bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversible fronto-occipitotemporal signaling complements task encoding and switching under ambiguous cues
Authors: Tsumura Kaho , Kosugi Keita , Hattori Yoshiki , Aoki Ryuta , Takeda Masaki , Chikazoe Junichi , Nakahara Kiyoshi , Jimura Koji 
Published: July 2020

AbstractAdaptation to changing environments involves the appropriate extraction of environmental information to achieve a behavioral goal. It remains unclear how behavioral flexibility is guided under situations where the relevant behavior is ambiguous. Using functional brain mapping of machine-learning decoders and directional functional connectivity, we show that brain-wide reversible neural signaling underpins task encoding and behavioral flexibility in ambiguously changing environments. When relevant behavior is cued ambiguously during behavioral shifting, neural coding is attenuated in distributed cortical regions, but top-down signals from the prefrontal cortex complement the coding. When behavioral shifting is cued more explicitly, modality-specialized occipitotemporal regions implement distinct neural coding about relevant behavior, and bottom-up signals from the occipitotemporal region to the prefrontal cortex supplement the behavioral shift. These results suggest that our adaptation to an ever-changing world is orchestrated by the alternation of top-down and bottom-up signaling in the fronto-occipitotemporal circuit depending on the availability of environmental information.
Cone-shaped HIV-1 capsids are transported through intact nuclear pores
Authors: Zila Vojtech , Margiotta Erica , Turonova Beata , Müller Thorsten G. , Zimmerli Christian E. , Mattei Simone , Allegretti Matteo , Börner Kathleen , Rada Jona , Müller Barbara , Lusic Marina , Kräusslich Hans-Georg , Beck Martin 
Published: July 2020

AbstractHuman immunodeficiency virus (HIV-1) remains a major health threat. Viral capsid uncoating and nuclear import of the viral genome are critical for productive infection. The size of the HIV-1 capsid is generally believed to exceed the diameter of the nuclear pore complex (NPC), indicating that capsid uncoating has to occur prior to nuclear import. Here, we combined correlative light and electron microscopy with subtomogram averaging to capture the structural status of reverse transcription-competent HIV-1 complexes in infected T cells. We demonstrate that the diameter of the NPCin cellulois sufficient for the import of apparently intact, coneshaped capsids. Subsequent to nuclear import, we detected disrupted and empty capsid fragments, indicating that uncoating of the replication complex occurs by breaking the capsid open, and not by disassembly into individual subunits. Our data directly visualize a key step in HIV-1 replication and enhance our mechanistic understanding of the viral life cycle.
In-vivoevaluation of the anti-diarrheal effect ofLactococcus lactis subspecies lactisandLactococcus pisciumisolated from yogurt
Authors: Mahmud Abu Sayeed Mohammad , Chowdhury Mobarak , Akter Rasheda , Islam Saiful , Mazumdar Santosh , Taznin Tarannum , Chowdhury Rocky , Talukder Hridika , Bhuiyan Habibur Rahman 
Published: July 2020

AbstractLactobacillus and Lactococcus species found in the yogurt of different sources are most widely assayed and used all over the world as a probiotic agent. This study aimed to isolate and identify novel probiotic agents with therapeutic value against diarrhea. Initially, the probiotic properties of the isolated lactic acid bacteria from the yogurt samples of the Chittagong division, Bangladesh, were evaluated. All probiotic candidates inhibited the growth of selected pathogens, includingEscheriachia coli, Serratia sp.Salmonella paratyphi, Streptococcus Group-B,Staphylococcus aureus, Haemophillus influenzae, Bacillus subtillis, andKlebsiella pneumoniae. Lactococcus lactissubsp lactis were found most useful in inhibiting all the selected pathogens. When the probiotics were applied against castor oil-induced diarrhea in the rat model,Lactococcus lactissubspecieslactisandLactococcus pisciumwere found significantly effective relative to the controls indicating their potentiality as an alternative therapeutic against diarrhea.HighlightsLactococcus lactissubspecies lactis andLactococcus pisciumhas shown potentiality to be a therapeutic agent against castor-oil induced diarrhea in an animal model.Lactococcus lactissubspecies lactis andLactococcus pisciuminhibited the growth of specified pathogens.
Young Infants Process Prediction Errors at the Theta Rhythm
Authors: Köster Moritz , Langeloh Miriam , Michel Christine , Hoehl Stefanie 
Published: July 2020

