Value Sinks: A Process Theory of Corruption Risk during Complex Organizing.

Theories and studies of corruption typically focus on individual ethics and agency problems in organizations. In this paper, we use concepts from complexity science to propose a process theory that describes how corruption risk emerges from conditions of uncertainty that are intrinsic in social systems and social interactions. We posit that our theory is valid across multiple levels of scale in social systems. We theorize that corruption involves dynamics that emerge when agents in a system take actions that exploit disequilibrium conditions of uncertainty and ethical ambiguity. Further, systemic corruption emerges when agent interactions are amplified locally in ways that create a hidden value sink which we define as a structure that extracts, or 'drains,' resources from the system for the exclusive use of certain agents. For those participating in corruption, the presence of a value sink reduces local uncertainties about access to resources. This dynamic can attract others to join the value sink, allowing it to persist and grow as a dynamical system attractor, eventually challenging broader norms. We close by identifying four distinct types of corruption risk and suggest policy interventions to manage them. Finally, we discuss ways in which our theoretical approach could motivate future research.

A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.

Absolute pitch is disrupted by a memory illusion.

An experiment is reported, showing that short-term memory for pitch in absolute pitch (AP) possessors, while substantially more accurate than in AP nonpossessors, is also subject to illusory conjunctions of pitch and time and so can be distorted or enhanced by a single tone embedded in a sequence of six other tones. Both AP possessors and AP nonpossessors performed a short-term memory task. A test tone was presented, then a sequence of six intervening tones, and then a probe tone. The test and probe tones either were identical in pitch or differed by a semitone. The AP nonpossessors judged whether the test and probe tones were the same or different, and the AP possessors identified the test and probe tones by name. In some conditions, a tone of identical pitch to the probe tone or an octave removed from this tone was included in the intervening sequence. In both the AP possessors and AP nonpossessors, this illusion-producing tone increased judgments that the test and probe tones were identical. These results accord with a model of the system underlying short-term memory for pitch proposed earlier and show that this system is bidimensional in nature, involving both pitch height and pitch class.

Functionalized Biopolymer Particles Enhance Performance of a Tissue-Protective Peptide under Proteolytic and Thermal Stress.

Cutaneous burns are often exacerbated by poor perfusion and subsequent necrosis of the microvasculature surrounding the primary injury. Preservation of these vessels can reduce necrotic tissue expansion and increase success rates of skin graft procedures. Recent work has identified a peptide derived from erythropoietin, ARA290, with the ability to mediate tissue protection in a variety of cell types. Here we demonstrate the advantages of fusing ARA290 to an elastin-like polypeptide (ELP) to salvage microvascular endothelial cells in harsh proteolytic conditions following thermal shock. These fusion proteins were expressed recombinantly in bacterial hosts and rapidly purified by inverse transition cycling. They were shown to spontaneously aggregate into particles at subphysiological temperatures. The bifunctional submicron particles were resistant to digestion in enzymes upregulated after burn injury. Furthermore, the data strongly suggest these ARA290-functionalized particles were superior to treatment with the peptide alone in preventing microvascular cell death in these conditions. The results bring to light an efficient and cost-effective strategy for the delivery therapeutic peptides to proteolytically active wound sites.

Enzymatically triggered rupture of polymersomes.

Polymersomes are robust vesicles made from amphiphilic block co-polymers. Large populations of uniform giant polymersomes with defined, entrapped species can be made by templating of double-emulsions using microfluidics. In the present study, a series of two enzymatic reactions, one inside and the other outside of the polymersome, were designed to induce rupture of polymersomes. We measured how the kinetics of rupture were affected by altering enzyme concentration. These results suggest that protocells with entrapped enzymes can be engineered to secrete contents on cue.

Replacing antibodies: engineering new binding proteins.

Nature's reliance on proteins to carry out nearly all biological processes has led to the evolution of biomolecules that exhibit a seemingly endless range of functions. Much research has been devoted toward advancing this process in the laboratory in order to create new proteins with improved or unique capabilities. The protein-engineering field has rapidly evolved from pioneering studies in engineering protein stability and activity to an application-driven powerhouse on the forefront of emerging technologies in biomedical engineering and biotechnology. A classic protein-engineering technique in the medical field has focused on manipulating antibodies and antibody fragments for various applications. New classes of alternative scaffolds have recently challenged this paradigm, and these structures have been successfully engineered for applications including targeted cancer therapy, regulated drug delivery, in vivo imaging, and a host of others. This review aims to capture recent advances in the engineering of nonimmunoglobulin scaffolds as well as some of the applications for these molecular recognition elements in the biomedical field.

