bluuebunny/crossref_metadata_2025 huggingface dataset:
Aging of the Hematopoietic Stem Cell Niche: New Tools to Answer an Old Question
Authors: Matteini Francesca , Mulaw Medhanie A. , Florian M. Carolina
Published: November 2021

The hematopoietic stem cell (HSC) niche is a specialized microenvironment, where a complex and dynamic network of interactions across multiple cell types regulates HSC function. During the last years, it became progressively clearer that changes in the HSC niche are responsible for specific alterations of HSC behavior. The aging of the bone marrow (BM) microenvironment has been shown to critically contribute to the decline in HSC function over time. Interestingly, while upon aging some niche structures within the BM are degenerated and negatively affect HSC functionality, other niche cells and specific signals are preserved and essential to retaining HSC function and regenerative capacity. These new findings on the role of the aging BM niche critically depend on the implementation of new technical tools, developed thanks to transdisciplinary approaches, which bring together different scientific fields. For example, the development of specific mouse models in addition to coculture systems, new 3D-imaging tools, ossicles, and ex-vivo BM mimicking systems is highlighting the importance of new technologies to unravel the complexity of the BM niche on aging. Of note, an exponential impact in the understanding of this biological system has been recently brought by single-cell sequencing techniques, spatial transcriptomics, and implementation of artificial intelligence and deep learning approaches to data analysis and integration. This review focuses on how the aging of the BM niche affects HSCs and on the new tools to investigate the specific alterations occurring in the BM upon aging. All these new advances in the understanding of the BM niche and its regulatory function on HSCs have the potential to lead to novel therapeutical approaches to preserve HSC function upon aging and disease.
Novel Assay Platform to Evaluate Intracellular Killing of Mycobacterium tuberculosis: In Vitro and In Vivo Validation
Authors: Horváti Kata , Fodor Kinga , Pályi Bernadett , Henczkó Judit , Balka Gyula , Gyulai Gergő , Kiss Éva , Biri-Kovács Beáta , Senoner Zsuzsanna , Bősze Szilvia
Published: November 2021

One of the main hallmarks of tuberculosis (TB) is the ability of the causative agent to transform into a stage of dormancy and the capability of long persistence in the host phagocytes. It is believed that approximately one-third of the population of the world is latently infected with Mycobacterium tuberculosis (Mtb), and 5%–10% of these individuals can develop clinical manifestations of active TB even decades after the initial infection. In this latent, intracellular form, the bacillus is shielded by an extremely robust cell wall and becomes phenotypically resistant to most antituberculars. Therefore, there is a clear rationale to develop novel compounds or carrier-conjugated constructs of existing drugs that are effective against the intracellular form of the bacilli. In this paper, we describe an experimental road map to define optimal candidates against intracellular Mtb and potential compounds effective in the therapy of latent TB. To validate our approach, isoniazid, a first-line antitubercular drug was employed, which is active against extracellular Mtb in the submicromolar range, but ineffective against the intracellular form of the bacteria. Cationic peptide conjugates of isoniazid were synthesized and employed to study the host-directed drug delivery. To measure the intracellular killing activity of the compounds, Mtb-infected MonoMac-6 human monocytic cells were utilized. We have assessed the antitubercular activity, cytotoxicity, membrane interactions in combination with internalization efficacy, localization, and penetration ability on interface and tissue-mimicking 3D models. Based on these in vitro data, most active compounds were further evaluated in vivo in a murine model of TB. Intraperitoneal infectious route was employed to induce a course of slowly progressive and systemic disease. The well-being of the animals, monitored by the body weight, allows a prolonged experimental setup and provides a great opportunity to test the long-term activity of the drug candidates. Having shown the great potency of this simple and suitable experimental design for antimicrobial research, the proposed novel assay platform could be used in the future to develop further innovative and highly effective antituberculars.
Simultaneous Infection With Porcine Reproductive and Respiratory Syndrome and Influenza Viruses Abrogates Clinical Protection Induced by Live Attenuated Porcine Reproductive and Respiratory Syndrome Vaccination
Authors: Chrun Tiphany , Maze Emmanuel A. , Vatzia Eleni , Martini Veronica , Paudyal Basudev , Edmans Matthew D. , McNee Adam , Manjegowda Tanuja , Salguero Francisco J. , Wanasen Nanchaya , Koonpaew Surapong , Graham Simon P. , Tchilian Elma
Published: November 2021

The porcine respiratory disease complex (PRDC) is responsible for significant economic losses in the pig industry worldwide. Porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus are major viral contributors to PRDC. Vaccines are cost-effective measures for controlling PRRS, however, their efficacy in the context of co-infections has been poorly investigated. In this study, we aimed to determine the effect of PRRSV-2 and swine influenza H3N2 virus co-infection on the efficacy of PRRSV modified live virus (MLV) vaccination, which is widely used in the field. Following simultaneous challenge with contemporary PRRSV-2 and H3N2 field isolates, we found that the protective effect of PRRS MLV vaccination on clinical disease and pathology was abrogated, although viral load was unaffected and antibody responses were enhanced. In contrast, co-infection in non-immunized animals reduced PRRSV-2 viremia and H3N2 virus load in the upper respiratory tract and potentiated T cell responses against both PRRSV-2 and H3N2 in the lung. Further analysis suggested that an upregulation of inhibitory cytokines gene expression in the lungs of vaccinated pigs may have influenced responses to H3N2 and PRRSV-2. These findings provide important insights into the effect of viral co-infections on PRRS vaccine efficacy that may help identify more effective vaccination strategies against PRDC in the field.
Anti-TLR7 Antibody Protects Against Lupus Nephritis in NZBWF1 Mice by Targeting B Cells and Patrolling Monocytes
Authors: Murakami Yusuke , Fukui Ryutaro , Tanaka Reika , Motoi Yuji , Kanno Atsuo , Sato Ryota , Yamaguchi Kiyoshi , Amano Hirofumi , Furukawa Yoichi , Suzuki Hitoshi , Suzuki Yusuke , Tamura Naoto , Yamashita Naomi , Miyake Kensuke
Published: November 2021

