bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thermo-amplifier circuit in probioticE. colifor stringently temperature-controlled release of a novel antibiotic
Authors: Dey Sourik , Seyfert Carsten E. , Fink-Straube Claudia , Kany Andreas M. , Müller Rolf , Sankaran Shrikrishnan 
Published: February 2024

AbstractPeptide drugs have seen rapid advancement in biopharmaceutical development, with over 80 candidates approved globally. Despite their therapeutic potential, the clinical translation of peptide drugs is hampered by challenges in production yields and stability. Engineered bacterial therapeutics is a unique approach being explored to overcome these issues by using bacteria to produce and deliver therapeutic compounds at the body site of use. A key advantage of this technology is the possibility to control drug delivery within the body in real time using genetic switches. However, the performance of such genetic switches suffers when used to control drugs that require post-translational modifications or are toxic to the host. In this study, these challenges were experienced when attempting to establish a thermal switch for the production of a ribosomally synthesized and post-translationally modified peptide antibiotic, darobactin, in probioticE. coli. These challenges were overcome by developing a thermo-amplifier circuit that combined the thermal-switch with a T7 RNA Polymerase and its promoter that overcame limitations imposed by the host transcriptional machinery due to its orthogonality to it. This circuit enabled production of pathogen-inhibitory levels of darobactin at 40°C while maintaining leakiness below the detection limit at 37°C. More impressively, the thermo-amplifier circuit sustained production beyond the thermal induction duration. Thus, raised temperature for 2 h was sufficient for the bacteria to produce pathogen-inhibitory levels of darobactin even in the physiologically relevant simulated conditions of the intestines that include bile salts and low nutrient levels.Graphical Abstract
Uncovering the simple adhesive strategy of the Toxoplasma parasite for high-speed motility
Authors: Vigetti Luis , Touquet Bastien , Debarre Delphine , Rose Thierry , Bureau Lionel , Abdallah Dima , Dubacheva Galina V. , Tardieux Isabelle 
Published: February 2024

ABSTRACTToxoplasma gondiiis a protozoan parasite that has evolved a developmental morphotype called tachyzoite that navigates between cells and moves in and out of them in a wide repertoire of homeothermic hosts. Relying on a uniquely constant apicobasal bipolarity coupled to an actomyosin-driven retrograde surface flow, the tachyzoite has elaborated a molecular machinery to assemble transient anchoring contacts with the environment, which support the traction force required to power a typical helical gliding motility. Combining micropatterning with live, reflection interference contrast and expansion microscopies, we bring first nanoscale evidence that the tachyzoite needs to build only one apical anchoring contact with the substrate, thus spatially defining a minimal force transmission platform over which it can slide. We uncover that the apicobasal driven surface flow is set up in response to extracellular biochemical cues independent of adhesin release and tachyzoite-surface interactions, hence prior to motile activity. Furthermore, to identify the minimal adhesion requirements for helical gliding at the level of individual molecular species, we combine biochemical and biophysical quantitative assays based on tunable surface chemistry and quartz crystal microbalance with dissipation monitoring. These approaches uncover that glycosaminoglycan (GAG)-parasite interactions are sufficient to promote a productive contact for helical gliding and pave the way for the characterization of the structure and density of the molecules functionally engaged at this essential parasite-substrate mechanosensitive interface.
WITHDRAWN: Truncated NLRC5 isoforms in human placenta: expression, regulation by miR-218-5p, and function in trophoblasts
Authors: Shan Yanan , O’Brian Jacob A , Nadeem Lubna , Dunk Caroline , Chen Yan , Brkic Jelena , Hayder Heyam , Lye Stephen J , Peng Chun 
Published: February 2024

Withdraw statementThe authors have withdrawn this manuscript because [the current results no longer support the conclusion in the article]. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Feature pre-selection for the development of epigenetic biomarkers
Authors: Cheng Yipeng , Gieger Christian , Campbell Archie , McIntosh Andrew M , Waldenberger Melanie , McCartney Daniel L , Marioni Riccardo E , Vallejos Catalina A 
Published: February 2024

