bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional diversity of the oxytocin receptor in prairie voles: mechanistic implications for behavioral neuroscience and maternal physiology
Authors: Danoff Joshua S. , Page Emma A. , Perkeybile Allison M. , Kenkel William M. , Yee Jason R. , Ferris Craig F. , Carter C. Sue , Connelly Jessica J.
Published: August 2023

The neurohormone oxytocin regulates many aspects of physiology primarily by binding to its receptor, the oxytocin receptor. The oxytocin receptor gene (Oxtr) has been shown to have alternative transcripts in the mouse brain which may each have different biological functions or be used in specific contexts. A popular animal model for studying oxytocin-dependent social behaviors is the prairie vole, a biparental and monogamous rodent. Alternative transcriptional capacity of Oxtr in prairie voles is unknown. We used 5′ rapid amplification of cDNA ends to identify alternative Oxtr transcription start sites in prairie vole brain tissue and uterine tissue. We then validated expression of specific transcripts in fetal brains and assessed the impact of exogenous oxytocin administration in utero on offspring brain development. We identified seven distinct Oxtr transcripts, all of which are present in both brain and uterine tissue. We then demonstrated that maternal oxytocin administration alters expression of a specific subset of Oxtr transcripts and that these different transcripts are under unique epigenetic regulation, such that in the perinatal period only one of the alternative transcripts is associated with DNA methylation in the Oxtr promoter. These data establish the existence of multiple Oxtr transcripts in prairie vole brain and uterine tissue and implicate oxytocin in the regulation of alternative transcript expression. These data have significant implications for our understanding of null mutant models in both mice and voles and translation in human birth and behavior.
Clinical and genetic features of Koreans with retinitis pigmentosa associated with mutations in rhodopsin
Authors: Jung Young Hoon , Kwak Jay Jiyong , Joo Kwangsic , Lee Hyuk Jun , Park Kyu Hyung , Kim Min Seok , Lee Eun Kyoung , Byeon Suk Ho , Lee Christopher Seungkyu , Han Jinu , Lee Junwon , Yoon Chang Ki , Woo Se Joon
Published: August 2023

Purpose: To investigate the clinical features, natural course, and genetic characteristics of Koreans with rhodopsin-associated retinitis pigmentosa (RHO-associated RP).

Design: We conducted a retrospective, multicenter, observational cohort study.

Participants: We reviewed the medical records of 42 patients with RHO-associated RP of 36 families who visited 4 hospitals in Korea.

Methods: Patients with molecular confirmation of pathogenic variants of the RHO gene were included. The patients were divided into two subgroups: the generalized and sector RP groups. A central visual field of the better-seeing eye of <10° or a best-corrected visual acuity of the better-seeing eye <20/40 indicated the progression to late-stage RP.

Results: The mean age at which symptoms first appeared was 26.3 ± 17.9 years (range: 8–78 years), and the mean follow-up period was 80.9 ± 68.7 months (range: 6–268 months). At the last follow-up visit, the generalized RP group showed a significantly higher rate of visual field impairment progression to late-stage RP than that of the sector RP group (22 of 35 [62.9%] vs. 0 of 7 [0.0%], p = 0.003). No cases in the sector RP group progressed to generalized RP. Best-corrected visual acuity deterioration to late-stage RP was observed only in the generalized RP group (13 of 35 patients; 37.1%), whereas no deterioration was observed in the sector RP group. We identified 16 known and three novel RHO mutations, including two missense mutations (p.T108P and p.G121R) and one deletion mutation (p.P347_A348del). The pathogenic variants were most frequently detected in exon 1 (14 of 36 [38.9%]). The most common pathogenic variants were p.P347L and T17M (5 of 36 [13.9%] families). Among 42 patients of 36 families, 35 patients of 29 families (80.6%) presented with the generalized RP phenotype, and seven patients of seven families (19.4%) presented with the sector RP phenotype. Three variants (p.T17M, p.G101E, and p.E181K) presented with both the generalized and sector RP phenotypes.

Conclusion: This multicenter cohort study provided information on the clinical and genetic features of RHO-associated RP in Koreans. It is clinically important to expand the genetic spectrum and understand genotype-phenotype correlations to ultimately facilitate the development of gene therapy.
Identification of human genetic variants modulating the course of COVID-19 infection with importance in other viral infections
Authors: Salihefendić Lana , Čeko Ivana , Bešić Larisa , Mulahuseinović Naida , Durgut Selma , Pećar Dino , Prnjavorac Lejla , Kandić Enis , Meseldžić Neven , Bego Tamer , Prnjavorac Besim , Marjanović Damir , Konjhodžić Rijad , Ašić Adna
Published: August 2023

Introduction: COVID-19 has been a major focus of scientific research since early 2020. Due to its societal, economic, and clinical impact worldwide, research efforts aimed, among other questions, to address the effect of host genetics in susceptibility and severity of COVID-19.

Methods: We, therefore, performed next-generation sequencing of coding and regulatory regions of 16 human genes, involved in maintenance of the immune system or encoding receptors for viral entry into the host cells, in a subset of 60 COVID-19 patients from the General Hospital Tešanj, Bosnia and Herzegovina, classified into three groups of clinical conditions of different severity (“mild,” “moderate,” and “severe”).

