bluuebunny/crossref_metadata_2025_split huggingface dataset:
In situ identification and G4-PPI-His-Mal-dendrimer-induced reduction of early-stage amyloid aggregates in Alzheimer’s disease transgenic mice using synchrotron-based infrared imaging
Authors: Benseny-Cases Núria , Álvarez-Marimon Elena , Aso Ester , Carmona Margarita , Klementieva Oxana , Appelhans Dietmar , Ferrer Isidre , Cladera Josep 
Published: September 2021

AbstractAmyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer Disease. In situ identification of early-stage amyloid aggregates in Alzheimer’s disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months. A significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with poly(propylene imine) dendrimers with histidine-maltose shell (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating their putative therapeutic properties of in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. No less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques.
Use of human PBMC to analyse the impact of obesity on lipid metabolism and metabolic status: a proof-of-concept pilot study
Authors: Costa Andrea , Reynés Bàrbara , Konieczna Jadwiga , Martín Marian , Fiol Miquel , Palou Andreu , Romaguera Dora , Oliver Paula 
Published: September 2021

AbstractPeripheral blood mononuclear cells (PBMC) are widely used as a biomarker source in nutrition/obesity studies because they reflect gene expression profiles of internal tissues. In this pilot proof-of-concept study we analysed in humans if, as we previously suggested in rodents, PBMC could be a surrogate tissue to study overweight/obesity impact on lipid metabolism. Pre-selected key lipid metabolism genes based in our previous preclinical studies were analysed in PBMC of normoglycemic normal-weight (NW), and overweight-obese (OW-OB) subjects before and after a 6-month weight-loss plan. PBMC mRNA levels of CPT1A, FASN and SREBP-1c increased in the OW-OB group, according with what described in liver and adipose tissue of humans with obesity. This altered expression pattern was related to increased adiposity and early signs of metabolic impairment. Greater weight loss and/or metabolic improvement as result of the intervention was related to lower CPT1A, FASN and SREBP-1c gene expression in an adjusted linear mixed-effects regression analysis, although no gene expression recovery was observed when considering mean comparisons. Thus, human PBMC reflect lipid metabolism expression profile of energy homeostatic tissues, and early obesity-related alterations in metabolic at-risk subjects. Further studies are needed to understand PBMC usefulness for analysis of metabolic recovery in weigh management programs.
Characterization and engineering of Streptomyces griseofuscus DSM 40191 as a potential host for heterologous expression of biosynthetic gene clusters
Authors: Gren Tetiana , Whitford Christopher M. , Mohite Omkar S. , Jørgensen Tue S. , Kontou Eftychia E. , Nielsen Julie B. , Lee Sang Yup , Weber Tilmann 
Published: September 2021

AbstractStreptomyces griseofuscus DSM 40191 is a fast growing Streptomyces strain that remains largely underexplored as a heterologous host. Here, we report the genome mining of S. griseofuscus, followed by the detailed exploration of its phenotype, including the production of native secondary metabolites and ability to utilise carbon, nitrogen, sulphur and phosphorus sources. Furthermore, several routes for genetic engineering of S. griseofuscus were explored, including use of GusA-based vectors, CRISPR-Cas9 and CRISPR-cBEST-mediated knockouts. Two out of the three native plasmids were cured using CRISPR-Cas9 technology, leading to the generation of strain S. griseofuscus DEL1. DEL1 was further modified by the full deletion of a pentamycin BGC and an unknown NRPS BGC, leading to the generation of strain DEL2, lacking approx. 500 kbp of the genome, which corresponds to a 5.19% genome reduction. DEL2 can be characterized by faster growth and inability to produce three main native metabolites: lankacidin, lankamycin, pentamycin and their derivatives. To test the ability of DEL2 to heterologously produce secondary metabolites, the actinorhodin BGC was used. We were able to observe a formation of a blue halo, indicating a potential production of actinorhodin by both DEL2 and a wild type.
Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice
Authors: Hanaguri Junya , Yokota Harumasa , Watanabe Masahisa , Yamagami Satoru , Kushiyama Akifumi , Kuo Lih , Nagaoka Taiji 
Published: September 2021

