bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of Biofilms on Carbapenem Susceptibility and Patient Outcome in Device Associated K. pneumoniae Infections: Insights Into Phenotype vs Genome-Wide Analysis and Correlation
Authors: Devanga Ragupathi Naveen Kumar , Muthuirulandi Sethuvel Dhiviya Prabaa , Triplicane Dwarakanathan Hariharan , Murugan Dhivya , Umashankar Yamini , Monk Peter N. , Karunakaran Esther , Veeraraghavan Balaji
Published: December 2020

Klebsiella pneumoniae is one of the leading causes of nosocomial infections. Carbapenem-resistant K. pneumoniae are on the rise globally. The biofilm forming ability of K. pneumoniae further complicates patient management. There is still a knowledge gap on the association of biofilm formation with patient outcome and carbapenem susceptibility, which is investigated in present study. K. pneumoniae isolates from patients admitted in critical care units with catheters and ventilators were included. K. pneumoniae (n = 72) were subjected to 96-well plate biofilm formation assay followed by MBEC assay for subset of strong biofilm formers. Whole genome sequencing and a core genome phylogenetic analysis in comparison with global isolates were performed. Phenotypic analyses showed a positive correlation between biofilm formation and carbapenem resistance. Planktonic cells observed to be susceptible in vitro exhibited higher MICs in biofilm structure, hence MICs cannot be extrapolated for treatment. The biofilm forming ability had a significant association with morbidity/mortality. Infections by stronger biofilm forming pathogens significantly (p < 0.05) resulted in fewer “average days alive” for the patient (3.33 days) in comparison to those negative for biofilms (11.33 days). Phylogenetic analysis including global isolates revealed clear association of sequence types with genes for biofilm formation and carbapenem resistance. Known hypervirulent clone-ST23 with wcaG, magA, rmpA, rmpA2, and wzc with lack of mutation for hyper-capsulation might be poor biofilm formers. ST15, ST16, ST307, and ST258 (reported global high-risk clones) were wcaJ negative indicating the high potential of biofilm forming capacity. Genes wabG and treC for CPS, bcsA and pgaC for adhesins, luxS for quorum sensing were common in all clades in addition to genes for aerobactin (iutA), allantoin (allS), type I and III fimbriae (fimA, fimH, and mrkD) and pili (pilQ and ecpA). This study is the first of its kind to compare genetic features of antimicrobial resistance with a spectrum covering most of the genetic factors for K. pneumoniae biofilm. These results highlight the importance of biofilm screening to effectively manage nosocomial infections by K. pneumoniae. Further, data obtained on epidemiology and associations of biofilm and resistance genetic factors will serve to enhance our understanding on biofilm mechanisms in K. pneumoniae.
Gut Microbial Dysbiosis and Plasma Metabolic Profile in Individuals With Vitiligo
Authors: Ni Qingrong , Ye Zhubiao , Wang Yinghan , Chen Jianru , Zhang Weigang , Ma Cuiling , Li Kai , Liu Yu , Liu Ling , Han Zheyi , Gao Tianwen , Jian Zhe , Li Shuli , Li Chunying
Published: December 2020

Autoimmune diseases are increasingly linked to aberrant gut microbiome and relevant metabolites. However, the association between vitiligo and the gut microbiome remains to be elucidated. Thus, we conducted a case-control study through 16S rRNA sequencing and serum untargeted-metabolomic profiling based on 30 vitiligo patients and 30 matched healthy controls. In vitiligo patients, the microbial composition was distinct from that of healthy controls according to the analysis on α- and β-diversity (P < 0.05), with a characteristic decreased Bacteroidetes: Firmicutes ratio. Meanwhile, the levels of 23 serum metabolites (including taurochenodeoxycholate and L-NG-monomethyl-arginine) in the vitiligo patients were different from those in the healthy individuals and showed significant correlations with some microbial markers. We found that Corynebacterium 1, Ruminococcus 2, Jeotgalibaca and Psychrobacter were correlated significantly with disease duration and serum IL-1β level in vitiligo patients. And Psychrobacter was identified as the most predictive features for vitiligo by machine learning analysis (“importance” = 0.0236). Finally, combining multi-omics data and joint prediction models with accuracies up to 0.929 were established with dominant contribution of Corynebacterium 1 and Psychrobacter. Our findings replenished the previously unknown relationship between gut dysbiosis and vitiligo circulating metabolome and enrolled the gut-skin axis into the understanding of vitiligo pathogenesis.
Identification of New Helicobacter pylori Subpopulations in Native Americans and Mestizos From Peru
Authors: Gutiérrez-Escobar Andrés Julián , Velapatiño Billie , Borda Victor , Rabkin Charles S. , Tarazona-Santos Eduardo , Cabrera Lilia , Cok Jaime , Hooper Catherine C. , Jahuira-Arias Helena , Herrera Phabiola , Noureen Mehwish , Wang Difei , Romero-Gallo Judith , Tran Bao , Peek Richard M. , Berg Douglas E. , Gilman Robert H. , Camargo M. Constanza
Published: December 2020