Results: We confirmed that the male sex and older age are risk factors for severe clinical picture and identified 13 variants on seven genes (CD55, IL1B, IL4, IRF7, DDX58, TMPRSS2, and ACE2) with potential functional significance, either as genetic markers of modulated susceptibility to SARS-CoV-2 infection or modifiers of the infection severity. Our results include variants reported for the first time as potentially associated with COVID-19, but further research and larger patient cohorts are required to confirm their effect.

Discussion: Such studies, focused on candidate genes and/or variants, have a potential to answer the questions regarding the effect of human genetic makeup on the expected infection outcome. In addition, loci we identified here were previously reported to have clinical significance in other diseases and viral infections, thus confirming a general, broader significance of COVID-19-related research results following the end of the pandemic period.
Construction and validation of a signature for T cell-positive regulators related to tumor microenvironment and heterogeneity of gastric cancer
Authors: Guo Yangyang , Zhang Yingjue , Cen Kenan , Dai Ying , Mai Yifeng , Hong Kai
Published: August 2023

Background

Positive regulators of T cell function play a vital role in the proliferation and differentiation of T cells. However, their functions in gastric cancer have not been explored so far.

Methods

The TCGA-STAD dataset was utilized to perform consensus clustering in order to identify subtypes related to T cell-positive regulators. The prognostic differentially expressed genes of these subtypes were identified using the least absolute shrinkage and selection operator (LASSO) regression analysis. To validate the robustness of the identified signature, verification analyses were conducted across the TCGA-train, TCGA-test, and GEO datasets. Additionally, a nomogram was constructed to enhance the clinical efficacy of this predictive tool. Transwell migration, colony formation, and T cell co-culture assays were used to confirm the function of the signature gene in gastric cancer and its influence on T cell activation.

Results

Two distinct clusters of gastric cancer, related to T cell-positive regulation, were discovered through the analysis of gene expression. These clusters exhibited notable disparities in terms of survival rates (P = 0.028), immune cell infiltration (P< 0.05), and response to immunotherapy (P< 0.05). Furthermore, a 14-gene signature was developed to classify gastric cancer into low- and high-risk groups, revealing significant differences in survival rates, tumor microenvironment, tumor mutation burden, and drug sensitivity (P< 0.05). Lastly, a comprehensive nomogram model was constructed, incorporating risk factors and various clinical characteristics, to provide an optimal predictive tool. Additionally, an assessment was conducted on the purported molecular functionalities of low- and high-risk gastric cancers. Suppression of DNAAF3 has been observed to diminish the migratory and proliferative capabilities of gastric cancer, as well as attenuate the activation of T cells induced by gastric cancer within the tumor microenvironment.

Conclusion

We identified an ideal prognostic signature based on the positive regulators of T cell function in this study.
Hepatic arterial infusion chemotherapy plus lenvatinib with or without programmed cell death protein-1 inhibitors for advanced cholangiocarcinoma
Authors: Wei Zhanqi , Wang Yajing , Wu Boyang , Liu Ying , Wang Yaqin , Ren Zhizhong , Yang Xiaowei , Chen Qian , Zhang Yuewei
Published: August 2023

Background

New treatment strategies are needed to improve outcomes for patients with advanced cholangiocarcinoma (CCA) due to the limited efficacy of current first-line chemotherapy regimens. Although the combination of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and programmed cell death protein-1 (PD-1) inhibitors has been extensively evaluated in the treatment of advanced hepatocellular carcinoma, their roles in advanced CCA remain poorly understood. The purpose of this study is to compare the efficacy and safety of HAIC plus lenvatinib with or without PD-1 inhibitors in patients with advanced CCA.

Methods

Between March 2019 to June 2022, patients diagnosed with advanced CAA who received HAIC plus lenvatinib with or without PD-1 inhibitors treatment were reviewed for eligibility. Efficacy was evaluated according to survival and tumor response, and safety was evaluated according to the incidence of adverse events (AEs).

Results

Fifty-five patients with advanced CCA were included in the study, and they were divided into the HAIC+lenvatinib (LEN)+PD-1 inhibitors (PD-1i) group (n = 35) and HAIC+LEN group (n = 20). The median follow-up time was 14.0 (5–42) months. Patients in the HAIC+LEN+PD-1i group had significantly better PFS (HR = 0.390; 95% CI 0.189-0.806; p = 0.001) and OS (HR = 0.461; 95% CI 0.229-0.927; p = 0.01) than those in the HAIC+LEN group. The HAIC+LEN+PD-1i group showed a higher objective response rate and disease control rate than the HAIC+LEN group but did not find a significant difference. The incidence of grade 1-2 and grade 3-4 AEs was not significantly higher in the HAIC+LEN+PD-1i group compared to the HAIC+LEN group, whereas two patients (5.7%) in the HAIC+LEN+PD-1i group experienced grade 5 immune-mediated pneumonia.