AbstractWe investigated and compared the susceptibility of retinal blood flow regulation and neural function in mice developing type 2 diabetes. The longitudinal changes in retinal neuronal function and blood flow responses to a 10-min systemic hyperoxia and a 3-min flicker stimulation were evaluated every 2 weeks in diabetic db/db mice and nondiabetic controls (db/m) from age 8 to 20 weeks. The retinal blood flow and neural activity were assessed using laser speckle flowgraphy and electroretinography (ERG), respectively. The db/db mice had significantly higher blood glucose levels and body weight. The resting retinal blood flow was steady and comparable between two groups throughout the study. Hyperoxia elicited a consistent decrease, and flicker light an increase, in retinal blood flow in db/m mice independent of age. However, these flow responses were significantly diminished in db/db mice at 8 weeks old and then the mice became unresponsive to stimulations at 12 weeks. Subsequently, the ERG implicit time for oscillatory potential was significantly increased at 14 weeks of age while the a-wave and b-wave amplitudes and implicit times remained unchanged. The deficiencies of flow regulation and neurovascular coupling in the retina appear to precede neural dysfunction in the mouse with type 2 diabetes.
Speckle reduction in ultrasound endoscopy using refraction based elevational angular compounding
Authors: Afshari Parastoo , Zakian Christian , Bachmann Jeannine , Ntziachristos Vasilis 
Published: September 2021

AbstractEndoscopic ultrasonography (EUS) is a safe, real-time diagnostic and therapeutic tool. Speckle noise, inherent to ultrasonography, degrades the diagnostic precision of EUS. Elevational angular compounding (EAC) can provide real-time speckle noise reduction; however, EAC has never been applied to EUS because current implementations require costly and bulky arrays and are incompatible with the tight spatial constraints of hollow organs. Here we develop a radial implementation of a refraction-based elevational angular compounding technique (REACT) for EUS and demonstrate for the first time spatial compounding in a radial endoscopy. The proposed implementation was investigated in cylindrical phantoms and demonstrated superior suppression of ultrasound speckle noise and up to a two-fold improvement in signal- and contrast- ratios, compared to standard image processing techniques and averaging. The effect of elevational angular deflection on image fidelity was further investigated in a phantom with lymph node-like structures to determine the optimum elevational angular width for high speckle reduction efficiency while maintaining image fidelity. This study introduces REACT as a potential compact and low-cost solution to impart current radial echo-endoscopes with spatial compounding, which could enable accurate identification and precise sizing of lymph nodes in staging of gastrointestinal tract cancers.
Compound climate extremes driving recent sub-continental tree mortality in northern Australia have no precedent in recent centuries
Authors: Allen Kathryn J. , Verdon-Kidd Danielle C. , Sippo James Z. , Baker Patrick J. 
Published: September 2021

AbstractCompound climate extremes (CCEs) can have significant and persistent environmental impacts on ecosystems. However, knowledge of the occurrence of CCEs beyond the past ~ 50 years, and hence their ecological impacts, is limited. Here, we place the widespread 2015–16 mangrove dieback and the more recent 2020 inland native forest dieback events in northern Australia into a longer historical context using locally relevant palaeoclimate records. Over recent centuries, multiple occurrences of analogous antecedent and coincident climate conditions associated with the mangrove dieback event were identified in this compilation. However, rising sea level—a key antecedent condition—over the three decades prior to the mangrove dieback is unprecedented in the past 220 years. Similarly, dieback in inland forests and savannas was associated with a multi-decadal wetting trend followed by the longest and most intense drought conditions of the past 250 years, coupled with rising temperatures. While many ecological communities may have experienced CCEs in past centuries, the addition of new environmental stressors associated with varying aspects of global change may exceed their thresholds of resilience. Palaeoclimate compilations provide the much-needed longer term context to better assess frequency and changes in some types of CCEs and their environmental impacts.
PITX1 inhibits the growth and proliferation of melanoma cells through regulation of SOX family genes
Authors: Ohira Takahito , Nakagawa Suguru , Takeshita Jumpei , Aburatani Hiroyuki , Kugoh Hiroyuki 
Published: September 2021

