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An Oncology Renaissance

Jonathan W. Friedberg

Journal of Clinical Oncology
Jul 10, 2021
10.1200/jco.21.01649
Journal

Dynamic Characteristic Analysis of Antibodies in Patients With COVID 19: A 13 Month Study

Danrong Shi, Tianhao Weng, Jie Wu, Chunyan Dai, Rui Luo, Keda Chen, Miaojin Zhu, Xiangyun Lu, Linfang Cheng, Qiuqiang Chen, Fumin Liu, Zhigang Wu, Haibo Wu, Changzhong Jin, Miao Guo, Zhe Chen, Nanping Wu, Hangping Yao, Min Zheng

Frontiers in Marine Science
Jul 20, 2021
10.3389/fimmu.2021.708184
Journal


There is a worldwide pandemic of Severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) infection; yet our understanding remains limited on the characteristic of antibodies, especially for dynamic long term tracking. Sequential serum samples were collected up to 416 days post onset of symptoms (POS) from 102 patients who were hospitalized with coronavirus disease 2019 (COVID 19). Immunoglobulin (Ig)G, IgM, and IgA levels targeting SARS CoV 2 spike 1 receptor binding domain (S1 RBD), spike 2 extracellular domain (S2 ECD), and nucleocapsid protein (N) were quantified as well as neutralizing activity. We were pleasantly surprised to find that the antibody remained detective and effective for more than a year POS. We also found the varied reactions of different antibodies as time passed: N IgA rose most rapidly in the early stage of infection, while S2 IgG was present at a high level in the long time of observation. This study described the long traceable antibody response of the COVID 19 and offered hints about targets to screen for postinfectious immunity and for vaccination development of SARS CoV 2.

The aetiology and molecular landscape of insulin resistance

David E. James, Jacqueline Stöckli, Morris J. Birnbaum

Nature Reviews Molecular Cell Biology
Jul 20, 2021
10.1038/s41580-021-00390-6
Journal


Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues — prominently in muscle, fat and liver — is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance.

Cardiovascular disease in diabetes, beyond glucose

Robert H. Eckel, Karin E. Bornfeldt, Ira J. Goldberg

Cell Metabolism
Jul 20, 2021
10.1016/j.cmet.2021.07.001
Journal


Diabetes increases cardiovascular disease risk, but the reasons for the association are not fully understood. Here, Eckel et al. review clinical and animal studies that explore the pathogenesis of atherosclerosis in the diabetes context. They discuss the need to identify and understand risk factors beyond glucose in order to prevent increased cardiovascular disease risk in diabetes.

Myocarditis with COVID-19 mRNA Vaccines

Biykem Bozkurt, Ishan Kamat, Peter J. Hotez

Circulation
Jul 20, 2021
10.1161/circulationaha.121.056135
Journal


Myocarditis has been recognized as a rare complication of coronavirus 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males. According to the United States Centers for Disease Control (CDC), myocarditis/pericarditis rates are approximately 12.6 cases per million doses of second dose mRNA vaccine among 12-39-year-olds. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2-3 days after a second dose of mRNA vaccination and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID-19 or other viral infections. In one case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA and activation of immunological pathways, and dysregulated cytokine expression have been proposed. The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also under-diagnosis of cardiac disease in women. Almost all patients had resolution of symptoms and signs, and improvement in diagnostic markers and imaging with or without treatment. Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore COVID-19 vaccination is recommended for everyone 12 years of age and older.

The human connectome in Alzheimer disease — relationship to biomarkers and genetics

Meichen Yu, Olaf Sporns, Andrew J. Saykin

Nature Reviews Neurology
Jul 20, 2021
10.1038/s41582-021-00529-1
Journal


The pathology of Alzheimer disease (AD) damages structural and functional brain networks, resulting in cognitive impairment. The results of recent connectomics studies have now linked changes in structural and functional network organization in AD to the patterns of amyloid-β and tau accumulation and spread, providing insights into the neurobiological mechanisms of the disease. In addition, the detection of gene-related connectome changes might aid in the early diagnosis of AD and facilitate the development of personalized therapeutic strategies that are effective at earlier stages of the disease spectrum. In this article, we review studies of the associations between connectome changes and amyloid-β and tau pathologies as well as molecular genetics in different subtypes and stages of AD. We also highlight the utility of connectome-derived computational models for replicating empirical findings and for tracking and predicting the progression of biomarker-indicated AD pathophysiology.

