bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profiling of the β-glucosidases identified in the genome of
Penicillium funiculosum
: insights from genomics, transcriptomics, proteomics, and homology-modeling studies
Authors: Okereke Omoaruemike Ebele , Gupta Mayank , Ogunyewo Olusola A. , Sharma Kanika , Kapoor Sonal , Sinha Tulika , Yazdani Syed Shams 
Published: August 2023

ABSTRACT

The enzymatic conversion of lignocellulosic biomass to bioethanol depends on efficient enzyme systems with β-glucosidase as one of the key components. In this study, we performed in-depth profiling of the various β-glucosidases present in the genome of the hypercellulolytic fungus
Penicillium funiculosum
using genomics, transcriptomics, proteomics, and molecular dynamics simulation approaches. Of the eight β-glucosidase genes identified in the
P. funiculosum
genome, three were predicted to be extracellular based on signal peptide prediction and abundance in the secretome. Among the three secreted β-glucosidases, two belonged to the GH3 family and one belonged to the GH1 family. Homology models of these proteins predicted a deep and narrow active site for the GH3 β-glucosidases (
Pf
Bgl3A and
Pf
Bgl3B) and a shallow open active site for the GH1 β-glucosidase (
Pf
Bgl1A). The enzymatic assays indicated that
P. funiculosum
-secreted proteins showed high β-glucosidase activities with prominent bands on the 4‐methylumbelliferyl β‐D‐glucopyranoside zymogram. To understand the contributory effects of each of the three secreted β-glucosidases (
Pf
Bgls), the corresponding gene was deleted separately, and the effect of the deletion on the β-glucosidase activity of the secretome was examined. Although not the most abundant,
Pf
Bgl3A was found to be one of the most important β-glucosidases, as evidenced by a 42% reduction in β-glucosidase activity in the Δ
Pf
Bgl3A strain. Our results advance the understanding of the genetic and biochemical nature of all β-glucosidases produced by
P. funiculosum
and pave the way to design a superior biocatalyst for the hydrolysis of lignocellulosic biomass.

IMPORTANCE

Commercially available cellulases are primarily produced from
Trichoderma reesei
. However, external supplementation of the cellulase cocktail from this host with exogenous β-glucosidase is often required to achieve the desired optimal saccharification of cellulosic feedstocks. This challenge has led to the exploration of other cellulase-producing strains. The nonmodel hypercellulolytic fungus
Penicillium funiculosum
has been studied in recent times and identified as a promising source of industrial cellulases mainly due to its ability to produce a balanced concoction of cellulolytic enzymes, including β-glucosidases. Various genetic interventions targeted at strain improvement for cellulase production have been performed; however, the β-glucosidases of this strain have remained largely understudied. This study, therefore, reports profiling of all eight β-glucosidases of
P. funiculosum
via molecular and computational approaches. The results of this study provide useful insights that will establish the background for future engineering strategies to transform this fungus into an industrial workhorse.
Draft genome sequence of yeast
Vanrija
sp. strain TS01, isolated from leukemia patient’s urine
Authors: Meng Lingning , Liu Chang , Zhu Liguo , Wang Xinlei , Li Chuchu 
Published: August 2023

ABSTRACT

Vanrija
sp. strain TS01 was isolated from urine sample from a leukemia patient in Nanjing, China. The closest known relative strain is
Vanrija humicol
a with average nucleotide identity value of 93.1. The draft genome comprises 22.0 Mb in 52 contigs, with G + C content of 62.57%.
Mode of action of antimicrobial agents albofungins in eradicating penicillin- and cephalosporin-resistant
Vibrio parahaemolyticus
biofilm
Authors: She Weiyi , Cheng Aifang , Ye Wenkang , Zeng Ping , Wang Hao , Qian Pei-Yuan 
Published: August 2023

ABSTRACT

Albofungin is a promising broad-spectrum antimicrobial compound against multidrug-resistant bacteria. In the present study, we further investigated albofungin’s biofilm eradication activity and its potential mode of action against drug-resistant
Vibrio parahaemolyticus
. Among all derivatives, albofungin exhibited the best antibiofilm and antibacterial activity with rapid killing effects at 0.12 µg mL
−1
. Confocal microscopy observation exhibited that albofungin disrupted
V. parahaemolyticus
biofilms by killing or dispersing biofilm cells. Meanwhile, scanning electron microscope and fluorescent staining experiments demonstrated that albofungin rapidly destroyed the integrity and permeability of the bacterial cell membrane. Moreover, this study revealed an antibiofilm mechanism of albofungin involving inhibition of peptidoglycan biosynthesis, flagella assembly pathways, and secretion system proteins in
V. parahaemolyticus
by quantitative proteomics and validation experiments. Our results highlighted albofungin’s mechanism of action in planktonic cells and biofilms and suggested further development and potential applications of albofungin for treating infections caused by penicillins-and-cephalosporins-resistant
V. parahaemolyticus
.