AbstractMelanoma is one of the most aggressive types of cancer wherein resistance to treatment prevails. Therefore, it is important to discover novel molecular targets of melanoma progression as potential treatments. Here we show that paired-like homeodomain transcription factor 1 (PITX1) plays a crucial role in the inhibition of melanoma progression through regulation of SRY-box transcription factors (SOX) gene family mRNA transcription. Overexpression of PITX1 in melanoma cell lines resulted in a reduction in cell proliferation and an increase in apoptosis. Additionally, analysis of protein levels revealed an antagonistic cross-regulation between SOX9 and SOX10. Interestingly, PITX1 binds to the SOX9 promoter region as a positive regulatory transcription factor; PITX1 mRNA expression levels were positively correlated with SOX9 expression, and negatively correlated with SOX10 expression in melanoma tissues. Furthermore, transcription of the long noncoding RNA (lncRNA), survival-associated mitochondrial melanoma-specific oncogenic noncoding RNA (SAMMSON), was decreased in PITX1-overexpressing cells. Taken together, the findings in this study indicate that PITX1 may act as a negative regulatory factor in the development and progression of melanoma via direct targeting of the SOX signaling.
Radiomics-based model for predicting early recurrence of intrahepatic mass-forming cholangiocarcinoma after curative tumor resection
Authors: Zhu Yong , Mao Yingfan , Chen Jun , Qiu Yudong , Guan Yue , Wang Zhongqiu , He Jian 
Published: September 2021

AbstractTo investigate the ability of CT-based radiomics signature for pre-and postoperatively predicting the early recurrence of intrahepatic mass-forming cholangiocarcinoma (IMCC) and develop radiomics-based prediction models. Institutional review board approved this study. Clinicopathological characteristics, contrast-enhanced CT images, and radiomics features of 125 IMCC patients (35 with early recurrence and 90 with non-early recurrence) were retrospectively reviewed. In the training set of 92 patients, preoperative model, pathological model, and combined model were developed by multivariate logistic regression analysis to predict the early recurrence (≤ 6 months) of IMCC, and the prediction performance of different models were compared using the Delong test. The developed models were validated by assessing their prediction performance in test set of 33 patients. Multivariate logistic regression analysis identified solitary, differentiation, energy- arterial phase (AP), inertia-AP, and percentile50th-portal venous phase (PV) to construct combined model for predicting early recurrence of IMCC [the area under the curve (AUC) = 0.917; 95% CI 0.840–0.965]. While the AUC of pathological model and preoperative model were 0.741 (95% CI 0.637–0.828) and 0.844 (95% CI 0.751–0.912), respectively. The AUC of the combined model was significantly higher than that of the preoperative model (p = 0.049) or pathological model (p = 0.002) in training set. In test set, the combined model also showed higher prediction performance. CT-based radiomics signature is a powerful predictor for early recurrence of IMCC. Preoperative model (constructed with homogeneity-AP and standard deviation-AP) and combined model (constructed with solitary, differentiation, energy-AP, inertia-AP, and percentile50th-PV) can improve the accuracy for pre-and postoperatively predicting the early recurrence of IMCC.
Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis
Authors: Ting Darren Shu Jeng , Goh Eunice Tze Leng , Mayandi Venkatesh , Busoy Joanna M. F. , Aung Thet Tun , Periayah Mercy Halleluyah , Nubile Mario , Mastropasqua Leonardo , Said Dalia G. , Htoon Hla M. , Barathi Veluchamy Amutha , Beuerman Roger W. , Lakshminarayanan Rajamani , Mohammed Imran , Dua Harminder S. 
Published: September 2021

