bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation
Authors: Zois Christos E. , Hendriks Anne M. , Haider Syed , Pires Elisabete , Bridges Esther , Kalamida Dimitra , Voukantsis Dimitrios , Lagerholm B. Christoffer , Fehrmann Rudolf S. N. , den Dunnen Wilfred F. A. , Tarasov Andrei I. , Baba Otto , Morris John , Buffa Francesca M. , McCullagh James S. O. , Jalving Mathilde , Harris Adrian L. 
Published: June 2022

AbstractChannelling of glucose via glycogen, known as the glycogen shunt, may play an important role in the metabolism of brain tumours, especially in hypoxic conditions. We aimed to dissect the role of glycogen degradation in glioblastoma (GBM) response to ionising radiation (IR). Knockdown of the glycogen phosphorylase liver isoform (PYGL), but not the brain isoform (PYGB), decreased clonogenic growth and survival of GBM cell lines and sensitised them to IR doses of 10–12 Gy. Two to five days after IR exposure of PYGL knockdown GBM cells, mitotic catastrophy and a giant multinucleated cell morphology with senescence-like phenotype developed. The basal levels of the lysosomal enzyme alpha-acid glucosidase (GAA), essential for autolysosomal glycogen degradation, and the lipidated forms of gamma-aminobutyric acid receptor-associated protein-like (GABARAPL1 and GABARAPL2) increased in shPYGL U87MG cells, suggesting a compensatory mechanism of glycogen degradation. In response to IR, dysregulation of autophagy was shown by accumulation of the p62 and the lipidated form of GABARAPL1 and GABARAPL2 in shPYGL U87MG cells. IR increased the mitochondrial mass and the colocalisation of mitochondria with lysosomes in shPYGL cells, thereby indicating reduced mitophagy. These changes coincided with increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase 2, slower ATP generation in response to glucose loading and progressive loss of oxidative phosphorylation. The resulting metabolic deficiencies affected the availability of ATP required for mitosis, resulting in the mitotic catastrophy observed in shPYGL cells following IR. PYGL mRNA and protein levels were higher in human GBM than in normal human brain tissues and high PYGL mRNA expression in GBM correlated with poor patient survival. In conclusion, we show a major new role for glycogen metabolism in GBM cancer. Inhibition of glycogen degradation sensitises GBM cells to high-dose IR indicating that PYGL is a potential novel target for the treatment of GBMs.
Can the MOLES acronym and scoring system improve the management of patients with melanocytic choroidal tumours?
Authors: Damato Bertil E. 
Published: June 2022

AbstractIt can be difficult for practitioners to determine the likelihood of malignancy in melanocytic choroidal tumours. This author has therefore devised the MOLES acronym to highlight the most informative clinical features, which comprise mushroom shape, orange pigment, large size, enlargement, and subretinal fluid. Each of these is scored 0 if absent, 1 if subtle or uncertain, and 2 if present. Tumours are categorised as ‘common naevus’, ‘low-risk naevus’, ‘high-risk naevus’ and ‘probable melanoma’ according to whether the sum of these five scores is 0, 1, 2 or 3 or more, respectively. Tentative recommendations, subject to future studies, include: review of ‘common naevi’ by a community optometrist whenever the patient attends for another reason, such as a two-yearly ‘check-up’ (i.e., ‘self-care’); non-urgent referral of patients with ‘low-risk naevi’ or ‘high-risk naevi’ to an ophthalmologist to plan long-term surveillance (i.e., determining the frequency of assessments and whether these should be undertaken by an ophthalmologist or a community optometrist); and urgent referral of patients with a MOLES score >2 (i.e., ‘probable melanoma’) to an ophthalmologist for immediate referral to an ocular oncologist if a suspicion of malignancy is confirmed. The MOLES system does not require assessment of internal acoustic reflectivity by ultrasonography. MOLES scores correlate well with diagnosis of choroidal naevi and melanomas by ocular oncologists; however, further evaluation of this aid in routine optometric practice and other situations is needed. MOLES should prevent unnecessary referral of patients with naevi for second opinion and non-essential monitoring of these patients at hospital eye services.
Variation in mitochondrial DNA affects locomotor activity and sleep in Drosophila melanogaster
Authors: Anderson Lucy , Camus M. Florencia , Monteith Katy M. , Salminen Tiina S. , Vale Pedro F. 
Published: June 2022

