bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence
Authors: Jenson Justin M. , Li Tuo , Du Fenghe , Ea Chee-Kwee , Chen Zhijian J. 
Published: February 2023

AbstractcGAS is an evolutionarily conserved enzyme that has a pivotal role in immune defence against infection1–3. In vertebrate animals, cGAS is activated by DNA to produce cyclic GMP–AMP (cGAMP)4,5, which leads to the expression of antimicrobial genes6,7. In bacteria, cyclic dinucleotide (CDN)-based anti-phage signalling systems (CBASS) have been discovered8–11. These systems are composed of cGAS-like enzymes and various effector proteins that kill bacteria on phage infection, thereby stopping phage spread. Of the CBASS systems reported, approximately 39% contain Cap2 and Cap3, which encode proteins with homology to ubiquitin conjugating (E1/E2) and deconjugating enzymes, respectively8,12. Although these proteins are required to prevent infection of some bacteriophages8, the mechanism by which the enzymatic activities exert an anti-phage effect is unknown. Here we show that Cap2 forms a thioester bond with the C-terminal glycine of cGAS and promotes conjugation of cGAS to target proteins in a process that resembles ubiquitin conjugation. The covalent conjugation of cGAS increases the production of cGAMP. Using a genetic screen, we found that the phage protein Vs.4 antagonized cGAS signalling by binding tightly to cGAMP (dissociation constant of approximately 30 nM) and sequestering it. A crystal structure of Vs.4 bound to cGAMP showed that Vs.4 formed a hexamer that was bound to three molecules of cGAMP. These results reveal a ubiquitin-like conjugation mechanism that regulates cGAS activity in bacteria and illustrates an arms race between bacteria and viruses through controlling CDN levels.
Deconvolution of clinical variance in CAR-T cell pharmacology and response
Authors: Kirouac Daniel C. , Zmurchok Cole , Deyati Avisek , Sicherman Jordan , Bond Chris , Zandstra Peter W. 
Published: February 2023

AbstractChimeric antigen receptor T cell (CAR-T) expansion and persistence vary widely among patients and predict both efficacy and toxicity. However, the mechanisms underlying clinical outcomes and patient variability are poorly defined. In this study, we developed a mathematical description of T cell responses wherein transitions among memory, effector and exhausted T cell states are coordinately regulated by tumor antigen engagement. The model is trained using clinical data from CAR-T products in different hematological malignancies and identifies cell-intrinsic differences in the turnover rate of memory cells and cytotoxic potency of effectors as the primary determinants of clinical response. Using a machine learning workflow, we demonstrate that product-intrinsic differences can accurately predict patient outcomes based on pre-infusion transcriptomes, and additional pharmacological variance arises from cellular interactions with patient tumors. We found that transcriptional signatures outperform T cell immunophenotyping as predictive of clinical response for two CD19-targeted CAR-T products in three indications, enabling a new phase of predictive CAR-T product development.
Outcomes of microsurgical vasoepididymostomy using intussusception technique: a systematic review and meta‑analysis
Authors: Wang Shou-yang , Fang Yang-yi 
Published: February 2023

AbstractA systematic review and meta-analysis of microsurgical vasoepididymostomy (MVE) for treating epididymal obstructive azoospermia (EOA) with different intussusception techniques. We conducted a comprehensive literature search using PubMed, Embase, and the Cochrane Central Register of Controlled Trials, retained literature related to obstructive azoospermia or male infertility and vasoepididymostomy, proactively reviewed other relevant literature, supplemented valuable references, and excluded studies that did not use intussusception and where valuable statistical data were difficult to obtain. Event rate and risk ratio (RR) were estimated. Patency rates were investigated. The influence of motile sperms found in the epididymal fluid, anastomotic sides and sites on patency was evaluated. 273 articles were comprised in this analysis, and 25 observational studies were eventually included, with a total patient sample of 1400. The overall mean patency rate was 69.3% (95% confidence interval [CI] 64.6–73.6%;I2 = 63.735%). We conducted a meta-analysis of the factors affecting patency after microsurgical IVE, finding that the presence of motile sperms in epididymal fluid (RR = 1.52; 95% CI 1.18–1.97%;P = 0.001), anastomosing bilaterally (RR = 1.32; 95% CI 1.15–1.50%;P < 0.0001) and distally (RR = 1.42; 95% CI 1.09–1.85%;P = 0.009) lead to higher patency rates. IVE is an effective treatment for EOA. The presence of motile sperms found in the epididymal fluid, anastomosing bilaterally and distally are significantly correlated with higher patency rates.
Breed and ruminal fraction effects on bacterial and archaeal community composition in sheep
Authors: McLoughlin Steven , Spillane Charles , Campion Francis P. , Claffey Noel , Sosa Chrystian C. , McNicholas Yvonne , Smith Paul E. , Diskin Michael G. , Waters Sinéad M. 
Published: February 2023