AbstractBacterial keratitis (BK) is a major cause of corneal blindness globally. This study aimed to develop a novel class of antimicrobial therapy, based on human-derived hybrid host defense peptides (HyHDPs), for treating BK. HyHDPs were rationally designed through combination of functional amino acids in parent HDPs, including LL-37 and human beta-defensin (HBD)-1 to -3. Minimal inhibitory concentrations (MICs) and time-kill kinetics assay were performed to determine the concentration- and time-dependent antimicrobial activity and cytotoxicity was evaluated against human corneal epithelial cells and erythrocytes. In vivo safety and efficacy of the most promising peptide was examined in the corneal wound healing and Staphylococcus aureus (ATCC SA29213) keratitis murine models, respectively. A second-generation HyHDP (CaD23), based on rational hybridization of the middle residues of LL-37 and C-terminal of HBD-2, was developed and was shown to demonstrate good efficacy against methicillin-sensitive and methicillin-resistant S. aureus [MIC = 12.5–25.0 μg/ml (5.2–10.4 μM)] and S. epidermidis [MIC = 12.5 μg/ml (5.2 μM)], and moderate efficacy against P. aeruginosa [MIC = 25-50 μg/ml (10.4–20.8 μM)]. CaD23 (at 25 μg/ml or 2× MIC) killed all the bacteria within 30 min, which was 8 times faster than amikacin (25 μg/ml or 20× MIC). After 10 consecutive passages, S. aureus (ATCC SA29213) did not develop any antimicrobial resistance (AMR) against CaD23 whereas it developed significant AMR (i.e. a 32-fold increase in MIC) against amikacin, a commonly used treatment for BK. Pre-clinical murine studies showed that CaD23 (0.5 mg/ml) achieved a median reduction of S. aureus bioburden by 94% (or 1.2 log10 CFU/ml) while not impeding corneal epithelial wound healing. In conclusion, rational hybridization of human-derived HDPs has led to generation of a potentially efficacious and safe topical antimicrobial agent for treating Gram-positive BK, with no/minimal risk of developing AMR.
Atypical for northern ungulates, energy metabolism is lowest during summer in female wild boars (Sus scrofa)
Authors: Ruf Thomas , Vetter Sebastian G. , Painer Johanna , Stalder Gabrielle , Bieber Claudia 
Published: September 2021

AbstractTypically, large ungulates show a single seasonal peak of heart rate, a proxy of energy expenditure, in early summer. Different to other large ungulates, wild boar females had peak heart rates early in the year (at ~ April, 1), which likely indicates high costs of reproduction. This peak was followed by a trough over summer and a secondary summit in autumn/early winter, which coincided with the mast seeding of oak trees and the mating season. Wild boars counteracted the effects of cold temperatures by decreasing subcutaneous body temperature by peripheral vasoconstriction. They also passively gained solar radiation energy by basking in the sun. However, the shape of the seasonal rhythm in HR indicates that it was apparently not primarily caused by thermoregulatory costs but by the costs of reproduction. Wild boar farrow early in the year, visible in high HRs and sudden changes in intraperitoneal body temperature of females. Arguably, a prerequisite for this early reproduction as well as for high energy metabolism over winter is the broad variety of food consumed by this species, i.e., the omnivorous lifestyle. Extremely warm and dry summers, as experienced during the study years (2017, 2018), may increasingly become a bottleneck for food intake of wild boar.
Rapid MRSA detection via tandem mass spectrometry of the intact 80 kDa PBP2a resistance protein
Authors: Neil Jason R. , Verma Arvind , Kronewitter Scott R. , McGee William M. , Mullen Christopher , Viirtola Marjaana , Kotovuori Annika , Friedrich Herdis , Finell Johan , Rannisto Joni , Syka John E. P. , Stephenson James L. 
Published: September 2021

AbstractTreatment of antibiotic-resistant infections is dependent on the detection of specific bacterial genes or proteins in clinical assays. Identification of methicillin-resistantStaphylococcus aureus(MRSA) is often accomplished through the detection of penicillin-binding protein 2a (PBP2a). With greater dependence on mass spectrometry (MS)-based bacterial identification, complementary efforts to detect resistance have been hindered by the complexity of those proteins responsible. Initial characterization of PBP2a indicates the presence of glycan modifications. To simplify detection, we demonstrate a proof-of-concept tandem MS approach involving the generation of N-terminal PBP2a peptide-like fragments and detection of unique product ions during top-down proteomic sample analyses. This approach was implemented for two PBP2a variants, PBP2amecAand PBP2amecC, and was accurate across a representative panel of MRSA strains with different genetic backgrounds. Additionally, PBP2amecAwas successfully detected from clinical isolates using a five-minute liquid chromatographic separation and implementation of this MS detection strategy. Our results highlight the capability of direct MS-based resistance marker detection and potential advantages for implementing these approaches in clinical diagnostics.
Porphyromonas gingivalis induces entero-hepatic metabolic derangements with alteration of gut microbiota in a type 2 diabetes mouse model
Authors: Kashiwagi Yoichiro , Aburaya Shunsuke , Sugiyama Naoyuki , Narukawa Yuki , Sakamoto Yuta , Takahashi Masatomo , Uemura Hayato , Yamashita Rentaro , Tominaga Shotaro , Hayashi Satoko , Nozaki Takenori , Yamada Satoru , Izumi Yoshihiro , Kashiwagi Atsunori , Bamba Takeshi , Ishihama Yasushi , Murakami Shinya 
Published: September 2021