AbstractMitochondria are organelles that produce cellular energy in the form of ATP through oxidative phosphorylation, and this primary function is conserved among many taxa. Locomotion is a trait that is highly reliant on metabolic function and expected to be greatly affected by disruptions to mitochondrial performance. To this end, we aimed to examine how activity and sleep vary between Drosophila melanogaster strains with different geographic origins, how these patterns are affected by mitochondrial DNA (mtDNA) variation, and how breaking up co-evolved mito-nuclear gene combinations affect the studied activity traits. Our results demonstrate that Drosophila strains from different locations differ in sleep and activity, and that females are generally more active than males. By comparing activity and sleep of mtDNA variants introgressed onto a common nuclear background in cytoplasmic hybrid (cybrid) strains, we were able to quantify the among-line variance attributable to mitochondrial DNA, and we establish that mtDNA variation affects both activity and sleep, in a sex-specific manner. Altogether our study highlights the important role that mitochondrial genome variation plays on organismal physiology and behaviour.
BIGDML—Towards accurate quantum machine learning force fields for materials
Authors: Sauceda Huziel E. , Gálvez-González Luis E. , Chmiela Stefan , Paz-Borbón Lauro Oliver , Müller Klaus-Robert , Tkatchenko Alexandre 
Published: June 2022

AbstractMachine-learning force fields (MLFF) should be accurate, computationally and data efficient, and applicable to molecules, materials, and interfaces thereof. Currently, MLFFs often introduce tradeoffs that restrict their practical applicability to small subsets of chemical space or require exhaustive datasets for training. Here, we introduce the Bravais-Inspired Gradient-Domain Machine Learning (BIGDML) approach and demonstrate its ability to construct reliable force fields using a training set with just 10–200 geometries for materials including pristine and defect-containing 2D and 3D semiconductors and metals, as well as chemisorbed and physisorbed atomic and molecular adsorbates on surfaces. The BIGDML model employs the full relevant symmetry group for a given material, does not assume artificial atom types or localization of atomic interactions and exhibits high data efficiency and state-of-the-art energy accuracies (errors substantially below 1 meV per atom) for an extended set of materials. Extensive path-integral molecular dynamics carried out with BIGDML models demonstrate the counterintuitive localization of benzene–graphene dynamics induced by nuclear quantum effects and their strong contributions to the hydrogen diffusion coefficient in a Pd crystal for a wide range of temperatures.
Vertex protein PduN tunes encapsulated pathway performance by dictating bacterial metabolosome morphology
Authors: Mills Carolyn E. , Waltmann Curt , Archer Andre G. , Kennedy Nolan W. , Abrahamson Charlotte H. , Jackson Alexander D. , Roth Eric W. , Shirman Sasha , Jewett Michael C. , Mangan Niall M. , Olvera de la Cruz Monica , Tullman-Ercek Danielle 
Published: June 2022

AbstractEngineering subcellular organization in microbes shows great promise in addressing bottlenecks in metabolic engineering efforts; however, rules guiding selection of an organization strategy or platform are lacking. Here, we study compartment morphology as a factor in mediating encapsulated pathway performance. Using the 1,2-propanediol utilization microcompartment (Pdu MCP) system from Salmonella enterica serovar Typhimurium LT2, we find that we can shift the morphology of this protein nanoreactor from polyhedral to tubular by removing vertex protein PduN. Analysis of the metabolic function between these Pdu microtubes (MTs) shows that they provide a diffusional barrier capable of shielding the cytosol from a toxic pathway intermediate, similar to native MCPs. However, kinetic modeling suggests that the different surface area to volume ratios of MCP and MT structures alters encapsulated pathway performance. Finally, we report a microscopy-based assay that permits rapid assessment of Pdu MT formation to enable future engineering efforts on these structures.
Heat-fueled enzymatic cascade for selective oxyfunctionalization of hydrocarbons
Authors: Yoon Jaeho , Jang Hanhwi , Oh Min-Wook , Hilberath Thomas , Hollmann Frank , Jung Yeon Sik , Park Chan Beum 
Published: June 2022