Conclusion

HAIC plus lenvatinib with PD-1 inhibitors is safe and well-tolerated, and has the potential to prolong the survival of patients with advanced CCA. The addition of PD-1 inhibitors may enhance the efficacy of HAIC and lenvatinib. Therefore, the combined therapy has the potential to become a treatment option for advanced CCA.
Genes, inflammatory response, tolerance, and resistance to virus infections in migratory birds, bats, and rodents
Authors: Pereira Patrick Douglas Corrêa , Diniz Daniel Guerreiro , da Costa Emanuel Ramos , Magalhães Nara Gyzely de Morais , da Silva Anderson de Jesus Falcão , Leite Jéssica Gizele Sousa , Almeida Natan Ibraim Pires , Cunha Kelle de Nazaré , de Melo Mauro André Damasceno , Vasconcelos Pedro Fernando da Costa , Diniz José Antonio Picanço , Brites Dora , Anthony Daniel Clive , Diniz Cristovam Wanderley Picanço , Guerreiro-Diniz Cristovam
Published: August 2023

Normally, the host immunological response to viral infection is coordinated to restore homeostasis and protect the individual from possible tissue damage. The two major approaches are adopted by the host to deal with the pathogen: resistance or tolerance. The nature of the responses often differs between species and between individuals of the same species. Resistance includes innate and adaptive immune responses to control virus replication. Disease tolerance relies on the immune response allowing the coexistence of infections in the host with minimal or no clinical signs, while maintaining sufficient viral replication for transmission. Here, we compared the virome of bats, rodents and migratory birds and the molecular mechanisms underlying symptomatic and asymptomatic disease progression. We also explore the influence of the host physiology and environmental influences on RNA virus expression and how it impacts on the whole brain transcriptome of seemingly healthy semipalmated sandpiper (Calidris pusilla) and spotted sandpiper (Actitis macularius). Three time points throughout the year were selected to understand the importance of longitudinal surveys in the characterization of the virome. We finally revisited evidence that upstream and downstream regulation of the inflammatory response is, respectively, associated with resistance and tolerance to viral infections.
M2 macrophage polarization: a potential target in pain relief
Authors: Zhao Wenjing , Ma Lulin , Deng Daling , Zhang Tianhao , Han Linlin , Xu Feng , Huang Shiqian , Ding Yuanyuan , Chen Xiangdong
Published: August 2023

Pain imposes a significant urden on patients, affecting them physically, psychologically, and economically. Despite numerous studies on the pathogenesis of pain, its clinical management remains suboptimal, leading to the under-treatment of many pain patients. Recently, research on the role of macrophages in pain processes has been increasing, offering potential for novel therapeutic approaches. Macrophages, being indispensable immune cells in the innate immune system, exhibit remarkable diversity and plasticity. However, the majority of research has primarily focused on the contributions of M1 macrophages in promoting pain. During the late stage of tissue damage or inflammatory invasion, M1 macrophages typically transition into M2 macrophages. In recent years, growing evidence has highlighted the role of M2 macrophages in pain relief. In this review, we summarize the mechanisms involved in M2 macrophage polarization and discuss their emerging roles in pain relief. Notably, M2 macrophages appear to be key players in multiple endogenous pathways that promote pain relief. We further analyze potential pathways through which M2 macrophages may alleviate pain.
Distinct fecal microbial signatures are linked to sex and chronic immune activation in pediatric HIV infection
Authors: Rosel-Pech Cecilia , Pinto-Cardoso Sandra , Chávez-Torres Monserrat , Montufar Nadia , Osuna-Padilla Iván , Ávila-Ríos Santiago , Reyes-Terán Gustavo , Aguirre-Alvarado Charmina , Matías Juan Norma Angelica , Pérez-Lorenzana Héctor , Vázquez-Rosales José Guillermo , Bekker-Méndez Vilma Carolina
Published: August 2023

Introduction

Our understanding of HIV-associated gut microbial dysbiosis in children perinatally-infected with HIV (CLWH) lags behind that of adults living with HIV. Childhood represents a critical window for the gut microbiota. Any disturbances, including prolonged exposure to HIV, antiretroviral drugs, and antibiotics are likely to have a significant impact on long-term health, resulting in a less resilient gut microbiome. The objective of our study was to characterize the gut microbiota in CLWH, and compare it with HIV-unexposed and -uninfected children.

Methods

We enrolled 31 children aged 3 to 15 years; 15 were CLWH and 16 were HUU. We assessed dietary patterns and quality; quantified soluble and cellular markers of HIV disease progression by flow cytometry, enzyme-linked immunosorbent and multiplex-bead assays, and profiled the gut microbiota by 16S rRNA sequencing. We explored relationships between the gut microbiota, antibiotic exposure, dietary habits, soluble and cellular markers and host metadata.

Results

Children had a Western-type diet, their median health eating index score was 67.06 (interquartile range 58.76-74.66). We found no discernable impact of HIV on the gut microbiota. Alpha diversity metrics did not differ between CLWH and HUU. Sex impacted the gut microbiota (R-squared= 0.052, PERMANOVA p=0.024). Male children had higher microbial richness compared with female children. Two taxa were found to discriminate female from male children independently from HIV status: Firmicutes for males, and Bacteroides for females. Markers of HIV disease progression were comparable between CLWH and HUU, except for the frequency of exhausted CD4+ T cells (PD-1+) which was increased in CLWH (p=0.0024 after adjusting for confounders). Both the frequency of exhausted CD4+ and activated CD4+ T cells (CD38+ HLADR+) correlated positively with the relative abundance of Proteobacteria (rho=0.568. false discovery rate (FDR)-adjusted p= 0.029, and rho=0.62, FDR-adjusted p=0.0126, respectively).

