bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site
Authors: Mendes Vitor , Green Simon R. , Evans Joanna C. , Hess Jeannine , Blaszczyk Michal , Spry Christina , Bryant Owain , Cory-Wright James , Chan Daniel S-H. , Torres Pedro H. M. , Wang Zhe , Nahiyaan Navid , O’Neill Sandra , Damerow Sebastian , Post John , Bayliss Tracy , Lynch Sasha L. , Coyne Anthony G. , Ray Peter C. , Abell Chris , Rhee Kyu Y. , Boshoff Helena I. M. , Barry Clifton E. , Mizrahi Valerie , Wyatt Paul G. , Blundell Tom L. 
Published: January 2021

AbstractCoenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.
Disease risk scores for skin cancers
Authors: Fontanillas Pierre , Alipanahi Babak , Furlotte Nicholas A. , Johnson Michaela , Wilson Catherine H. ,   23andMe Research Team, Agee Michelle , Bell Robert K. , Bryc Katarzyna , Elson Sarah L. , Hinds David A. , Huber Karen E. , Kleinman Aaron , Litterman Nadia K. , McCreight Jennifer C. , McIntyre Matthew H. , Mountain Joanna L. , Noblin Elizabeth S. , Northover Carrie A. M. , Sathirapongsasuti J. Fah , Sazonova Olga V. , Shelton Janie F. , Shringarpure Suyash , Tian Chao , Tung Joyce Y. , Vacic Vladimir , Pitts Steven J. , Gentleman Robert , Auton Adam 
Published: January 2021

AbstractWe trained and validated risk prediction models for the three major types of skin cancer— basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma—on a cross-sectional and longitudinal dataset of 210,000 consented research participants who responded to an online survey covering personal and family history of skin cancer, skin susceptibility, and UV exposure. We developed a primary disease risk score (DRS) that combined all 32 identified genetic and non-genetic risk factors. Top percentile DRS was associated with an up to 13-fold increase (odds ratio per standard deviation increase >2.5) in the risk of developing skin cancer relative to the middle DRS percentile. To derive lifetime risk trajectories for the three skin cancers, we developed a second and age independent disease score, called DRSA. Using incident cases, we demonstrated that DRSA could be used in early detection programs for identifying high risk asymptotic individuals, and predicting when they are likely to develop skin cancer. High DRSA scores were not only associated with earlier disease diagnosis (by up to 14 years), but also with more severe and recurrent forms of skin cancer.
Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8
Authors: Gong Qin , Robinson Kim , Xu Chenrui , Huynh Phuong Thao , Chong Kelvin Han Chung , Tan Eddie Yong Jun , Zhang Jiawen , Boo Zhao Zhi , Teo Daniel Eng Thiam , Lay Kenneth , Zhang Yaming , Lim John Soon Yew , Goh Wah Ing , Wright Graham , Zhong Franklin L. , Reversade Bruno , Wu Bin 
Published: January 2021

AbstractNod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.
Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes
Authors: Robert Hollingsworth L. , David Liron , Li Yang , Griswold Andrew R. , Ruan Jianbin , Sharif Humayun , Fontana Pietro , Orth-He Elizabeth L. , Fu Tian-Min , Bachovchin Daniel A. , Wu Hao 
Published: January 2021

AbstractNLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase−1 activation, cytokine maturation and/or pyroptotic cell death. NLRP1 and CARD8 use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA (conserved in UNC5, PIDD, and ankyrins) subdomain for self-oligomerization, which in turn form the platform to recruit the inflammasome adaptor ASC (apoptosis-associated speck-like protein containing a CARD) or caspase-1, respectively. Here, we report cryo-EM structures of NLRP1-CT and CARD8-CT assemblies, in which the respective CARDs form central helical filaments that are promoted by oligomerized, but flexibly linked, UPAs surrounding the filaments. Through biochemical and cellular approaches, we demonstrate that the UPA itself reduces the threshold needed for NLRP1-CT and CARD8-CT filament formation and signalling. Structural analyses provide insights on the mode of ASC recruitment by NLRP1-CT and the contrasting direct recruitment of caspase-1 by CARD8-CT. We also discover that subunits in the central NLRP1CARD filament dimerize with additional exterior CARDs, which roughly doubles its thickness and is unique among all known CARD filaments. Finally, we engineer and determine the structure of an ASCCARD–caspase-1CARD octamer, which suggests that ASC uses opposing surfaces for NLRP1, versus caspase-1, recruitment. Together these structures capture the architecture and specificity of the active NLRP1 and CARD8 inflammasomes in addition to key heteromeric CARD-CARD interactions governing inflammasome signalling.
A four-electron Zn-I2 aqueous battery enabled by reversible I−/I2/I+ conversion
Authors: Zou Yiping , Liu Tingting , Du Qijun , Li Yingying , Yi Haibo , Zhou Xing , Li Zhuxin , Gao Lujie , Zhang Lan , Liang Xiao 
Published: January 2021

AbstractElectrochemically reversible redox couples that embrace more electron transfer at a higher potential are the eternal target for energy storage batteries. Here, we report a four-electron aqueous zinc-iodine battery by activating the highly reversible I2/I+ couple (1.83 V vs. Zn/Zn2+) in addition to the typical I−/I2 couple (1.29 V). This is achieved by intensive solvation of the aqueous electrolyte to yield ICl inter-halogens and to suspend its hydrolysis. Experimental characterization and modelling reveal that limited water activity and sufficient free chloride ions in the electrolyte are crucial for the four-electron process. The merits of the electrolyte also afford to stabilize Zn anode, leading to a reliable Zn-I2 aqueous battery of 6000 cycles. Owing to high operational voltage and capacity, energy density up to 750 Wh kg−1 based on iodine mass was achieved (15–20 wt% iodine in electrode). It pushes the Zn-I2 battery to a superior level among these available aqueous batteries.
Resilin-mimetics as a smart biomaterial platform for biomedical applications
Authors: Balu Rajkamal , Dutta Naba K. , Dutta Ankit K. , Choudhury Namita Roy 
Published: January 2021

AbstractIntrinsically disordered proteins have dramatically changed the structure–function paradigm of proteins in the 21st century. Resilin is a native elastic insect protein, which features intrinsically disordered structure, unusual multi-stimuli responsiveness and outstanding resilience. Advances in computational techniques, polypeptide synthesis methods and modular protein engineering routines have led to the development of novel resilin-like polypeptides (RLPs) including modular RLPs, expanding their applications in tissue engineering, drug delivery, bioimaging, biosensors, catalysis and bioelectronics. However, how the responsive behaviour of RLPs is encoded in the amino acid sequence level remains elusive. This review summarises the milestones of RLPs, and discusses the development of modular RLP-based biomaterials, their current applications, challenges and future perspectives. A perspective of future research is that sequence and responsiveness profiling of RLPs can provide a new platform for the design and development of new modular RLP-based biomaterials with programmable structure, properties and functions.
EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma
Authors: Fang Runping , Chen Xin , Zhang Sicong , Shi Hui , Ye Youqiong , Shi Hailing , Zou Zhongyu , Li Peng , Guo Qing , Ma Li , He Chuan , Huang Suyun 
Published: January 2021

