Search

ABSTRACT Staphylococcus epidermidis, a common commensal bacterium found on human skin, can cause infections in clinical settings, and the presence of antibiotic resistance genes (ARGs) impedes the treatment of S. epidermidis infections. However, studies characterizing the ARGs in S. epidermidis with regard to genomic and ecological diversities are limited. Thus, we performed a comprehensive and comparative analysis of 405 high-quality S. epidermidis genomes, including those of 35 environmental isolates from the Han River, to investigate the genomic diversity of antibiotic resistance in this pathogen. Comparative genomic analysis revealed the prevalence of ARGs in S. epidermidis genomes associated with multi-locus sequence types. The genes encoding dihydrofolate reductase (dfrC) and multidrug efflux pump (norA) were genome-wide core ARGs. β-Lactam class ARGs were also highly prevalent in the S. epidermidis genomes, which was consistent with the resistance phenotype observed in river isolates. Furthermore, we identified chloramphenicol acetyltransferase genes (cat) in the plasmid-like sequences of the six river isolates, which have not been reported previously in S. epidermidis genomes. These genes were identical to those harbored by the Enterococcus faecium plasmids and associated with the insertion sequence 6 family transposases, homologous to those found in Staphylococcus aureus plasmids, suggesting the possibility of horizontal gene transfer between these Gram-positive pathogens. Comparison of the ARG and virulence factor profiles between S. epidermidis and S. aureus genomes revealed that these two species were clearly distinguished, suggesting genomic demarcation despite ecological overlap. Our findings provide a comprehensive understanding of the genomic diversity of antibiotic resistance in S. epidermidis.IMPORTANCEA comprehensive understanding of the antibiotic resistance gene (ARG) profiles of the skin commensal bacterium and opportunistic pathogen Staphylococcus epidermidis needs to be documented from a genomic point of view. Our study encompasses a comparative analysis of entire S. epidermidis genomes from various habitats, including those of 35 environmental isolates from the Han River sequenced in this study. Our results shed light on the distribution and diversity of ARGs within different S. epidermidis multi-locus sequence types, providing valuable insights into the ecological and genetic factors associated with antibiotic resistance. A comparison between S. epidermidis and Staphylococcus aureus revealed marked differences in ARG and virulence factor profiles, despite their overlapping ecological niches.

Abstract The human epidermal growth factor receptor-2 (HER2) enriched subtype of breast cancer is associated with early recurrence, mostly within 5 years. However, anti-HER2 therapies have improved outcomes and their benefits persist in the long term. This study aimed to determine predictive factors for late survival in patients with HER2-positive breast cancer. We analyzed 20,672 patients with HER2-positive stage I–III breast cancer. The patients were divided into two groups based on a follow-up period of 60 months. The multivariate analysis of factors associated with poor overall survival included old age, advanced pathologic tumor size stage (pT), advanced pathologic regional lymph node stage (pN), high histological grade, presence of lymphatic and vascular invasion, and HR-negative status within 60 months. In the breast cancer-specific survival (BCSS) of the > 60 months follow-up group, the hazard ratios (HRa) based on pN-negative were 3.038, 3.722, and 4.877 in pN1 (p = 0.001), pN2 (p

Abstract Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of taxane treatment and can significantly affect patient quality of life. Currently, there are no effective treatments to alleviate symptoms of CIPN; thus, starting with prevention steps in high-risk patients is considered advantageous. However, for these prevention steps to be applicable to all patients, their side effects or accompanying discomforts should be minimal, and the intervention cost-effective. Compression therapy can be considered a prevention intervention, and using surgical gloves is feasible and cost-effective (approximately $0.6 per pair). Although previous studies on compression therapy using surgical gloves have reported decreased incidence of PN, these studies were non-randomized, limited to nab-paclitaxel treatment, and involved the use of small gloves, which may have caused discomfort. Therefore, this study aimed to assess the preventive effects of compression therapy using normal-sized surgical gloves on CIPN in patients treated with paclitaxel. Methods This clinical trial is designed to evaluate the preventive effects of compression therapy using surgical gloves on CIPN in women with stage II–III breast cancer who received paclitaxel chemotherapy for at least 12 weeks. This multicenter, randomized-controlled, open-label study will be conducted in six academic hospitals. Patients with medication or a medical history related to neuropathy or hand disease will be excluded. The primary outcome will be the preventive effect of compression therapy using surgical gloves, measured based on changes in the neurotoxicity component of the Functional Assessment of Cancer Therapy-Taxane questionnaire. Furthermore, we will assess the National Cancer Institute’s Common Terminology Criteria for Adverse Events grade of CIPN after 6 months. Notably, the estimated sample size, based on a p-value

During Gq protein activation, the separated Gαq-GTP forms a stable complex with the ligand-activated hM3R and PLCβ. Here the authors demonstrate that a single M3 receptor FRET probe can display the real-time conformational dynamics of innate receptor by the downstream Gq protein cycle.