Conclusion

The gut microbiota of CLWH appears similar to that of HUU, and most markers of HIV disease progression are normalized with long-term ART, suggesting a beneficial effect of the latter on the gut microbial ecology. The relationship between exhausted and activated CD4+ T cells and Proteobacteria suggests a connection between the gut microbiome, and premature aging in CLWH.
Kruppel homolog 1 modulates ROS production and antimicrobial peptides expression in shrimp hemocytes during infection by the Vibrio parahaemolyticus strain that causes AHPND
Authors: Zheng Zhou , Liu Shangjie , Lin Zhongyang , Aweya Jude Juventus , Zheng Zhihong , Zhao Yongzhen , Chen Xiuli , Li Shengkang , Zhang Yueling
Published: August 2023

Shrimp aquaculture has been seriously affected by acute hepatopancreatic necrosis disease (AHPND), caused by a strain of Vibrio parahaemolyticus that carries the Pir toxin plasmids (V. parahaemolyticus(AHPND)). In this study, the transcription factor, Kruppel homolog 1-like of Peneaus vannamei (PvKr-h1), was significantly induced in shrimp hemocytes after V. parahaemolyticus(AHPND) challenge, suggesting that PvKr-h1 is involved in shrimp immune response. Knockdown of PvKr-h1 followed by V. parahaemolyticus(AHPND) challenge increased bacterial abundance in shrimp hemolymph coupled with high shrimp mortality. Moreover, transcriptome and immunofluorescence analyses revealed that PvKr-h1 silencing followed by V. parahaemolyticus(AHPND) challenge dysregulated the expression of several antioxidant-related enzyme genes, such as Cu-Zu SOD, GPX, and GST, and antimicrobial peptide genes, i.e., CRUs and PENs, and reduced ROS activity and nuclear translocation of Relish. These data reveal that PvKr-h1 regulates shrimps’ immune response to V. parahaemolyticus(AHPND) infection by suppressing antioxidant-related enzymes, enhancing ROS production and promoting nuclei import of PvRelish to stimulate antimicrobial peptide genes expression.
Insights into vitamin A in bladder cancer, lack of attention to gut microbiota?
Authors: Luo Peiyue , Zheng Liying , Zou Junrong , Chen Tao , Zou Jun , Li Wei , Chen Qi , Qian Biao
Published: August 2023

Vitamin A has long been associated with bladder cancer, and many exogenous vitamin A supplements, vitamin A derivatives, and synthetic drugs have been investigated over the years. However, the effectiveness of these strategies in clinical practice has not met expectations, and they have not been widely adopted. Recent medical research on intestinal flora has revealed that bladder cancer patients exhibit reduced serum vitamin A levels and an imbalance of gut microbiota. In light of the close relationship between gut microbiota and vitamin A, one can speculate that a complex regulatory mechanism exists between the two in the development and occurrence of bladder cancer. As such, further exploration of their interaction in bladder cancer may help guide the use of vitamin A for preventive purposes. During the course of this review, attention is paid to the influence of intestinal microbiota on the vitamin A metabolism and the RA signaling pathway, as well as the mutual promotion relationships between them in the prevention of bladder cancer, In addition, it emphasizes the importance of intestinal microbiota for bladder cancer prevention and treatment.
Importance of nanophytoplankton biomass during summer 2019 in a retreating marine-terminating glacier-fjord system, Marian Cove, West Antarctica (62°S)
Authors: Jeon Misa , Iriarte José Luis , Yang Eun Jin , Park Jisoo , Alves-de-Souza Catharina , Park Sang Jong
Published: August 2023

The biogeochemical dynamics of fjords around Antarctica are strongly influenced by cryospheric, climatic, and oceanographic processes that occur on a seasonal scale. Furthermore, as global climate change continues, there is a growing awareness of the impact of ocean warming on glacier melting, which is expected to affect the composition of phytoplankton community structure in West Antarctica’s nearshore marine areas. In this study, we describe the role of hydrographic forcing on the short-term summer variability of the phytoplankton community in Marian Cove, an Antarctic glacial fjord (62°S). Phytoplankton and hydrographic variables were measured at five stations along the Marian Cove during summer 2019 (January–February). The highest concentrations of microphytoplankton biomass were found in the outer area of the fjord, whereas nanophytoplankton biomass displayed continued dominance during most of the summer period in Marian Cove. Hydrographic assessment showed that freshwater inputs from the glacier influenced the surface layer of the fjord, modulating phytoplankton biomass, which was dominated by nanodiatoms (Minidiscus sp., Thalassiosira spp.) and nanophytoflagellates (Cryptomonas spp., Phaeocystis sp.). Concurrent measurement of phytoplankton biomass and environmental conditions during December 2018–January 2019 indicated that a period of weak southeastern winds generated vertical stability, which led to the development of a major peak of microphytoplankton biomass in the outer cove, driven by warm, allochthonous, oceanic, nutrient-rich waters. High carbon biomass dominated by nanodiatoms and nanophytoflagellates was observed in cold, fresh, and low-light subsurface waters of the cove. Our results highlight the effects of a warming ocean, which may favor the summer resurgence of nanodiatom and nanophytoflagellate communities in Antarctic fjords due to increased glacial meltwater inputs.
Distribution and habitat preference of polar cod (Boreogadus saida) in the Bering and Chukchi Seas inferred from species-specific detection of environmental DNA
Authors: Kawakami Tatsuya , Yamazaki Aya , Jiang Hai-Chao , Ueno Hiromichi , Kasai Akihide
Published: August 2023