AbstractGlioblastoma (GBM) is the most common type of adult malignant brain tumor, but its molecular mechanisms are not well understood. In addition, the knowledge of the disease-associated expression and function of YTHDF2 remains very limited. Here, we show that YTHDF2 overexpression clinically correlates with poor glioma patient prognosis. EGFR that is constitutively activated in the majority of GBM causes YTHDF2 overexpression through the EGFR/SRC/ERK pathway. EGFR/SRC/ERK signaling phosphorylates YTHDF2 serine39 and threonine381, thereby stabilizes YTHDF2 protein. YTHDF2 is required for GBM cell proliferation, invasion, and tumorigenesis. YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and HIVEP2, which impacts the glioma patient survival. YTHDF2 promotes tumorigenesis of GBM cells, largely through the downregulation of LXRα and HIVEP2. Furthermore, YTHDF2 inhibits LXRα-dependent cholesterol homeostasis in GBM cells. Together, our findings extend the landscape of EGFR downstream circuit, uncover the function of YTHDF2 in GBM tumorigenesis, and highlight an essential role of RNA m6A methylation in cholesterol homeostasis.
Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma
Authors: Pomella Silvia , Sreenivas Prethish , Gryder Berkley E. , Wang Long , Milewski David , Cassandri Matteo , Baxi Kunal , Hensch Nicole R. , Carcarino Elena , Song Young , Chou Hsien-Chao , Yohe Marielle E. , Stanton Benjamin Z. , Amadio Bruno , Caruana Ignazio , De Stefanis Cristiano , De Vito Rita , Locatelli Franco , Chen Yidong , Chen Eleanor Y. , Houghton Peter , Khan Javed , Rota Rossella , Ignatius Myron S. 
Published: January 2021

AbstractRhabdomyosarcoma (RMS) is an aggressive pediatric malignancy of the muscle, that includes Fusion Positive (FP)-RMS harboring PAX3/7-FOXO1 and Fusion Negative (FN)-RMS commonly with RAS pathway mutations. RMS express myogenic master transcription factors MYOD and MYOG yet are unable to terminally differentiate. Here, we report that SNAI2 is highly expressed in FN-RMS, is oncogenic, blocks myogenic differentiation, and promotes growth. MYOD activates SNAI2 transcription via super enhancers with striped 3D contact architecture. Genome wide chromatin binding analysis demonstrates that SNAI2 preferentially binds enhancer elements and competes with MYOD at a subset of myogenic enhancers required for terminal differentiation. SNAI2 also suppresses expression of a muscle differentiation program modulated by MYOG, MEF2, and CDKN1A. Further, RAS/MEK-signaling modulates SNAI2 levels and binding to chromatin, suggesting that the differentiation blockade by oncogenic RAS is mediated in part by SNAI2. Thus, an interplay between SNAI2, MYOD, and RAS prevents myogenic differentiation and promotes tumorigenesis.
π-Extended perylene diimide double-heterohelicenes as ambipolar organic semiconductors for broadband circularly polarized light detection
Authors: Zhang Li , Song Inho , Ahn Jaeyong , Han Myeonggeun , Linares Mathieu , Surin Mathieu , Zhang Hui-Jun , Oh Joon Hak , Lin Jianbin 
Published: January 2021

AbstractDespite great challenges, the development of new molecular structures with multiple and even conflicting characteristics are eagerly pursued for exploring advanced applications. To develop high-performance chiral organic semiconducting molecules, a distorted π-system is required for strong coupling with circularly polarized light (CPL), whereas planar π-stacking systems are necessary for high charge-carrier mobility. To address this dilemma, in this work, we introduce a skeleton merging approach through distortion of a perylene diimide (PDI) core with four fused heteroaromatics to form an ortho-π-extended PDI double-[7]heterohelicene. PDI double helicene inherits a high dissymmetry factor from the helicene skeleton, and the extended π-planar system concurrently maintains a high level of charge transport properties. In addition, ortho-π-extension of the PDI skeleton brings about near-infrared (NIR) light absorption and ambipolar charge transport abilities, endowing the corresponding organic phototransistors with high photoresponsivity of 450 and 120 mA W−1 in p- and n-type modes respectively, along with a high external quantum efficiency (89%) under NIR light irradiations. Remarkably, these multiple characteristics enable high-performance broadband CPL detections up to NIR spectral region with chiral organic semiconductors.
Asynchronicity of endemic and emerging mosquito-borne disease outbreaks in the Dominican Republic
Authors: Petrone Mary E. , Earnest Rebecca , Lourenço José , Kraemer Moritz U. G. , Paulino-Ramirez Robert , Grubaugh Nathan D. , Tapia Leandro 
Published: January 2021