AbstractExamining how young infants respond to unexpected events is key to our understanding of their emerging concepts about the world around them. From a predictive processing perspective, it is intriguing to investigate how the infant brain responds to unexpected events (i.e., prediction errors), because they require infants to refine their predictions about the environment. Here, to better understand prediction error processes in the infant brain, we presented 9-month-olds (N= 36) a variety of physical and social events with unexpected versus expected outcomes, while recording their electroencephalogram (EEG). We found a pronounced response in the ongoing 4 – 5 Hz theta rhythm for the processing of unexpected (in contrast to expected) events, for a prolonged time window (2 s) and across all scalp-recorded electrodes. The condition difference in the theta rhythm was not related to the condition difference in infants’ event-related activity to unexpected (versus expected) events in the negative central (Nc) component (.4 – .6 s), a component, which is commonly analyzed in infant violation of expectation studies using EEG. These findings constitute critical evidence that the theta rhythm is involved in the processing of prediction errors from very early in human brain development. We discuss how the theta rhythm may support infants’ refinement of basic concepts about the physical and social environment.
Structural Insights into Photoactivation of Plant Cryptochrome-2
Authors: Palayam Malathy , Ganapathy Jagadeesan , Guercio Angelica M. , Tal Lior , Deck Samuel L. , Shabek Nitzan 
Published: July 2020

AbstractCryptochromes (CRYs) are evolutionarily conserved photoreceptors that mediate various light-induced responses in bacteria, plants, and animals. Plant cryptochromes govern a variety of critical growth and developmental processes including seed germination, flowering time and entrainment of the circadian clock. CRY’s photocycle involves reduction of their flavin adenine dinucleotide (FAD)-bound chromophore, which is completely oxidized in the dark and semi to fully reduced in the light signaling-active state. Despite the significant progress in characterizing cryptochromes, important aspects of their photochemistry, regulation, and light-induced structural changes remain to be addressed. In this study, we determine the crystal structure of the photosensory domain of Arabidopsis CRY2 in a tetrameric active state. Systematic structure-based analyses of photo-activated and inactive plant CRYs elucidate new structural elements and critical residues that dynamically partake in photo-induced oligomerization. Our study offers an updated model of CRYs photoactivation mechanism as well as the mode of its regulation by interacting proteins.
Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer
Authors: Olukoya Ayodeji O. , Stires Hillary , Bahnassy Shaymaa , Persaud Sonali , Guerra Yanira , Ranjit Suman , Ma Shihong , Cruz M. Idalia , Benitez Carlos , Rozeboom Aaron M. , Ceuleers Hannah , Berry Deborah L. , Jacobsen Britta M. , Raj Ganesh V. , Riggins Rebecca B. 
Published: July 2020

AbstractBackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. We previously reported that the acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsWe tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent,ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell linesin vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). Riluzole induced apoptosis and ferroptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole, in combination with either Fulvestrant or 4-hydroxytamoxifen, additively suppressed ER+ breast cancer cell growthin vitro. Single-agent Riluzole significantly inhibited HCI-013EI patient-derived xenograft growthin vivo, and the combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures.ConclusionsRiluzole, alone or combined with endocrine therapy, may offer therapeutic benefits in diverse ER+ breast cancers, including lobular breast cancer.
Dynamics of nonlinguistic statistical learning: From neural entrainment to the emergence of explicit knowledge
Authors: Moser Julia , Batterink Laura , Hegner Yiwen Li , Schleger Franziska , Braun Christoph , Paller Ken A. , Preissl Hubert 
Published: July 2020