AbstractWhile the breed of cattle can impact on the composition and structure of microbial communities in the rumen, breed-specific effects on rumen microbial communities have rarely been examined in sheep. In addition, rumen microbial composition can differ between ruminal fractions, and be associated with ruminant feed efficiency and methane emissions. In this study, 16S rRNA amplicon sequencing was used to investigate the effects of breed and ruminal fraction on bacterial and archaeal communities in sheep. Solid, liquid and epithelial rumen samples were obtained from a total of 36 lambs, across 4 different sheep breeds (Cheviot (n = 10), Connemara (n = 6), Lanark (n = 10) and Perth (n = 10)), undergoing detailed measurements of feed efficiency, who were offered a nut based cereal diet ad-libitum supplemented with grass silage. Our results demonstrate that the feed conversion ratio (FCR) was lowest for the Cheviot (most efficient), and highest for the Connemara breed (least efficient). In the solid fraction, bacterial community richness was lowest in the Cheviot breed, while Sharpea azabuensis was most abundant in the Perth breed. Lanark, Cheviot and Perth breeds exhibited a significantly higher abundance of epithelial associated Succiniclasticum compared to the Connemara breed. When comparing ruminal fractions, Campylobacter, Family XIII, Mogibacterium, and Lachnospiraceae UCG-008 were most abundant in the epithelial fraction. Our findings indicate that breed can impact the abundance of specific bacterial taxa in sheep while having little effect on the overall composition of the microbial community. This finding has implications for genetic selection breeding programs aimed at improving feed conversion efficiency of sheep. Furthermore, the variations in the distribution of bacterial species identified between ruminal fractions, notably between solid and epithelial fractions, reveals a rumen fraction bias, which has implications for sheep rumen sampling techniques.
Knowledge grounded medical dialogue generation using augmented graphs
Authors: Varshney Deeksha , Zafar Aizan , Behera Niranshu Kumar , Ekbal Asif 
Published: February 2023

AbstractSmart healthcare systems that make use of abundant health data can improve access to healthcare services, reduce medical costs and provide consistently high-quality patient care. Medical dialogue systems that generate medically appropriate and human-like conversations have been developed using various pre-trained language models and a large-scale medical knowledge base based on Unified Medical Language System (UMLS). However, most of the knowledge-grounded dialogue models only use local structure in the observed triples, which suffer from knowledge graph incompleteness and hence cannot incorporate any information from dialogue history while creating entity embeddings. As a result, the performance of such models decreases significantly. To address this problem, we propose a general method to embed the triples in each graph into large-scalable models and thereby generate clinically correct responses based on the conversation history using the recently recently released MedDialog(EN) dataset. Given a set of triples, we first mask the head entities from the triples overlapping with the patient’s utterance and then compute the cross-entropy loss against the triples’ respective tail entities while predicting the masked entity. This process results in a representation of the medical concepts from a graph capable of learning contextual information from dialogues, which ultimately aids in leading to the gold response. We also fine-tune the proposed Masked Entity Dialogue (MED) model on smaller corpora which contain dialogues focusing only on the Covid-19 disease named as the Covid Dataset. In addition, since UMLS and other existing medical graphs lack data-specific medical information, we re-curate and perform plausible augmentation of knowledge graphs using our newly created Medical Entity Prediction (MEP) model. Empirical results on the MedDialog(EN) and Covid Dataset demonstrate that our proposed model outperforms the state-of-the-art methods in terms of both automatic and human evaluation metrics.
Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials
Authors: Bastin Donald J. , Montroy Joshua , Kennedy Michael A. , Martel Andre B. , Shorr Risa , Ghiasi Maryam , Boucher Dominique M. , Wong Boaz , Gresham Louise , Diallo Jean-Simon , Fergusson Dean A. , Lalu Manoj M. , Kekre Natasha , Auer Rebecca C. 
Published: February 2023

AbstractWe conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01–1.63) and disease-free survival (HR 1.33, 95% CI 1.05–1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors.Registration: PROSPERO CRD42019140187.
Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
Authors: Berntsson Elina , Vosough Faraz , Svantesson Teodor , Pansieri Jonathan , Iashchishyn Igor A. , Ostojić Lucija , Dong Xiaolin , Paul Suman , Jarvet Jüri , Roos Per M. , Barth Andreas , Morozova-Roche Ludmilla A. , Gräslund Astrid , Wärmländer Sebastian K. T. S. 
Published: February 2023

AbstractAlzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods—mainly spectroscopy and imaging techniques—to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1–40), Aβ(1–40)(H6A, H13A, H14A), Aβ(4–40), and Aβ(1–42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aβ binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aβ dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aβ monomers, while in a membrane-mimicking environment (SDS micelles) coil–coil helix interactions appear to be induced. For SDS-stabilized Aβ oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aβ aggregation processes that are involved in AD brain pathology.
SBAS-InSAR based validated landslide susceptibility mapping along the Karakoram Highway: a case study of Gilgit-Baltistan, Pakistan
Authors: Kulsoom Isma , Hua Weihua , Hussain Sadaqat , Chen Qihao , Khan Garee , Shihao Dai 
Published: February 2023

AbstractGeological settings of the Karakoram Highway (KKH) increase the risk of natural disasters, threatening its regular operations. Predicting landslides along the KKH is challenging due to limitations in techniques, a challenging environment, and data availability issues. This study uses machine learning (ML) models and a landslide inventory to evaluate the relationship between landslide events and their causative factors. For this, Extreme Gradient Boosting (XGBoost), Random Forest (RF), Artificial Neural Network (ANN), Naive Bayes (NB), and K Nearest Neighbor (KNN) models were used. A total of 303 landslide points were used to create an inventory, with 70% for training and 30% for testing. Susceptibility mapping used Fourteen landslide causative factors. The area under the curve (AUC) of a receiver operating characteristic (ROC) is employed to compare the accuracy of the models. The deformation of generated models in susceptible regions was evaluated using SBAS-InSAR (Small-Baseline subset-Interferometric Synthetic Aperture Radar) technique. The sensitive regions of the models showed elevated line-of-sight (LOS) deformation velocity. The XGBoost technique produces a superior Landslide Susceptibility map (LSM) for the region with the integration of SBAS-InSAR findings. This improved LSM offers predictive modeling for disaster mitigation and gives a theoretical direction for the regular management of KKH.
Inhibition of nicotinamide dinucleotide salvage pathway counters acquired and intrinsic poly(ADP-ribose) polymerase inhibitor resistance in high-grade serous ovarian cancer
Authors: Sauriol Skye Alexandre , Carmona Euridice , Udaskin Molly L. , Radulovich Nikolina , Leclerc-Desaulniers Kim , Rottapel Robert , Oza Amit M. , Lheureux Stephanie , Provencher Diane M. , Mes-Masson Anne-Marie 
Published: February 2023

AbstractEpithelial ovarian cancer is the most lethal gynecological malignancy, owing notably to its high rate of therapy-resistant recurrence in spite of good initial response to chemotherapy. Although poly(ADP-ribose) polymerase inhibitors (PARPi) have shown promise for ovarian cancer treatment, extended therapy usually leads to acquired PARPi resistance. Here we explored a novel therapeutic option to counter this phenomenon, combining PARPi and inhibitors of nicotinamide phosphoribosyltransferase (NAMPT). Cell-based models of acquired PARPi resistance were created through an in vitro selection procedure. Using resistant cells, xenograft tumors were grown in immunodeficient mice, while organoid models were generated from primary patient tumor samples. Intrinsically PARPi-resistant cell lines were also selected for analysis. Our results show that treatment with NAMPT inhibitors effectively sensitized all in vitro models to PARPi. Adding nicotinamide mononucleotide, the resulting NAMPT metabolite, abrogated the therapy-induced cell growth inhibition, demonstrating the specificity of the synergy. Treatment with olaparib (PARPi) and daporinad (NAMPT inhibitor) depleted intracellular NAD+ , induced double-strand DNA breaks, and promoted apoptosis as monitored by caspase-3 cleavage. The two drugs were also synergistic in mouse xenograft models and clinically relevant patient-derived organoids. Therefore, in the context of PARPi resistance, NAMPT inhibition could offer a promising new option for ovarian cancer patients.
Effects of mammalian sex hormones on in vitro organogenesis of common bean (Phaseolus vulgaris L.)
Authors: Haliloğlu Kamil , Türkoğlu Aras , Balpınar Özge , Öztürk Halil İbrahim , Özkan Güller , Poczai Peter 
Published: February 2023