AbstractOver the last decade, a plethora of blood-based DNA methylation biomarkers have been developed to track differences in ageing, lifestyle, health, and biological outcomes. Typically, penalised regression models are used to generate these predictors, with hundreds or thousands of CpGs included as potential features. However, in such ultra high-dimensional settings, the effectiveness of these methods may be reduced.Here, we introduce Related Trait-based Feature Screening (RTFS), a method for performing CpG pre-selection for incident disease prediction models by utilising associations between CpGs and health-related continuous traits. In a comparison with commonly used CpG pre-selection methods, we evaluate resulting downstream Cox proportional-hazards prediction models for 10-year type 2 diabetes (T2D) onset risk in Generation Scotland (n=18,414). The top performing models utilised incident T2D EWAS (AUC=0.881, PRAUC=0.279) and RTFS (AUC=0.877, PRAUC=0.277). The resulting models also improve prediction over a model using standard risk factors only (AUC=0.841, PRAUC=0.194) and replication was observed in the German-based KORA study (n=4,261)RTFS is a flexible and generalisable framework that can help to refine biomarker development for incident disease outcomes.
North-south pathways, emerging variants, and high climate suitability characterize the recent spread of dengue virus serotypes 2 and 3 in the Dominican Republic
Authors: Miguel Isaac , Feliz Edwin P. , Agramonte Robinson , Martinez Pedro V. , Vergara Carlos , Imbert Yvonne , De la Cruz Lucia , de Castro Nurys , Cedano Odalis , De la Paz Yamilka , Fonseca Vagner , Santiago Gilberto A. , Muñoz-Jordán Jorge L. , Peguero Armando , Paulino-Ramírez Robert , Grubaugh Nathan D. , de Filippis Ana Maria Bispo , Alcantara Luiz Carlos Junior , Rico Jairo Mendez , Lourenço José , Franco Leticia , Giovanetti Marta 
Published: February 2024

SummaryWe employ a multidisciplinary approach, integrating genomics and epidemiology, to uncover recent dengue virus transmission dynamics in the Dominican Republic. Our results highlight a previously unknown north-south transmission pathway within the country, with the co-circulation of multiple virus lineages. Additionally, we examine the historical climate data, revealing long-term trends towards higher theoretical potential for dengue transmission due to rising temperatures. These findings provide information for targeted interventions and resource allocation, informing as well towards preparedness strategies for public health agencies in mitigating climate and geo-related dengue risks.
Cleft lip sidedness and the association with additional congenital malformations
Authors: Fell Matthew , Fitzsimons Kate J , Hamilton Mark J , Medina Jibby , Butterworth Sophie , Park Min Hae , Van der Meulen Jan , Lewis Sarah , Chong David , Russell Craig JH 
Published: February 2024

AbstractObjectiveTo investigate the association between the sidedness of orofacial clefts and additional congenital malformations.DesignLinkage of a national registry of cleft births to national administrative data of hospital admissionsSettingNational Health Service, EnglandParticipants2,007 children born with cleft lip +-alveolus (CL+-A) and 2,724 with cleft lip and palate (CLP) born between 2000 and 2012.Main outcome measureThe proportion of children with ICD-10 codes for additional congenital malformations by the sidedness (left, right or bilateral) of orofacial clefts.ResultsFor CL+-A phenotypes, there was no evidence for a difference in the prevalence of additional anomalies between left (22%, reference), right (22%, aOR 1.02, 95% CI 0.80 to 1.28; p= 0.90) and bilateral clefts (23%, aOR 1.09, 95% CI 0.75 to 1.57; p= 0.66). For CLP phenotypes, there was evidence of a lower prevalence of additional malformations in left (23%, reference) compared to right (32%, aOR 1.54, 95% CI 1.25 to 1.91; p <0.001) and bilateral clefts (33%, aOR 1.64, 95% CI 1.35 to 1.99; p<0.001).ConclusionsThe prevalence of additional congenital malformations was similar across sidedness subtypes with CL+-A phenotypes but was different for sidedness subtypes within CLP cases. These data support the hypothesis that CL+-A has a different underlying aetiology from CLP and that within the CLP phenotype, right sided CLP may lie closer in aetiology to bilateral CLP than it does to left sided CLP.
Evaluating Knowledge Fusion Models on Detecting Adverse Drug Events in Text
Authors: Wegner Philipp , Fröhlich Holger , Madan Sumit 
Published: February 2024