AbstractHumans are highly attuned to patterns in the environment. This ability to detect environmental patterns, referred to as statistical learning, plays a key role in many diverse aspects of cognition. However, the spatiotemporal neural mechanisms underlying implicit statistical learning, and how these mechanisms may relate or give rise to explicit learning, remain poorly understood. In the present study, we investigated these different aspects of statistical learning by using an auditory nonlinguistic statistical learning paradigm combined with magnetoencephalography. Twenty-four healthy volunteers were exposed to structured and random tone sequences, and statistical learning was quantified by neural entrainment. Already early during exposure, participants showed strong entrainment to the embedded tone patterns. A significant increase in entrainment over exposure was detected only in the structured condition, reflecting the trajectory of learning. While source reconstruction revealed a wide range of brain areas involved in this process, entrainment in areas around the left pre-central gyrus as well as right temporo-frontal areas significantly predicted behavioral performance. Sensor level results confirmed this relationship between neural entrainment and subsequent explicit knowledge. These results give insights into the dynamic relation between neural entrainment and explicit learning of triplet structures, suggesting that these two aspects are systematically related yet dissociable. Neural entrainment reflects robust, implicit learning of underlying patterns, whereas the emergence of explicit knowledge, likely built on the implicit encoding of structure, varies across individuals and may depend on factors such as sufficient exposure time and attention.
A persistent giant algal virus, with a unique morphology, encodes an unprecedented number of genes involved in energy metabolism
Authors: Blanc-Mathieu Romain , Dahle Håkon , Hofgaard Antje , Brandt David , Ban Hiroki , Kalinowski Jörn , Ogata Hiroyuki , Sandaa Ruth-Anne 
Published: July 2020

AbstractViruses have long been viewed as entities possessing extremely limited metabolic capacities. Over the last decade, however, this view has been challenged, as metabolic genes have been identified in viruses possessing large genomes and virions—the synthesis of which is energetically demanding. Here, we unveil peculiar phenotypic and genomic features ofPrymnesium kappavirus RF01 (PkV RF01), a giant virus of theMimiviridaefamily. We found that this virus encodes an unprecedented number of proteins involved in energy metabolism, such as all four succinate dehydrogenase (SDH) subunits (A–D) as well as key enzymes in theβ-oxidation pathway. TheSDHAgene was transcribed upon infection, indicating that the viral SDH is actively used by the virus— potentially to modulate its host’s energy metabolism. We detected orthologousSDHAandSDHBgenes in numerous genome fragments from uncultivated marineMimiviridaeviruses, which suggests that the viral SDH is widespread in oceans. PkV RF01 was less virulent compared with other cultured prymnesioviruses, a phenomenon possibly linked to the metabolic capacity of this virus and suggestive of relatively long co-evolution with its hosts. It also has a unique morphology, compared to other characterized viruses in theMimiviridaefamily. Finally, we found that PkV RF01 is the only alga-infectingMimiviridaevirus encoding two aminoacyl-tRNA synthetases and enzymes corresponding to an entire base-excision repair pathway, as seen in heterotroph-infectingMimiviridae. TheseMimiviridaeencoded-enzymes were found to be monophyletic and branching at the root of the eukaryotic tree of life. This placement suggests that the last common ancestor ofMimiviridaewas endowed with a large, complex genome prior to the divergence of known extant eukaryotes.ImportanceViruses on Earth are tremendously diverse in terms of morphology, functionality, and genomic composition. Over the last decade, the conceptual gap separating viruses and cellular life has tightened because of the detection of metabolic genes in viral genomes that express complex virus phenotypes upon infection. Here, we describePrymnesium kappavirus RF01, a large alga-infecting virus with a unique morphology, an atypical infection profile, and an unprecedented number of genes involved in energy metabolism (such as the tricarboxylic (TCA) cycle and theβ-oxidation pathway). Moreover, we show that the gene corresponding to one of these enzymes (the succinate dehydrogenase subunit A) is transcribed during infection and is widespread among marine viruses. This discovery provides evidence that a virus has the potential to actively regulate energy metabolism with its own gene.
Distinct dopamine circuits transmit the reinforcing and anxiogenic effects of nicotine
Authors: Nguyen C , Mondoloni S , Centeno I , Durand-de Cuttoli R , Tolu S , Valverde S , Le Borgne T , Hannesse B , Pons S , Maskos U , Dalkara D , Hardelin JP , Mourot A , Marti F , Faure P 
Published: July 2020

