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Annalisa M. VanHook
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abm3135

Abstract:
The bacterial bile acid metabolite isoalloLCA stimulates the differentiation of Treg cells.
, , Joshua Lange, Viktoria Konya, Marianne Forkel, Jovana Maric, Anna Rao, Luca Mazzurana, Efthymia Kokkinou, Whitney Weigel, et al.
Abstract:
Cross-reactive CD4+ T cells that recognize SARS-CoV-2 are more commonly detected in the peripheral blood of unexposed individuals compared to SARS-CoV-2-reactive CD8+ T cells. However, large numbers of memory CD8+ T cells reside in tissues, feasibly harboring localized SARS-CoV-2-specific immune responses. To test this idea, we performed a comprehensive functional and phenotypic analysis of virus-specific T cells in tonsils, a major lymphoid tissue site in the upper respiratory tract, and matched peripheral blood samples obtained from children and adults before the emergence of COVID-19. We found that SARS-CoV-2-specific memory CD4+ T cells could be found at similar frequencies in the tonsils and peripheral blood in unexposed individuals, whereas functional SARS-CoV-2-specific memory CD8+ T cells were almost only detectable in the tonsils. Tonsillar SARS-CoV-2-specific memory CD8+ T cells displayed a follicular homing and tissue-resident memory phenotype, similar to tonsillar Epstein-Barr virus-specific memory CD8+ T cells, but were functionally less potent than other virus-specific memory CD8+ T cell responses. The presence of pre-existing tissue-resident memory CD8+ T cells in unexposed individuals could potentially enable rapid sentinel immune responses against SARS-CoV-2.
Hyeseon Cho, Kristina Kay Gonzales-Wartz, Deli Huang, Meng Yuan, Mary Peterson, Janie Liang, , , Yu Cong, Elena Postnikova, et al.
Science Translational Medicine; https://doi.org/10.1126/scitranslmed.abj5413

Abstract:
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor-binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/mL. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain-RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.
Chao Wei, Shanzhi Wang, Pengwei Liu, Shou-Ting Cheng, Guoliang Qian, Shuwei Wang, Ying Fu, ,
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abi9589

Abstract:
Bacterial type IV pili (T4P) contribute to virulence and can be rapidly extended and retracted to mediate twitching motility. T4P biogenesis, which is normally limited to the cell poles, is regulated by extracellular stimuli and internal signals such as cyclic di-GMP (c-di-GMP). The c-di-GMP–binding protein FimX interacts with the T4P assembly complex and, when intracellular c-di-GMP concentrations are low, assumes a unipolar localization and promotes T4P biogenesis. Here, we demonstrated that FimX formed a complex with the two-component system consisting of the histidine kinase PdeK and its downstream response regulator PdeR. This complex promoted T4P assembly in the phytopathogen Xanthomonas oryzae pv. oryzicola and virulence in rice. PdeK and the c-di-GMP phosphodiesterase activity of PdeR were required for the unipolar localization of FimX, leading to T4P extension. High amounts of c-di-GMP reduced the affinity of FimX for PdeR in vitro, consistent with FimX promoting T4P extension only under conditions of low c-di-GMP. We propose that low intracellular amounts of c-di-GMP created by PdeR facilitate the recruitment of FimX to the leading pole of motile cells. Our findings indicate that the PdeK-PdeR two-component system connects environmental cues to second messenger turnover, resulting in a change in the intracellular concentration of c-di-GMP that promotes T4P biogenesis and virulence.
Cong Zeng, Abdul A. Waheed, Tianliang Li, , Yi-Min Zheng, Jacob S. Yount, Haitao Wen, Eric O. Freed, Shan-Lu Liu
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abc7611