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6Clow patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages.
Structure and Trophic Niches in Mobile Epifauna Assemblages Associated With Seaweeds and Habitats of Syngnathid Fishes in Cíes Archipelago (Atlantic Islands Marine National Park, North West Iberia)
Authors: Piñeiro-Corbeira Cristina , Iglesias Laura , Nogueira Raquel , Campos Sara , Jiménez Arturo , Regueira Marcos , Barreiro Rodolfo , Planas Miquel
Published: November 2021

Syngnathids are vulnerable fishes closely associated with seaweeds and seagrass, which provide shelter and food resources. Even though most syngnathids commonly feed on small crustaceans, the feeding regimes may differ depending on the species and prey availability. This is the first monitoring study to explain syngnathid abundances and dietary regimes within macroalgal beds in Cíes Archipelago (Atlantic Islands Marine National Park, North West Iberian Peninsula). We sampled the epifaunal assemblages in seaweed communities dominated by the canopy-forming macroalgaeGongolaria baccataandCodiumspp. seasonally during 2 years. The epifaunal structure was mostly represented by harpacticoid copepods, amphipods (especially gammarids) and gastropods. Epifauna exhibited low plant-host specificity and a higher dominance of amphipods on the more structurally complex macroalgaeG. baccata.The epifaunal assemblages and syngnathid specimens were assessed for trophic structure using stable isotopes (δ13C and δ15N). The three syngnathids (Hippocampus guttulatus,Syngnathus acus, andEntelurus aequoreus) inhabiting Cíes Archipelago were sympatric. They occupied highly similar trophic positions (TPs), but differed in niche size, in such a way that the snake pipefishE. aequoreuswould likely feed on smaller prey. The assessment of the feeding regime in the dominant great pipefishS. acusrevealed that amphipods mostly contributed to bulk diet, followed by isopods, carideans, and copepods, whereas mysidaceans were not highly consumed. Seasonal changes in both epifaunal structure and syngnathids abundance confirmed that syngnathids are seasonal residents in Cíes Archipelago, migrating to other areas in autumn when the seaweed cover is drastically reduced and the epifaunal structure modified. This study showed the importance ofGongolariaassemblages in Cíes Archipelago, providing rich dietary sources and potentially contributing to higher abundances and diversity of syngnathids. Ongoing cover reduction inGongolariaassemblages in certain regions (e.g., Mediterranean) should be considered a potential ecological concern for syngnathids and accompanying fauna, requiring further investigations.
Obesity Facts and Their Influence on Renal Function Across the Life Span
Authors: Koch Vera H.
Published: November 2021

Obesity is a chronic disease, with a rapidly increasing prevalence worldwide. Body mass index (BMI) provides the most useful population-level measure of overweight and obesity. For adults, overweight is defined as a BMI (Kg/m2) ≥ 25, and obesity as a BMI ≥ 30, for non-Asians and ≥ 27.5 for Asians. Abdominal obesity can be defined as a waist circumference equal to or higher than 102 cm for men and ≥88 cm for women. The definition of children and adolescents BMI changes with age and sex. Obesity may be exogenous or endogenous obesity, the latter is multifactorial and predominantly manifested during childhood. Presently, overweight and obesity are linked to more deaths worldwide than underweight. The total kidney glomerular filtration rate (GFR) is determined by the sum of nephrons and the GFR within each nephron or single nephron GFR. In clinical practice, GFR is more frequently calculated by GFR estimating equations based upon the plasma levels of creatinine, cystatin C, or both. The measured value of plasma creatinine is strongly influenced by non-GFR factors, by its tubular and gastrointestinal secretion, and by the problems associated with the lack of standardization of creatinine's laboratory assay discrediting it as an ideal GFR biomarker. Unlike creatinine, cystatin C plasma levels are mainly determined by GFR. Obesity may affect the kidney,viadevelopment of systemic arterial hypertension and/or diabetes mellitus, or directly, by ectopic accumulation of adipose tissue in the kidney. As obesity is a clinical condition associated with altered body composition, creatinine may not be the ideal biomarker for GFR measurement in obese individuals.
Factors for Visual Acuity Improvement After Anti-VEGF Treatment of Wet Age-Related Macular Degeneration in China: 12 Months Follow up
Authors: Lu Yan , Huang Wenzhi , Zhang Yuehong , Huang Xiongfei , Zhang Xu , Ma Haizhi , Ren Guoliang , Shi Feng , Kuang Lihui , Yan Shigang , Luo Shuke , Zhang Junyan , He Jingfang , Yang Weizhong , Gao Zongyin , Leng Yunxia
Published: November 2021

Purpose: To evaluate the treatment solutions and effectiveness of intravitreal ranibizumab (RBZ) or conbercept in patients with wet age-related macular degeneration (wAMD) in a real-life setting in China.