Ongoing warming and sea-ice reductions in the Arctic can seriously impact cold-water species, such as polar cod (Boreogadus saida), necessitating biomonitoring to reveal the ecological consequences. Recent methodological advancements in environmental DNA (eDNA) techniques have increased our ability to conduct ecological monitoring at various locations, including the Arctic. This study aimed to provide an overview of the distribution of polar cod across the Bering and Chukchi Seas by employing species-specific detection of eDNA. First, we successfully developed novel species-specific qPCR assay targeting the mitochondrial D-loop region, which exclusively amplifies eDNA derived from polar cod. Subsequently, polar cod eDNA was detected using the assay from the samples that we collected latitudinally across the study area during the open-water season. Polar cod eDNA was primarily detected in the surface water from the central Chukchi Sea shelf and the northernmost observation line (75°N), which was located on the shelf slope, off the Point Barrow, and in the marginal ice zone. In contrast, only trace amounts of eDNA were detected in the Bering Sea. This pattern corresponded well with the distribution of water masses classified based on environmental conditions. The detection of eDNA in surface water was clearly limited to cold (-1 to 5°C) and low salinity (25–32) water, whereas it was detected in a higher salinity range (32–34) in the middle and bottom layers. These findings are consistent with current knowledge about the distribution and habitat of the polar cod, suggesting that eDNA can be regarded as a reliable tool to replace or supplement conventional methods. Incorporating eDNA techniques into large-scale oceanographic surveys can improve the spatial and temporal resolution of fish species detection with a reasonable sampling effort and will facilitate the continuous monitoring of Arctic ecosystems.
Skin substitutes as treatment for chronic wounds: current and future directions
Authors: Vecin Nicole M. , Kirsner Robert S.
Published: August 2023

Chronic wounds such as diabetic foot ulcers and venous leg ulcers place a significant burden on the healthcare system and in some cases, have 5-year mortality rates comparable to cancer. They negatively impact patients’ quality of life due to pain, odor, decreased mobility, and social isolation. Skin substitutes are an advanced therapy recommended for wounds that fail to show decrease in size with standard care. The choice of substitute used should be based on evidence, which often differs based on wound etiology. There are more than 75 skin substitutes currently available, and that number is rising. In this review, we discuss current management and future directions of chronic wounds while providing a review of available randomized control trial data for various skin substitutes.
The FDA-approved drug nitazoxanide is a potent inhibitor of human seasonal coronaviruses acting at postentry level: effect on the viral spike glycoprotein
Authors: Piacentini Sara , Riccio Anna , Santopolo Silvia , Pauciullo Silvia , La Frazia Simone , Rossi Antonio , Rossignol Jean-Francois , Santoro M. Gabriella
Published: August 2023

Coronaviridae is recognized as one of the most rapidly evolving virus family as a consequence of the high genomic nucleotide substitution rates and recombination. The family comprises a large number of enveloped, positive-sense single-stranded RNA viruses, causing an array of diseases of varying severity in animals and humans. To date, seven human coronaviruses (HCoV) have been identified, namely HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1, which are globally circulating in the human population (seasonal HCoV, sHCoV), and the highly pathogenic SARS-CoV, MERS-CoV and SARS-CoV-2. Seasonal HCoV are estimated to contribute to 15–30% of common cold cases in humans; although diseases are generally self-limiting, sHCoV can sometimes cause severe lower respiratory infections and life-threatening diseases in a subset of patients. No specific treatment is presently available for sHCoV infections. Herein we show that the anti-infective drug nitazoxanide has a potent antiviral activity against three human endemic coronaviruses, the Alpha-coronaviruses HCoV-229E and HCoV-NL63, and the Beta-coronavirus HCoV-OC43 in cell culture with IC50 ranging between 0.05 and 0.15 μg/mL and high selectivity indexes. We found that nitazoxanide does not affect HCoV adsorption, entry or uncoating, but acts at postentry level and interferes with the spike glycoprotein maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Altogether the results indicate that nitazoxanide, due to its broad-spectrum anti-coronavirus activity, may represent a readily available useful tool in the treatment of seasonal coronavirus infections.
Doxycycline PEP can induce doxycycline resistance in Klebsiella pneumoniae in a Galleria mellonella model of PEP
Authors: Kenyon Chris , Gestels Zina , Vanbaelen Thibaut , Abdellati Said , Van Den Bossche Dorien , De Baetselier Irith , Xavier Basil Britto , Manoharan-Basil Sheeba Santhini
Published: August 2023

Background

Four randomized controlled trials have now established that doxycycline post exposure (sex) prophylaxis (PEP) can reduce the incidence of chlamydia and syphilis in men who have sex with men. These studies have concluded that the risk of selecting for antimicrobial resistance is low. We evaluated this risk in vitro and in vivo using a Galleria mellonella infection model.

Methods

We evaluated how long it took for doxycycline resistance to emerge during passage on doxycycline containing agar plates in 4 species – Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae and Neisseria subflava. We then assessed if K. pneumoniae could acquire resistance to doxycycline (and cross resistance to other antimicrobials) during intermittent exposure to doxycycline in a Galleria mellonella model of doxycycline PEP.