Abstract:
The SERINC (serine incorporator) proteins are host restriction factors that inhibit infection by HIV through their incorporation into virions. Here, we found that SERINC3 and SERINC5 exhibited additional antiviral activities by enhancing the expression of genes encoding type I interferons (IFNs) and nuclear factor κB (NF-κB) signaling. SERINC5 interacted with the outer mitochondrial membrane protein MAVS (mitochondrial antiviral signaling) and the E3 ubiquitin ligase and adaptor protein TRAF6, resulting in MAVS aggregation and polyubiquitylation of TRAF6. Knockdown of SERINC5 in target cells increased single-round HIV-1 infectivity, as well as infection by recombinant vesicular stomatitis virus (rVSV) bearing VSV-G or Ebola virus (EBOV) glycoproteins. Infection by an endemic Asian strain of Zika virus (ZIKV), FSS13025, was also enhanced by SERINC5 knockdown, suggesting that SERINC5 has direct antiviral activities in host cells in addition to the indirect inhibition mediated by its incorporation into virions. Further experiments suggested that the antiviral activity of SERINC5 was type I IFN–dependent. Together, these results highlight a previously uncharacterized function of SERINC proteins in promoting NF-κB inflammatory signaling and type I IFN production, thus contributing to its antiviral activities.
, , Zeli Zhang, Carolyn Rydyznski Moderbacher, Marshall Lammers, Benjamin Goodwin, , ,
Abstract:
Vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25-μg Moderna mRNA-1273 vaccine were examined over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing cross-reactive T cell memory impacts vaccine-generated immunity. Vaccine-generated spike-specific memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of T follicular helper cells and IFNγ-expressing cells. Spike-specific CD8+ T cells were generated in 88% of subjects, with equivalent memory at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing cross-reactive CD4+ T cell memory had increased CD4+ T cell and antibody responses to the vaccine, demonstrating the biological relevance of SARS-CoV-2–cross-reactive CD4+ T cells.
Changhong Wang, , Jing Luo, Jue Liu, Xiaona Li, Feipeng Zhao, Ruying Li, Huan Huang, Shangqian Zhao, Li Zhang, et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abh1896

Abstract:
Solid-state halide electrolytes have gained revived research interests owing to their high ionic conductivity and high-voltage stability. However, synthesizing halide electrolytes from a liquid phase is extremely challenging because of the vulnerability of metal halides to hydrolysis. In this work, ammonium-assisted wet chemistry is reported to synthesize various solid-state halide electrolytes with an exceptional ionic conductivity (>1 microsiemens per centimeter). Microstrain-induced localized microstructure change is found to be beneficial to lithium ion transport in halide electrolytes. Furthermore, the interfacial incompatibility between halide electrolytes and lithium metal is alleviated by transforming the mixed electronic/ionic conductive interface into a lithium ion–conductive interface. Such all-solid-state lithium-metal batteries (ASSLMBs) demonstrate a high initial coulombic efficiency of 98.1% based on lithium cobalt oxide and a high discharge capacity of 166.9 microampere hours per gram based on single-crystal LiNi0.6Mn0.2Co0.2O2. This work provides universal approaches in both material synthesis and interface design for developing halide-based ASSLMBs.
, MacIntosh Cornwell, Khrystyna Myndzar, Christina C. Rolling, , Kamelia Drenkova, Antoine Biebuyck, Alexander T. Fields, Michael Tawil, Elliot Luttrell-Williams, et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abh2434

Abstract:
Given the evidence for a hyperactive platelet phenotype in COVID-19, we investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). Integration of EC and platelet RNA sequencing revealed that platelet-released factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. We identified S100A8 and S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2. Consistent with increased gene expression, the heterodimer protein product of S100A8/A9, myeloid-related protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls. We demonstrate that platelet-derived MRP8/14 activates ECs, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to poor clinical outcomes in COVID-19 patients. Last, we present evidence that targeting platelet P2Y12 represents a promising candidate to reduce proinflammatory platelet-endothelial interactions. Together, these findings demonstrate a previously unappreciated role for platelets and their activation-induced endotheliopathy in COVID-19.
, , Michael S. Müller, Jürgen Groeneveld, Sebastian Lehmann, , Andreas Huth
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abg7012

Abstract:
Large areas of tropical forests have been lost through deforestation, resulting in fragmented forest landscapes. However, the dynamics of forest fragmentation are still unknown, especially the critical forest edge areas, which are sources of carbon emissions due to increased tree mortality. We analyzed the changes in forest fragmentation for the entire tropics using high-resolution forest cover maps. We found that forest edge area increased from 27 to 31% of the total forest area in just 10 years, with the largest increase in Africa. The number of forest fragments increased by 20 million with consequences for connectivity of tropical landscapes. Simulations suggest that ongoing deforestation will further accelerate forest fragmentation. By 2100, 50% of tropical forest area will be at the forest edge, causing additional carbon emissions of up to 500 million MT carbon per year. Thus, efforts to limit fragmentation in the world’s tropical forests are important for climate change mitigation.
Dmitry Ghilarov, Satomi Inaba-Inoue, Piotr Stepien, Feng Qu, , , Norimichi Nomura, Satoshi Ogasawara, Graham Charles Walker, , et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abj5363