Summary: Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer’s disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

Abstract Background The increasing prevalence of resistance against the last-resort antibiotic colistin is a significant threat to global public health. Here, we discovered a novel colistin resistance mechanism via enzymatic inactivation of the drug and proposed its clinical importance in microbial communities during polymicrobial infections. Results A bacterial strain of the Gram-negative opportunistic pathogen Stenotrophomonas maltophilia capable of degrading colistin and exhibiting a high-level colistin resistance was isolated from the soil environment. A colistin-degrading protease (Cdp) was identified in this strain, and its contribution to colistin resistance was demonstrated by growth inhibition experiments using knock-out (Δcdp) and complemented (Δcdp::cdp) mutants. Coculture and coinfection experiments revealed that S. maltophilia carrying the cdp gene could inactivate colistin and protect otherwise susceptible Pseudomonas aeruginosa, which may seriously affect the clinical efficacy of the drug for the treatment of cystic fibrosis patients with polymicrobial infection. Conclusions Our results suggest that Cdp should be recognized as a colistin resistance determinant that confers collective resistance at the microbial community level. Our study will provide vital information for successful clinical outcomes during the treatment of complex polymicrobial infections, particularly including S. maltophilia and other colistin-susceptible Gram-negative pathogens such as P. aeruginosa. Video abstract

Abstract Background There is an increasing interest in HER2-low breast cancer with promising data from clinical trials using novel anti-HER2 antibody–drug conjugates. We explored the differences in clinicopathological characteristics and survival outcomes between HER2-low and HER2-IHC 0 breast cancer. Methods Using nationwide data from the Korean Breast Cancer Registry between 2006 and 2011, 30,491 patients with stages I to III breast cancer were included in the analysis: 9,506 (31.2%) in the HER2-low group and 20,985 (68.8%) in the HER2-IHC 0 group. Kaplan–Meier and Cox proportional hazards regression survival analysis were used to compare breast cancer-specific survival between the two groups. Results HER2-low breast cancer was more frequent in patients with hormone receptor-positive breast cancer than in those with triple-negative breast cancer. In patients with hormone receptor-positive breast cancer, HER2-low breast cancer was associated with fewer T4 tumors, higher histological grade, and a negative lymphatic invasion. In patients with triple-negative breast cancer, HER2-low breast cancer was associated with a high lymph node ratio and positive lymphatic invasion. HER2-low breast cancer was significantly associated with a lower Ki-67 labeling index. No significant difference was observed in overall survival between the two groups. HER2-low breast cancer showed significantly better breast cancer-specific survival than HER2-IHC 0 breast cancer, regardless of the hormone receptor status. In multivariate analysis, the impact of low HER2 expression on breast cancer-specific survival was significant only in triple-negative breast cancer (HRs, 0.68; 95% CI, 0.49–0.93; P = 0.019). Conclusions These findings suggest that the biology and clinical impact of low HER2 expression can differ according to the hormone receptor status and support the need for further investigation on the understanding of the biology of HER2-low breast cancer.

Summary: Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRASG12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRASG12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRASG12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRASG12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRASG12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.

Abstract Clozapine is thought to induce obsessive compulsive symptoms (OCS) in schizophrenic patients. However, because OCS are often comorbid with schizophrenia regardless of clozapine treatment, it remains unclear whether clozapine can generate OCS de novo. Thus, it has been difficult to establish a causal link between clozapine and OCS in human studies. To address this question, we asked whether chronic treatment with clozapine can induce obsessive compulsive disorder (OCD)-like behavior in mice. We injected mice with long-term continuous release pellets embedded with clozapine four times at 60-day intervals and then monitored the mice for signs of OCD-like behavior up to 40 wk. of age. We found clozapine increases grooming behavior as early as 30 wk. of age. We also investigated the effect clozapine on grooming behavior in Sapap3 knockout (KO) mice, which are a well-known animal model of OCD. In Sapap3 heterozygous KO mice, clozapine increases grooming behavior much earlier than in wild-type mice, suggesting a clozapine-OCD gene interaction. Fluoxetine, which is often used in the treatment of OCS and OCD, reduced the grooming behavior induced by clozapine. These data demonstrate that chronic clozapine treatment can generate OCD-like behavior in mice and support the hypothesis that clozapine produces de novo OCS regardless of schizophrenia status.