AbstractMosquito-borne viruses threaten the Caribbean due to the region’s tropical climate and seasonal reception of international tourists. Outbreaks of chikungunya and Zika have demonstrated the rapidity with which these viruses can spread. Concurrently, dengue fever cases have climbed over the past decade. Sustainable disease control measures are urgently needed to quell virus transmission and prevent future outbreaks. Here, to improve upon current control methods, we analyze temporal and spatial patterns of chikungunya, Zika, and dengue outbreaks reported in the Dominican Republic between 2012 and 2018. The viruses that cause these outbreaks are transmitted by Aedes mosquitoes, which are sensitive to seasonal climatological variability. We evaluate whether climate and the spatio-temporal dynamics of dengue outbreaks could explain patterns of emerging disease outbreaks. We find that emerging disease outbreaks were robust to the climatological and spatio-temporal constraints defining seasonal dengue outbreak dynamics, indicating that constant surveillance is required to prevent future health crises.
Dynamics of cascades on burstiness-controlled temporal networks
Authors: Unicomb Samuel , Iñiguez Gerardo , Gleeson James P. , Karsai Márton 
Published: January 2021

AbstractBurstiness, the tendency of interaction events to be heterogeneously distributed in time, is critical to information diffusion in physical and social systems. However, an analytical framework capturing the effect of burstiness on generic dynamics is lacking. Here we develop a master equation formalism to study cascades on temporal networks with burstiness modelled by renewal processes. Supported by numerical and data-driven simulations, we describe the interplay between heterogeneous temporal interactions and models of threshold-driven and epidemic spreading. We find that increasing interevent time variance can both accelerate and decelerate spreading for threshold models, but can only decelerate epidemic spreading. When accounting for the skewness of different interevent time distributions, spreading times collapse onto a universal curve. Our framework uncovers a deep yet subtle connection between generic diffusion mechanisms and underlying temporal network structures that impacts a broad class of networked phenomena, from spin interactions to epidemic contagion and language dynamics.
Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds
Authors: Kolarič Anja , Germe Thomas , Hrast Martina , Stevenson Clare E. M. , Lawson David M. , Burton Nicolas P. , Vörös Judit , Maxwell Anthony , Minovski Nikola , Anderluh Marko 
Published: January 2021

AbstractNovel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase–DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.
Giant topological longitudinal circular photo-galvanic effect in the chiral multifold semimetal CoSi
Authors: Ni Zhuoliang , Wang K. , Zhang Y. , Pozo O. , Xu B. , Han X. , Manna K. , Paglione J. , Felser C. , Grushin A. G. , de Juan F. , Mele E. J. , Wu Liang 
Published: January 2021

AbstractThe absence of mirror symmetry, or chirality, is behind striking natural phenomena found in systems as diverse as DNA and crystalline solids. A remarkable example occurs when chiral semimetals with topologically protected band degeneracies are illuminated with circularly polarized light. Under the right conditions, the part of the generated photocurrent that switches sign upon reversal of the light’s polarization, known as the circular photo-galvanic effect, is predicted to depend only on fundamental constants. The conditions to observe quantization are non-universal, and depend on material parameters and the incident frequency. In this work, we perform terahertz emission spectroscopy with tunable photon energy from 0.2 –1.1 eV in the chiral topological semimetal CoSi. We identify a large longitudinal photocurrent peaked at 0.4 eV reaching ~550 μ A/V2, which is much larger than the photocurrent in any chiral crystal reported in the literature. Using first-principles calculations we establish that the peak originates only from topological band crossings, reaching 3.3 ± 0.3 in units of the quantization constant. Our calculations indicate that the quantized circular photo-galvanic effect is within reach in CoSi upon doping and increase of the hot-carrier lifetime. The large photo-conductivity suggests that topological semimetals could potentially be used as novel mid-infrared detectors.
Visualising G-quadruplex DNA dynamics in live cells by fluorescence lifetime imaging microscopy
Authors: Summers Peter A. , Lewis Benjamin W. , Gonzalez-Garcia Jorge , Porreca Rosa M. , Lim Aaron H. M. , Cadinu Paolo , Martin-Pintado Nerea , Mann David J. , Edel Joshua B. , Vannier Jean Baptiste , Kuimova Marina K. , Vilar Ramon 
Published: January 2021