Abstract:
Antibiotic metabolites and antimicrobial peptides mediate competition between bacterial species. Many of them hijack inner and outer membrane proteins to enter cells. Sensitivity of enteric bacteria to multiple peptide antibiotics is controlled by the single inner membrane protein SbmA. To establish the molecular mechanism of peptide transport by SbmA and related BacA, we determined their cryo–electron microscopy structures at 3.2 and 6 Å local resolution, respectively. The structures show a previously unknown fold, defining a new class of secondary transporters named SbmA-like peptide transporters. The core domain includes conserved glutamates, which provide a pathway for proton translocation, powering transport. The structures show an outward-open conformation with a large cavity that can accommodate diverse substrates. We propose a molecular mechanism for antibacterial peptide uptake paving the way for creation of narrow-targeted therapeutics.
Jacob Moe-Lange, Nicoline M. Gappel, Mackenzie Machado, , Cosima S. A. Sies, Stephan N. Schott-Verdugo, Michele Bonus, Swastik Mishra, , , et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abg4298

Abstract:
Glutamate has dual roles in metabolism and signaling; thus, signaling functions must be isolatable and distinct from metabolic fluctuations, as seen in low-glutamate domains at synapses. In plants, wounding triggers electrical and calcium (Ca2+) signaling, which involve homologs of mammalian glutamate receptors. The hydraulic dispersal and squeeze-cell hypotheses implicate pressure as a key component of systemic signaling. Here, we identify the stretch-activated anion channel MSL10 as necessary for proper wound-induced electrical and Ca2+ signaling. Wound gene induction, genetics, and Ca2+ imaging indicate that MSL10 acts in the same pathway as the glutamate receptor–like proteins (GLRs). Analogous to mammalian NMDA glutamate receptors, GLRs may serve as coincidence detectors gated by the combined requirement for ligand binding and membrane depolarization, here mediated by stretch activation of MSL10. This study provides a molecular genetic basis for a role of mechanical signal perception and the transmission of long-distance electrical and Ca2+ signals in plants.
Kirsten Grorud-Colvert, Jenna Sullivan-Stack, , Vanessa Constant, , Elizabeth P. Pike, Naomi Kingston, , , , et al.
Abstract:
Marine Protected Areas (MPAs) are conservation tools intended to protect biodiversity, promote healthy and resilient marine ecosystems, and provide societal benefits. Despite codification of MPAs in international agreements, MPA effectiveness is currently undermined by confusion about the many MPA types and consequent wildly differing outcomes. We present a clarifying science-driven framework—The MPA Guide—to aid design and evaluation. The guide categorizes MPAs by stage of establishment and level of protection, specifies the resulting direct and indirect outcomes for biodiversity and human well-being, and describes the key conditions necessary for positive outcomes. Use of this MPA Guide by scientists, managers, policy-makers, and communities can improve effective design, implementation, assessment, and tracking of existing and future MPAs to achieve conservation goals by using scientifically grounded practices.
Morgan E O’Neill, , Gerald M. Heymsfield, Kelton Halbert
Science, Volume 373, pp 1248-1251; https://doi.org/10.1126/science.abh3857

Abstract:
The strongest supercell thunderstorms typically feature an above-anvil cirrus plume (AACP), which is a plume of ice and water vapor in the lower stratosphere that occurs downwind of the ambient stratospheric flow in the lee of overshooting deep convection. AACP-origin hydration of the stratosphere has a poorly constrained role in ozone destruction and surface warming. In this study, we use large eddy simulations corroborated by radar observations to understand the physics of AACP generation. We show that the overshooting top of a simulated supercell can act as a topographic obstacle and drive a hydraulic jump downstream at the tropopause, similar to a windstorm moving down the slope of a mountain but without solid topography. Once the jump is established, water vapor injection deep into the stratosphere may exceed 7 tonnes per second.
Leslie K. Ferrarelli, Melissa Norton, Jelena Stajic, Michael A. Funk, Marc S. Lavine, Brent Grocholski, Ian S. Osborne, Sacha Vignieri, Gemma Alderton, Di Jiang, et al.
Science, Volume 373, pp 1212-1214; https://doi.org/10.1126/science.acx9029