Region-specific Helicobacter pylori subpopulations have been identified. It is proposed that the hspAmerind subpopulation is being displaced from the Americans by an hpEurope population following the conquest. Our study aimed to describe the genomes and methylomes of H. pylori isolates from distinct Peruvian communities: 23 strains collected from three groups of Native Americans (Asháninkas [ASHA, n = 9], Shimaas [SHIM, n = 5] from Amazonas, and Punos from the Andean highlands [PUNO, n = 9]) and 9 modern mestizos from Lima (LIM). Closed genomes and DNA modification calls were obtained using SMRT/PacBio sequencing. We performed evolutionary analyses and evaluated genomic/epigenomic differences among strain groups. We also evaluated human genome-wide data from 74 individuals from the selected Native communities (including the 23 H. pylori strains donors) to compare host and bacterial backgrounds. There were varying degrees of hspAmerind ancestry in all strains, ranging from 7% in LIM to 99% in SHIM. We identified three H. pylori subpopulations corresponding to each of the Native groups and a novel hspEuropePeru which evolved in the modern mestizos. The divergence of the indigenous H. pylori strains recapitulated the genetic structure of Native Americans. Phylogenetic profiling showed that Orthogroups in the indigenous strains seem to have evolved differentially toward epigenomic regulation and chromosome maintenance, whereas OGs in the modern mestizo (LIM) seem to have evolved toward virulence and adherence. The prevalence of cagA+/vacA s1i1m1 genotype was similar across populations (p = 0.32): 89% in ASHA, 67% in PUNO, 56% in LIM and 40% in SHIM. Both cagA and vacA sequences showed that LIM strains were genetically differentiated (p < 0.001) as compared to indigenous strains. We identified 642 R-M systems with 39% of the associated genes located in the core genome. We found 692 methylation motifs, including 254 population-specific sequences not previously described. In Peru, hspAmerind is not extinct, with traces found even in a heavily admixed mestizo population. Notably, our study identified three new hspAmerind subpopulations, one per Native group; and a new subpopulation among mestizos that we named hspEuropePeru. This subpopulation seems to have more virulence-related elements than hspAmerind. Purifying selection driven by variable host immune response may have shaped the evolution of Peruvian subpopulations, potentially impacting disease outcomes.
Bambusicolous Arthrinium Species in Guangdong Province, China
Authors: Senanayake Indunil C. , Bhat Jayarama D. , Cheewangkoon Ratchadawan , Xie Ning
Published: December 2020

A survey of bambusicolous fungi in Bijiashan Mountain Park, Shenzhen, Guangdong Province, China, revealed severalArthrinium-like taxa from dead sheaths, twigs, and clumps ofBambusaspecies. Phylogenetic relationships were investigated based on morphology and combined analyses of the internal transcribed spacer region (ITS), large subunit nuclear ribosomal DNA (LSU), beta tubulin (β-tubulin), and translation elongation factor 1-alpha (tef 1-α) gene sequences. Based on morphological characteristics and phylogenetic data,Arthrinium acutiapicumsp. nov. andArthrinium pseudorasikravindraesp. nov. are introduced herein with descriptions and illustrations. Additionally, two new locality records ofArthrinium bambusaeandArthrinium guizhouenseare described and illustrated.
Effects of Peptide Thanatin on the Growth and Transcriptome of Penicillium digitatum
Authors: Feng Guirong , Li Xindan , Wang Wenjun , Deng Lili , Zeng Kaifang
Published: December 2020

Penicillium digitatum is the most damaging pathogen provoking green mold in citrus fruit during storage, and there is an urgent need for novel antifungal agents with high efficiency. The aim of this study was to investigate the antifungal effects of peptide thanatin against P. digitatum and the molecular mechanisms. Results showed that peptide thanatin had a prominent inhibitory effect on P. digitatum by in vitro and in vivo test. A total of 938 genes, including 556 downregulated and 382 upregulated genes, were differentially expressed, as revealed by RNA-seq of whole P. digitatum genomes analysis with or without thanatin treatment. The downregulated genes mainly encoded RNA polymerase, ribosome biogenesis, amino acid metabolism, and major facilitator superfamily. The genes associated with heat shock proteins and antioxidative systems were widely expressed in thanatin-treated group. DNA, RNA, and the protein content of P. digitatum were significantly decreased after thanatin treatment. In conclusion, thanatin could inhibit the growth of P. digitatum, and the underlying mechanism might be the genetic information processing and stress response were affected. The research will provide more precise and directional clues to explore the inhibitory mechanism of thanatin on growth of P. digitatum.
Multicellular String-Like Structure Formation by Salmonella Typhimurium Depends on Cellulose Production: Roles of Diguanylate Cyclases, YedQ and YfiN
Authors: Varghese Alan , Ray Semanti , Verma Taru , Nandi Dipankar
Published: December 2020

Bacteria face diverse stresses in the environment and, sometimes, respond by forming multi-cellular structures, e.g., biofilms. Here, we report a novel macroscopic and multi-cellular structure formed by Salmonella Typhimurium, which resembles small strings. These string-like structures, ∼1 cm long, are induced under some stress conditions: iron deprivation by 2,2-Bipyridyl or low amounts of antibiotics or ethanol in minimal media. However, cells in strings revert back to planktonic growth upon return to nutrient rich media. Compared to planktonic cells, strings are more resistant to antibiotics and oxidative stress. Also, strains lacking csgD or rpoS, which are defective in the classical rdar biofilm formation, form strings. Furthermore, some biofilm inducing conditions do not result in strings and vice-versa, demonstrating that strings are not related to classical CsgD-dependent biofilms. Cells in a string are held together by cellulose and a strain lacking bcsA, which is defective in cellulose production, does not form strings. In addition, reductive stress conditions such as dithiothreitol (DTT) or mutations in the Disulfide bonding system (DSB) also give rise to strings. The amounts of c-di-GMP are increased upon string formation and studies with single and double deletion strains of the diguanylate cyclases, yedQ (STM1987) primarily and yfiN (STM2672) partly, revealed their importance for string formation. This is the first study showcasing the ability of Salmonella to produce high amounts of cellulose in liquid culture, instead of an interface, in a CsgD-independent manner. The relevance and possible applications of strings in the production of bacterial cellulose and bioremediation are discussed.
Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke
Authors: He Joy Q. , Sussman Eric S. , Steinberg Gary K.
Published: December 2020