AbstractHeat is a fundamental feedstock, where more than 80% of global energy comes from fossil-based heating process. However, it is mostly wasted due to a lack of proper techniques of utilizing the low-quality waste heat (<100 °C). Here we report thermoelectrobiocatalytic chemical conversion systems for heat-fueled, enzyme-catalyzed oxyfunctionalization reactions. Thermoelectric bismuth telluride (Bi2Te3) directly converts low-temperature waste heat into chemical energy in the form of H2O2 near room temperature. The streamlined reaction scheme (e.g., water, heat, enzyme, and thermoelectric material) promotes enantio- and chemo-selective hydroxylation and epoxidation of representative substrates (e.g., ethylbenzene, propylbenzene, tetralin, cyclohexane, cis-β-methylstyrene), achieving a maximum total turnover number of rAaeUPO (TTNrAaeUPO) over 32000. Direct conversion of vehicle exhaust heat into the enantiopure enzymatic product with a rate of 231.4 μM h−1 during urban driving envisions the practical feasibility of thermoelectrobiocatalysis.
Light-intensity-dependent photoresponse time of organic photodetectors and its molecular origin
Authors: Labanti Chiara , Wu Jiaying , Shin Jisoo , Limbu Saurav , Yun Sungyoung , Fang Feifei , Park Song Yi , Heo Chul-Joon , Lim Younhee , Choi Taejin , Kim Hyeong-Ju , Hong Hyerim , Choi Byoungki , Park Kyung-Bae , Durrant James R. , Kim Ji-Seon 
Published: June 2022

AbstractOrganic photodetectors (OPDs) exhibit superior spectral responses but slower photoresponse times compared to inorganic counterparts. Herein, we study the light-intensity-dependent OPD photoresponse time with two small-molecule donors (planar MPTA or twisted NP-SA) co-evaporated with C60 acceptors. MPTA:C60 exhibits the fastest response time at high-light intensities (>0.5 mW/cm2), attributed to its planar structure favoring strong intermolecular interactions. However, this blend exhibits the slowest response at low-light intensities, which is correlated with biphasic photocurrent transients indicative of the presence of a low density of deep trap states. Optical, structural, and energetical analyses indicate that MPTA molecular packing is strongly disrupted by C60, resulting in a larger (370 meV) HOMO level shift. This results in greater energetic inhomogeneity including possible MPTA-C60 adduct formation, leading to deep trap states which limit the low-light photoresponse time. This work provides important insights into the small molecule design rules critical for low charge-trapping and high-speed OPD applications.
The genetic architecture of pneumonia susceptibility implicates mucin biology and a relationship with psychiatric illness
Authors: Reay William R. , Geaghan Michael P. ,   23andMe Research Team, Agee Michelle , Alipanahi Babak , Bell Robert K. , Bryc Katarzyna , Elson Sarah L. , Fontanillas Pierre , Furlotte Nicholas A. , Hicks Barry , Hinds David A. , Huber Karen E. , Jewett Ethan M. , Jiang Yunxuan , Kleinman Aaron , Lin Keng-Han , Litterman Nadia K. , McCreight Jey C. , McIntyre Matthew H. , McManus Kimberly F. , Mountain Joanna L. , Noblin Elizabeth S. , Northover Carrie A. M. , Pitts Steven J. , Poznik G. David , Sathirapongsasuti J. Fah , Shelton Janie F. , Shringarpure Suyash , Tian Chao , Tung Joyce Y. , Vacic Vladimir , Wang Xin , Wilson Catherine H. , Cairns Murray J. 
Published: June 2022