Engineered Type Six Secretion Systems Deliver Active Exogenous Effectors and Cre Recombinase

Steven J. Hersch, Linh Lam, Tao G. Dong aDepartment of Ecosystem and Public Health, University of Calgarygrid.22072.35, Calgary, Alberta, Canada bState Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China, Gerard D. Wright

American Society for Microbiology: mBio
Jul 20, 2021
10.1128/mbio.01115-21
Journal


mBio, Ahead of Print.

(De)constructing Refugee Vulnerability: Overcoming Institutional Barriers to Ethnographic Research With Refugee Communities

Bronwyn Bragg

Journal of Contemporary Ethnography
Jul 20, 2021
10.1177/08912416211031645
Journal


Journal of Contemporary Ethnography, Ahead of Print. Drawn from 18 months of ethnographic research with resettled refugees living in a mini enclave in one Canadian city, this article explores what ethnography offers research with resettled refugees. By interrogating the process of securing ethics approval from the Research Ethics Board (REB), I examine the figure of the refugee at the heart of liberal projects aimed at “saving” refugees. I demonstrate that the REB’s reluctance to approve this project stemmed not only from conventional bureaucratic overreach related to ethnographic research but also from an unexamined and problematic idea of what it means to be a refugee. I discuss the gaps between institutionally perceived forms of vulnerability and the actual vulnerabilities that shape life for refugee women. I argue that vulnerability and risk must be understood as contextual and contingent, rather than inherent. Second, I explore the implications of positioning refugees as always already vulnerable on research practice and the value that ethnography offers for overcoming these blind spots.

A synthetic tubular molecular transport system

Pierre Stömmer, Henrik Kiefer, Enzo Kopperger, Maximilian N. Honemann, Massimo Kube, Friedrich C. Simmel, Roland R. Netz, Hendrik Dietz

Nature Communications
Jul 20, 2021
10.1038/s41467-021-24675-8
Journal Paper


Creating artificial macromolecular transport systems that can support the movement of molecules along defined routes is a key goal of nanotechnology. Here, we report the bottom-up construction of a macromolecular transport system in which molecular pistons diffusively move through micrometer-long, hollow filaments. The pistons can cover micrometer distances in fractions of seconds. We build the system using multi-layer DNA origami and analyze the structures of the components using transmission electron microscopy. We study the motion of the pistons along the tubes using single-molecule fluorescence microscopy and perform Langevin simulations to reveal details of the free energy surface that directs the motions of the pistons. The tubular transport system achieves diffusivities and displacement ranges known from natural molecular motors and realizes mobility improvements over five orders of magnitude compared to previous artificial random walker designs. Electric fields can also be employed to actively pull the pistons along the filaments, thereby realizing a nanoscale electric rail system. Our system presents a platform for artificial motors that move autonomously driven by chemical fuels and for performing nanotribology studies, and it could form a basis for future molecular transportation networks.

Efficient Protein Transfection by Swarms of Chemically Powered Plasmonic Virus-Sized Nanorobots

Alzbeta Ressnerova, Filip Novotny, Hana Michalkova, Martin Pumera, Vojtech Adam, Zbynek Heger

ACS Nano
Jul 20, 2021
10.1021/acsnano.1c01172
Journal


Transfection is based on nonviral delivery of nucleic acids or proteins into cells. Viral approaches are being used; nevertheless, their translational capacity is nowadays decreasing due to persistent fear of their safety, therefore creating space for the field of nanotechnology. However, nanomedical approaches introducing static nanoparticles for the delivery of biologically active molecules are very likely to be overshadowed by the vast potential of nanorobotics. We hereby present a rapid nonviral transfection of protein into a difficult-to-transfect prostate cancer cell line facilitated by chemically powered rectangular virus-sized (68 nm × 33 nm) nanorobots. The enhanced diffusion of these biocompatible nanorobots is the key to their fast internalization into cells, happening in a matter of minutes and being up to 6-fold more efficient compared to static nanorobots in a nonfueled environment. The Au/Ag plasmonic nature of these nanorobots makes them simply traceable and allows for their detailed subcellular localization. Protein transfection mediated by such nanorobots is an important step forward, challenging the field of nanomedicine and having potential in future translational medical research.