AbstractBackgroundDetecting adverse drug events (ADE) of drugs that are already available on the market is an essential part of the pharmacovigilance work conducted by both medical regulatory bodies and the pharmaceutical industry. Concerns regarding drug safety and economic interests serve as motivating factors for the efforts to identify ADEs. Hereby, social media platforms play an important role as a valuable source of reports on ADEs, particularly through collecting posts discussing adverse events associated with specific drugs.MethodologyWe aim with our study to assess the effectiveness of knowledge fusion approaches in combination with transformer-based NLP models to extract ADE mentions from diverse datasets, for instance, texts from Twitter, websites like askapatient.com, and drug labels. The extraction task is formulated as a named entity recognition (NER) problem. The proposed methodology involves applying fusion learning methods to enhance the performance of transformer-based language models with additional contextual knowledge from ontologies or knowledge graphs. Additionally, the study introduces a multi-modal architecture that combines transformer-based language models with graph attention networks (GAT) to identify ADE spans in textual data.ResultsA multi-modality model consisting of the ERNIE model with knowledge on drugs reached an F1-score of 71.84% on CADEC corpus. Additionally, a combination of a graph attention network with BERT resulted in an F1-score of 65.16% on SMM4H corpus. Impressively, the same model achieved an F1-score of 72.50% on the PSYTAR corpus, 79.54% on the ADE corpus, and 94.15% on the TAC corpus. Except for the CADEC corpus, the knowledge fusion models consistently outperformed the baseline model, BERT.ConclusionOur study demonstrates the significance of context knowledge in improving the performance of knowledge fusion models for detecting ADEs from various types of textual data.Author SummaryAdverse Drug Events (ADEs) are one of the main aspects of drug safety and play an important role during all phases of drug development, including post-marketing pharmacovigilance. Negative experiences with medications are frequently reported in textual form by individuals themselves through official reporting systems or social media posts, as well as by doctors in their medical notes. Automated extraction of ADEs allows us to identify these in large amounts of text as they are produced every day on various platforms. The text sources vary highly in structure and the type of language included which imposes certain challenges on extraction systems. This work investigates to which extent knowledge fusion models may overcome these challenges by fusing structured knowledge coming from ontologies with language models such as BERT. This is of great interest since the scientific community provides highly curated resources in the form of ontologies that can be utilized for tasks such as extracting ADEs from texts.
Co-occurring infections in cancer patients treated with checkpoint inhibitors significantly increase the risk of immune related adverse events
Authors: Makunts Tigran , Grabska Siranuysh , Grabski Hovakim , Abagyan Ruben 
Published: February 2024

AbstractTherapeutic antibodies designed to target immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4 have been applied in the treatment of various tumor types, including small and non-small cell lung cancers, melanoma, renal cell carcinoma, and others. These treatments combat cancers by reactivating CD8 cytotoxic T-cells. Nevertheless, this unique targeted mode of action was found to be associated with a broader range of immune-related adverse events, irAEs, affecting multiple physiological systems. Depending on their severity, these irAEs often necessitate the suspension or discontinuation of treatment and, in rare instances, may lead to fatal consequences. In this study we investigated over eighty thousand adverse event reports of irAEs in patients treated with PD-1, PD-L1, and CTLA-4 inhibitors. FDA Adverse Event Reporting System MedWatch submissions were used as the data source. These therapeutics included pembrolizumab, nivolumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab. The data analysis of these reports revealed a statistically significant association of immune related adverse events, including serious and life-threatening events in patients who experienced infectious disease during treatment. Additionally, the association trend was preserved across all the three classes of checkpoint inhibitors and each of the seven individual therapeutic agent cohorts.
Fibrinogen is the key factor associated with tremor relieve and recurrence in the ET patients subjected with unilateral MRgFUS thalamotomy
Authors: Lin Jiaji , Lu Haoxuan , Zhang Dekang , Bian Xianbing , Hu Jianxing , Pan Longsheng , Lou Xin 
Published: February 2024