AbstractPneumonia remains one of the leading causes of death worldwide. In this study, we use genome-wide meta-analysis of lifetime pneumonia diagnosis (N = 391,044) to identify four association signals outside of the previously implicated major histocompatibility complex region. Integrative analyses and finemapping of these signals support clinically tractable targets, including the mucin MUC5AC and tumour necrosis factor receptor superfamily member TNFRSF1A. Moreover, we demonstrate widespread evidence of genetic overlap with pneumonia susceptibility across the human phenome, including particularly significant correlations with psychiatric phenotypes that remain significant after testing differing phenotype definitions for pneumonia or genetically conditioning on smoking behaviour. Finally, we show how polygenic risk could be utilised for precision treatment formulation or drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide insights into the genetic architecture of pneumonia susceptibility and genetics informed targets for drug development or repositioning.
TPGS-based and S-thanatin functionalized nanorods for overcoming drug resistance in Klebsiella pneumonia
Authors: Wang Xiaojuan , Xu Xiaoling , Zhang Shaojun , Chen Na , Sun Yunfeng , Ma Kuifen , Hong Dongsheng , Li Lu , Du Yongzhong , Lu Xiaoyang , Jiang Saiping 
Published: June 2022

AbstractTigecycline is regarded as the last line of defense to combat multidrug-resistant Klebsiella pneumoniae. However, increasing utilization has led to rising drug resistance and treatment failure. Here, we design a D-alpha tocopheryl polyethylene glycol succinate-modified and S-thanatin peptide-functionalized nanorods based on calcium phosphate nanoparticles for tigecycline delivery and pneumonia therapy caused by tigecycline-resistant Klebsiella pneumoniae. After incubation with bacteria, the fabricated nanorods can enhance tigecycline accumulation in bacteria via the inhibitory effect on efflux pumps exerted by D-alpha tocopheryl polyethylene glycol succinate and the targeting capacity of S-thanatin to bacteria. The synergistic antibacterial capacity between S-thanatin and tigecycline further enhances the antibacterial activity of nanorods, thus overcoming the tigecycline resistance of Klebsiella pneumoniae. After intravenous injection, nanorods significantly reduces the counts of white blood cells and neutrophils, decreases bacterial colonies, and ameliorates neutrophil infiltration events, thereby largely increasing the survival rate of mice with pneumonia. These findings may provide a therapeutic strategy for infections caused by drug-resistant bacteria.
CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas
Authors: Niborski Leticia Laura , Gueguen Paul , Ye Mengliang , Thiolat Allan , Ramos Rodrigo Nalio , Caudana Pamela , Denizeau Jordan , Colombeau Ludovic , Rodriguez Raphaël , Goudot Christel , Luccarini Jean-Michel , Soudé Anne , Bournique Bruno , Broqua Pierre , Pace Luigia , Baulande Sylvain , Sedlik Christine , Quivy Jean-Pierre , Almouzni Geneviève , Cohen José L. , Zueva Elina , Waterfall Joshua J. , Amigorena Sebastian , Piaggio Eliane 
Published: June 2022

AbstractTumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity.
Towards the future exploration of mucosal mRNA vaccines against emerging viral diseases; lessons from existing next-generation mucosal vaccine strategies
Authors: Hameed Sodiq A. , Paul Stephane , Dellosa Giann Kerwin Y. , Jaraquemada Dolores , Bello Muhammad Bashir 
Published: June 2022