Maternal cecal microbiota transfer rescues early life antibiotic induced enhancement of type 1 diabetes in mice

Xue-Song Zhang, Yue Sandra Yin, Jincheng Wang, Thomas Battaglia, Kimberly Krautkramer, Fredrik Bäckhed, Stanley L. Hazen, Martin J. Blaser et 21 al.

Cell Host & Microbe
Jul 20, 2021
10.1016/j.chom.2021.06.014
Journal


Using a mouse model in which early life antibiotics enhance T1D, Zhang et al. show that subsequent maternal cecal microbiota transfer reduces illness. The restorative effects on the intestinal microbiome and metabolism, ileal wall gene expression and regulation, and innate and adaptive immune effectors suggest a gut microbiota regulated T1D protective mechanism.

Low seropositivity and sub-optimal neutralisation rates in patients fully vaccinated against COVID-19 with B cell malignancies.

Fox T. A., Kirkwood A. A., Enfield L., O'reilly M., Arulogun S., D'sa S., O'nions J., Kavi J., Vitsaras E., Townsend W., Burns S. O., Gohil S. H., Cwynarski K., Thomson K. J., Noursadeghi M., Heyderman R. S., Rampling T., Ardeshna K. M., Mccoy L. E., Morris E. C.

Medrxiv
Jul 19, 2021
10.1101/2021.07.19.21260762
Journal PDF Preprint


Patients with haematological malignancies are at increased risk of severe disease and death from COVID-19 and are less likely to mount humoral immune responses to COVID-19 vaccination, with the B cell malignancies a particularly high-risk group. Our COV-VACC study is evaluating the immune response to COVID-19 vaccination in patients with B cell malignancies. Eligible patients were either receiving active treatment or had received treatment within the last 24 months. Patients were vaccinated with either the BNT162b2 (Pfizer-BioNTech) (n=41) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) (n=14) vaccines. The median age of participants was 60 years (range: 27-82) and 50% were receiving systemic anti-cancer therapy (SACT) at the time of vaccination. This interim analysis from the first 55 participants describes anti-S seropositivity rates, neutralising antibody activity and association with peripheral lymphocyte subsets. After the first vaccine dose, 36% overall had detectable anti-S antibodies rising to 42% after the second dose. Sera from seropositive patients was assessed for neutralisation activity in vitro. Of the seropositive patients after first dose (n=17), only 41% were able to neutralise SARS-CoV-2 pseudotyped virus with a 50% inhibitory dilution factor (ID50) of >1:50. After two doses (n=21) 57% of the seropositive patients had detectable neutralisation activity (median ID50 of 1:469, range 1:70 - 1:3056). Total blood lymphocyte, CD19, CD4 and CD56 counts were significantly associated with seropositivity. Patients vaccinated more than 6 months after completing therapy were significantly more likely to develop antibodies than those within 6 months of treatment or on active treatment; OR: 5.93 (1.29 - 27.28). Our data has important implications for patients with B cell malignancies as we demonstrate a disconnect between anti-S seropositivity and virus neutralisation in vitro following vaccination against COVID-19. Urgent consideration should be given to revaccinating patients with B-cell malignancies after completion of anti-cancer treatment as large numbers currently remain at high risk of infection with the increasing transmission of SARS-CoV-2 in many countries.

Machine learning for alloys

Gus L. W. Hart, Tim Mueller, Cormac Toher, Stefano Curtarolo

Nature Reviews Materials
Jul 20, 2021
10.1038/s41578-021-00340-w
Journal


Alloy modelling has a history of machine-learning-like approaches, preceding the tide of data-science-inspired work. The dawn of computational databases has made the integration of analysis, prediction and discovery the key theme in accelerated alloy research. Advances in machine-learning methods and enhanced data generation have created a fertile ground for computational materials science. Pairing machine learning and alloys has proven to be particularly instrumental in pushing progress in a wide variety of materials, including metallic glasses, high-entropy alloys, shape-memory alloys, magnets, superalloys, catalysts and structural materials. This Review examines the present state of machine-learning-driven alloy research, discusses the approaches and applications in the field and summarizes theoretical predictions and experimental validations. We foresee that the partnership between machine learning and alloys will lead to the design of new and improved systems.