Methods: The medical records of 368 patients with wAMD who started RBZ or conbercept treatment between 1 May 2014 and 30 April 2018 were evaluated. All patients were defined on fundus angiography at baseline to determine the subtype of AMD (PCV or CNV). We report visual acuity (VA) and central retinal thickness (CRT) measurements at baseline and 12 months.

Results: The average number of anti-VEGF injections was 2.1 ± 1.2. The BCVA improvement of these two groups was similar with a difference of 1.00 letter (95% CI: −1.4~3.4, p = 0.8505). At the end of the study, a BCVA increase of at least 5 letters was determined to be a satisfactory efficacy endpoint. Several factors were related to the possible improvement in the satisfactory efficacy endpoint, including female sex (OR 2.07, 95% CI 1.22~3.51), number of injections (OR 1.40, 95% CI 1.12~1.75) and VA change at the first month (OR 13.75, 95% CI 7.41~25.51). Additionally, some factors were related to the possible reduction in the satisfactory efficacy endpoint, including diabetes (OR 0.27, 95% CI 0.10~0.73) and disease history (OR 0.75, 95% CI 0.57~0.98).

Conclusion: Our study demonstrates that anti-VEGF drugs can effectively improve BCVA and reduce CRT in AMD patients. Sex, number of injections, VA change at the first month, diabetes and disease history are the most important factors affecting visual acuity.
Conserved Amino Acid Moieties of Candidatus Desulforudis audaxviator MazF Determine Ribonuclease Activity and Specificity
Authors: Tamiya-Ishitsuka Hiroko , Tsuruga Masako , Noda Naohiro , Yokota Akiko
Published: November 2021

The toxin-antitoxin (TA) system, inherent to various prokaryotes, plays a critical role in survival and adaptation to diverse environmental stresses. The toxin MazF, belonging to the type II TA system, functions as a sequence-specific ribonuclease that recognizes 3 to 7 bases. In recent studies, crystallographic analysis of MazFs from several species have suggested the presence of amino acid sites important for MazF substrate RNA binding and for its catalytic activity. Herein, we characterized MazF obtained from Candidatus Desulforudis audaxviator (MazF-Da) and identified the amino acid residues necessary for its catalytic function. MazF-Da, expressed using a cell-free protein synthesis system, is a six-base-recognition-specific ribonuclease that preferentially cleaves UACAAA sequences and weakly cleaves UACGAA and UACUAA sequences. We found that MazF-Da exhibited the highest activity at around 60°C. Analysis using mutants with a single mutation at an amino acid residue site that is well conserved across various MazF toxins showed that G18, E20, R25, and P26 were important for the ribonuclease activity of MazF-Da. The recognition sequence of the N36A mutant differed from that of the wild type. This mutant cleaved UACAAG sequences in addition to UACAAA sequences, but did not cleave UACGAA or UACUAA sequences, suggesting that Asn36 affects the loosening and narrowing of MazF-Da cleavage sequence recognition. Our study posits UACAAA as the recognition sequence of MazF-Da and provides insight into the amino acid sites that are key to its unique enzymatic properties.
Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia Are Associated With the Diabetic Retinopathy Stage and Cognitive Decline in Patients With Type 2 Diabetes
Authors: Choi Eun Young , Park Yae Won , Lee Minyoung , Kim Min , Lee Christopher Seungkyu , Ahn Sung Soo , Kim Jinna , Lee Seung-Koo
Published: November 2021

Purpose: The aim of this study was to evaluate whether perivascular space (PVS) severity and retinal ganglion cell layer (GCL) thickness differed based on the stage of diabetic retinopathy (DR) and the cognitive status in patients with DR.

Methods: A total of 81 patients with DR (51 in the non-proliferative group and 30 in the proliferative group) were included in this retrospective, cross-sectional study. PVS severity was assessed in the basal ganglia (BG) and centrum semiovale using MRI. The total cerebral small vessel disease (SVD) score was determined based on the numbers of lacunes and microbleeds and the severity of white matter hyperintensity. Optical coherence tomography was used to measure foveal and perifoveal GCL thicknesses. Cerebral SVD markers and cognitive function were compared between the groups, and correlations between the BG-PVS severity and the Mini-Mental Status Examination (MMSE) scores and GCL parameters were evaluated.

Results: Patients with proliferative DR had higher BG-PVS severity (P = 0.012), higher total cerebral SVD scores (P = 0.035), reduced GCL thicknesses in the inferior (P = 0.027), superior (P = 0.046), and temporal (P = 0.038) subfields compared to patients with non-proliferative DR. In addition, the BG-PVS severity was negatively correlated with the MMSE score (P = 0.007), and the GCL thickness was negatively correlated with the BG-PVS severity (P-values < 0.05 for inferior, superior, and temporal subfields).