Yazhong Huang, Kyle W. Knouse, Shenjie Qiu, Wei Hao, Natalia M. Padial, Julien C. Vantourout, Bin Zheng, Stephen E. Mercer, , Rohan Narayan, et al.
Science, Volume 373, pp 1265-1270; https://doi.org/10.1126/science.abi9727

Abstract:
The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food and Drug Administration approvals for therapeutic oligonucleotides, by far most of which contain modified phosphate linkages. These unnatural linkages have desirable biological and physical properties but are often accessed with difficulty using phosphoramidite chemistry. We report a flexible and efficient [P(V)]–based platform that can install a wide variety of phosphate linkages at will into oligonucleotides. This approach uses readily accessible reagents and can install not only stereodefined or racemic thiophosphates but any combination of (S, R or rac)–PS with native phosphodiester (PO2) and phosphorodithioate (PS2) linkages into DNA and other modified nucleotide polymers. This platform easily accesses this diversity under a standardized coupling protocol with sustainably prepared, stable P(V) reagents.
Siyang Li, Ke Ding, , Lejun He, , , Congbin Fu
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abh2601

Abstract:
As a symbol of civilization and culture, architecture was originally developed for sheltering people from unpleasant weather or other environmental conditions. Therefore, architecture is expected to be sensitive to climate change, particularly to changes in the occurrence of extreme weather events. However, although meteorological factors are widely considered in modern architecture design, it remains unclear whether and how ancient people adapted to climate change from the perspective of architecture design, particularly on a millennium time scale. Here, we show periodic change and a positive trend in roof slope of traditional buildings in the northern part of central and eastern China and demonstrate climate change adaptation in traditional Chinese architecture, driven by fluctuations in extreme snowfall events over the past thousand years. This study provides an excellent example showing how humans have long been aware of the impact of climate change on daily life and learned to adapt to it.
Sacha Vignieri, Jelena Stajic, Pamela J. Hines, Jake Yeston, Seth Thomas Scanlon, Michael A. Funk, Beverly A. Purnell
Science, Volume 373, pp 1213-1214; https://doi.org/10.1126/science.acx9030

Stephanie S. Holden, Fiorella C. Grandi, Oumaima Aboubakr, Bryan Higashikubo, , Andrew H. Chang, , Allison R. Morningstar, Vidhu Mathur, Logan J. Kuhn, et al.
Abstract:
Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities.
, Eric M. Cramer, , , Ming-Chih Kao,
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abj0320

Abstract:
Chronic pain conditions present in various forms, yet all feature symptomatic impairments in physical, mental, and social domains. Rather than assessing symptoms as manifestations of illness, we used them to develop a chronic pain classification system. A cohort of real-world treatment-seeking patients completed a multidimensional patient-reported registry as part of a routine initial evaluation in a multidisciplinary academic pain clinic. We applied hierarchical clustering on a training subset of 11,448 patients using nine pain-agnostic symptoms. We then validated a three-cluster solution reflecting a graded scale of severity across all symptoms and eight independent pain-specific measures in additional subsets of 3817 and 1273 patients. Negative affect–related factors were key determinants of cluster assignment. The smallest subset included follow-up assessments that were predicted by baseline cluster assignment. Findings provide a cost-effective classification system that promises to improve clinical care and alleviate suffering by providing putative markers for personalized diagnosis and prognosis.
, , Jihang Zhu, Elías Portoles, Giulia Zheng, Michele Masseroni, Annika Kurzmann, Takashi Taniguchi, , Allan H. MacDonald, et al.
Science, Volume 373, pp 1257-1260; https://doi.org/10.1126/science.abc3534

Abstract:
When twisted to angles near 1°, graphene multilayers provide a window on electron correlation physics. Here, we report the discovery of a correlated electron-hole state in double-bilayer graphene twisted to 2.37°. At this angle, the moiré states retain much of their isolated bilayer character, allowing their bilayer projections to be separately controlled by gates. We use this property to generate an energetic overlap between narrow isolated electron and hole bands with good nesting properties. Our measurements reveal the formation of ordered states with reconstructed Fermi surfaces, consistent with a density-wave state. This state can be tuned without introducing chemical dopants, enabling studies of correlated electron-hole states and their interplay with superconductivity.
, Kong Chen, Haoran Yang, Shiping Lu, Joseph P. Hoffmann, Alanna Wanek, Janet E. McCombs, Kejing Song, , Elizabeth B. Norton, et al.
Science Immunology, Volume 6; https://doi.org/10.1126/sciimmunol.abf1198