AbstractObjectiveMagnetic resonance guided focused ultrasound (MRgFUS) thalamotomy has been shown to be safe and effective to treat various types of tremor diseases, but whether the clinical status of these patients was involved was still unknown.MethodsWe retrospectively studied the tremor symptoms and clinical variables (at hospitalization) of 59 essential tremor (ET) patients subjected with MRgFUS thalamotomy. Patients were categorized by the short-term tremor relieve and tremor recurrence within 12 months. Multivariate logistic regression was used to screen independent factors and construct the nomograms. Additional fibrinogen knock-out mice were applied to establish ET mouse model induced by harmaline and the frequency and intensity of tremor were measured and analyzed using a force-plated accelerometer.ResultsIt is found that 39 ET patients (66.102%) with significantly better efficiency in short-term tremor relieve (control ratio > 75%) at 1-month postoperatively, while nine ET patients (15.254%) experienced significant tremor recurrence within postoperative one-year. Multivariate analysis suggested fibrinogen (OR = 0.182, 95% CI = 0.042-0.796,) and monocyte count (OR = 0, 95% CI = 0-0.001) were independently associated with better short-term tremor relieve (>75%) at 1-month postoperatively. A total of nine ET patients (15.254%) experienced significant tremor recurrence. Admission systolic blood pressure (OR = 1.013, 95% CI = 1.010-1.062), hypertension comorbidity (OR = 2.163, 95% CI = 1.412-53.565) and fibrinogen (OR = 1.620, 95% CI = 1.047-24.376) independently contributed to tremor recurrence. The nomograms were established for better tremor relieve and tremor recurrence and have excellent performance as the AUCs were 0.829 and 0.853 (bootstrap repetition = 1000). Moreover, fibrinogen knock-out promoted a great suppression on maximum tremor motion power and overall tremor activity in ET tremor model (P< 0.001).ConclusionsThe study found that baseline fibrinogen is the key factor associated with tremor relieve and recurrence for patients subjected with MRgFUS thalamotomy. Preoperative evaluation of clinical factors has important predictive significance for short- and long-term postoperative outcomes for patients treated with MRgFUS thalamotomy.
Associations between cord serum antibodies against phosphorylcholine and bacterial infections in neonates: a prospective cohort study in singletons and twins
Authors: Chen Ruoqing , Zheng Yeqi , Tan Weiri , Wu Feng , Liang Hui , Chen Xi , Chen Youmei , Liu Xian , Fang Fang , Zhang Quanfu , Zhang Rui , Chen Xu 
Published: February 2024

AbstractBackgroundAntibodies against phosphorylcholine (anti-PC) are reported to protect against infection. However, the association between cord serum anti-PC and bacterial infection in neonates is yet to be investigated. This study aimed to investigate these associations among both singletons and twins.MethodsA total of 1007 neonates (329 singletons and 678 twins) within the hospital-based Shenzhen Baoan Birth & Twin cohort were included in this study. Levels of IgM anti-PC, IgG anti-PC, as well as IgM, IgG, and IgA in cord serum were measured by enzyme-linked immunosorbent assay. Diagnoses of bacterial infections were identified within 0-27 days after birth. Multivariable logistic regression with propensity score adjustment was performed to assess the associations between levels of antibodies and neonatal bacterial infections.ResultsThe mean (standard deviation) levels of IgM and IgG anti-PC were 46.68 (14.15) ng/ml and 73.68 (30.44) ng/ml, respectively. Neonatal bacterial infections were diagnosed in 24 singletons (7.29%) and 48 twins (7.08%). A higher level of IgM anti-PC was associated with a lower risk of neonatal bacterial infections in the analyses of singletons (Odds ratio [OR]: 0.64, 95% confidence interval [CI]: 0.41-0.99) or discordant twin pairs (concerning bacterial infection) (OR: 0.44, 95% CI: 0.20-0.95). Statistically significant association was also shown for IgG among singletons and the first-born twins, but not for IgG anti-PC, IgM, or IgA.ConclusionA higher cord serum level of IgM anti-PC is associated with a lower risk of bacterial infections in neonates.Key pointA higher level of IgM anti-PC in cord serum is associated with a lower risk of bacterial infection in both singleton and twin neonates.
In-situ architecture of the human prohibitin complex
Authors: Lange Felix , Ratz Michael , Dohrke Jan-Niklas , Wenzel Dirk , Ilgen Peter , Riedel Dietmar , Jakobs Stefan 
Published: February 2024