Conclusion: BG-PVS severity and retinal GCL thickness may represent novel imaging biomarkers reflecting the stage of DR and cognitive decline in diabetic patients. Furthermore, these results suggest a possible link between cerebral and retinal neurodegeneration at the clinical level.
Assessing a Sensory-Motor-Cognition Triad in Amnestic Mild Cognitive Impairment With Dichotic Listening While Walking: A Dual-Task Paradigm
Authors: Gorecka Marta Maria , Vasylenko Olena , Waterloo Knut , Rodríguez-Aranda Claudia
Published: November 2021

A contemporary topic in aging research relates to the significance of cognitive changes proper to mild cognitive impairment (MCI) to higher risk of falls and gait deteriorations. The present study addresses this question in the amnestic type of MCI (aMCI) by examining a triad of interrelated comorbidities occurring in the MCI condition: attentional impairments, hearing loss and gait disturbances. To this end, we applied a dichotic listening (DL) test during over-ground walking. DL assesses spontaneous and lateralized auditory attention in three conditions (i.e., free report or Non-forced (NF), Forced-Right (FR) ear and Forced-Left (FL) ear). Earlier reports suggest that this dual-task paradigm evoke asymmetric gait effects on healthy controls, which are moderated by degree of hearing loss. Therefore, the aim of the present study was to evaluate the effects of DL on bilateral (data from both limbs) and lateralized (each limb separately) gait outcomes in a group of forty-three aMCI participants (mean = 71.19) and fifty-two healthy older controls (mean = 70.90) by using hearing loss as a covariate in all analyses. Results showed the aMCI group presented overall compromised gait parameters, especially higher gait variability in all DL conditions during lateralized attentional control. These findings were observed bilaterally, and no lateralized effects on gait were observed. Only after controlling for hearing acuity, gait asymmetries on step length variability emerged almost exclusively in healthy controls. It was concluded that hearing loss in the aMCI group together with higher attentional impairments preclude aMCI individuals to properly execute DL and therefore, they do not display gait asymmetries. The present data demonstrate that varied demands on attentional control dependent on hearing acuity affects gait negatively in healthy older adults and aMCI individuals in very different ways. The appearance of asymmetric effects seems to be a perturbation related to normal aging, while the lack of asymmetries but exaggerated gait variability characterizes aMCI. The present findings show the intricate interplay of sensory, cognitive, and motor deteriorations in different group of older adults, which stresses the need of addressing co-occurring comorbidities behind gait perturbations in individuals prone to develop a dementia state.
Analysis of Factors Associated With Depression in Community-Dwelling Older Adults in Wuhan, China
Authors: Liu Aihong , Peng Yingjie , Zhu Wenli , Zhang Yanling , Ge Shihui , Zhou Yun , Zhang Kemeng , Wang Zhaohui , He Ping
Published: November 2021

Objectives: This study aimed to identify the independent factors associated with depression in community-dwelling older adults in Wuhan, China.

Methods: Four hundred and seventy older adults (aged ≥65 years) from four communities dwelling on Junshan Street in Wuhan, China were included in this study. Participants completed a questionnaire that asked questions pertaining to age, gender, educational level, income, living situation, care situation, social support, and social engagement. The 30-item Geriatric Depression Scale (GDS-30), the Fried frailty phenotype scale, the activities of daily living (ADL) scale, the mini nutritional assessment scale-short form (MNA-SF), and the Mini-cog scale were used to assess depression, frailty, self-care ability, malnutritional risk, and cognitive dysfunction, respectively. Differences in age, gender, educational level, income, living situation, care situation, social support, social engagement, ADL score, risk of malnutrition, frailty, and cognitive dysfunction between the non-depression (GDS-30 score <10 points) and depression groups (GDS-30 score ≥10 points) were compared using a chi-square test. Moreover, correlations between factors and depression were analyzed using Pearson’s correlation. Then, significant variables (p < 0.05) from the chi-square test were included in a multivariable logistic regression model to identify the independent factors associated with depression.

Results: The incidence of depression among the participants was 14.04%. Age (p < 0.001), educational level (p < 0.001), living situation (p < 0.001), social support (p = 0.001), ADL score (p = 0.023), frailty (p < 0.001), and cognitive dysfunction (p < 0.001) were all significantly associated with depression, in which age, poor social support, frailty, and cognitive dysfunction were identified as independent factors.

Conclusion: Improving social support and effective interventions for frailty and cognitive dysfunction may help relieve depression in community-dwelling older adults.
Limited Add-On Effects of Unilateral and Bilateral Transcranial Direct Current Stimulation on Visuo-Motor Grip Force Tracking Task Training Outcome in Chronic Stroke. A Randomized Controlled Trial
Authors: Taud Benedikt , Lindenberg Robert , Darkow Robert , Wevers Jasmin , Höfflin Dorothee , Grittner Ulrike , Meinzer Marcus , Flöel Agnes
Published: November 2021

Background:This randomized controlled trial investigated if uni- and bihemispheric transcranial direct current stimulation (tDCS) of the motor cortex can enhance the effects of visuo-motor grip force tracking task training and transfer to clinical assessments of upper extremity motor function.

Methods:In a randomized, double-blind, sham-controlled trial, 40 chronic stroke patients underwent 5 days of visuo-motor grip force tracking task training of the paretic hand with either unilateral or bilateral (N= 15/group) or placebo tDCS (N= 10). Immediate and long-term (3 months) effects on training outcome and motor recovery (Upper Extremity Fugl-Meyer, UE-FM, Wolf Motor Function Test, and WMFT) were investigated.

