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Fernandez-Martinez J, Rout MP
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One Ring to Rule them All? Structural and Functional Diversity in the Nuclear Pore Complex (opens in new window)

TRENDS IN BIOCHEMICAL SCIENCES 2021 JUL; 46(7):595-607
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The nuclear pore complex (NPC) is the massive protein assembly that regulates the transport of macromolecules between the nucleus and the cytoplasm. Recent breakthroughs have provided major insights into the structure of the NPC in different eukaryotes, revealing a previously unsuspected diversity of NPC architectures. In parallel, the NPC has been shown to be a key player in regulating essential nuclear processes such as chromatin organization, gene expression, and DNA repair. However, our knowledge of the NPC structure has not been able to address the molecular mechanisms underlying its regulatory roles. We discuss potential explanations, including the coexistence of alternative NPC architectures with specific functional roles.
Lenne PF, Munro E, Heemskerk I, Warmflash A, Bocanegra-Moreno L, Kishi K, Kicheva A, Long YC, Fruleux A, Boudaoud A, Saunders TE, Caldarelli P, Michaut A, Gros J, Maroudas-Sacks Y, Keren K, Hannezo E, Gartner ZJ, Stormo B, Gladfelter A, Rodrigues A, Shyer A, Minc N, Maitre JL, Di Talia S, Khamaisi B, Sprinzak D, Tlili S
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Roadmap for the multiscale coupling of biochemical and mechanical signals during development (opens in new window)

PHYSICAL BIOLOGY 2021 JUL; 18(4):? Article 041501
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The way in which interactions between mechanics and biochemistry lead to the emergence of complex cell and tissue organization is an old question that has recently attracted renewed interest from biologists, physicists, mathematicians and computer scientists. Rapid advances in optical physics, microscopy and computational image analysis have greatly enhanced our ability to observe and quantify spatiotemporal patterns of signalling, force generation, deformation, and flow in living cells and tissues. Powerful new tools for genetic, biophysical and optogenetic manipulation are allowing us to perturb the underlying machinery that generates these patterns in increasingly sophisticated ways. Rapid advances in theory and computing have made it possible to construct predictive models that describe how cell and tissue organization and dynamics emerge from the local coupling of biochemistry and mechanics. Together, these advances have opened up a wealth of new opportunities to explore how mechanochemical patterning shapes organismal development. In this roadmap, we present a series of forward-looking case studies on mechanochemical patterning in development, written by scientists working at the interface between the physical and biological sciences, and covering a wide range of spatial and temporal scales, organisms, and modes of development. Together, these contributions highlight the many ways in which the dynamic coupling of mechanics and biochemistry shapes biological dynamics: from mechanoenzymes that sense force to tune their activity and motor output, to collectives of cells in tissues that flow and redistribute biochemical signals during development.
Dong XX, Chao YJ, Zhou Y, Zhou R, Zhang W, Fischetti VA, Wang XH, Feng Y, Li JQ
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The global emergence of a novel Streptococcus suis clade associated with human infections (opens in new window)

EMBO MOLECULAR MEDICINE 2021 JUL 7; 13(7):? Article e13810
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Streptococcus suis, a ubiquitous bacterial colonizer in pigs, has recently extended host range to humans, leading to a global surge of deadly human infections and three large outbreaks since 1998. To better understand the mechanisms for the emergence of cross-species transmission and virulence in human, we have sequenced 366 S. suis human and pig isolates from 2005 to 2016 and performed a large-scale phylogenomic analysis on 1,634 isolates from 14 countries over 36 years. We show the formation of a novel human-associated clade (HAC) diversified from swine S. suis isolates. Phylogeographic analysis identified Europe as the origin of HAC, coinciding with the exportation of European swine breeds between 1960s and 1970s. HAC is composed of three sub-lineages and contains several healthy-pig isolates that display high virulence in experimental infections, suggesting healthy-pig carriers as a potential source for human infection. New HAC-specific genes are identified as promising markers for pathogen detection and surveillance. Our discovery of a human-associated S. suis clade provides insights into the evolution of this emerging human pathogen and extend our understanding of S. suis epidemics worldwide.
Savage KT, Singh V, Patel ZS, Yannuzzi CA, McKenzie-Brown AM, Lowes MA, Orenstein LAV
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Pain management in hidradenitis suppurativa and a proposed treatment algorithm (opens in new window)