SummaryNicotine, the addictive component of tobacco, stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces negative emotional states such as anxiety, yet through an unknown circuitry. Here we show that nicotine at reinforcing doses drives opposite functional responses on two distinct populations of VTA DA neurons with anatomically segregated projections: it activates those that project to the nucleus accumbens (NAc) while it inhibits those that project to the amygdala nuclei (Amg). We further show that nicotine, by acting on β2 subunit-containing nicotinic acetylcholine receptors of the VTA, mediates both reinforcement and anxiety. Finally, using optogenetic experiments we dissociate the roles of the VTA-NAc excitation and VTA-Amg inhibition in reinforcement and anxiety-like behavior, respectively. We thus propose that the positive and negative behavioral outcomes of nicotine consumption involve distinct subpopulations of VTA DA neurons with opposite responses to nicotine.
Immuno-informatics Design of a Multimeric Epitope Peptide Based Vaccine Targeting SARS-CoV-2 Spike Glycoprotein
Authors: Chukwudozie Onyeka S. , Gray Clive M. , Fagbayi Tawakalt A. , Chukwuanukwu Rebecca C. , Oyebanji Victor O. , Bankole Taiwo T. , Adewole A. Richard , Daniel Eze M. 
Published: July 2020

ABSTRACTDeveloping an efficacious vaccine to SARS-CoV-2 infection is critical to stem COVID-19 fatalities and providing the global community with immune protection. We have used a bioinformatic approach to aid in the design of an epitope peptide-based vaccine against the spike protein of the virus. Five antigenic B cell epitopes with viable antigenicity and a total of 27 discontinuous B cell epitopes were mapped out structurally in the spike protein for antibody recognition. We identified eight CD8+T cell 9-mers along with 12 CD4+T cell 14-15-mer as promising candidate epitopes putatively restricted by a large number of MHC-I and II alleles respectively. We used this information to construct anin silicochimeric peptide vaccine whose translational rate was highly expressed when cloned in pET28a (+) vector. The vaccine construct was predicted to elicit high antigenicity and cell-mediated immunity when given as a homologous prime-boost, with triggering of toll-like receptor 5 by the adjuvant linker. The vaccine was characterized by an increase in IgM and IgG and an array of Th1 and Th2 cytokines. Uponin silicochallenge with SARS-CoV-2, there was a decrease in antigen levels using our immune simulations. We therefore propose that potential vaccine designs consider this approach.
Biomaterial encapsulation of human mesenchymal stromal cells modulates paracrine signaling response and enhances efficacy for treatment of established osteoarthritis
Authors: McKinney Jay M. , Pucha Krishna A. , Doan Thanh N. , Wang Lanfang , Weinstock Laura D. , Tignor Benjamin T. , Fowle Kelsey L. , Levit Rebecca D. , Wood Levi B. , Willett Nick J. 
Published: July 2020

AbstractMesenchymal stromal cells (MSCs) have shown promise as a treatment for osteoarthritis (OA); however, effective translation has been limited by numerous factors ranging from high variability and heterogeneity of hMSCs, to suboptimal delivery strategies, to poor understanding of critical quality and potency attributes. The objective of the current study was to assess the effects of biomaterial encapsulation in alginate microcapsules on human MSC (hMSC) secretion of immunomodulatory cytokines in an OA microenvironment and therapeutic efficacy in treating established OA. Lewis rats underwent Medial Meniscal Transection (MMT) surgery to induce OA. Three weeks post-surgery, after OA was established, rats received intra-articular injections of either encapsulated hMSCs or controls (saline, empty capsules, or non-encapsulated hMSCs). Six weeks post-surgery, microstructural changes in the knee joint were quantified using contrast enhanced microCT. Encapsulated hMSCs attenuated progression of OA including articular cartilage degeneration (swelling and cartilage loss) and subchondral bone remodeling (thickening and hardening). A multiplexed immunoassay panel (41 cytokines) was used to profile thein vitrosecretome of encapsulated and non-encapsulated hMSCs in response to IL-1□, a key cytokine involved in OA. Non-encapsulated hMSCs showed an indiscriminate increase in all cytokines in response to IL-1□ while encapsulated hMSCs showed a highly targeted secretory response with increased expression of some pro-inflammatory (IL-1β, IL-6, IL-7, IL-8), anti-inflammatory (IL-1RA), and chemotactic (G-CSF, MDC, IP10) cytokines. These data show that biomaterial encapsulation using alginate microcapsules can modulate hMSC paracrine signaling in response to OA cytokines and enhance the therapeutic efficacy of the hMSCs in treating established OA.
Substrate specificity of SARS-CoV-2 nsp10-nsp16 methyltransferase
Authors: Benoni Roberto , Krafcikova Petra , Baranowski Marek R. , Kowalska Joanna , Boura Evzen , Cahová Hana 
Published: July 2020