Results:Trained task performance significantly improved independently of tDCS in a curvilinear fashion. In the anodal stimulation group UE-FM scores were higher than in the sham group at day 5 (adjusted mean difference: 2.6, 95%CI: 0.6–4.5,p= 0.010) and at 3 months follow up (adjusted mean difference: 2.8, 95%CI: 0.8–4.7,p= 0.006). Neither training alone, nor the combination of training and tDCS improved WMFT performance.

Conclusions:Visuo-motor grip force tracking task training can facilitate recovery of upper extremity function. Only minimal add-on effects of anodal but not dual tDCS were observed.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=NCT01969097&cntry=&state=&city=&dist=, identifier: NCT01969097, retrospectively registered on 25/10/2013.
Comparison of the Diet Photograph Record to Weighed Dietary Record and 24 h Dietary Recall for Estimating Energy and Nutrient Intakes Among Chinese Preschoolers
Authors: Xu Yujie , Duan Ruonan , Feng Ping , Gao Wanke , Xing Dong , Cheng Guo
Published: November 2021

This study aimed to assess the relative validity of the diet photograph record (DP) for measuring the energy and nutrient intakes against the weighed dietary record (WD) and the 24 h dietary recall (HR) in the Chinese preschoolers. In this study, 40 preschool children aged 4–6 years and their parents were recruited from a kindergarten in southwest China. Dietary intake of the preschoolers on a same day, as estimated by the DP and the HR were compared with the WD. These three methods were administered by the three group of investigators independently. The mean differences, correlation coefficients, cross-classifications, and weighted κ, as well as the Bland–Altman plots were performed to assess the differences and agreements among the estimates from the DP, the HR, and the WD. For the DP and the HR, the estimates of energy and nutrient intakes were moderate to high correlated with the WD, with the higher coefficients ranging from 0.73 to 0.94 for the DP. Both the methods tended to underestimate the dietary intake, but the differences from the known weights using the DP were significantly smaller than those using the HR. The weighed κ values ranking the preschoolers ranged from 0.48 to 0.80 for the DP and ranged from 0.28 to 0.64 for the HR. Furthermore, the Bland–Altman plots indicated a better agreement between the DP and the WD for estimating energy and nutrient intakes. This DP is a valid tool for measuring energy and nutrient intakes among the preschoolers.
Multiomics Landscape Uncovers the Molecular Mechanism of the Malignant Evolution of Lung Adenocarcinoma Cells to Chronic Low Dose Cadmium Exposure
Authors: Dai Shun-Dong , Wang Shuang , Qin Ya-Nan , Zhu Jin-Chao
Published: November 2021

Cadmium (Cd) from cigarette smoke and polluted air can lead to lung adenocarcinoma after long-term inhalation. However, most studies are based on short-term exposure to this toxic metal at high concentrations. Here, we investigate the effects of long-term exposure of A549 cells (lung adenocarcinoma) to cadmium at low concentrations using morphological and multiomics analyses. First, we treated A549 cells continuously with CdCl2 at 1μM for 8 months and found that CdCl2 promoted cellular migration and invasion. After that, we applied transmission electron and fluorescence microscopies and did not observe significant morphological changes in Golgi apparatus, endoplasmic reticulum, lysosomes, or mitochondria on Cd treated cells; microfilaments, in contrast, accumulated in lamellipodium and adhesion plaques, which suggested that Cd enhanced cellular activity. Second, by using whole-exome sequencing (WES) we detected 4222 unique SNPs in Cd-treated cells, which included 382 unique non-synonymous mutation sites. The corresponding mutated genes, after GO and KEGG enrichments, were involved mainly in cell adhesion, movement, and metabolic pathways. Third, by RNA-seq analysis, we showed that 1250 genes (784 up and 466 down), 1623 mRNAs (1023 up and 591 down), and 679 lncRNAs (375 up and 304 down) were expressed differently. Furthermore, GO enrichment of these RNA-seq results suggested that most differentially expressed genes were related to cell adhesion and organization of the extracellular matrix in biological process terms; KEGG enrichment revealed that the differentially expressed genes took part in 26 pathways, among which the metabolic pathway was the most significant. These findings could be important for unveiling mechanisms of Cd-related cancers and for developing cancer therapies in the future.
Distribution Characteristics and Prognostic Value of Immune Infiltration in Oligometastatic Breast Cancer
Authors: Zhou Danyang , Jiang Kuikui , Hong Ruoxi , Lu Qianyi , Xia Wen , Li Mei , Zheng Chengyou , Zheng Qiufan , Xu Fei , Wang Shusen
Published: November 2021

Background

To assess the distribution characteristics and the prognostic value of immune infiltration in female oligometastatic breast cancer patients.

Methods

We retrospectively analyzed the clinicopathological data of oligometastatic breast cancer (OMBC) patients diagnosed between June 2000 and January 2020. Immune markers were quantified by immunohistochemistry on FFPE tissues in paired normal breast tissues, primary breast cancers and oligometastatic lesions. Survival analyses were performed using the Kaplan-Meier curves and Cox-proportional hazards model.