AbstractProhibitins are a highly conserved family of proteins that have been implicated in a variety of functions including mitochondrial stress signalling and housekeeping, cell cycle progression, apoptosis, lifespan regulation and many others1, 2. The human prohibitins PHB1 and PHB2 have been proposed to act as scaffolds within the mitochondrial inner membrane, but their molecular organisation remained elusive. Using an integrative structural biology approach combining quantitative Western blotting, cryo-electron tomography, subtomogram averaging and molecular modelling, we determined the molecular organisation of the human prohibitin complex within the mitochondrial inner membrane. The proposed bell-shaped structure consists of eleven alternating PHB1 and PHB2 molecules. This study reveals an average of about 43 prohibitin complexes per crista, covering 1-3 % of the cristae membranes. These findings provide a structural basis for understanding the functional contributions of prohibitins to the integrity and spatial organisation of the mitochondrial inner membrane.
Distribution of soil and clinicalBurkholderia pseudomalleiisolates in Myanmar by using MLST
Authors: Aung Nay Myo , Htut Kyaw Myo , Aung Han Tin , Thant Aye Min , Oo Khine Zaw , Su Khine Khine 
Published: February 2024

AbstractBurkholderia pseudomalleican be identified as Gram-negative bacillus without spore-forming in an environment such as soil and stagnant water. Human factors and climate changes make the incidence of melioidosis higher. Soil with high moisture and clay-rich is a suitable residence forB. pseudomallei. Twenty-one isolates ofB. pseudomalleiwere collected and performed by multilocus sequence typing. Among them, eight novel sequence types (STs) ofB. pseudomalleiwere found, while the rest show known STs. Interestingly, ST 56 from two patients was identified as the same region, while ST 90 showed local and global distribution. Among six ST 90B. pseudomallei, the three isolates were from soil and patients. Clinical ST 90 isolates were traced in the same region as soil ST 90 isolates. Those isolates may correlate with each other by using multilocus sequence typing (MLST) cost-effectively. However, it still needs to prove its correct relatedness. This study pointed out the reasonable assumption ofBurkholderia pseudomalleifor local and global distribution in Myanmar.
Structural basis of Cdk7 activation by dual T-loop phosphorylation
Authors: Düster Robert , Anand Kanchan , Binder Sophie C. , Schmitz Maximilian , Gatterdam Karl , Fisher Robert P. , Geyer Matthias 
Published: February 2024

AbstractCyclin-dependent kinase 7 (Cdk7) occupies a central position in cell-cycle and transcriptional regulation owing to its function as both a CDK-activating kinase (CAK) and part of the general transcription factor TFIIH. Cdk7 forms an active complex upon association with Cyclin H and Mat1, and its catalytic activity is regulated by two phosphorylations in the activation segment (T loop): the canonical activating modification at T170 and another at S164. Here we report the crystal structure of the fully activated human Cdk7/Cyclin H/Mat1 complex containing both T-loop phosphorylations. Whereas pT170 coordinates a set of basic residues conserved in other CDKs, pS164 nucleates an arginine network involving all three subunits that is unique to the ternary Cdk7 complex. We identify differential dependencies of kinase activity and substrate recognition on individual phosphorylations within the Cdk7 T loop. The CAK function of Cdk7 is not affected by T-loop phosphorylation, whereas activity towards non-CDK substrates is increased several-fold by phosphorylation at T170. Moreover, dual T-loop phosphorylation at both T170 and S164 stimulates multi-site phosphorylation of transcriptional substrates—the RNA polymerase II (RNAPII) carboxy-terminal domain (CTD) and the SPT5 carboxy-terminal repeat (CTR) region. In human cells, Cdk7-regulatory phosphorylation is a two-step process in which phosphorylation of S164 precedes, and may prime, T170 phosphorylation. Thus, dual T-loop phosphorylation can regulate Cdk7 through multiple mechanisms, with pS164 supporting tripartite complex formation and possibly influencing Cdk7 processivity, while the canonical pT170 enhances kinase activity towards critical substrates involved in transcription.