the sex-specific MMI cutoff values, and (2) sarcopenia diagnosed using the L3-psoas muscle index (L3-PMI). Postoperative pneumonia was noted in 27 (31.3%) patients. In multivariate analysis, FEV1.0

Abstract Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Adult neural stem cells (NSCs) in the mouse subventricular zone (SVZ) serve as a lifelong reservoir for newborn olfactory bulb neurons. Recent studies have identified a slowly dividing subpopulation of embryonic neural stem-progenitor cells (NPCs) as the embryonic origin of adult NSCs. Yet, little is known about how these slowly dividing embryonic NPCs are maintained until adulthood while other NPCs are extinguished by the completion of brain development. The extracellular matrix (ECM) is an essential component of stem cell niches and thus a key determinant of stem cell fate. Here we investigated tissue inhibitors of metalloproteinases (TIMPs)—regulators of ECM remodeling—for their potential roles in the establishment of adult NSCs. We found that Timp2, Timp3, and Timp4 were expressed at high levels in slowly dividing NPCs compared to rapidly dividing NPCs. Deletion of TIMP3 reduced the number of adult NSCs and neuroblasts in the lateral SVZ. In addition, overexpression of TIMP3 in the embryonic NPCs suppressed neuronal differentiation and upregulated the expression levels of Notch signaling relating genes. These results thus suggest that TIMP3 keeps the undifferentiated state of embryonic NPCs, leading to the establishment and maintenance of adult NSCs.

Heterosigma akashiwo is a eukaryotic, cosmopolitan, and unicellular alga (class: Raphidophyceae), and produces fish-killing blooms. There is a substantial scientific and practical interest in its ecophysiological characteristics that determine bloom dynamics and its adaptation to broad climate zones. A well-annotated genomic/genetic sequence information enables researchers to characterize organisms using modern molecular technology. In the present study, we conducted H. akashiwo RNA sequencing, a de novo transcriptome assembly of 84,693,530 high-quality deduplicated short-read sequences.Obtained RNA reads were assembled by Trinity assembler and 144,777 contigs were identified with N50 values of 1085. Total 60,877 open reading frames with the length of 150 bp or greater were predicted. For further analyses, top Gene Ontology terms, pfam hits, and blast hits were annotated for all the predicted genes. The raw data were deposited in the NCBI SRA database (BioProject PRJDB6241 and PRJDB15108), and the assemblies are available in NCBI TSA database (ICRV01). The annotation information can be obtained in Dryad and can be accessed via doi: 10.5061/dryad.m0cfxpp56.

An in vivo transcriptomic analysis of Staphylococcus aureus infection in mice provides further insight into how this pathogen responds to changes in the host environment over time.

Abstract Bacterial colonization in the rumen of pre-weaned ruminants is important for their growth and post-weaning productivity. This study evaluated the effects of oral fiber administration during the pre-weaning period on the development of rumen microbiota from pre-weaning to the first lactation period. Twenty female calves were assigned to control and treatment groups (n = 10 each). Animals in both groups were reared using a standard feeding program throughout the experiment, except for oral fiber administration (50–100 g/day/animal) from 3 days of age until weaning for the treatment group. Rumen content was collected during the pre-weaning period, growing period, and after parturition. Amplicon sequencing of the 16S rRNA gene revealed that oral fiber administration facilitated the early establishment of mature rumen microbiota, including a relatively higher abundance of Prevotella, Shuttleworthia, Mitsuokella, and Selenomonas. The difference in the rumen microbial composition between the dietary groups was observed even 21 days after parturition, with a significantly higher average milk yield in the first 30 days of lactation. Therefore, oral fiber administration to calves during the pre-weaning period altered rumen microbiota, and its effect might be long-lasting until the first parturition.