Results

A total of 95 female OMBC patients visited Sun Yat-sen University Cancer Center between June 2000 and January 2020, and 33 of them had matched normal breast tissues, primary cancers and oligometastatic lesions and were reviewed in immune infiltration analysis. CD8 of primary tumors had a higher expression than that in matched normal tissues. The expressions of CD8 and FOXP3 were higher in the primary sites than that in the oligometastatic lesions. CD3, CD4 and CD8 were significantly lower in the intratumoral regions than that in the peritumoral regions both in primary and oligometastatic lesions. Notably, the high percentage of CD3 in the intratumoral oligometastatic lesions predicted the longer PFS and OS, and higher CD4 in the same lesions also predicted a better OS. There was obviously positive correlation between CD4/CD3 and Ki-67 in primary cancers and negative correlation between CD4/CD3 and ER in oligometastatic sites.

Conclusion

We explored immune distribution and evolution in time and space in OMBC to provide new understandings for biological behaviors of this disease and further divided patients in different prognosis.
Suppression of Ribosome Biogenesis by Targeting WD Repeat Domain 12 (WDR12) Inhibits Glioma Stem-Like Cell Growth
Authors: Mi Lanjuan , Qi Qinghui , Ran Haowen , Chen Lishu , Li Da , Xiao Dake , Wu Jiaqi , Cai Yan , Zhang Songyang , Li Yuanyuan , Li Bohan , Xie Jiong , Huang Haohao , Li Tao , Zhou Tao , Li Ailing , Qi Ji , Li Fangye , Man Jianghong
Published: November 2021

Glioma stem-like cells (GSCs) are a subset of tumor cells that initiate malignant growth and promote the therapeutic resistance of glioblastoma, the most lethal primary brain tumor. Ribosome biogenesis is an essential cellular process to maintain cell growth, but its regulatory mechanism in GSCs remains largely unknown. Here, we show that WD repeat domain 12 (WDR12), a component of the Pes1-Bop1 complex (PeBoW), is required for ribosome biogenesis in GSCs. WDR12 is preferentially expressed in GSCs compared to non-stem tumor cells and normal brain cells. High levels of WDR12 are associated with glioblastoma progression and poor prognosis. Silencing WDR12 results in the degradation of PeBoW complex components and prevents the maturation of 28S rRNA, thereby inhibiting ribosome biogenesis in GSCs. Subsequently, WDR12 depletion compromises GSC proliferation, inhibits GSC-derived orthotopic tumor growth, and extends animal survival. Together, our results suggest that WDR12 is crucial for ribosome biogenesis in GSCs, and is thus a potential target for GSC-directed therapy of glioblastoma.
Resistance Exercise and Whey Protein Supplementation Reduce Mechanical Allodynia and Spinal Microglia Activation After Acute Muscle Trauma in Rats
Authors: Rodrigues Gusthavo , Moraes Thamyris , Elisei Lívia , Malta Iago , dos Santos Rafaela , Novaes Rômulo , Lollo Pablo , Galdino Giovane
Published: November 2021

Muscle injury caused by direct trauma to the skeletal muscle is among the main musculoskeletal disorders. Non-pharmacological treatments have been effective in controlling muscle injury–induced pain; however, there are just a few studies in the literature investigating this response. Thus, the present study aimed to evaluate the effect of a resistance exercise training protocol combined or not with whey protein supplementation on mechanical allodynia induced by muscle injury. In addition, we also investigated the involvement of spinal glial cells in this process. For this purpose, male Wistar rats underwent a muscle injury model induced by direct trauma to the gastrocnemius muscle. Mechanical allodynia was measured by a digital von Frey algesimeter test. To evaluate the effect of exercise and/or supplementation on mechanical allodynia, the animals practiced exercises three times a week for 14 days and received supplementation daily for 14 days, respectively. Moreover, the effect of both the participation of spinal glial cells in the muscle injury and the resistance exercise training and/or whey protein supplementation on these cells was also investigated by the Western blot assay. The results demonstrated that resistance exercise training and whey protein supplementation, combined or alone, reduced mechanical allodynia. These treatments also reduced the number of interstitial cells and pro-inflammatory cytokine IL-6 levels in the injured muscle. It was also found that spinal microglia and astrocytes are involved in muscle injury, and that resistance exercise training combined with whey protein supplementation inhibits spinal microglia activation. The results suggest that both resistance exercise training and whey protein supplementation may be effective non-pharmacological treatments to control pain in the muscle after injury induced by acute trauma.
The Effect of Cardiovascular Medications on Disease-Related Outcomes in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis
Authors: Zhang Wan-Tong , Wang Xu-Jie , Xue Chun-Miao , Ji Xin-Yu , Pan Lin , Weng Wei-Liang , Li Qiu-Yan , Hua Guo-Dong , Zhu Bao-Chen
Published: November 2021

Background: Multiple studies have revealed that idiopathic pulmonary fibrosis (IPF) patients are more at risk for cardiovascular diseases and that many IPF patients receive cardiovascular medications like statins, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and anticoagulants. Existing studies have reported divergent findings on the link between cardiovascular medications and fibrotic disease processes. The aim of this study is to synthesize the evidence on the efficacy of cardiovascular medications in IPF.

Methods: We searched studies reporting the effect of cardiovascular medications on IPF in the PubMed, Embase, Web of Science, Cochrane Library, and two Chinese databases (China National Knowledge Infrastructure database and China Wanfang database). We calculated survival data, forced vital capacity (FVC) decline, and IPF-related mortality to assess the efficacy of cardiovascular medications in IPF. We also estimated statistical heterogeneity by using I2 and Cochran Q tests, and publication bias was evaluated by risk of bias tools ROBINS-I.