Stroke is the leading cause of serious long-term disability, significantly reducing mobility in almost half of the affected patients aged 65 years and older. There are currently no proven neurorestorative treatments for chronic stroke. To address the complex problem of restoring function in ischemic brain tissue, stem cell transplantation-based therapies have emerged as potential restorative therapies. Aligning with the major cell types found within the ischemic brain, stem-cell-based clinical trials for ischemic stroke have fallen under three broad cell lineages: hematopoietic, mesenchymal, and neural. In this review article, we will discuss the scientific rationale for transplanting cells from each of these lineages and provide an overview of published and ongoing trials using this framework.
Distinct Changes in Global Brain Synchronization in Early-Onset vs. Late-Onset Parkinson Disease
Authors: Wang Tianyu , Liao Haiyan , Zi Yuheng , Wang Min , Mao Zhenni , Xiang Yijuan , Zhang Lin , Li Junli , Shen Qin , Cai Sainan , Tan Changlian
Published: December 2020

Early- and late-onset Parkinson’s disease (EOPD and LOPD, respectively) have different risk factors, clinical features, and disease course; however, the functional outcome of these differences have not been well characterized. This study investigated differences in global brain synchronization changes and their clinical significance in EOPD and LOPD patients. Patients with idiopathic PD including 25 EOPD and 24 LOPD patients, and age- and sex-matched healthy control (HC) subjects including 27 younger and 26 older controls (YCs and OCs, respectively) were enrolled. Voxel-based degree centrality (DC) was calculated as a measure of global synchronization and compared between PD patients and HC groups matched in terms of disease onset and severity. DC was decreased in bilateral Rolandic operculum and left insula and increased in the left superior frontal gyrus (SFG) and precuneus of EOPD patients compared to YCs. DC was decreased in the right putamen, mid-cingulate cortex, bilateral Rolandic operculum, and left insula and increased in the right cerebellum-crus1 of LOPD patients compared to OCs. Correlation analyses showed that DC in the right cerebellum-crus1 was inversely associated with the Hamilton Depression Scale (HDS) score in LOPD patients. Thus, EOPD and LOPD patients show distinct alterations in global synchronization relative to HCs. Furthermore, our results suggest that the left SFG and right cerebellum-crus1 play important roles in the compensation for corticostriatal–thalamocortical loop injury in EOPD and LOPD patients, whereas the cerebellum is a key hub in the neural mechanisms underlying LOPD with depression. These findings provide new insight into the clinical heterogeneity of the two PD subtypes.
Skeletal Muscle-Restricted Expression of Human SOD1 in Transgenic Mice Causes a Fatal ALS-Like Syndrome
Authors: Martin Lee J. , Wong Margaret
Published: December 2020

Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that causes motor neuron (MN) loss and skeletal muscle paralysis. It is uncertain whether this degeneration of MNs is triggered intrinsically and is autonomous, or if the disease initiating mechanisms are extrinsic to MNs. We hypothesized that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. Some inherited forms of ALS are caused by mutations in thesuperoxide dismutase-1(SOD1) gene, that encodes an antioxidant protein, so we created transgenic (tg) mice expressing wild-type-, G37R-, and G93A-humanSOD1gene variants only in skeletal muscle. Presence of human SOD1 (hSOD1) protein in skeletal muscle was verified by western blotting, enzyme activity gels, and immunofluorescence in myofibers and satellite cells. These tg mice developed limb weakness and paresis with motor deficits, limb and chest muscle wasting, diaphragm atrophy, and age-related fatal disease with a lifespan shortening of 10–16%. Brown and white adipose tissue also became wasted. Myofibers of tg mice developed crystalline-like inclusions, individualized sarcomere destruction, mitochondriopathy with vesiculation, DNA damage, and activated p53. Satellite cells became apoptotic. The diaphragm developed severe loss of neuromuscular junction presynaptic and postsynaptic integrity, including decreased innervation, loss of synaptophysin, nitration of synaptophysin, and loss of nicotinic acetylcholine receptor and scaffold protein rapsyn. Co-immunoprecipitation identified hSOD1 interaction with rapsyn. Spinal cords of tg mice developed gross atrophy. Spinal MNs formed cytoplasmic and nuclear inclusions, axonopathy, mitochondriopathy, accumulated DNA damage, activated p53 and cleaved caspase-3, and died. Tg mice had a 40–50% loss of MNs. This work shows that hSOD1 in skeletal muscle is a driver of pathogenesis in ALS, that involves myofiber and satellite cell toxicity, and apparent muscle-adipose tissue disease relationships. It also identifies a non-autonomous mechanism for MN degeneration explaining their selective vulnerability as likely a form of target-deprivation retrograde neurodegeneration.
Comparative Analysis of Systemic and Tumor Microenvironment Proteomes From Children With B-Cell Acute Lymphocytic Leukemia at Diagnosis and After Induction Treatment
Authors: Broto Geise Ellen , Corrêa Stephany , Trigo Fausto Celso , Santos Everton Cruz dos , Tomiotto-Pelissier Fernanda , Pavanelli Wander Rogério , Silveira Guilherme Ferreira , Abdelhay Eliana , Panis Carolina
Published: December 2020