Results

In our passage experiments, we found that resistance first emerged in K. pneumoniae. By day 7 the K. pneumoniae MIC had increased from 2 mg/L to a median of 96 mg/L (IQR 64–96). Under various simulations of doxycycline PEP in the G. mellonella model, the doxycycline MIC of K. pneumoniae increased from 2 mg/L to 48 mg/L (IQR 48–84). Ceftriaxone and ciprofloxacin MICs increased over ten-fold. Whole genome sequencing revealed acquired mutations in ramR which regulates the expression of the AcrAB-TolC efflux pump.

Conclusion

Doxycycline PEP can select for doxycycline, ceftriaxone and ciprofloxacin resistance in K. pneumoniae in a G. mellonella model. The emergent ramR mutations were similar to those seen in circulating strains of K. pneumoniae. These findings suggest that we need to assess the effect of doxycycline PEP on resistance induction on a broader range of bacterial species than has hitherto been the case.
Interactive effects between the invasive weed Stellera chamaejasme and grass: can arbuscular mycorrhizal fungi and fungal pathogens coregulate interspecific relationships?
Authors: Zhang Ruohui , Qu Shanmin , Zhang Bin , Gao Ying , Xing Fu
Published: August 2023

The interaction between poisonous weeds and neighboring plants is complex. Poisonous weeds frequently have a competitive advantage in the interaction between poisonous weeds and neighboring plants. Arbuscular mycorrhizal fungi (AMF) and plant pathogenic fungi (PPF) are closely related to the interspecific relationships of plants. However, the role of AMF and PPF between poisonous weeds and neighboring grasses remains unclear. Here, we designed a pot experiment to determine the interspecific relationship between Leymus chinensis and Stellera chamaejasme and the regulation of AMF and PPF. The results showed that interactive effects between L. chinensis and S. chamaejasme significantly inhibited the aboveground growth of both but promoted the underground growth of L. chinensis. As the proportions of S. chamaejasme increased, the total nitrogen content and pH in the rhizosphere soil of L. chinensis were reduced, the soil pH of S. chamaejasme was reduced, and the relative abundance of AMF in the rhizosphere soil of L. chinensis significantly increased and that of S. chamaejasme decreased considerably. The relative abundances of PPF in the rhizosphere soil of both in the mono-cultures were significantly higher than those in the mixed cultures. Structural equation modeling indicated that soil abiotic (pH and N availability) and biotic (AMF and PPF) factors are major drivers explaining the interactive effects between L. chinensis and S. chamaejasme. We provided new evidence for the interspecific interactions between poisonous weeds and neighboring grasses and revealed the regulatory role of AMF and PPF in the interactive effects of both plants. This study will provide a scientific basis for the prevention and control of poisonous weeds and the vegetation restoration of degraded grasslands in the future.
Enrichment of halotolerant hydrogen-oxidizing bacteria and production of high-value-added chemical hydroxyectoine using a hybrid biological–inorganic system
Authors: Feng Xiang , Kazama Daichi , He Sijia , Nakayama Hideki , Hayashi Takeshi , Tokunaga Tomochika , Sato Kozo , Kobayashi Hajime
Published: August 2023

Hybrid biological–inorganic (HBI) systems show great promise as CO2 conversion platforms combining CO2 fixation by hydrogen-oxidizing bacteria (HOB) with water splitting. Herein, halotolerant HOB were enriched using an HBI system with a high-ionic-strength medium containing 180 mM phosphate buffer to identify new biocatalysts. The reactors were inoculated with samples from saline environments and applied with a voltage of 2.0 V. Once an increase in biomass was observed with CO2 consumption, an aliquot of the medium was transferred to a new reactor. After two successive subcultures, Achromobacter xylosoxidans strain H1_3_1 and Mycolicibacterium mageritense strain H4_3_1 were isolated from the reactor media. Genome sequencing indicated the presence of genes for aerobic hydrogen-oxidizing chemolithoautotrophy and synthesis of the compatible solute hydroxyectoine in both strains. Furthermore, both strains produced hydroxyectoine in the reactors under the high-ionic-strength condition, suggesting the potential for new HBI systems using halotolerant HOB to produce high-value-added chemicals.
Integrative analysis of lysine acetylation-related genes and identification of a novel prognostic model for oral squamous cell carcinoma
Authors: Deng Shi-Zhou , Wu Xuechen , Tang Jiezhang , Dai Lin , Cheng Bo
Published: August 2023

Introduction: Oral squamous cell carcinoma (OSCC), which accounts for a high proportion of oral cancers, is characterized by high aggressiveness and rising incidence. Lysine acetylation is associated with cancer pathogenesis. Lysine acetylation-related genes (LARGs) are therapeutic targets and potential prognostic indicators in various tumors, including oral squamous cell carcinoma. However, systematic bioinformatics analysis of the Lysine acetylation-related genes in Oral squamous cell carcinoma is still unexplored.

Methods: We analyzed the expression of 33 Lysine acetylation-related genes in oral squamous cell carcinoma and the effects of their somatic mutations on oral squamous cell carcinoma prognosis. Consistent clustering analysis identified two lysine acetylation patterns and the differences between the two patterns were further evaluated. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a lysine acetylation-related prognostic model using TCGA oral squamous cell carcinoma datasets, which was then validated using gene expression omnibus (GEO) dataset GSE41613.