Results: A total of 12 studies were included in the analysis. The included studies had moderate-to-serious risk of bias. Statin use was associated with a reduction in mortality (hazard ratio (HR), 0.89; 95% CI 0.83–0.97). Meta-analysis did not demonstrate any significant relationship between statin use and the FVC decline (HR, 0.86; 95% CI 0.73–1.02), ACEI/ARB use, and survival data (HR, 0.92; 95% CI 0.73–1.15) as well as anticoagulant use and survival data (HR, 1.16; 95% CI 0.62–2.19).

Conclusion: Our study suggested that there is a consistent relationship between statin therapy and survival data in IPF population. However, there is currently insufficient evidence to conclude the effect of ACEI, ARB, and anticoagulant therapy on IPF population especially to the disease-related outcomes in IPF.
Endobronchial Therapy With Gentamicin and Dexamethasone After Airway Clearance by Bronchoscopy in Exacerbation of Non-Cystic Fibrosis Bronchiectasis: A Real-World Observational Study
Authors: Li Qiuhong , Huang Beijie , Gu Hongyan , Zhou Ying , Shan Xizheng , Meng Siming , Qin Meng , Shi Jingyun , Chen Yanan , Li Huiping
Published: November 2021

Background: The exacerbation of non-cystic fibrosis bronchiectasis (NCFB) may lead to poor prognosis. The objective of this study was to retrospectively analyze the clinical efficacy and safety of endobronchial therapy with gentamicin and dexamethasone after airway clearance by bronchoscopy in the exacerbation of NCFB.

Methods: We retrospectively reviewed 2,156 patients with NCFB between January 2015 and June 2016 and 367 consecutive patients with exacerbation of bronchiectasis who had complete data and underwent airway clearance (AC) by bronchoscopy. The final cohort included 181 cases of intratracheal instillation with gentamicin and dexamethasone after AC (a group with airway drugs named the drug group) and 186 cases of AC only (a group without airway drugs named the control group). The last follow-up was on June 30, 2017.

Results: The total cough score and the total symptom score in the drug group were improved compared to those in the control group during 3 months after discharge (p < 0.001). Re-examination of chest HRCT within 4–6 months after discharge revealed that the improvements of peribronchial thickening, the extent of mucous plugging, and the Bhalla score were all significantly improved in the drug group. Moreover, the re-exacerbations in the drug group were significantly decreased within 1 year after discharge. Univariate analysis showed a highly significant prolongation of the time to first re-exacerbation in bronchiectasis due to treatment with airway drugs compared with that of the control group. Multivariate Cox regression analysis showed that the risk of first re-exacerbation in the drug group decreased by 29.7% compared with that of the control group.

Conclusion: Endobronchial therapy with gentamicin and dexamethasone after AC by bronchoscopy is a safe and effective method for treating NCFB.
Computational Network Pharmacology–Based Strategy to Capture Key Functional Components and Decode the Mechanism of Chai-Hu-Shu-Gan-San in Treating Depression
Authors: Wang Kexin , Li Kai , Chen Yupeng , Wei Genxia , Yu Hailang , Li Yi , Meng Wei , Wang Handuo , Gao Li , Lu Aiping , Peng Junxiang , Guan Daogang
Published: November 2021

Traditional Chinese medicine (TCM) usually plays therapeutic roles on complex diseases in the form of formulas. However, the multicomponent and multitarget characteristics of formulas bring great challenges to the mechanism analysis and secondary development of TCM in treating complex diseases. Modern bioinformatics provides a new opportunity for the optimization of TCM formulas. In this report, a new bioinformatics analysis of a computational network pharmacology model was designed, which takes Chai-Hu-Shu-Gan-San (CHSGS) treatment of depression as the case. In this model, effective intervention space was constructed to depict the core network of the intervention effect transferred from component targets to pathogenic genes based on a novel node importance calculation method. The intervention-response proteins were selected from the effective intervention space, and the core group of functional components (CGFC) was selected based on these intervention-response proteins. Results show that the enriched pathways and GO terms of intervention-response proteins in effective intervention space could cover 95.3 and 95.7% of the common pathways and GO terms that respond to the major functional therapeutic effects. Additionally, 71 components from 1,012 components were predicted as CGFC, the targets of CGFC enriched in 174 pathways which cover the 86.19% enriched pathways of pathogenic genes. Based on the CGFC, two major mechanism chains were inferred and validated. Finally, the core components in CGFC were evaluated by in vitro experiments. These results indicate that the proposed model with good accuracy in screening the CGFC and inferring potential mechanisms in the formula of TCM, which provides reference for the optimization and mechanism analysis of the formula in TCM.
Artificial Intelligence Approach to the Monitoring of Respiratory Sounds in Asthmatic Patients
Authors: Hafke-Dys Honorata , Kuźnar-Kamińska Barbara , Grzywalski Tomasz , Maciaszek Adam , Szarzyński Krzysztof , Kociński Jędrzej
Published: November 2021

Background: Effective and reliable monitoring of asthma at home is a relevant factor that may reduce the need to consult a doctor in person.