Abstract:
Tissue-resident memory (TRM) cells are thought to play a role in lung mucosal immunity to pathogens, but strategies to elicit TRM by mucosal vaccines have not yet been fully realized. Here, we formulated a vaccine composed of outer membrane protein (Omp) X from Klebsiella pneumoniae and LTA1 adjuvant that was administered by the intrapulmonary route. This vaccine elicited both TH1 and TH17 cells that shared transcriptional features with cells elicited by heat-killed K. pneumoniae. Antibody responses were required to prevent bacterial dissemination but dispensable for lung-specific immunity. In contrast, lung immunity required CD4+ T cells, STAT3 expression, and IL-17R signaling in fibroblasts. Lung-specific CD4+ T cells from OmpX+LTA1–immunized mice were observed homing to the lung and could mediate protection against infection in an adoptive transfer model. Vaccine-elicited TH17 cells showed reduced plasticity and were resistant to the immunosuppressant FK506 compared with TH1 cells, and TH17 cells conferred protection under conditions of transplant immunosuppression. These data demonstrate a promising vaccine strategy that elicits lung TRM cells and promotes serotype-independent immunity to K. pneumoniae.
Conrad H. Stansbury, M. Iqbal Bakti Utama, Claudia G. Fatuzzo, Emma C. Regan, Danqing Wang, Ziyu Xiang, Mingchao Ding, , Takashi Taniguchi, Mark Blei, et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abf4387

Abstract:
The search for materials with flat electronic bands continues due to their potential to drive strong correlation and symmetry breaking orders. Electronic moirés formed in van der Waals heterostructures have proved to be an ideal platform. However, there is no holistic experimental picture for how superlattices modify electronic structure. By combining spatially resolved angle-resolved photoemission spectroscopy with optical spectroscopy, we report the first direct evidence of how strongly correlated phases evolve from a weakly interacting regime in a transition metal dichalcogenide superlattice. By comparing short and long wave vector moirés, we find that the electronic structure evolves into a highly localized regime with increasingly flat bands and renormalized effective mass. The flattening is accompanied by the opening of a large gap in the spectral function and splitting of the exciton peaks. These results advance our understanding of emerging phases in moiré superlattices and point to the importance of interlayer physics.
, , Mariana Fazio, Alena Ananyeva, GariLynn Billingsley, Ashot Markosyan, , , Martin M. Fejer, Martin Chicoine, et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abh1117

Abstract:
Glasses are nonequilibrium solids with properties highly dependent on their method of preparation. In vapor-deposited molecular glasses, structural organization could be readily tuned with deposition rate and substrate temperature. Here, we show that the atomic arrangement of strong network-forming GeO2 glass is modified at medium range (<2 nm) through vapor deposition at elevated temperatures. Raman spectral signatures distinctively show that the population of six-membered GeO4 rings increases at elevated substrate temperatures. Deposition near the glass transition temperature is more efficient than postgrowth annealing in modifying atomic structure at medium range. The enhanced medium-range organization correlates with reduction of the room temperature internal friction. Identifying the microscopic origin of room temperature internal friction in amorphous oxides is paramount to design the next-generation interference coatings for mirrors of the end test masses of gravitational wave interferometers, in which the room temperature internal friction is a main source of noise limiting their sensitivity.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abj0786