AbstractBeans are an important plant species and are one of the most consumed legumes in human nutrition, especially as a protein, vitamin, mineral, and fiber source. Common bean (Phaseolus vulgaris L.) is a plant that also has an important role in natural nitrogen fixation. Currently, in vitro regeneration and micropropagation applications are limited in relation to genetic factors in bean Accordingly, there is great need to optimize micropropagation and tissue culture methods of the bean plant. To date, the effect of mammalian sex hormones (MSH) on in vitro conditions in P. vulgaris L. is poorly understood. This study examined the effects of different types of explants (embryo, hypocotyl, plumule, and radicle), MSH type (progesterone, 17 β-estradiol, estrone, and testosterone), and MSH concentration (10−4, 10−6, 10−8 and 10−10 mmol L−1) on the responding explants induction rate (REI), viability of plantlets rate (VPR), shoot proliferation rate (SPR), root proliferation rate (RPR), and callus induction rate (CIR). The effects of mammalian sex hormones, concentrations, explant type, and their interactions were statistically significant (p ≤ 0.01) in all examined parameters. The best explants were embryo and plumule. Our results showed that the highest REI rate (100%) was recorded when 10−10 mmol L−1 of all MSH was applied to MS medium using the plumule explant. The highest VPR (100%) was obtained when 10−10 mmol L−1 of all MSH was applied to MS medium using the plumule explant. The highest root proliferation rates (77.5%) were recorded in MS medium supplemented with 10−8 mmol L−1 17β-estradiol using embryo explant. The highest percentage of shoot-forming explants (100%) generally was obtained from embryo and plumule cultured in the MS culture medium with low MSH concentration. In addition, the highest CIR (100%) was obtained from embryo and plumule explant cultured in MS medium containing 10−10 mmol L−1 of all MSH types. In conclusion, we observed that mammalian sex hormones may be used in bean in vitro culture.
Patient profile, management, and quality of life associated with Dravet syndrome: a cross-sectional, multicentre study of 80 patients in Spain
Authors: Gil-Nagel Antonio , Sánchez-Carpintero Rocío , Villanueva Vicente 
Published: February 2023

AbstractThe aim of this study was to describe the profile of patients diagnosed with Dravet syndrome (DS), their clinical management, and the impact of DS on their quality of life (QoL) and family. Data of 80 patients from 11 centres in Spain was collected. Patients (47.5% female) were 12.7 (9.6) years on average (SD, standard deviation). Despite the first episode occurred when patients were a mean (SD) of 0.4 (0.2) years, DS was not diagnosed until they were 6.9 (10.1) years old. The majority (86.7%) had SCN1A gene mutations and 73.4% had seizures during the last year (mostly generalized motor seizures [47.8%]). The mean (SD) number of status epilepticus episodes was 3.6 (8.0) since diagnosis and 0.1 (0.5) in the last year. On the Health Utilities Index Mark (HUI) multi-attribute scale, the mean global score (SD) was 0.56 (0.24) in HUI2 and 0.32 (0.37) in HUI3. The impact of the disease was severe in most patients (HUI2, 81%; HUI3, 83.5%). In the Care-related QoL (CarerQol) the mean (SD) well-being score was 7.2 (2.1). Most caregivers (90%) were satisfied with their caregiving tasks, although 75% had difficulties combining these tasks with daily activities, 68.8% reported mental health problems and 61.2% physical problems.
Improvements in 2D p-type WSe2 transistors towards ultimate CMOS scaling
Authors: Patoary Naim Hossain , Xie Jing , Zhou Guantong , Al Mamun Fahad , Sayyad Mohammed , Tongay Sefaattin , Esqueda Ivan Sanchez 
Published: February 2023

AbstractThis paper provides comprehensive experimental analysis relating to improvements in the two-dimensional (2D) p-type metal–oxide–semiconductor (PMOS) field effect transistors (FETs) by pure van der Waals (vdW) contacts on few-layer tungsten diselenide (WSe2) with high-k metal gate (HKMG) stacks. Our analysis shows that standard metallization techniques (e.g., e-beam evaporation at moderate pressure ~ 10–5 torr) results in significant Fermi-level pinning, but Schottky barrier heights (SBH) remain small (< 100 meV) when using high work function metals (e.g., Pt or Pd). Temperature-dependent analysis uncovers a more dominant contribution to contact resistance from the channel access region and confirms significant improvement through less damaging metallization techniques (i.e., reduced scattering) combined with strongly scaled HKMG stacks (enhanced carrier density). A clean contact/channel interface is achieved through high-vacuum evaporation and temperature-controlled stepped deposition providing large improvements in contact resistance. Our study reports low contact resistance of 5.7 kΩ-µm, with on-state currents of ~ 97 µA/µm and subthreshold swing of ~ 140 mV/dec in FETs with channel lengths of 400 nm. Furthermore, theoretical analysis using a Landauer transport ballistic model for WSe2 SB-FETs elucidates the prospects of nanoscale 2D PMOS FETs indicating high-performance (excellent on-state current vs subthreshold swing benchmarks) towards the ultimate CMOS scaling limit.