Aim: We analyzed the possibility to determine intensities of pathological breath phenomena based on artificial intelligence (AI) analysis of sounds recorded during standard stethoscope auscultation.

Methods: The evaluation set comprising 1,043 auscultation examinations (9,319 recordings) was collected from 899 patients. Examinations were assigned to one of four groups: asthma with and without abnormal sounds (AA and AN, respectively), no-asthma with and without abnormal sounds (NA and NN, respectively). Presence of abnormal sounds was evaluated by a panel of 3 physicians that were blinded to the AI predictions. AI was trained on an independent set of 9,847 recordings to determine intensity scores (indexes) of wheezes, rhonchi, fine and coarse crackles and their combinations: continuous phenomena (wheezes + rhonchi) and all phenomena. The pair-comparison of groups of examinations based on Area Under ROC-Curve (AUC) was used to evaluate the performance of each index in discrimination between groups.

Results: Best performance in separation between AA and AN was observed with Continuous Phenomena Index (AUC 0.94) while for NN and NA. All Phenomena Index (AUC 0.91) showed the best performance. AA showed slightly higher prevalence of wheezes compared to NA.

Conclusions: The results showed a high efficiency of the AI to discriminate between the asthma patients with normal and abnormal sounds, thus this approach has a great potential and can be used to monitor asthma symptoms at home.
Residual Impact of Concurrent, Resistance, and High-Intensity Interval Training on Fasting Measures of Glucose Metabolism in Women With Insulin Resistance
Authors: Alvarez Cristian , Ciolac Emmanuel Gomes , Guimarães Guilherme Veiga , Andrade David C , Vasquez-Muñoz Manuel , Monsalves-Álvarez Matías , Delgado-Floody Pedro , Alonso-Martínez Alicia M. , Izquierdo Mikel
Published: November 2021

We sought to assess the residual effects (post 72-h training cessation) on fasting plasma glucose (FPG) and fasting insulin (FI) after 12-weeks of high-intensity interval training (HIIT), resistance training (RT), or concurrent training (CT) in women with insulin resistance (IR). We also aimed to determine the training-induced, post-training residual impact of CT. A total of adult 45 women (age 38.5±9.2years) were included in the final analysis and were assigned to a control (CG; n=13, BMI 28.3±3.6kg/m2), HIIT [n=14, BMI 28.6±3.6kg/m2, three sessions/wk., 80–100% of the maximum heart rate (HRmax)], RT [n=8, BMI 29.4±5.5kg/m2, two sessions/wk., 8–10 points of the modified Borg, corresponding to 20 to 50% range of one maximum repetition test (1RM)], or CT group (n=10, BMI 29.1±3.0kg/m2, three sessions/wk., 80–100% of HRmax, and 8–10 Borg, or 20 to 50% range of 1RM, to each HIIT and RT compounds), with the latter including both HIIT and RT regimens. Training interventions lasted 12-weeks. The main outcomes were FPG and FI measured at pre- and 24-h and 72-h post-training (FPG24h, FI24h, and FPG72h, FI72h, respectively). Secondary endpoints were body composition/anthropometry and the adiposity markers waist circumference (WC) and tricípital skinfold (TSF). The residual effects 72-h post-training [delta (∆)] were significantly poorer (all p<0.01) in the CT group (∆FPG72h+6.6mg/dl, η2: 0.76) than in the HIIT (∆FPG72h+1.2mg/dl, η2: 0.07) and RT (∆FPG72h+1.0mg/dl, η2: 0.05) groups. These findings reveal that HIIT reduces FPG and RT reduces FI 24-h post-training; both exercise interventions alone have remarkably better residual effects on FPG and FI (post-72h) than CT in women with insulin resistance.
Physiological and Morphological Responses of Hydroponically Grown Pear Rootstock Under Phosphorus Treatment
Authors: Chen Guodong , Li Yang , Jin Cong , Wang Jizhong , Wang Li , Wu Juyou
Published: November 2021

Phosphorus (P) is an essential macronutrient for the growth and development of fruit trees, playing an important role in photosynthesis, nucleic acid synthesis, and enzyme activity regulation. The plasticity of plant phenotypic has been investigated in diverse species under conditions of P-deficiency or P-excess. Based on these researches, P level fluctuations in different species result in different characteristics of the response. Nevertheless, little is known about the response of pear seedling rootstock (Pyrus betulifolia Bunge) to the changing of P levels. To explore the effects of different levels of P on the growth of pear seedling rootstock, we performed the hydroponic assays to determine and analyze the biological indexes including growth parameters, photosynthetic rate, root and shoot morphological traits, and concentrations of macro- and micronutrients. The results show that either deficiency or excess of P inhibited the growth and development of pear seedling rootstock. Root growth (down 44.8%), photosynthetic rate (down 59.8%), and acid phosphatase (ACP) activity (down 44.4%) were inhibited under the P-deficiency conditions (0mM), compared with normal P conditions (1mM). On the other hand, dark green leaves, suppression of root elongation (down 18.8%), and photosynthetic rate (down 25%) were observed under regimes of excessive P, compared with normal P conditions (1mM). Furthermore, the root concentration of not only P, but also those of other mineral nutrients were affected by either P treatment. In brief, these results indicated that a careful choice of P fertilizer supply is crucial to ensuring normal growth and development of pear seedling rootstock.