Abstract:
Protein-mediated allosteric regulations are essential in biology, but their quantitative characterization continues to posit formidable challenges for both experiments and computations. Here, we combine coevolutionary information, multiscale molecular simulations, and free-energy methods to interrogate and quantify the allosteric regulation of functional changes in protein complexes. We apply this approach to investigate the regulation of adenylyl cyclase (AC) by stimulatory and inhibitory G proteins—a prototypical allosteric system that has long escaped from in-depth molecular characterization. We reveal a surprisingly simple ON/OFF regulation of AC functional dynamics through multiple pathways of information transfer. The binding of G proteins reshapes the free-energy landscape of AC following the classical population-shift paradigm. The model agrees with structural and biochemical data and reveals previously unknown experimentally consistent intermediates. Our approach showcases a general strategy to explore uncharted functional space in complex biomolecular regulations.
Sameer Singh, , Linamarie Miller, ,
Abstract:
The human small subunit processome mediates early maturation of the small ribosomal subunit by coupling RNA folding to subsequent RNA cleavage and processing steps. We report the high-resolution cryo–electron microscopy structures of maturing human small subunit (SSU) processomes at resolutions of 2.7 to 3.9 angstroms. These structures reveal the molecular mechanisms that enable crucial progressions during SSU processome maturation. RNA folding states within these particles are communicated to and coordinated with key enzymes that drive irreversible steps such as targeted exosome-mediated RNA degradation, protein-guided site-specific endonucleolytic RNA cleavage, and tightly controlled RNA unwinding. These conserved mechanisms highlight the SSU processome’s impressive structural plasticity, which endows this 4.5-megadalton nucleolar assembly with the distinctive ability to mature the small ribosomal subunit from within.
Mauricio A. Urbina, Pablo C. Guerrero, Viviane Jerez, Fulgencio Lisón, Guillermo Luna-Jorquera, Camilo Matus-Olivares, Juan C. Ortiz, Guido Pavez, María J. Pérez-Alvarez, Ramiro Riquelme-Bugueño, et al.
Science, Volume 373, pp 1208-1209; https://doi.org/10.1126/science.abm0157

Yue Li, , Ruud Van Zessen, Jérôme Flakowski, Jin-Xia Wan, Fei Deng, , , Vincent Pascoli,
Science, Volume 373, pp 1252-1256; https://doi.org/10.1126/science.abi9086

Abstract:
Compulsive drug use despite adverse consequences defines addiction. While mesolimbic dopamine signaling is sufficient to drive compulsion, psychostimulants such as cocaine also boost extracellular serotonin (5-HT) by inhibiting reuptake. We used SERT Met172 knockin (SertKI) mice carrying a transporter that no longer binds cocaine to abolish 5-HT transients during drug self-administration. SertKI mice showed an enhanced transition to compulsion. Conversely, pharmacologically elevating 5-HT reversed the inherently high rate of compulsion transition with optogenetic dopamine self-stimulation. The bidirectional effect on behavior is explained by presynaptic depression of orbitofrontal cortex–to–dorsal striatum synapses induced by 5-HT via 5-HT1B receptors. Consequently, in projection-specific 5-HT1B receptor knockout mice, the fraction of individuals compulsively self-administering cocaine was elevated.
, Anugraha Mathew, Christian Jenul, Tobias Kohler, Max Bär, , , Urs Stalder, Ya-Chu Hsieh, , et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abg2293

Abstract:
Pseudomonas syringae is an important plant pathogen of many valuable crops worldwide, with more than 60 identified pathovars. The phytotoxins produced by these organisms were related to the severity of the damage caused to the plant. An emerging strategy to treat bacterial infections relies on interference with their signaling systems. In this study, we investigated P. syringae pv. syringae, which produces the virulence factor mangotoxin that causes bacterial apical necrosis on mango leaves. A previously unknown signaling molecule named leudiazen was identified, determined to be unstable and volatile, and responsible for mangotoxin production. A strategy using potassium permanganate, compatible with organic farming, was developed to degrade leudiazen and thus to attenuate the pathogenicity of P. syringae pv. syringae.
Xiaoling Qiu, Xiaoling Wang, Yunxiang He, Jieying Liang, , , Joseph J. Richardson, , , , et al.
Science Advances, Volume 7; https://doi.org/10.1126/sciadv.abh3482

Abstract:
Soft structures in nature, such as supercoiled DNA and proteins, can organize into complex hierarchical architectures through multiple noncovalent molecular interactions. Identifying new classes of natural building blocks capable of facilitating long-range hierarchical structuring has remained an elusive goal. We report the bottom-up synthesis of a hierarchical metal-phenolic mesocrystal where self-assembly proceeds on different length scales in a spatiotemporally controlled manner. Phenolic-based coordination complexes organize into supramolecular threads that assemble into tertiary nanoscale filaments, lastly packing into quaternary mesocrystals. The hierarchically ordered structures are preserved after thermal conversion into a metal-carbon hybrid framework and can impart outstanding performance to sodium ion batteries, which affords a capability of 72.5 milliampere hours per gram at an ultrahigh rate of 200 amperes per gram and a 90% capacity retention over 15,000 cycles at a current density of 5.0 amperes per gram. This hierarchical structuring of natural polyphenols is expected to find widespread applications.
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