IMPORTANCE

Infections caused by multidrug-resistant bacteria, as well as a scarcity of new antibiotics, have become a major health threat worldwide. To tackle the demand for new and effective treatments, we investigated the mechanism of action of albofungin, a natural product derived from
Streptomyces
, which exhibits potent antimicrobial activity against multidrug-resistant bacteria. Albofungin showed potent biofilm eradication activity against penicillins-and-cephalosporins-resistant
Vibrio parahaemolyticus
, which expresses a novel metallo-β-lactamase and, thus, reduces their sensitivity to various antibiotics. We observed membrane disruption and permeation mechanisms in planktonic cells and biofilms after albofungin treatment, while albofungin had a weak interaction with bacterial DNA. Moreover, the antibiofilm mechanism of albofungin included inhibition of peptidoglycan biosynthesis, flagellar assembly pathways, and secretion system proteins. Our finding suggested potential applications of albofungin as an antibacterial and antibiofilm therapeutic agent.
Constraining the elemental stoichiometry of early marine life
Authors: Fakhraee Mojtaba , Tarhan Lidya G. , Reinhard Christopher T. , Planavsky Noah J. 
Published: August 2023

Abstract
The relative proportions of carbon, nitrogen, and phosphorus, commonly referred to as the Redfield ratio (106:16:1), have likely varied dramatically through Earth’s history in response to changes in oceanic redox state and nutrient availability. However, there have been few attempts to track long-term secular patterns in the elemental stoichiometry of marine life. We use a sediment reactive-transport (diagenetic) modeling approach to provide new constraints on the elemental stoichiometry of marine ecosystems during Earth’s early history, by simulating environmental conditions associated with the formation and deposition of suites of Archean sedimentary iron and phosphorus-bearing minerals. Our results suggest that siderite formation in porewaters linked to dissimilatory iron reduction but limited formation of authigenic P phases can only be reproduced when C to P ratios in marine biomass are at least 500 (mol/mol), approximately five times higher than the values that characterize the modern ocean. This constraint indicates that Archean oceans were strongly nutrient-limited.
Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration
Authors: Bertels Xander , Edris Ahmed , Garcia-Aymerich Judith , Faner Rosa , Meteran Howraman , Sigsgaard Torben , Alter Peter , Vogelmeier Claus , Olvera Nuria , Kermani Nazanin Zounemat , Agusti Alvar , Donaldson Gavin C , Wedzicha Jadwiga A , Brusselle Guy G , Backman Helena , Rönmark Eva , Lindberg Anne , Vonk Judith M , Chung Kian Fan , Adcock Ian M , van den Berge Maarten , Lahousse Lies 
Published: August 2023

BackgroundThe prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts.MethodsThis cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV1/FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model.ResultsThe prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI.ConclusionsAO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only.
hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC
Authors: Trono Paola , Tocci Annalisa , Palermo Belinda , Di Carlo Anna , D'Ambrosio Lorenzo , D'Andrea Daniel , Di Modugno Francesca , De Nicola Francesca , Goeman Frauke , Corleone Giacomo , Warren Sarah , Paolini Francesca , Panetta Mariangela , Sperduti Isabella , Baldari Silvia , Visca Paolo , Carpano Silvia , Cappuzzo Federico , Russo Vincenzo , Tripodo Claudio , Zucali Paolo , Gregorc Vanesa , Marchesi Federica , Nistico Paola 
Published: August 2023

BackgroundUnderstanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA11aisoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA11adownregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA11adownregulation.MethodsEffects of hMENA11adownregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort.ResultsTranscriptomic and biochemical analyses demonstrated that the depletion of hMENA11ainduces IFN pathway activation, the production of different inflammatory mediators including IFNβviaRIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA11a, high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy.ConclusionsCollectively, these data establish a new function for the actin cytoskeleton regulator hMENA11ain modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC.
Saponin-based adjuvants enhance antigen cross-presentation in human CD11c+CD1c+CD5−CD163+conventional type 2 dendritic cells
Authors: Ho Nataschja I , Huis in 't Veld Lisa G M , van Eck van der Sluijs Jesper , Heuts Branco M H , Looman Maaike W G , Kers-Rebel Esther D , van den Dries Koen , Dolstra Harry , Martens Joost H A , Hobo Willemijn , Adema Gosse J 
Published: August 2023

BackgroundAdjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition to antibody responses. Recent preclinical studies revealed that SBAs induced cross-presentation and lipid bodies in otherwise poorly cross-presenting CD11b+murine dendritic cells (DCs).MethodHere, we investigated the response of human DC subsets to SBAs with RNA sequencing and pathway analyses, lipid body induction visualized by laser scanning microscopy, antigen translocation to the cytosol, and antigen cross-presentation to CD8+T cells.ResultsRNA sequencing of SBA-treated conventional type 1 DC (cDC1) and type 2 DC (cDC2) subsets uncovered that SBAs upregulated lipid-related pathways in CD11c+CD1c+cDC2s, especially in the CD5−CD163+CD14+cDC2 subset. Moreover, SBAs induced lipid bodies and enhanced endosomal antigen translocation into the cytosol in this particular cDC2 subset. Finally, SBAs enhanced cross-presentation only in cDC2s, which requires the CD163+CD14+cDC2 subset.ConclusionsThese data thus identify the CD163+CD14+cDC2 subset as the main SBA-responsive DC subset in humans and imply new strategies to optimize the application of saponin-based adjuvants in a potent cancer vaccine.
Does industry funding and study location impact findings from randomized controlled trials of spinal cord stimulation? A systematic review and meta-analysis
Authors: Eldabe Sam , Nevitt Sarah , Copley Sue , Maden Michelle , Goudman Lisa , Hayek Salim , Mekhail Nagy , Moens Maarten , Rigoard Phillipe , Duarte Rui 
Published: August 2023

Background/importanceConcerns have been raised that effects observed in studies of spinal cord stimulation (SCS) funded by industry have not been replicated in non-industry-funded studies and that findings may differ based on geographical location where the study was conducted.ObjectiveTo investigate the impact of industry funding and geographical location on pain intensity, function, health-related quality of life and adverse events reported in randomized controlled trials (RCTs) of SCS.Evidence reviewSystematic review conducted using MEDLINE, CENTRAL, EMBASE and WikiStim databases until September 2022. Parallel-group RCTs evaluating SCS for patients with neuropathic pain were included. Results of studies were combined in random-effects meta-analysis using the generic-inverse variance method. Subgroup meta-analyses were conducted according to funding source and study location. Risk of bias was assessed using Cochrane RoB 2.0 tool.FindingsTwenty-nine reports of 17 RCTs (1823 participants) were included. For the comparison of SCS with usual care, test for subgroup differences indicate no significant differences (p=0.48, moderate certainty evidence) in pain intensity score at 6 months for studies with no funding or funding not disclosed (pooled mean difference (MD) −1.96 (95% CI −3.23 to −0.69; 95% prediction interval (PI) not estimable, I2=0%, τ2=0)), industry funding (pooled MD −2.70 (95% CI −4.29 to −1.11; 95% PI −8.75 to 3.35, I2=97%, τ2=2.96) or non-industry funding (MD −3.09 (95% CI −4.47 to −1.72); 95% PI, I2and τ2not applicable). Studies with industry funding for the comparison of high-frequency SCS (HF-SCS) with low-frequency SCS (LF-SCS) showed statistically significant advantages for HF-SCS compared to LF-SCS while studies with no funding showed no differences between HF-SCS and LF-SCS (low certainty evidence).ConclusionAll outcomes of SCS versus usual care were not significantly different between studies funded by industry and those independent from industry. Pain intensity score and change in pain intensity from baseline for comparisons of HF-SCS to LF-SCS seem to be impacted by industry funding.
Cerebral venous sinus thrombosis: changing trends in the incidence, age and gender (findings from the CMC Vellore CVT registry)
Authors: Miraclin T Angel , Prasad John Davis , Ninan George Abraham , Gowri Mahasampath , Bal Deepti , Shaikh Atif Iqbal Ahmed , Benjamin Rohit N , Prabhakar Appaswamy Thirumal , Sivadasan Ajith , Mathew Vivek , Aaron Sanjith 
Published: August 2023

Background
Multiple cerebral venous sinus thrombosis (CVT) registries from various geographical regions indicate that female gender, the use of contraceptive pills, pregnancy and puerperium are important risk factors. In this study, we report the changes in the epidemiology of patients with CVT managed over the past 26 years.