AbstractGuanine rich regions of oligonucleotides fold into quadruple-stranded structures called G-quadruplexes (G4s). Increasing evidence suggests that these G4 structures form in vivo and play a crucial role in cellular processes. However, their direct observation in live cells remains a challenge. Here we demonstrate that a fluorescent probe (DAOTA-M2) in conjunction with fluorescence lifetime imaging microscopy (FLIM) can identify G4s within nuclei of live and fixed cells. We present a FLIM-based cellular assay to study the interaction of non-fluorescent small molecules with G4s and apply it to a wide range of drug candidates. We also demonstrate thatDAOTA-M2can be used to study G4 stability in live cells. Reduction ofFancJandRTEL1expression in mammalian cells increases theDAOTA-M2lifetime and therefore suggests an increased number of G4s in these cells, implying thatFancJandRTEL1play a role in resolving G4 structures in cellulo.
Continued preference for suboptimal habitat reduces bat survival with white-nose syndrome
Authors: Hopkins Skylar R. , Hoyt Joseph R. , White J. Paul , Kaarakka Heather M. , Redell Jennifer A. , DePue John E. , Scullon William H. , Kilpatrick A. Marm , Langwig Kate E. 
Published: January 2021

AbstractHabitat alteration can influence suitability, creating ecological traps where habitat preference and fitness are mismatched. Despite their importance, ecological traps are notoriously difficult to identify and their impact on host–pathogen dynamics remains largely unexplored. Here we assess individual bat survival and habitat preferences in the midwestern United States before, during, and after the invasion of the fungal pathogen that causes white-nose syndrome. Despite strong selection pressures, most hosts continued to select habitats where disease severity was highest and survival was lowest, causing continued population declines. However, some individuals used refugia where survival was higher. Over time, a higher proportion of the total population used refugia than before pathogen arrival. Our results demonstrate that host preferences for habitats with high disease-induced mortality can create ecological traps that threaten populations, even in the presence of accessible refugia.
Room-temperature photonic logical qubits via second-order nonlinearities
Authors: Krastanov Stefan , Heuck Mikkel , Shapiro Jeffrey H. , Narang Prineha , Englund Dirk R. , Jacobs Kurt 
Published: January 2021

AbstractRecent progress in nonlinear optical materials and microresonators has brought quantum computing with bulk optical nonlinearities into the realm of possibility. This platform is of great interest, not only because photonics is an obvious choice for quantum networks, but also as a promising route to quantum information processing at room temperature. We propose an approach for reprogrammable room-temperature photonic quantum logic that significantly simplifies the realization of various quantum circuits, and in particular, of error correction. The key element is the programmable photonic multi-mode resonator that implements reprogrammable bosonic quantum logic gates, while using only the bulk χ(2) nonlinear susceptibility. We theoretically demonstrate that just two of these elements suffice for a complete, compact error-correction circuit on a bosonic code, without the need for measurement or feed-forward control. Encoding and logical operations on the code are also easily achieved with these reprogrammable quantum photonic processors. An extrapolation of current progress in nonlinear optical materials and photonic circuits indicates that such circuitry should be achievable within the next decade.