AbstractPeriodontal infection induces systemic inflammation; therefore, aggravating diabetes. Orally administered periodontal pathogens may directly alter the gut microbiota. We orally treated obese db/db diabetes mice using Porphyromonas gingivalis (Pg). We screened for Pg-specific peptides in the intestinal fecal specimens and examined whether Pg localization influenced the intestinal microbiota profile, in turn altering the levels of the gut metabolites. We evaluated whether the deterioration in fasting hyperglycemia was related to the changes in the intrahepatic glucose metabolism, using proteome and metabolome analyses. Oral Pg treatment aggravated both fasting and postprandial hyperglycemia (P < 0.05), with a significant (P < 0.01) increase in dental alveolar bone resorption. Pg-specific peptides were identified in fecal specimens following oral Pg treatment. The intestinal Pg profoundly altered the gut microbiome profiles at the phylum, family, and genus levels; Prevotella exhibited the largest increase in abundance. In addition, Pg-treatment significantly altered intestinal metabolite levels. Fasting hyperglycemia was associated with the increase in the levels of gluconeogenesis-related enzymes and metabolites without changes in the expression of proinflammatory cytokines and insulin resistance. Oral Pg administration induced gut microbiota changes, leading to entero-hepatic metabolic derangements, thus aggravating hyperglycemia in an obese type 2 diabetes mouse model.
Facilitation of object encoding in infants by the observation of giving
Authors: Tatone Denis , Hernik Mikołaj , Csibra Gergely 
Published: September 2021

AbstractWe propose that humans are prepared to interpret giving as a diagnostic cue of reciprocal–exchange relations from infancy. A prediction following from this hypothesis is that infants will represent the identity of an object they see being given, because this information is critical for evaluating potential future reciprocation. Across three looking-time experiments we tested whether the observation of a transfer action induces 12-month-olds to encode the identity of a single object handled by an agent. We found that infants encoded the object identity when the agent gave the object (Experiment 1), but not when she took it (Experiment 2), despite being able to represent the goal of both actions (Experiments 1 and 3). Consistent with our hypothesis, these results suggest that the infants’ representation of giving comprises information necessary for comparing the value of transferred goods across sharing episodes.
Biomolecular simulation based machine learning models accurately predict sites of tolerability to the unnatural amino acid acridonylalanine
Authors: Giannakoulias Sam , Shringari Sumant R. , Ferrie John J. , Petersson E. James 
Published: September 2021

AbstractThe incorporation of unnatural amino acids (Uaas) has provided an avenue for novel chemistries to be explored in biological systems. However, the successful application of Uaas is often hampered by site-specific impacts on protein yield and solubility. Although previous efforts to identify features which accurately capture these site-specific effects have been unsuccessful, we have developed a set of novel Rosetta Custom Score Functions and alternative Empirical Score Functions that accurately predict the effects of acridon-2-yl-alanine (Acd) incorporation on protein yield and solubility. Acd-containing mutants were simulated in PyRosetta, and machine learning (ML) was performed using either the decomposed values of the Rosetta energy function, or changes in residue contacts and bioinformatics. Using these feature sets, which represent Rosetta score function specific and bioinformatics-derived terms, ML models were trained to predict highly abstract experimental parameters such as mutant protein yield and solubility and displayed robust performance on well-balanced holdouts. Model feature importance analyses demonstrated that terms corresponding to hydrophobic interactions, desolvation, and amino acid angle preferences played a pivotal role in predicting tolerance of mutation to Acd. Overall, this work provides evidence that the application of ML to features extracted from simulated structural models allow for the accurate prediction of diverse and abstract biological phenomena, beyond the predictivity of traditional modeling and simulation approaches.