Results: Patients with lower risk scores had better prognoses, in both the overall cohort and within the subgroups These patients also had “hot” immune microenvironments and were more sensitive to immunotherapy.

Disscussion: Our findings offer a new model for classifying oral squamous cell carcinoma and determining its prognosis and offer novel insights into oral squamous cell carcinoma diagnosis and treatment.
Phenotypic characteristics of myelin oligodendrocyte glycoprotein antibody-associated disease in children: a single-center, retrospective study
Authors: Hua Yi , Yan Xuke , Liu Liu , Wang Yilong , Xu Lu , Jiang Peifang , Yuan Zhefeng , Gao Feng
Published: August 2023

Objective

To analyze the clinical characteristics and follow-up data of children with different clinical phenotypes of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

Methods

The basic demographic and clinical features, laboratory and imaging examination results, and follow-up data of 74 Chinese children with different phenotypes of MOGAD were retrospectively reviewed and analyzed.

Results

The male-to-female ratio in this cohort was 1:1.39. The clinical phenotypes of MOGAD included acute disseminated encephalomyelitis (ADEM; n = 37), encephalitis (n = 11), optic neuritis (ON, n = 9), neuromyelitis optica spectrum disorder (NMOSD; n = 9), transverse myelitis (TM; n = 6), leukodystrophy-like manifestations (n = 1), and meningitis (n = 1). The mean age of disease onset was 86 months. The number of leukocytes in the cerebrospinal fluid of patients with ADEM was significantly higher than that in patients with ON but lower than that in patients with TM (p < 0.05). The pathogen detection rate among all patients was 36.5%. Recurrence occurred in 17 patients (23%), with the highest recurrence rate in patients with NMOSD and TM. Patients with recurrence had a significantly higher median age than those without any recurrence (109.00 vs. 82.44 months, p < 0.05). The male-to-female ratio in patients with recurrence was 1:4.67, which differed significantly from that at first onset (p < 0.05).

Conclusion

The most common clinical phenotypes of MOGAD in this cohort were ADEM and encephalitis. Recurrence of MOGAD may be related to age and sex, with a higher recurrence rate observed in females. These findings provide a basis for further exploration of the characteristics of different MOGAD phenotypes.
Risk factors and a prediction model for unruptured intracranial aneurysms in patients with ischemic stroke using carotid intima-media thickness and systemic atherosclerosis
Authors: Gao Gaiming , Kang Dezhi , Zhang Jinning , Jiang Zhixian , He Xueyang , Wu Yanyu
Published: August 2023

Background

Systemic atherosclerosis and carotid intima-media thickness (IMT) have been widely used in clinical practice for ischemic stroke; however, little is known about the risk factors for unruptured intracranial aneurysms (UIAs) in patients with ischemic stroke (IS). Therefore, we performed this study to identify the risk factors and construct a prediction model for UIA in patients with IS.

Methods

Data were retrospectively collected from patients with IS from 2015 to 2022 at the First Hospital of Quanzhou City, Quanzhou, Fujian, China. Risk factors for UIA in patients with IS were identified using a multivariate logistic regression model, and a receiver operating characteristic (ROC) curve was applied to construct the prediction model.

Results

Out of the 122 patients with IS, 52 who presented with UIA (ISUIA) were categorized into the study group and the remaining 70 IS patients without UIA into the control group. Patients in the ISUIA group had lower carotid IMT and carotid artery plaque scores than those in the IS group (P < 0.05). Multivariate analyses found that aspirin use (OR: 12.987; P = 0.031), elevated C-reactive protein (CRP) level (OR: 1.019; P = 0.004), and carotid IMT > 0.09 mm (OR: 0.218; P < 0.001) were significantly associated with the risk of UIA in patients with IS. However, UIA in patients with IS was unaffected by the carotid artery plaque score (P = 0.114). The constricted prediction model based on the abovementioned factors for UIA in IS patients was 0.79 (95% CI: 0.71–0.87).

Conclusion

The findings revealed that the risk factors for UIA in patients with IS included aspirin use, elevated CRP level, and smaller carotid IMT, and the predictive value of the prediction model was relatively better.
Relief of post-stroke spasticity with acute vibrotactile stimulation: controlled crossover study of muscle and skin stimulus methods
Authors: Seim Caitlyn , Chen Bingxian , Han Chuzhang , Vacek David , Wu Laura Song , Lansberg Maarten , Okamura Allison
Published: August 2023

Background

Prior work suggests that vibratory stimulation can reduce spasticity and hypertonia. It is unknown which of three predominant approaches (stimulation of the spastic muscle, antagonist muscle, or cutaneous regions) most reduces these symptoms.

Objective

Determine which vibrotactile stimulation approach is most effective at reducing spastic hypertonia among post-stroke patients.

Methods

Sham-controlled crossover study with random assignment of condition order in fourteen patients with post-stroke hand spasticity. All patients were studied in four conditions over four visits: three stimulation conditions and a sham control. The primary outcome measure was the Modified Ashworth Scale, and the secondary outcome measure was the Modified Tardieu Scale measured manually and using 3D motion capture. For each condition, measures of spastic hypertonia were taken at four time points: baseline, during stimulation, after stimulation was removed, and after a gripping exercise.