Among the childhood diseases, B-cell acute lymphocytic leukemia (B-ALL) is the most frequent type of cancer. Despite recent advances concerning disease treatment, cytotoxic chemotherapy remains the first line of treatment in several countries, and the modifications induced by such drugs in the organism are still poorly understood. In this context, the present study provided a comparative high-throughput proteomic analysis of the cumulative changes induced by chemotherapeutic drugs used in the induction phase of B-ALL treatment in both peripheral blood (PB) and bone marrow compartment (BM) samples. To reach this goal, PB and BM plasma samples were comparatively analyzed by using label-free proteomics at two endpoints: at diagnosis (D0) and the end of the cumulative induction phase treatment (D28). Proteomic data was available via ProteomeXchange with identifier PXD021584. The resulting differentially expressed proteins were explored by bioinformatics approaches aiming to identify the main gene ontology processes, pathways, and transcription factors altered by chemotherapy, as well as to understand B-ALL biology in each compartment at D0. At D0, PB was characterized as a pro-inflammatory environment, with the involvement of several downregulated coagulation proteins as KNG, plasmin, and plasminogen. D28 was characterized predominantly by immune response-related processes and the super expression of the transcription factor IRF3 and transthyretin. RUNX1 was pointed out as a common transcription factor found in both D0 and D28. We chose to validate the proteins transthyretin and interferon-gamma (IFN-γ) by commercial kits and expressed the results as PB/BM ratios. Transthyretin ratio was augmented after induction chemotherapy, while IFN-γ was reduced at the end of the treatment. Considering that most of these proteins were not yet described in B-ALL literature, these findings added to understanding disease biology at diagnosis and highlighted a possible role for transthyretin and IFN-γ as mechanisms related to disease resolution.
The Anti-Inflammatory Drug Aspirin Does Not Protect Against Chemotherapy-Induced Memory Impairment by Paclitaxel in Mice
Authors: Chang Aeson , Chung Ni-Chun , Lawther Adam J. , Ziegler Alexandra I. , Shackleford David M. , Sloan Erica K. , Walker Adam K.
Published: December 2020

Inflammation has been proposed to play a causal role in chemobrain which—if true—would represent an opportunity to repurpose existing anti-inflammatory drugs for the prevention and treatment of chemobrain. Here, we show that the chemoagent paclitaxel induces memory impairment and anhedonia in mice within 24 h of treatment cessation, but inflammation is not present until 2 weeks after treatment. We find no evidence of brain inflammation as measured by cytokine analysis at any time point. Furthermore, treating with aspirin to block inflammation did not affect paclitaxel-induced memory impairment. These findings suggest that inflammation may not be responsible for memory impairment induced by paclitaxel. These results contrast with recent findings of a causal role for inflammation in cancer-induced memory deficits in mice that were prevented by treatment with oral aspirin, suggesting that cognitive impairment in cancer patients undergoing treatment may arise from multiple convergent mechanisms.
Identification of Somatic Mutations in Papanicolaou Smear DNA and Plasma Circulating Cell-Free DNA for Detection of Endometrial and Epithelial Ovarian Cancers: A Pilot Study
Authors: Jiang Xuan , Li Weihua , Yang Jiaxin , Wang Shuzhen , Cao Dongyan , Yu Mei , Shen Keng , Bai Jian , Gao Yang
Published: December 2020

Objectives

The aim of this study was to identify tumor-derived DNA from Papanicolaou (Pap) smear and plasma specimens collected from patients with endometrial cancer or atypical hyperplasia (EC/AH) or epithelial ovarian cancer (OC).

Methods

Tumor tissues, peripheral blood, and Pap smear samples were collected from patients with EC/AH and patients with epithelial OC. Somatic mutations of tumor specimens in EC/AH and OC were examined by whole-exome sequencing using a 127-driver gene panel from The Cancer Genome Atlas (TCGA). A nine-gene EC/AH panel and an eight-gene OC panel were established based on the identified significantly mutated genes in the EC/AH and OC tumor specimens. Circulating single-molecule amplification and resequencing technology (cSMART) was applied to evaluate somatic mutations in Pap smear DNA and plasma circulating cell-free DNA (ccfDNA) using the EC/AH and OC gene panels.

Results

In EC/AH group, there existed 22 tumors and 14 of the 22 tumors contributed hot spot mutations for the EC/AH nine-gene panel. In the Pap smear subgroup, all 21 Pap smears tested positive. Nine out of 11 (81.8%) identified the same gene mutations with their matched tumors and the remaining 10 Pap smears all tested positive. In the plasma subgroup, 10 out of 26 (38.5%) plasmas tested positive. One out of 13 (7.7%) identified the same gene mutation with its matched tumor and 5 out of the remaining 13 plasmas (38.5%) tested positive. In OC group, there existed 17 tumors and 16 of the 17 tumors contributed hot spot mutations for the OC eight-gene panel. In the Pap smear subgroup, all 11 Pap smears tested positive. Five out of 10 (50.0%) identified the same gene mutations with their matched tumors and the remaining one Pap smear also tested positive. In the plasma subgroup, all 22 plasmas tested positive. Ten out of 14 (71.4%) identified the same gene mutation with their matched tumors and the remaining 4 plasmas all tested positive.

Conclusions

Tumor-derived DNA can be detected in Pap smears and plasmas from patients with EC/AH or epithelial OC. Using a small gene-panel, early detection of EC/AH and OC might be promising. However, the value of plasma ccfDNA for EC/AH requires further investigation.
Copy Number Analysis Reveal Genetic Risks of Penile Cancer
Authors: Yu Yongbo , Gao Chengwen , Chen Yuanbin , Wang Meilan , Zhang Jianfeng , Ma Xiaocheng , Liu Shuaihong , Yuan Hang , Li Zhiqiang , Niu Haitao
Published: December 2020

Objectives

To evaluate copy number alterations (CNAs) in genes associated with penile cancer (PeC) and determine their correlation and prognostic ability with PeC.