Depression is accompanied by neuronal atrophy and decreased neuroplasticity. Leucine-rich glioma-inactivated protein 1 (LGI1), a metastasis suppressor, plays an important role in the development of CNS synapses. We found that LGI1 expression was reduced in the hippocampi of mice that underwent chronic unpredictable stress (CUS), and could be rescued by the antidepressant, fluoxetine. Recombinant soluble neuritin, an endogenous protein previously implicated in antidepressant-like behaviors, elevated hippocampal LGI1 expression in a manner dependent on histone deacetylase 5 (HDAC5) phosphorylation. Accordingly, Nrn1 flox/flox;Pomc-cre (Nrn1 cOE) mice, which conditionally overexpress neuritin, displayed increases in hippocampal LGI1 level under CUS and exhibited resilience to CUS that were blocked by hippocampal depletion of LGI1. Interestingly, neuritin-mediated LGI1 expression was inhibited by HNMPA-(AM)3, an insulin receptor inhibitor, as was neuritin-mediated HDAC5 phosphorylation. We thus establish hippocampal LGI1 as an effector of neurite outgrowth and stress resilience, and suggest that HDAC5-LGI1 plays a critical role in ameliorating pathological depression.

Abstract Background The impact of human activities on the environmental resistome has been documented in many studies, but there remains the controversial question of whether the increased antibiotic resistance observed in anthropogenically impacted environments is just a result of contamination by resistant fecal microbes or is mediated by indigenous environmental organisms. Here, to determine exactly how anthropogenic influences shape the environmental resistome, we resolved the microbiome, resistome, and mobilome of the planktonic microbial communities along a single river, the Han, which spans a gradient of human activities. Results The bloom of antibiotic resistance genes (ARGs) was evident in the downstream regions and distinct successional dynamics of the river resistome occurred across the spatial continuum. We identified a number of widespread ARG sequences shared between the river, human gut, and pathogenic bacteria. These human-related ARGs were largely associated with mobile genetic elements rather than particular gut taxa and mainly responsible for anthropogenically driven bloom of the downstream river resistome. Furthermore, both sequence- and phenotype-based analyses revealed environmental relatives of clinically important proteobacteria as major carriers of these ARGs. Conclusions Our results demonstrate a more nuanced view of the impact of anthropogenic activities on the river resistome: fecal contamination is present and allows the transmission of ARGs to the environmental resistome, but these mobile genes rather than resistant fecal bacteria proliferate in environmental relatives of their original hosts. Video abstract.

Summary: Stress causes changes in neurotransmission in the brain, thereby influencing stress-induced behaviors. However, it is unclear how neurotransmission systems orchestrate stress responses at the molecular and cellular levels. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel involved mainly in pain sensation, affects mood and neuroplasticity in the brain, where its role is poorly understood. Here, we show that Trpv1-deficient (Trpv1−/−) mice are more stress resilient than control mice after chronic unpredictable stress. We also found that glucocorticoid receptor (GR)-mediated histone deacetylase 2 (HDAC) 2 expression and activity are reduced in the Trpv1−/− mice and that HDAC2-regulated, cell-cycle- and neuroplasticity-related molecules are altered. Hippocampal knockdown of TRPV1 had similar effects, and its behavioral effects were blocked by HDAC2 overexpression. Collectively, our findings indicate that HDAC2 is a molecular link between TRPV1 activity and stress responses. : Wang et al. show that Trpv1−/− mice are more stress resilient than control mice following chronic unpredictable stress and these are associated with reduced histone deacetylase (HDAC) 2 expression and activity. As a consequence, HDAC2-regulated, cell-cycle- and neuroplasticity-related molecules are altered in Trpv1−/− mice. Their findings indicate that HDAC2 is a molecular link between TRPV1 activity and stress responses. Keywords: TRPV1, behavior, depression, stress, HDAC2, GR, hippocampus

BACKGROUND:We aimed to evaluate the expression of APOBEC3A (A3A), 3B (A3B) mRNA, and germline APOBEC3A/B deletion polymorphism in patients with breast cancers and to investigate the correlation between their expressions and clinicopathological characteristics. METHODS:RNA and DNA samples were extracted from 138 breast cancer tissues and adjacent normal breast tissues. The levels of A3A and A3B mRNA transcripts were determined using quantitative real-time polymerase chain reaction. Insertion and deletion PCR assays were performed to detect the A3B deletion allele. The serum concentrations of soluble programmed death-ligand 1 (sPD-L1) and interferon gamma were determined using enzyme-linked immunosorbent assays. RESULTS:A3B mRNA expression levels were significantly higher in triple-negative breast cancers compared to hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancers. Older age of the patient and high ki-67 expression were associated with increased expression levels of A3A and A3B mRNA. Advanced tumor stage, presence of lymph node involvement, and high histological grade were associated with increased expression levels of A3A mRNA. The APOBEC3A/B deletion allele was found in 77 (55.8%) patients. TP53 and PIK3CA mutations were detected in 62 (44.9%) and 31 (22.5%) patients, respectively. The presence of a PIK3CA mutation was associated with lower A3A mRNA expression levels. There was a weak positive relationship between A3A mRNA expression levels and serum sPD-L1 levels. CONCLUSIONS:There was a difference in A3B mRNA expression levels according to breast cancer subtypes, and high levels of A3A and A3B mRNA expressions were associated with an aggressive phenotype. There was a high incidence of APOBEC3A/B deletion allele. Further studies are needed to identify the clinical significance of APOBEC in Asian patients with breast cancer.