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 2021 JUL; 85(1):187-199
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Pain contributes substantially to reduced quality of life in individuals living with hidradenitis suppurativa (HS). Although improved understanding of HS pathogenesis and treatment has resulted in improved evidence-based HS management guidelines, comprehensive pain management guidelines have yet to be developed. Few HS-specific data exist to guide pharmacologic analgesia; however, recognizing HS pain as either acute or chronic and predominantly nociceptive (aching and gnawing pain due to tissue damage) versus neuropathic (burning-type pain due to somatosensory nervous system dysfunction) provides a conceptual framework for applying outside pain management practices to HS management. This article incorporates the best available evidence from the HS and pain literature to propose an HS pain algorithm that integrates psychological, pharmacologic, and complementary and alternative treatment modalities.
Xu JL, Xu K, Jung S, Conte A, Lieberman J, Muecksch F, Lorenzi JCC, Park S, Schmidt F, Wang ZJ, Huang YX, Luo Y, Nair MS, Wang PF, Schulz JE, Tessarollo L, Bylund T, Chuang GY, Olia AS, Stephens T, Teng IT, Tsybovsky Y, Zhou TQ, Munster V, Ho DD, Hatziioannou T, Bieniasz PD, Nussenzweig MC, Kwong PD, Casellas R
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Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants (opens in new window)

NATURE 2021 JUL 8; 595(7866):278-282
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Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization(1-3). One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies(4). Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.
Yamashita M, Kuehn HS, Okuyama K, Okada S, Inoue Y, Mitsuiki N, Imai K, Takagi M, Kanegane H, Takeuchi M, Shimojo N, Tsumura M, Padhi AK, Zhang KYJ, Boisson B, Casanova JL, Ohara O, Rosenzweig SD, Taniuchi I, Morio T
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A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS (opens in new window)

NATURE IMMUNOLOGY 2021 JUL; 22(7):893-903
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The zinc-finger transcription factor IKAROS is essential for B cell development. Taniuchi, Morio and colleagues identify a human kindred presenting with B cell immunodeficiency that was caused by a heterozygous missense mutation in IKZF3 encoding the related AIOLOS protein. AIOLOS(G159R) is a mutant protein that interferes with both wild-type AIOLOS and IKAROS by forming heterodimers that bind to aberrant DNA-binding sites and prevent normal expression of IKAROS-dependent genes. In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.
Windisch KA, Morochnik M, Reed B, Kreek MJ
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Nalmefene, a mu opioid receptor antagonist/kappa opioid receptor partial agonist, potentiates cocaine motivation but not intake with extended access self-administration in adult male mice (opens in new window)

NEUROPHARMACOLOGY 2021 JUL 1; 192(?):? Article 108590
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The mu opioid receptor antagonist/kappa opioid receptor (KOR) partial agonist nalmefene (NMF), a close structural analog of naltrexone (NTX), has been shown to reduce cocaine reward in preclinical models. Given the greater KOR potency and improved bioavailability compared to NTX, NMF may be a promising pharmacotherapeutic for cocaine use disorder (CUD). Here we examine the effects of NMF pretreatment on chronic daily extended access (4h) cocaine intravenous self-administration (IVSA) in adult male C57Bl/6J mice. Methods: separate groups of mice had daily 4h cocaine IVSA sessions (0.25 or 0.5 mg/kg/inf, FR1) for 14 days. Starting on day 8, mice were pretreated with NMF (0, 1, or 10 mg/kg) 30m before each session. A separate group of mice acquired cocaine IVSA [seven days FR1 then four FR3 of 4h daily sessions (0.5 mg/kg/inf)] prior to a single progressive ratio 3 session to examine the effect of 1 mg/kg NMF on cocaine motivation. Results: No significant effect of NMF pretreatment on cocaine intake was observed. Acute pretreatment of 1 mg/kg NMF significantly potentiated cocaine motivation as measured by progressive ratio breakpoint. Conclusions: NMF did not significantly attenuate cocaine intake and increased motivation for cocaine suggesting that NMF may not be suitable for non-abstinent CUD patients. Further research is needed with KOR selective partial or full agonists to determine their effect on cocaine reinforcement.
Adura C, Aliaga C, Silva F, Vera C, Pino E, Celis F, Aracena A, Tirapegui C
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A simple method to estimate the mean number of lipophilic molecules on nanoparticle surfaces by fluorescence measurements (opens in new window)