Methods

Whole-exome sequencing was performed for tumor tissue and matched normal DNA of 35 patients diagnosed with penile squamous cell carcinoma from 2011 to 2016. Somatic CNAs were detected using the Genome Analysis Toolkit (GATK). Retrospective clinical data were collected and analyzed. All the data were statistically analyzed using SPSS 16.0 software. The cancer-specific survival rates were estimated by Kaplan-Meier curves and compared with the log-rank test.

Results

CNAs in the MYCN gene was detected in 19 (amplification: 54.29%) patients. Other CNAs gene targets were FAK (amplification: 45.72%, deletion: 8.57%), TP53 (amplification: 2.86%, deletion: 51.43%), TRKA (amplification: 34.29%, deletion: 2.86%), p75NTR (amplification: 5.71%, deletion: 42.86%), Miz-1 (amplification: 14.29%, deletion: 20.00%), Max (amplification: 17.14%, deletion: 2.86%), Bmi1 (amplification:14.29%, deletion: 48.57%), and MDM2 (amplification: 5.71%, deletion: 45.72%). The CNAs in MYCN and FAK correlated significantly with patient prognosis (P<0.05). The 3-year Recurrence-free survival rate was 87.10% among patients followed up. The 5-year survival rate of patients with MYCN amplification was 69.2%, compared to 94.4% in the non-amplification group. The 5-year survival rate of patients with FAK amplification was 65.6%, compared to 94.7% in the non-amplification group. The PPI network showed that TP53 and MYCN might play meaningful functional roles in PeC.

Conclusion

MYCN and FAK amplification and TP53 deletion were apparent in PeC. MYCN and TP53 were hub genes in PeC. MYCN and FAK amplification was also detected and analyzed, and the findings indicated that these two genes are predictors of poor prognosis in PeC.
The Evolving Role of Radiation Therapy in the Treatment of Biliary Tract Cancer
Authors: Gkika Eleni , Hawkins Maria A. , Grosu Anca-Ligia , Brunner Thomas B.
Published: December 2020

Biliary tract cancers (BTC) are a disease entity comprising diverse epithelial tumors, which are categorized according to their anatomical location as intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinomas, and gallbladder carcinomas (GBC), with distinct epidemiology, biology, and prognosis. Complete surgical resection is the mainstay in operable BTC as it is the only potentially curative treatment option. Nevertheless, even after curative (R0) resection, the 5-year survival rate ranges between 20 and 40% and the disease free survival rates (DFS) is approximately 48–65% after one year and 23–35% after three years without adjuvant treatment. Improvements in adjuvant chemotherapy have improved the DFS, but the role of adjuvant radiotherapy is unclear. On the other hand, more than 50% of the patients present with unresectable disease at the time of diagnosis, which limits the prognosis to a few months without treatment. Herein, we review the role of radiotherapy in the treatment of cholangiocarcinoma in the curative and palliative setting.
Validation of an IGF1 Screening Method for Retinopathy of Pre-maturity
Authors: Pérez-Muñuzuri Alejandro , López-Suárez Olalla , Mandiá-Rodríguez Natalia , López-Sanguos Carolina , Blanco-Teijeiro María José , Couce María Luz
Published: December 2020

Retinopathy of pre-maturity (ROP) is a retinal disease that causes arrest of vascularization of the retina and can result in retinal detachment and blindness. Current screening protocols may not be sufficiently accurate to identify all at-risk patients. The aim of this study is to validate a method for improved identification of newborns at risk of ROP. We conducted a prospective clinical trial of pre-term newborns <32 weeks of gestation and/or <1,500 g birth weight during a 6-year period in a tertiary care hospital. We applied our new method based on measurement of insulin-like growth factor 1 (IGF1) levels at 3 weeks of age and the presence of sepsis during the first 3 weeks of life. Our screening protocol allowed exclusion of 121 (79.1%) patients for whom American Academy of Pediatrics (AAP) guidelines recommended screening, had a negative predictive value of 100%, and correctly identified all patients with ROP. Following retrospective assessment of our data based on these findings, we propose further restriction of the current AAP indications for screening to <1,100 g and <28 weeks of gestation in order to improve diagnostic efficacy while ensuring optimal use of restriction of human and material resources.
Current Insights Into Adrenal Insufficiency in the Newborn and Young Infant
Authors: Buonocore Federica , McGlacken-Byrne Sinead M. , del Valle Ignacio , Achermann John C.
Published: December 2020

Adrenal insufficiency (AI) is a potentially life-threatening condition that can be difficult to diagnose, especially if it is not considered as a potential cause of a child's clinical presentation or unexpected deterioration. Children who present with AI in early life can have signs of glucocorticoid deficiency (hyperpigmentation, hypoglycemia, prolonged jaundice, poor weight gain), mineralocorticoid deficiency (hypotension, salt loss, collapse), adrenal androgen excess (atypical genitalia), or associated features linked to a specific underlying condition. Here, we provide an overview of causes of childhood AI, with a focus on genetic conditions that present in the first few months of life. Reaching a specific diagnosis can have lifelong implications for focusing management in an individual, and for counseling the family about inheritance and the risk of recurrence.
Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence
Authors: Zhang Li , Tong Xiang , Huang Jizhen , Wu Man , Zhang Shijie , Wang Dongguang , Liu SiTong , Fan Hong
Published: December 2020