The changes of agro-climate and heat extremes, and their impact on rice cultivation are assessed over South Korea in context of 2 and 3 °C global warming levels (GWL) compared to pre-industrial levels, with ensemble regional climate model projection produced under the Coordinated Regional Climate Downscaling Experiment–East Asia (CORDEX-EA) phase 2 protocols. It is found that the mean temperature increase under global warming has not only positive effects such as the extension of vegetable and crop periods and the widening of the cultivatable regions but also negative effects due to the shortening of the reproductive growth period. On the other hand, extreme heat changes in the future clearly show a negative effect on rice cultivation via the increase of hot days during heat-sensitive stages (27.16% under 2 °C GWL, 54.59% under 3 °C GWL) among rice phenology which determines the rice yield in tandem with rice flowering, ripening, and sterility problems. The major type of heat extreme is dominated by nationwide warm anomalies covering entire S. Korea, and the proportion of this type is projected to increase from 35.8% to 49.5% (57.4%) under 2 °C (3 °C) GWL in association with the thermal expansion of atmosphere which links to the favorable environment for occurring barotropic anti-cyclonic system.

The post-processing (punching or trimming) of high-strength parts reinforced by hot stamping requires punch molds with improved mechanical properties in hardness, resistance to wear, and toughness. In this study, a semi-additive manufacturing (semi-AM) method of heterogeneous materials was proposed to strengthen these properties using high wear resistance steel (HWS) powder and directed energy deposition (DED) technology. To verify these mechanical properties as a material for the punch mold for cutting, specimens were prepared and tested by a semi-AM method of heterogeneous material. The test results of the HWS additive material by the semi-AM method proposed in this study are as follows: the hardness was 60.59–62.0 HRc, which was like the Bulk D2 specimen. The wear resistance was about 4.2 times compared to that of the D2 specimen; the toughness was about 4.0 times that of the bulk D2 specimen; the compressive strength was about 1.45 times that of the bulk D2 specimen; the true density showed 100% with no porosity. Moreover, the absorption energy was 59.0 J in a multi-semi-AM specimen of heterogeneous materials having an intermediate buffer layer (P21 powder material). The semi-AM method of heterogeneous materials presented in this study could be applied as a method to strengthen the punch mold for cutting. In addition, the multi-semi-AM method of heterogeneous materials will be able to control the mechanical properties of the additive material.

Background/Aim: Interferon-induced transmembrane protein 1 (IFITM1) is known to be involved in breast cancer progression. We aimed to investigate its role in estrogen receptor (ER)-positive breast cancer cells with wildtype p53 and tamoxifen-resistant breast cancer cells. Materials and Methods: The ER-positive breast cancer cell lines, MCF7 with wild-type p53 and T47D with mutant p53, were used. We established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4- hydroxytamoxifen. Results: IFITM1 inhibition in MCF-7 cells significantly decreased cell growth and migration. MCF-7 cells with suppression of IFITM1 using siRNA or ruxolitinib showed reduced cell viability after tamoxifen treatment compared with that in the control MCF-7 cells. Unexpectedly, mRNA and protein levels of IFITM1 were decreased in TamR cells compared with those in MCF-7 cells. TamR cells with suppression of IFITM1 using siRNA or ruxolitinib showed no change in cell viability after treatment with tamoxifen. P53 knockdown using siRNA reduced the mRNA levels of IRF9 and increased mRNA and protein levels of SOCS3 in MCF-7 cells, suggesting that loss or mutation of p53 can affect the induction of IFITM1 via the JAK/STAT signaling pathway in breast cancer. Furthermore, MCF-7 cells with p53 knockdown using siRNA showed no decrease in cell viability after tamoxifen treatment or IFITM1 inhibition, indicating that p53 status may be important for cell death after tamoxifen treatment or IFITM1 inhibition. Conclusion: IFITM1 inhibition may enhance the sensitivity to tamoxifen based on p53-dependent enhancement of IFN signaling in wild-type p53, ER-positive breast cancer cells. [ABSTRACT FROM AUTHOR]