NANOTECHNOLOGY 2021 JUL 30; 32(31):? Article 315711
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Measurements of fluorescence intensity of the hydrophobic pyridinium salt (DTPSH) remaining in the organic phase after partition experiments in the DCM/H2O system allowed an approximate method to be developed to estimate the mean number of molecules (N = 942) on the surface of 22.8 nm gold nanoparticles and the separation (1.89 nm) between these organic molecules. This protocol is based on the ability that the organic molecules possess to coat the surface of the nanoparticle, which can migrate from the organic to the aqueous phase as a result of the driving force of the strong binding of sulfur to gold. To validate our estimation, we used a projection of the results obtained by Wales and Ulker to solve the Thomson problem, a mathematicians' challenge, used as a model to calculate the mean distance (1.82 nm) separating particles on the surface, in excellent agreement with the results obtained by our method. The quality of results, the simplicity of calculations, the low fluorescence detection limit, and the inexpensive materials, recommend this procedure for rapid estimates of the mean number of molecules on the surface of nanoparticles.
Belaid B, Mahammed LL, Oussaid AM, Migaud M, Khadri Y, Casanova JL, Puel A, Ben Halla N, Djidjik R
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Case Report: Interleukin-2 Receptor Common Gamma Chain Defect Presented as a Hyper-IgE Syndrome (opens in new window)

FRONTIERS IN IMMUNOLOGY 2021 JUN 24; 12(?):? Article 696350
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X-linked severe combined immunodeficiency (X-SCID) is caused by mutations of IL2RG, the gene encoding the interleukin common gamma chain (IL-2R gamma or gamma c) of cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Hypomorphic mutations of IL2RG may cause combined immunodeficiencies with atypical clinical and immunological presentations. Here, we report a clinical, immunological, and functional characterization of a missense mutation in exon 1 (c.115G>A; p. Asp39Asn) of IL2RG in a 7-year-old boy. The patient suffered from recurrent sinopulmonary infections and refractory eczema. His total lymphocyte counts have remained normal despite skewed T cell subsets, with a pronounced serum IgE elevation. Surface expression of IL-2R gamma was reduced on his lymphocytes. Signal transducer and activator of transcription (STAT) phosphorylation in response to IL-2, IL-4, and IL-7 showed a partially preserved receptor function. T-cell proliferation in response to mitogens and anti-CD3/anti-CD28 monoclonal antibodies was significantly reduced. Further analysis revealed a decreased percentage of CD4(+) T cells capable of secreting IFN-gamma, but not IL-4 or IL-17. Studies on the functional consequences of IL-2R gamma variants are important to get more insight into the pathogenesis of atypical phenotypes which may lay the ground for novel therapeutic strategies.
Ibrahim K, Khodursky S, Yasseri T
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Gender Imbalance and Spatiotemporal Patterns of Contributions to Citizen Science Projects: The Case of Zooniverse (opens in new window)

FRONTIERS IN PHYSICS 2021 JUN 4; 9(?):? Article 650720
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Citizen Science is research undertaken by professional scientists and members of the public collaboratively. Despite numerous benefits of citizen science for both the advancement of science and the community of the citizen scientists, there is still no comprehensive knowledge of patterns of contributions, and the demography of contributors to citizen science projects. In this paper we provide a first overview of spatiotemporal and gender distribution of citizen science workforce by analyzing 54 million classifications contributed by more than 340 thousand citizen science volunteers from 198 countries to one of the largest online citizen science platforms, Zooniverse. First we report on the uneven geographical distribution of the citizen scientist and model the variations among countries based on the socio-economic conditions as well as the level of research investment in each country. Analyzing the temporal features of contributions, we report on high "burstiness" of participation instances as well as the leisurely nature of participation suggested by the time of the day that the citizen scientists were the most active. Finally, we discuss the gender imbalance among online citizen scientists (about 30% female) and compare it with other collaborative projects as well as the gender distribution in more formal scientific activities. Online citizen science projects need further attention from outside of the academic community, and our findings can help attract the attention of public and private stakeholders, as well as to inform the design of the platforms and science policy making processes.