Idiopathic pulmonary fibrosis is an aging-associated disease, satisfactory therapies are not yet available. Accelerated senescence of alveolar epithelial cells plays an important part in Idiopathic pulmonary fibrosis pathogenesis. Fisetin (FIS) is a natural non-toxic flavonoid, which has many pharmacological functions. However, the role of FIS in pulmonary fibrosis has not been established. In this study, we found that FIS treatment apparently alleviated BLM-induced weight loss, inflammatory cells infiltration, inflammatory factors expression, collagen deposition and alveolar epithelial cell senescence, along with AMPK activation and the down regulation of NF-κB and TGF-β/Smad3 in vivo. In vitro, FIS administration significantly inhibited the senescence of alveolar epithelial cells and senescence-associated secretory phenotype, followed by reduced transdifferentiation of fibroblasts to myofibroblasts as well as collagen deposition in fibroblasts, which was blocked by an AMPK inhibitor, Compound C. Together, these results suggest that FIS can alleviate the development of BLM-induced pulmonary fibrosis, which is related to the inhibition of TGF-β/Smad3 signaling and the reduction of alveolar epithelium cell senescence by regulating AMPK/NF-κB signaling pathway. FIS may be a promising candidate for patients with pulmonary fibrosis.
TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma
Authors: Wan Jingwei , Guo Alyssa Aihui , King Pendelton , Guo Shanchun , Saafir Talib , Jiang Yugang , Liu Mingli
Published: December 2020

We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma stem cells (GSC) growth and proliferation through Notch, STAT3-ALDH1, and CD133 signaling pathways. In this study, we determined the major contributor(s) to TRPM7 mediated glioma stemness by further deciphering each individual Notch signaling. We first determined whether TRPM7 is an oncotarget in glioblastoma multiforme (GBM) using the Oncomine database. Next, we determined whether TRPM7 silencing by siRNA TRPM7 (siTRPM7) induces cell growth arrest or apoptosis to reduce glioma cell proliferation using cell cycle analysis and annexin V staining assay. We then examined the correlations between the expression of TRPM7 and Notch signaling activity as well as the expression of GSC markers CD133 and ALDH1 in GBM by downregulating TRPM7 through siTRPM7 or upregulating TRPM7 through overexpression of human TRPM7 (M7-wt). To distinguish the different function of channel and kinase domain of TRPM7, we further determined how the α-kinase-dead mutants of TRPM7 (α-kinase domain deleted/M7-DK and K1648R point mutation/M7-KR) affect Notch activities and CD133 and ALDH1 expression. Lastly, we determined the changes in TRPM7-mediated regulation of glioma cell growth/proliferation, cell cycle, and apoptosis by targeting Notch1. The Oncomine data revealed a significant increase in TRPM7 mRNA expression in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissues. TRPM7 silencing reduced glioma cell growth by inhibiting cell entry into S and G2/M phases and promoting cell apoptosis. TRPM7 expression in GBM cells was found to be positively correlated with Notch1 signaling activity and CD133 and ALDH1 expression; briefly, downregulation of TRPM7 by siTRPM7 decreased Notch1 signaling whereas upregulation of TRPM7 increased Notch1 signaling. Interestingly, kinase-inactive mutants (M7-DK and M7-KR) resulted in reduced activation of Notch1 signaling and decreased expression of CD133 and ALDH1 compared to that of wtTRPM7. Finally, targeting Notch1 effectively suppressed TRPM7-induced growth and proliferation of glioma cells through cell G1/S arrest and apoptotic induction. TRPM7 is responsible for sustained Notch1 signaling activation, enhanced expression of GSC markers CD133 and ALDH1, and regulation of glioma stemness, which contributes to malignant glioma cell growth and invasion.
Current Researches, Rationale, Plausibility, and Evidence Gaps on Metformin for the Management of Hypertensive Disorders of Pregnancy
Authors: Zhang Yang , Liu Xiaoxia , Yang Liu , Zou Li
Published: December 2020

Hypertensive disorders of pregnancy (HDP) are a group of morbid pregnancy complications, with preeclampsia (PE) being the most common subclassification among them. PE affects 2%–8% of pregnancies globally and threatens maternal and fetal health seriously. However, the only effective treatment of PE to date is the timely termination of pregnancy, albeit with increased perinatal risks. Hence, more emerging therapies for PE management are in urgent need. Originally introduced as the first-line therapy for type 2 diabetes mellitus, metformin (MET) has now been found in clinical trials to significantly reduce the incidence of gestational hypertension and PE in pregnant women with PE-related risks, including but not limited to pregestational diabetes mellitus, gestational diabetes mellitus, polycystic ovary syndrome, or obesity. Additionally, existing clinical data have preliminarily ensured the safety of taking MET during human pregnancies. Relevant lab studies have indicated that the underlying mechanism includes angiogenesis promotion, endothelial protection, anti-inflammatory effects, and particularly protective effects on trophoblast cells against the risk factors, which are beneficial to placental development. Together with its global availability, easy administration, and low cost, MET is expected to be a promising option for the prevention and treatment of PE. Nevertheless, there are still some limitations in current studies, and the design of the relevant research scheme is supposed to be further improved in the future. Herein, we summarize the relevant clinical and experimental researches to discuss the rationale, safety, and feasibility of MET for the management of HDP. At the end of the article, gaps in current researches are proposed. Concretely, experimental MET concentration and PE models should be chosen cautiously. Besides, the clinical trial protocol should be further optimized to evaluate the reduction in the prevalence of PE as a primary endpoint. All of those evidence gaps may be of guiding significance to improve the design of relevant experiments and clinical trials in the future.
Inhibition of SARS-CoV-2 by Highly Potent Broad-Spectrum Anti-Coronaviral Tylophorine-Based Derivatives
Authors: Yang Cheng-Wei , Lee Yue-Zhi , Hsu Hsing-Yu , Jan Jia-Tsrong , Lin Yi-Ling , Chang Sui-Yuan , Peng Tzu-Ting , Yang Ruey-Bing , Liang Jian-Jong , Liao Chun-Che , Chao Tai-Ling , Pang Yu-Hau , Kao Han-Chieh , Huang Wen-Zheng , Lin Jiunn-Horng , Chang Chun-Ping , Niu Guang-Hao , Wu Szu-Huei , Sytwu Huey-Kang , Chen Chiung-Tong , Lee Shiow-Ju
Published: December 2020