‘Language hackers’: YouTube polyglots as representative figures of language learning in late capitalism

Alberto Bruzos

International Journal of Bilingual Education and Bilingualism
Jul 19, 2021
10.1080/13670050.2021.1955498
Journal


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Comparisons of β‐Hairpin Propensity Among Peptides with Homochiral or Heterochiral Strands

Xinyu Liu, Samuel H Gellman

ChemBioChem
Jul 19, 2021
10.1002/cbic.202100324
Journal


Assemblies of racemic β‐sheet‐forming peptides have attracted attention for biomedical applications because racemic forms of peptides can self‐associate more avidly than do single enantiomers. In 1953, Pauling and Corey proposed "rippled β‐sheet" modes of H‐bond‐mediated interstrand assembly for alternating L‐ and D‐peptide strands; this structural hypothesis was complementary to their proposal of "pleated β‐sheet" assembly for L‐peptides. Although no high‐resolution structure has been reported for a rippled β‐sheet, there is strong evidence for the occurrence of rippled β‐sheets in racemic peptide assemblies. Here we compare propensities of peptide diastereomers in aqueous solution to form a minimum increment of β‐sheet in which two antiparallel strands associate. β‐Hairpin folding is observed for homochiral peptides with aligned nonpolar side chains, but no β‐hairpin population can be detected for diastereomers in which one strand contains L residues and the other contains D residues. These observations suggest that rippled β‐sheet assemblies are stabilized by interactions between β‐sheet layers rather than interactions within these layers.

Structure-Guided Design of a "Bump-and-Hole" Bromodomain-Based Degradation Tag.

Radosław P Nowak, Yuan Xiong, Nadia Kirmani, Joann Kalabathula, Katherine A Donovan, Nicholas A Eleuteri, J Christine Yuan, Eric S Fischer

Journal of medicinal chemistry
Jul 19, 2021
10.1021/acs.jmedchem.1c00958


Chemical biology tools to modulate protein levels in cells are critical to decipher complex biology. Targeted protein degradation offers the potential for rapid and dose-dependent protein depletion through the use of protein fusion tags toward which protein degraders have been established. Here, we present a newly developed protein degradation tag BRD4BD1L94V along with the corresponding cereblon (CRBN)-based heterobifunctional degrader based on a "bump-and-hole" approach. The resulting compound XY-06-007 shows a half-degradation concentration (DC50, 6 h) of 10 nM against BRD4BD1L94V with no degradation of off-targets, as assessed by whole proteome mass spectrometry, and demonstrates suitable pharmacokinetics for in vivo studies. We demonstrate that BRD4BD1L94V can be combined with the dTAG approach to achieve simultaneous degrader-mediated depletion of their respective protein fusions. This orthogonal system complements currently available protein degradation tags and enables investigation into the consequences resulting from rapid degradation of previously undruggable disease codependencies.

W` reconstitution rate at different intensities above critical torque: The role of muscle size and maximal strength

Leonardo Henrique Perinotto Abdalla, Ryan Michael Broxterman, Thomas Jackson Barstow, Camila Coelho Greco, Benedito Sérgio Denadai

Experimental Physiology
Jul 20, 2021
10.1113/ep089638
Journal


New Finding What is the central question of this study? Does muscle size, maximal force and exercise intensity influence the recovery time constant for the finite impulse above critical torque (τIET′)? What is the main finding and its importance? This study showed that muscle size and maximal strength have different influences on the parameters of the hyperbolic torque ‐ Tlim relationship. Greater muscle size and maximal strength, as well as exercise at an intensity of 60% MVC, prolong τIET′ during intermittent isometric exercise. Muscle perfusion and O2 delivery limitations through muscle force generation appear to play a major role in defining the hyperbolic torque ‐ Tlim relationship. Therefore, we aimed to determine the influence of muscle size and maximal strength on the recovery time constant for the finite impulse above critical torque (τIET′). Ten men participated in the study and performed intermittent isometric tests until task‐failure (Tlim) for the knee‐extensors (KE 35% and 60% MVC) and plantar flexors (PF 60% MVC). The τIET′ was determined for each of these Tlim tests using the IET"BAL model. The IETʹ (9738 ± 3080 vs 2959 ± 1289 N · m · s) and ET (84.5 ± 7.1 vs 74.3 ± 12.7 N · m) were significantly lower for PF compared to KE (P < 0.05). Exercise tolerance (Tlim) was significantly longer for PF (239 ± 81 s) than KE (150 ± 55 s) at 60% MVC, and significantly longer for KE at 35% MVC (641 ± 158 s) than 60% MVC. The τIET′ was significantly faster at 35% MVC (641± 177 s) than 60% MVC (1840 ± 354 s) for KE, both of which were significantly slower than PF 60% MVC (317 ± 102 s). This study showed that τIET′ during intermittent isometric exercise is slower with greater muscle size and maximal strength. This article is protected by copyright. ...