AbstractThe ongoing COVID-19 pandemic exemplifies the general need to better understand viral infections. The positive single strand RNA genome of its causative agent, the SARS coronavirus 2 (SARS-CoV-2) encodes all viral enzymes. In this work, we focus on one particular methyltransferase (MTase), nsp16, which in complex with nsp10 is capable of methylating the first nucleotide of a capped RNA strand at the 2′-O position. This process is part of a viral capping system and is crucial for viral evasion of the innate immune reaction. In light of recently discovered non-canonical RNA caps, we tested various dinucleoside polyphosphate-capped RNAs as substrates for nsp10-nsp16 MTase. We developed an LC-MS-based method and discovered five types of capped RNA (m7Gp3A(G)-, Gp3A(G)- and Gp4A-RNA) that are substrates of the nsp10-nsp16 MTase. Our technique is an alternative to the classical isotope labelling approach for measurement of 2′-O-MTase activity. Further, we determined the IC50value of sinefungin (286 ± 66 nM) to illustrate the value of our approach for inhibitor screening. In the future, this approach can be used for screening inhibitors of any type of 2′-O-MTase.
Helicase-Like Functions in Phosphate Loop Containing Beta-Alpha Polypeptides
Authors: Vyas Pratik , Trofimyuk Olena , Longo Liam M. , Deshmukh Fanindra Kumar , Sharon Michal , Tawfik Dan S. 
Published: July 2020

AbstractThe P-loop Walker A motif underlies hundreds of essential enzyme families that bind nucleotide triphosphates (NTPs) and mediate phosphoryl transfer (P-loop NTPases), including the earliest DNA/RNA helicases, translocases and recombinases. What were the primordial precursors of these enzymes? Could these large and complex proteins emerge from simple polypeptides? Previously, we showed that P-loops embedded in simple βα repeat proteins bind NTPs, but also, unexpectedly so, ssDNA and RNA. Here, we extend beyond the purely biophysical function of ligand binding to demonstrate rudimentary helicase-like activities. We further constructed simple 40-residue polypeptides comprising just one β-(P-loop)-α element. Despite their simplicity, these P-loop prototypes confer functions such as strand separation and exchange. Foremost, these polypeptides unwind dsDNA, and upon addition of NTPs, or inorganic polyphosphates, release the bound ssDNA strands to allow reformation of dsDNA. Binding kinetics and low-resolution structural analyses indicate that activity is mediated by oligomeric forms spanning from dimers to high-order assemblies. The latter are reminiscent of extant P-loop recombinases such as RecA. Overall, these P-loop prototypes comprise a plausible description of the sequence, structure and function of the earliest P-loop NTPases. They also indicate that multifunctionality and dynamic assembly were key in endowing short polypeptides with elaborate, evolutionarily relevant functions.Significance statementIt is widely assumed that today’s large and complex proteins emerged from much shorter and simpler polypeptides. Yet the nature of these early precursors remains enigmatic. We describe polypeptides that contain one of the earliest protein motifs, a phosphate-binding loop, or P-loop, embedded in a single beta-alpha element. These P-loop prototypes show intriguing characteristics of a primordial world comprised of nucleic acids and peptides. They are ‘generalists’ capable of binding different phospho-ligands, including inorganic polyphosphates and single-stranded DNA. Nonetheless, in promoting double-stranded DNA unwinding and strand-exchange they resemble modern P-loop helicases and recombinases. Our study describes a missing link in the evolution of complex proteins – simple polypeptides that tangibly relate to contemporary P-loop enzymes in sequence, structure and function.