Tylophorine-based compounds and natural cardiotonic steroids (cardenolides and bufadienolides) are two classes of transmissible gastroenteritis coronavirus inhibitors, targeting viral RNA and host cell factors, respectively. We tested both types of compounds against two types of coronaviruses, to compare and contrast their antiviral properties, and with view to their further therapeutic development. Examples of both types of compounds potently inhibited the replication of both feline infectious peritonitis virus and human coronavirus OC43 with EC50 values of up to 8 and 16 nM, respectively. Strikingly, the tylophorine-based compounds tested inhibited viral yields of HCoV-OC43 to a much greater extent (7–8 log magnitudes of p.f.u./ml) than the cardiotonic steroids (about 2–3 log magnitudes of p.f.u./ml), as determined by end point assays. Based on these results, three tylophorine-based compounds were further examined for their anti-viral activities on two other human coronaviruses, HCoV-229E and SARS-CoV-2. These three tylophorine-based compounds inhibited HCoV-229E with EC50 values of up to 6.5 nM, inhibited viral yields of HCoV-229E by 6–7 log magnitudes of p.f.u./ml, and were also found to inhibit SARS-CoV-2 with EC50 values of up to 2.5–14 nM. In conclusion, tylophorine-based compounds are potent, broad-spectrum inhibitors of coronaviruses including SARS-CoV-2, and could be used for the treatment of COVID-19.
Astragalus Flavone Ameliorates Atherosclerosis and Hepatic Steatosis Via Inhibiting Lipid-Disorder and Inflammation in apoE−/− Mice
Authors: Ma Chuanrui , Zhang Jing , Yang Shu , Hua Yunqing , Su Jing , Shang Yuna , Wang Zhongyan , Feng Ke , Zhang Jian , Yang Xiaoxiao , Zhang Hao , Mao Jingyuan , Fan Guanwei
Published: December 2020

Atherosclerosis is a major pathogenic driver of cardiovascular diseases. Foam cell formation plays a key role in atherogenesis, which is affected by lipid disorder and inflammation. Therefore, inhibition of foam cell formation is a therapeutic approach for atherosclerosis treatment. Total flavone of Astragalus membranaceus (TFA) is extracted from A. membranaceus that has protective effect on cardiovascular disease. However, the effect of TFA on atherosclerosis and the underlying mechanism remains unknown. In this study, we determined whether TFA could inhibit atherosclerosis and uncovered the underlying mechanism. In vivo, ApoE deficient mice were treated with TFA and high-fat diet for 16 weeks. Subsequently, atherosclerotic lesions, hepatic steatosis and associated genes expression in vitro and in vivo were determined. We found that TFA reduced atherosclerotic lesion size and enhanced plaque stability, which might be attributed to improved lipid disorder, reduced inflammation and decreased monocyte adhesion. Mechanistically, TFA inhibited hepatic steatosis via regulating the genes responsible for lipid metabolism, by which ameliorating the lipid disorder. Moreover, in macrophage, TFA reduced the expression of scavenger receptors such as CD36 and SRA; and promoted the expression of ATP-binding cassette transporter A1 and G1 (ABCA1/G1). More importantly, TFA reduced miR-33 expression and dampened NFκB activity, by which de-repressing ABCA1/G1 activity and inhibiting the inflammation. Collectively, TFA can attenuate atherosclerosis via dual suppression of miR-33 and NFκB pathway, and partially through inhibition of scavenger receptors in macrophage. In addition, TFA ameliorates the hepatic steatosis and lipid disorder, which in turn contributes to the amelioration of atherosclerosis, suggesting that TFA might be a novel therapeutic approach for inhibition of atherosclerosis and hepatic steatosis.
A New Crystal Form of the SARS-CoV-2 Receptor Binding Domain: CR3022 Complex—An Ideal Target for In-Crystal Fragment Screening of the ACE2 Binding Site Surface
Authors: Nichols Charlie , Ng Joseph , Keshu Annika , Fraternali Franca , De Nicola Gian F.
Published: December 2020

In-crystal fragment screening is a powerful tool to chemically probe the surfaces used by proteins to interact, and identify the chemical space worth exploring to design protein-protein inhibitors. A crucial prerequisite is the identification of a crystal form where the target area is exposed and accessible to be probed by fragments. Here we report a crystal form of the SARS-CoV-2 Receptor Binding Domain in complex with the CR3022 antibody where the ACE2 binding site on the Receptor Binding Domain is exposed and accessible. This crystal form of the complex is a valuable tool to develop antiviral molecules that could act by blocking the virus entry in cells.
Inequality Measures: The Kolkata Index in Comparison With Other Measures
Authors: Banerjee Suchismita , Chakrabarti Bikas K. , Mitra Manipushpak , Mutuswami Suresh
Published: December 2020