AbstractThe mRNA vaccine platform has offered the greatest potential in fighting the COVID-19 pandemic owing to rapid development, effectiveness, and scalability to meet the global demand. There are many other mRNA vaccines currently being developed against different emerging viral diseases. As with the current COVID-19 vaccines, these mRNA-based vaccine candidates are being developed for parenteral administration via injections. However, most of the emerging viruses colonize the mucosal surfaces prior to systemic infection making it very crucial to target mucosal immunity. Although parenterally administered vaccines would induce a robust systemic immunity, they often provoke a weak mucosal immunity which may not be effective in preventing mucosal infection. In contrast, mucosal administration potentially offers the dual benefit of inducing potent mucosal and systemic immunity which would be more effective in offering protection against mucosal viral infection. There are however many challenges posed by the mucosal environment which impede successful mucosal vaccination. The development of an effective delivery system remains a major challenge to the successful exploitation of mucosal mRNA vaccination. Nonetheless, a number of delivery vehicles have been experimentally harnessed with different degrees of success in the mucosal delivery of mRNA vaccines. In this review, we provide a comprehensive overview of mRNA vaccines and summarise their application in the fight against emerging viral diseases with particular emphasis on COVID-19 mRNA platforms. Furthermore, we discuss the prospects and challenges of mucosal administration of mRNA-based vaccines, and we explore the existing experimental studies on mucosal mRNA vaccine delivery.
The C3d-fused foot-and-mouth disease vaccine platform overcomes maternally-derived antibody interference by inducing a potent adaptive immunity
Authors: Lee Min Ja , Kim Hyun Mi , Shin Sehee , Jo Hyundong , Park So Hui , Kim Su-Mi , Park Jong-Hyeon 
Published: June 2022

AbstractVaccination prevents and controls foot-and-mouth disease (FMD). However, the current FMD vaccine remains disadvantageous since it cannot overcome maternally-derived antibody (MDA) interference in weeks-old animals, which suppress active immunity via vaccination. To address this, we developed the immune-enhancing O PA2-C3d and A22-C3d FMD vaccine strains that can stimulate receptors on the surface of B cells by inserting C3d (a B cell epitope) into the VP1 region of O PA2 (FMDV type O) and A22 (FMDV type A). We purified inactivated viral antigens from these vaccine strains and evaluated their immunogenicity and host defense against FMDV infection in mice. We also verified its efficacy in inducing an adaptive immune response and overcome MDA interference in MDA-positive (MDA(+), FMD-seropositive) and -negative (MDA(−), FMD-seronegative) pigs. These results suggest a key strategy for establishing novel FMD vaccine platform to overcome MDA interference and induce a robust adaptive immune response.
Pandemic-proof recruitment and engagement in a fully decentralized trial in atrial fibrillation patients (DeTAP)
Authors: Sarraju Ashish , Seninger Clark , Parameswaran Vijaya , Petlura Christina , Bazouzi Tamara , Josan Kiranbir , Grewal Upinder , Viethen Thomas , Mundl Hardi , Luithle Joachim , Basobas Leonard , Touros Alexis , Senior Michael J. T. , De Lombaert Koen , Mahaffey Kenneth W. , Turakhia Mintu P. , Dash Rajesh 
Published: June 2022

AbstractThe Coronavirus Disease 2019 (COVID-19) pandemic curtailed clinical trial activity. Decentralized clinical trials (DCTs) can expand trial access and reduce exposure risk but their feasibility remains uncertain. We evaluated DCT feasibility for atrial fibrillation (AF) patients on oral anticoagulation (OAC). DeTAP (Decentralized Trial in Afib Patients, NCT04471623) was a 6-month, single-arm, 100% virtual study of 100 AF patients on OAC aged >55 years, recruited traditionally and through social media. Participants enrolled and participated virtually using a mobile application and remote blood pressure (BP) and six-lead electrocardiogram (ECG) sensors. Four engagement-based primary endpoints included changes in pre- versus end-of-study OAC adherence (OACA), and % completion of televisits, surveys, and ECG and BP measurements. Secondary endpoints included survey-based nuisance bleeding and patient feedback. 100 subjects (mean age 70 years, 44% women, 90% White) were recruited in 28 days (traditional: 6 pts; social media: 94 pts in 12 days with >300 waitlisted). Study engagement was high: 91% televisits, 85% surveys, and 99% ECG and 99% BP measurement completion. OACA was unchanged at 6 months (baseline: 97 ± 9%, 6 months: 96 ± 15%, p = 0.39). In patients with low baseline OACA (<90%), there was significant 6-month improvement (85 ± 16% to 96 ± 6%, p < 0.01). 86% of respondents (69/80) expressed willingness to continue in a longer trial. The DeTAP study demonstrated rapid recruitment, high engagement, and physiologic reporting via the integration of digital technologies and dedicated study coordination. These findings may inform DCT designs for future cardiovascular trials.