Knowing How: A Computational Approach

With advances in Artificial Intelligences being achieved through the use of Artificial Neural Networks, we are now at the point where computers are able to do tasks that were previously only able to be accomplished by humans. These advancements must cause us to reconsider our previous understanding of how people come to know how to do a particular task. In order to unpack this question, I will first look to an account of knowing how presented by Jason Stanley in his book Know How. I will then look towards criticisms of this view before using evidence presented by the existence of Artificial Neural Networks to present a new view that addresses the problems present in Stanley’s work. Finally, I will argue that knowing how to do something is a matter of heuristics, or knowing certain shortcuts which approximate a solution to the task one is trying to accomplish

Structures of Two Melanoma-Associated Antigens Suggest Allosteric Regulation of Effector Binding

The MAGE (melanoma associated antigen) protein family are tumour-associated proteins normally present only in reproductive tissues such as germ cells of the testis. The human genome encodes over 60 MAGE genes of which one class (containing MAGE-A3 and MAGE-A4) are exclusively expressed in tumours, making them an attractive target for the development of targeted and immunotherapeutic cancer treatments. Some MAGE proteins are thought to play an active role in driving cancer, modulating the activity of E3 ubiquitin ligases on targets related to apoptosis. Here we determined the crystal structures of MAGE- A3 and MAGE-A4. Both proteins crystallized with a terminal peptide bound in a deep cleft between two tandem-arranged winged helix domains. MAGE-A3 (but not MAGE-A4), is pre- dominantly dimeric in solution. Comparison of MAGE-A3 and MAGE-A3 with a structure of an effector-bound MAGE-G1 suggests that a major conformational rearrangement is required for binding, and that this conformational plasticity may be targeted by allosteric binders

The SARS-CoV-2 Programmed −1 Ribosomal Frameshifting Element Crystal Structure Solved to 2.09 Å Using Chaperone-Assisted RNA Crystallography

The programmed −1 ribosomal frameshifting element (PFSE) of SARS-CoV-2 is a well conserved structured RNA found in all coronaviruses’ genomes. By adopting a pseudoknot structure in the presence of the ribosome, the PFSE promotes a ribosomal frameshifting event near the stop codon of the first open reading frame Orf1a during translation of the polyprotein pp1a. Frameshifting results in continuation of pp1a via a new open reading frame, Orf1b, that produces the longer pp1ab polyprotein. Polyproteins pp1a and pp1ab produce nonstructural proteins NSPs 1–10 and NSPs 1–16, respectively, which contribute vital functions during the viral life cycle and must be present in the proper stoichiometry. Both drugs and sequence alterations that affect the stability of the −1 programmed ribosomal frameshifting element disrupt the stoichiometry of the NSPs produced, which compromise viral replication. For this reason, the −1 programmed frameshifting element is considered a promising drug target. Using chaperone assisted RNA crystallography, we successfully crystallized and solved the three-dimensional structure of the PFSE. We observe a three-stem H-type pseudoknot structure with the three stems stacked in a vertical orientation stabilized by two triple base pairs at the stem 1/stem 2 and stem 1/stem 3 junctions. This structure provides a new conformation of PFSE distinct from the bent conformations inferred from midresolution cryo-EM models and provides a high-resolution framework for mechanistic investigations and structure-based drug design

A pilot study on the nanoscale properties of bone tissue near lacunae in fracturing women

The goal of this study is to investigate the causes of osteoporosis-related skeletal fragility in postmenopausal women. We hypothesize that bone fragility in these individuals is largely due to mineral, and/or intrinsic material properties in the osteocyte lacunar/peri-lacunar regions of bone tissue. Innovative measurements with nanoscale resolution, including scanning electron microscope (SEM), an atomic force microscope that is integrated with infrared spectroscopy (AFM-IR), and nanoindentation, were used to characterize osteocyte lacunar and peri-lacunar properties in bone biopsies from fracturing (Cases) and matched (Age, BMD), non-fracturing (Controls) postmenopausal healthy women. In the peri-lacunar space, the nanoindentation results show that the modulus and hardness of the Controls are lower than the Cases. The AFM-IR results conclusively show that the mineral matrix, maturity (peak) (except in outer/far regions in Controls) were greater in Controls than in Cases. Furthermore, these results indicate that while mineral-to-matrix area ratio tend to be greater, the mineral maturity and crystallinity peak ratio “near” lacunae is greater than at regions “far” or more distance from lacunae in the Controls only. Due to the heterogeneity of bone structure, additional measurements are needed to provide more convincing evidence of altered lacunar characteristics and changes in the peri-lacunar bone as mechanisms related to postmenopausal women and fragility. Such findings would motivate new osteocyte-targeted treatments to reduce fragility fracture risks in these groups

Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents

‘Super disabilities’ vs ‘Disabilities’?:Theorizing the role of ableism in (mis)representational mythology of disability in the marketplace

People with disabilities (PWD) constitute one of the largest minority groups with one in five people worldwide having a disability. While recognition and inclusion of this group in the marketplace has seen improvement, the effects of (mis)representation of PWD in shaping the discourse on fostering marketplace inclusion of socially marginalized consumers remain little understood. Although effects of misrepresentation (e.g., idealized, exoticized or selective representation) on inclusion/exclusion perceptions and cognitions has received attention in the context of ethnic/racial groups, the world of disability has been largely neglected. By extending the theory of ableism into the context of PWD representation and applying it to the analysis of the We’re the Superhumans advertisement developed for the Rio 2016 Paralympic Games, this paper examines the relationship between the (mis)representation and the inclusion/exclusion discourse. By uncovering that PWD misrepresentations can partially mask and/or redress the root causes of exclusion experienced by PWD in their lived realities, it contributes to the research agenda on the transformative role of consumption cultures perpetuating harmful, exclusionary social perceptions of marginalized groups versus contributing to advancement of their inclusion

Phenol-Explorer 2.0: a major update of the Phenol-Explorer database integrating data on polyphenol metabolism and pharmacokinetics in humans and experimental animals

Phenol-Explorer, launched in 2009, is the only comprehensive web-based database on the content in foods of polyphenols, a major class of food bioactives that receive considerable attention due to their role in the prevention of diseases. Polyphenols are rarely absorbed and excreted in their ingested forms, but extensively metabolized in the body, and until now, no database has allowed the recall of identities and concentrations of polyphenol metabolites in biofluids after the consumption of polyphenol-rich sources. Knowledge of these metabolites is essential in the planning of experiments whose aim is to elucidate the effects of polyphenols on health. Release 2.0 is the first major update of the database, allowing the rapid retrieval of data on the biotransformations and pharmacokinetics of dietary polyphenols. Data on 375 polyphenol metabolites identified in urine and plasma were collected from 236 peer-reviewed publications on polyphenol metabolism in humans and experimental animals and added to the database by means of an extended relational design. Pharmacokinetic parameters have been collected and can be retrieved in both tabular and graphical form. The web interface has been enhanced and now allows the filtering of information according to various criteria. Phenol-Explorer 2.0, which will be periodically updated, should prove to be an even more useful and capable resource for polyphenol scientists because bioactivities and health effects of polyphenols are dependent on the nature and concentrations of metabolites reaching the target tissues. The Phenol-Explorer database is publicly available and can be found online at http://www.phenol-explorer.eu. Database URL: http://www.phenol-explorer.eu

Estrogen receptor beta selectively restricts proliferation and favors surveillance in mammary epithelial cells

Estrogen (17β-estradiol) has paradoxical effects in both promoting and preventing breast cancer as estrogen activates proliferation, but also promotes p53-mediated surveillance pathways. Estrogen mediates its effects in target tissues through the activation of estrogen receptor subtypes: ERα and ERβ. To examine the capability of these receptors in mediating surveillance as opposed to proliferation, selective estrogen receptor agonists were compared with 17β-estradiol for induction of proliferation and radiation induced apoptosis in vivo. Transcriptional regulation of estrogen-responsive genes was also compared in mouse mammary epithelium in vivo and in the human mammary MCF7 cell line transduced with a repressible ERβ. Selective activation of ERβ with the agonist diarylpropionitrile (DPN) in vivo enhances p53-mediated apoptosis in the mouse mammary epithelium without stimulating proliferation. In addition, radiation-induced apoptosis is significantly reduced in mice lacking ERβ (βERKO). As expected, 17β-estradiol or selective activation of ERα with pyrazole triol (PPT) induced the expression of estrogen-response genes including progesterone receptor, amphiregulin and trefoil factor 1. DPN and ERβ failed to induce the expression of these genes. Interestingly, the ERβ agonist DPN selectively induced the expression of genes that repress proliferation including TGFβ2 while inhibiting proliferative canonical wnt signaling via beta-catenin by inducing WNT5a and AXIN2. DPN was also more potent in stimulating the expression of EGR1, a modulator of p53 activity. These results suggest that ERα and ERβ have distinct roles in gene regulation. In addition, the ability of DPN and ERβ to potentiate surveillance pathways while limiting proliferation suggests that ERβ agonists may have therapeutic and chemopreventive value in breast cancer