We provide a survey of the Kolkata index of social inequality, focusing in particular on income inequality. Based on the observation that inequality functions (such as the Lorenz function), giving the measures of income or wealth against that of the population, to be generally nonlinear, we show that the fixed point (like Kolkata index k) of such a nonlinear function (or related, like the complementary Lorenz function) offer better measure of inequality than the average quantities (like Gini index). Indeed the Kolkata index can be viewed as a generalized Hirsch index for a normalized inequality function and gives the fraction k of the total wealth possessed by the rich 1−k fraction of the population. We analyze the structures of the inequality indices for both continuous and discrete income distributions. We also compare the Kolkata index to some other measures like the Gini coefficient and the Pietra index. Lastly, we provide some empirical studies which illustrate the differences between the Kolkata index and the Gini coefficient.
Quadriceps and Patellar Tendon Thickness and Stiffness in Elite Track Cyclists: An Ultrasonographic and Myotonometric Evaluation
Authors: Klich Sebastian , Ficek Krzysztof , Krymski Igor , Klimek Andrzej , Kawczyński Adam , Madeleine Pascal , Fernández-de-las-Peñas Cesar
Published: December 2020

Track cyclists are required to perform short- and long-term efforts during sprint and endurance race events, respectively. The 200 m flying sprint races require maximal power output and anaerobic capacity, while the 4,000 m pursuit cyclists demand a high level of aerobic capacity. Our goal was to investigate spatial changes in morphological and mechanical properties displayed using 3D topographical maps of the quadriceps muscle and tendons after 200 m flying start and 4,000 m individual pursuit race in elite track cyclists. We hypothesized a non-uniform distribution of the changes in the quadriceps muscle stiffness (QMstiff), and acute alterations in quadriceps tendon (QTthick) and patellar tendon (PTthick) thickness. Fifteen men elite sprint and 15 elite men endurance track cyclists participated. Sprint track cyclists participated in a 200 m flying start, while endurance track cyclists in 4,000 m individual pursuit. Outcomes including QTthick (5–10–15 mm proximal to the upper edge of the patella), PTthick (5–10–15–20 mm inferior to the apex of the patella)—using ultrasonography evaluation, QMstiff, and quadriceps tendon stiffness (QTstiff) were measured according to anatomically defined locations (point 1–8) and patellar tendon stiffness (PTstiff)—using myotonometry, measured in a midway point between the patella distal and the tuberosity of tibial. All parameters were assessed before and after (up to 5 min) the 200 m or 4,000 m events. Sprint track cyclists had significantly larger QTthick and PTthick than endurance track cyclists. Post-hoc analysis showed significant spatial differences in QMstiff between rectus femoris, vastus lateralis, and vastus medialis in sprint track cyclists. At before race, sprint track cyclists presented significantly higher mean QTthick and PTthick, and higher QMstiff and the QTstiff, as compared with the endurance track cyclists. The observed changes in PTThick and QTThick were mostly related to adaptation-based vascularity and hypertrophy processes. The current study suggests that assessments using both ultrasonography and myotonometry provides crucial information about tendons and muscles properties and their acute adaptation to exercise. Higher stiffness in sprint compared with endurance track cyclists at baseline seems to highlight alterations in mechanical properties of the tendon and muscle that could lead to overuse injuries.
Cyanobacteria-Derived Proline Increases Stress Tolerance in Arabidopsis thaliana Root Hairs by Suppressing Programmed Cell Death
Authors: Chua Alysha , Sherwood Orla L. , Fitzhenry Laurence , Ng Carl K.-Y. , McCabe Paul F. , Daly Cara T.
Published: December 2020

Nitrogen-fixing heterocystous cyanobacteria are used as biofertilizer inoculants for stimulating plant growth but can also alleviate plant stress by exometabolite secretion. However, only a small number of studies have focused on elucidating the identity of said bioactives because of the wide array of exuded compounds. Here, we used the root hair assay (RHA) as a rapid programmed cell death (PCD) screening tool for characterizing the bioactivity of cyanobacteria Nostoc muscorum conditioned medium (CM) on Arabidopsis thaliana root hair stress tolerance. We found that heat-stressed A. thaliana pre-treated with N. muscorum CM fractions exhibited significantly lower root hair PCD levels compared to untreated seedlings. Treatment with CM increased stress tolerance by suppressing PCD in root hairs but not necrosis, indicating the bioactive compound was specifically modulating the PCD pathway and not a general stress response. Based on documented N. muscorum exometabolites, we identified the stress-responsive proline as a compound of interest and strong evidence from the ninhydrin assay and HPLC indicate that proline is present in N. muscorum CM. To establish whether proline was capable of suppressing PCD, we conducted proline supplementation experiments. Our results showed that exogenous proline had a similar effect on root hairs as N. muscorum CM treatment, with comparable PCD suppression levels and insignificant necrosis changes. To verify proline as one of the biologically active compounds in N. muscorum CM, we used three mutant A. thaliana lines with proline transporter mutations (lht1, aap1 and atprot1-1::atprot2-3::atprot3-2). Compared with the wild-type seedlings, PCD-suppression in lht1and aap1 mutants was significantly reduced when supplied with low proline (1–5 μM) levels. Similarly, pre-treatment with N. muscorum CM resulted in elevated PCD levels in all three mutant lines compared to wild-type seedlings. Our results show that plant uptake of cyanobacteria-derived proline alters their root hair PCD sensitivity threshold. This offers evidence of a novel biofertilizer mechanism for reducing stress-induced PCD levels, independent of the existing mechanisms documented in the literature.