Results

A clinically meaningful difference in spastic hypertonia was found during and after cutaneous stimulation of the hand. Modified Ashworth and Modified Tardieu scores were reduced by a median of 1.1 (SD = 0.84, p = 0.001) and 0.75 (SD = 0.65, p = 0.003), respectively, during cutaneous stimulation, and by 1.25 (SD = 0.94, p = 0.001) and 0.71 (SD = 0.67, p = 0.003), respectively, at 15 min after cutaneous stimulation. Symptom reductions with spastic muscle stimulation and antagonist muscle stimulation were non-zero but not significant. There was no change with sham stimulation.

Conclusions

Cutaneous vibrotactile stimulation of the hand provides significant reductions in spastic hypertonia, compared to muscle stimulation.

Clinical trial registration

www.ClinicalTrials.gov, identifier: NCT03814889.
Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial
Authors: Stockem C.F. , Mellema J.J.J. , van Rhijn B.W.G. , Boellaard T.N. , van Montfoort M.L. , Balduzzi S. , Boormans J.L. , Franckena M. , Meijer R.P. , Robbrecht D.G.J. , Suelmann B.B.M. , Schaake E.E. , van der Heijden M.S.
Published: August 2023

Introduction

Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer.

Methods

The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response.

Discussion

This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer.

Clinical Trial Registration

The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).
Association of KLK4 rs2235091 polymorphism with susceptibility to dental caries: a systematic review and meta-analysis
Authors: Li Youqin , Zhang Lei , Cen Wen , Yuan Yongping
Published: August 2023

Objective

To investigate the association between Kallikrein-related peptidase-4 (KLK4) rs2235091 polymorphism and susceptibility to dental caries (DC) by a method of systematic review and meta-analysis.

Methods

Four English databases were searched for studies on the correlation between KLK4 rs2235091 polymorphism and susceptibility to DC from inception to April 1, 2023. Data analysis was processed by Stata 15.0 software.

Results

Four articles were eligible, including 848 individuals with caries and 463 controls. The results of pooled analysis showed no significant differences in the five gene models (G vs. A: odds ratio (OR) = 1.14, 95% CI: 0.73–1.79, P = 0.567; GG + GA vs. AA: OR = 1.01, 95% CI: 0.77–1.32, P = 0.489; GG vs. GA + AA: OR = 0.84, 95% CI: 0.57–1.23, P = 0.368; GA vs. AA: OR = 1.06, 95% CI: 0.80–1.41, P = 0.681; GG vs. AA: OR = 1.15, 95% CI: 0.57–2.31, P = 0.690). However, subgroup analysis indicated a statistically significant difference in the dominant (GG + GA vs. AA: OR = 1.74, 95% CI: 1.02–2.96, P = 0.042) gene model in primary dentition, but no significance in allelic, recessive, homozygous and heterozygous models. Besides, in permanent dentition, no significant differences were found among the five genetic models (all P > 0.05).

Conclusion

KLK4 rs2235091 polymorphism may be associated with susceptibility to DC of pediatric primary dentition, but not with the risk of caries of permanent dentition. Genotype GG + GA may increase susceptibility to DC of pediatric primary dentition. However, considering the limited records enrolled in this review, more trials with larger sample sizes and more rigorous designs are needed to verify the conclusions of this meta-analysis in the future.

Systematic Review Registration

https://inplasy.com/, identifier INPLASY202380014.
Dual-targeting peptides@PMO, a mimetic to the pro-apoptotic protein Smac/DIABLO for selective activation of apoptosis in cancer cells
Authors: Di Giorgio Eros , Ferino Annalisa , Huang Weizhe , Simonetti Sigrid , Xodo Luigi , De Marco Rossella
Published: August 2023

The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3–integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types.
Genome-wide identification and characterization of 14-3-3 gene family related to negative regulation of starch accumulation in storage root of Manihot esculenta
Authors: Pan Ranran , Wang Yajie , An Feifei , Yao Yuan , Xue Jingjing , Zhu Wenli , Luo Xiuqin , Lai Hanggui , Chen Songbi
Published: August 2023

The 14-3-3 protein family is a highly conservative member of the acid protein family and plays an important role in regulating a series of important biological activities and various signal transduction pathways. The role of 14-3-3 proteins in regulating starch accumulation still remains largely unknown. To investigate the properties of 14-3-3 proteins, the structures and functions involved in starch accumulation in storage roots were analyzed, and consequently, 16Me14-3-3genes were identified. Phylogenetic analysis revealed that Me14-3-3 family proteins are split into two groups (ε and non-ε). All Me14-3-3 proteins contain nine antiparallel α-helices. Me14-3-3s-GFP fusion protein was targeted exclusively to the nuclei and cytoplasm. In the early stage of starch accumulation in the storage root,Me14-3-3genes were highly expressed in high-starch cultivars, while in the late stage of starch accumulation,Me14-3-3genes were highly expressed in low-starch cultivars.Me14-3-3 I,II,V, andXVIhad relatively high expression levels in the storage roots. The transgenic evidence fromMe14-3-3IIoverexpression inArabidopsis thalianaand the virus-induced gene silencing (VIGS) in cassava leaves and storage roots suggest thatMe14-3-3IIis involved in the negative regulation of starch accumulation. This study provides a new insight to understand the molecular mechanisms of starch accumulation linked withMe14-3-3genes during cassava storage root development.