Low dietary fiber promotes enteric expansion of a Crohn's disease-associated pathobiont independent of obesity.

Trevor C Lau, Aline A Fiebig-Comyn, Christopher R Shaler, Joseph B McPhee, Brian K Coombes, Jonathan D Schertzer

American journal of physiology. Endocrinology and metabolism
Jul 19, 2021
10.1152/ajpendo.00134.2021
Journal


Obesity is associated with metabolic, immunological, and infectious disease comorbidities, including an increased risk of enteric infection and inflammatory bowel disease such as Crohn's disease (CD). Expansion of intestinal pathobionts such as adherent-invasive Escherichia coli (AIEC) is a common dysbiotic feature of CD, which is amplified by prior use of oral antibiotics. Although high-fat, high-sugar diets are associated with dysbiotic expansion of E. coli, it is unknown if the content of fat or another dietary component in obesogenic diets is sufficient to promote AIEC expansion. Here, we found that administration of an antibiotic combined with feeding mice an obesogenic low fiber, high sucrose, high fat diet (HFD) that is typically used in rodent obesity studies promoted AIEC intestinal expansion. Even a short-term (id est, 1-day) pulse of HFD feeding before infection was sufficient to promote AIEC expansion, indicating that the magnitude of obesity was not the main driver of AIEC expansion. Controlled diet experiments demonstrated that neither dietary fat nor sugar were the key determinants of AIEC colonization, but that lowering dietary fiber from approximately 13% to 5-6% was sufficient to promote intestinal expansion of AIEC when combined with antibiotics in mice. When combined with antibiotics, lowering fiber promoted AIEC intestinal expansion to a similar extent as widely used HFDs in mice. However, lowering dietary fiber was sufficient to promote AIEC intestinal expansion without affecting body mass. Our results show that low dietary fiber combined with oral antibiotics are environmental factors that promote expansion of Crohn's disease-associated pathobionts in the gut.

Entropic boundary conditions towards safe artificial superintelligence

Santiago Núñez-Corrales, Eric Jakobsson

Journal of Experimental & Theoretical Artificial Intelligence
Jul 19, 2021
10.1080/0952813x.2021.1952653
Journal


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Glucose-Fueled Peptide Assembly: Glucagon Delivery via Enzymatic Actuation.

Sihan Yu, Sijie Xian, Zhou Ye, Irawan Pramudya, Matthew J Webber

Journal of the American Chemical Society
Jul 19, 2021
10.1021/jacs.1c04570
Journal


Nature achieves remarkable function from the formation of transient, nonequilibrium materials realized through continuous energy input. The role of enzymes in catalyzing chemical transformations to drive such processes, often as part of stimuli-directed signaling, governs both material formation and lifetime. Inspired by the intricate nonequilibrium nanostructures of the living world, this work seeks to create transient materials in the presence of a consumable glucose stimulus under enzymatic control of glucose oxidase. Compared to traditional glucose-responsive materials, which typically engineer degradation to release insulin under high-glucose conditions, the transient nanofibrillar hydrogel materials here are stabilized in the presence of glucose but destabilized under conditions of limited glucose to release encapsulated glucagon. In the context of blood glucose control, glucagon offers a key antagonist to insulin in responding to hypoglycemia by signaling the release of glucose stored in tissues so as to restore normal blood glucose levels. Accordingly, these materials are evaluated in a prophylactic capacity in diabetic mice to release glucagon in response to a sudden drop in blood glucose brought on by an insulin overdose. Delivery of glucagon using glucose-fueled nanofibrillar hydrogels succeeds in limiting the onset and severity of hypoglycemia in mice. This general strategy points to a new paradigm in glucose-responsive materials, leveraging glucose as a stabilizing cue for responsive glucagon delivery in combating hypoglycemia. Moreover, compared to most fundamental reports achieving nonequilibrium and/or fueled classes of materials, the present work offers a rare functional example using a disease-relevant fuel to drive deployment of a therapeutic.