Methods
The CMC Vellore CVT registry is a prospectively maintained database at the Christian Medical College, Vellore since January 1995. Stata software was used to analyse the data and assess the changes in the incidence, age and gender distribution over the previous 26 years.

Results
Among 1701 patients treated during the study period, 908 (53%) were women and 793 (47%) were men. The mean incidence of CVT was 49 per 100 000 admissions before 2010, which increased to 96 per 100 000 after 2010. Male gender had a higher odds of developing CVT (OR – 2.07 (CI 1.68 to 2.55, p<.001). This could be attributed to the declining incidence of postpartum CVT after 2010 compared with the decade before 2010 (50% vs 20%). The mean age at presentation had increased from 24.5 to 33.2 years in the last decade.

Conclusions
There was a clear change in the gender pattern from being a condition with female preponderance, to one where equal or more men are being affected. Lower incidence of postpartum CVT cases could be the driving factor. An increase in the overall incidence of CVT cases was noted, probably due to a higher index of clinical suspicion and better diagnostic imaging modalities.
Nephroprotective Effects of Caffeine, Vanillin, and Their Combination against Experimental AlCl3-Induced Renal Toxicity in Adult Male Wistar Rats
Authors: Afolabi Olakunle Bamikole , Olasehinde Oluwaseun Ruth , Olaoye Oyindamola Adeniyi , Jaiyesimi Kikelomo Folake , Ekakitie Ilobekemen Lisa , Oloyede Omotade Ibidun 
Published: August 2023

Aluminum (Al) is known to be a nephrotoxic metal that can cause renal toxicity in both humans and animals. The use of functional foods has been reported to have significance in managing the toxic effects associated with such metals. This study aimed to assess the potential protective effects of caffeine, vanillin, and their combination in mitigating AlCl3-induced renal toxicity in adult male Wistar rats. A total of thirty (30) adult male Wistar rats weighing between 150 and 200 g were randomly divided into five groups, each consisting of six rats (n = 6). Group 1 served as the control, while the remaining treatment groups received a daily oral dose of 100 mg/kg AlCl3 for a duration of 21 days. In addition, groups 3–5 were coadministered 50 mg/kg body weight (bw) of caffeine, vanillin, and a combination (50/50 mg/kg bw) of both substances, respectively. In the results, AlCl3-treated showed a significant (

p

< 0.05) increase in serum biomarkers such as ALT, ALP, urea, and creatinine, and a significant (

p

< 0.05) decrease in serum total proteins (TPs). The renal tissue’s antioxidant system, including SOD, CAT, GPx, and GSH, exhibited a significant (

p

< 0.05) reduction, accompanied by an elevated MDA level. However, the administration of caffeine, vanillin, and their combination resulted in a significant (

p

< 0.05) decrease in serum ALT, ALP, urea, and creatinine, and a significant (

p

< 0.05) increase in serum TP. Furthermore, following the treatment, there was a significant (

p

< 0.05) increase in renal SOD, CAT, GPx, and GSH levels, along with a reduction in the MDA level. In addition, the treatment for 21 days caused a significant (

p

< 0.05) reversal to the altered histomorphological architecture. These findings suggest that caffeine, vanillin, and their combination could potentially be an effective regimen in managing AlCl3-induced renal toxicity.
Matrix Stiffness Triggers Lipid Metabolic Cross-talk between Tumor and Stromal Cells to Mediate Bevacizumab Resistance in Colorectal Cancer Liver Metastases
Authors: Zheng Yannan , Zhou Rui , Cai Jianan , Yang Nanyan , Wen Zhaowei , Zhang Zhihua , Sun Huiying , Huang Genjie , Guan Yijin , Huang Na , Shi Min , Liao Yulin , Bin Jianping , Liao Wangjun 
Published: August 2023

Abstract

Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying a mechanism of antiangiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and posttreatment samples of liver metastases from 20 colorectal cancer patients treated with combination bevacizumab therapy, including 10 responders and 10 nonresponders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in nonresponders after antiangiogenic therapy compared with responders. In mouse models of liver metastatic colorectal cancer (mCRC), anti-VEGF increased ECM deposition and FAO in colorectal cancer cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSC) were essential for matrix stiffness–mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic cross-talk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance.

Significance:
Extracellular matrix stiffening drives bevacizumab resistance by stimulating hepatic stellate cells to provide fuel for mCRC cells in the liver, indicating a potential metabolism-based therapeutic strategy for overcoming resistance.