Doubling the cross-linking interface of a rationally designed beta roll peptide for calcium-dependent proteinaceous hydrogel formation.

We have rationally engineered a stimulus-responsive cross-linking domain based on a repeats-in-toxin (RTX) peptide to enable calcium-dependent formation of supramolecular hydrogel networks. The peptide isolated from the RTX domain is intrinsically disordered in the absence of calcium. In calcium rich environments, the peptide binds Ca(2+) ions and folds into a beta roll (ß-roll) secondary structure composed to two parallel ß-sheet faces. Previously, we mutated one of the faces to contain solvent exposed leucine side chains which are localized only in the calcium-bound ß-roll conformation. We demonstrated the ability of this mutant peptide to self-assemble into hydrogels in the presence of calcium with the aid of additional peptide-based cross-linking moieties. Here, we have expanded this approach by engineering both ß-roll faces to contain leucine residues, thereby doubling the cross-linking interface for each monomeric building block. These leucine rich surfaces impart a hydrophobic driving force for self-assembly. Extensive characterization was performed on this double-faced mutant to ensure the retention of calcium affinity and subsequent structural rearrangement similar to that of the wild type domain. We genetically fused an α-helical leucine zipper capable of forming tetrameric coiled-coil bundles to the peptide and the resulting chimeric protein self-assembles into a hydrogel only in calcium rich environments. Since this new mutant peptide enables cross-linking on both surfaces simultaneously, a higher oligomerization state was achieved. To further investigate the cross-linking capability, we constructed concatemers of the ß-roll with maltose binding protein (MBP), a monomeric globular protein, without the leucine zipper domains. These concatemers show a similar sol-gel transition in response to calcium. Several biophysical techniques were used to probe the structural and mechanical properties of the mutant ß-roll domain and the resulting supramolecular networks including circular dichroism, fluorescence resonance energy transfer, bis-ANS binding, and microrheology. These results demonstrate that the engineered ß-roll peptides can mediate calcium-dependent cross-linking for protein hydrogel formation without the need for any other cross-linking moieties.

Absolute pitch is associated with a large auditory digit span: a clue to its genesis.

Auditory and visual digit span tests were administered to a group of absolute pitch (AP) possessors, and a group of AP nonpossessors matched for age, and for age of onset and duration of musical training. All subjects were speakers of English. The AP possessors substantially and significantly outperformed the nonpossessors on the auditory test, while the two groups did not differ significantly on the visual test. It is conjectured that a large auditory memory span, including memory for speech sounds, facilitates the development of associations between pitches and their verbal labels early in life, so promoting the acquisition of AP.

Engineering of an environmentally responsive beta roll peptide for use as a calcium-dependent cross-linking domain for peptide hydrogel formation.

We have created a set of rationally designed peptides that form calcium-dependent hydrogels based on the beta roll peptide domain. In the absence of calcium, the beta roll domain is intrinsically disordered. Upon the addition of calcium, the peptide forms a beta helix secondary structure. We have designed two variations of our beta roll domain. First, we have mutated one face of the beta roll domain to contain leucine residues so that the calcium-dependent structural formation leads to dimerization through hydrophobic interactions. Second, an α-helical leucine zipper domain is appended to the engineered beta roll domain as an additional means of forming intermolecular cross-links. This full peptide construct forms a hydrogel only in calcium-rich environments. The resulting structural and mechanical properties of the supramolecular assemblies are compared with the wild-type domain using several biophysical techniques including circular dichroism, FRET, bis-ANS binding and microrheology. The calcium responsiveness and rheological properties of the leucine beta roll containing construct confirm the potential of this allosterically regulated scaffold to serve as a cross-linking domain for stimulus-responsive biomaterials development.

In vivo tracking of [89Zr]Zr-labeled engineered extracellular vesicles by PET reveals organ-specific biodistribution based upon the route of administration.

Extracellular vesicles (EVs) have garnered increasing interest as delivery vehicles for multiple classes of therapeutics based on their role as mediators in an important, natural intercellular communication system. We recently described a platform to allow the design, production and in vivo study of human EVs with specific properties (drug or tropism modifiers). This article seeks to compare and expand upon historical biodistribution and kinetic data by comparing systemically and compartmentally administered labeled engineered EVs using in vivo and ex vivo techniques. METHODS: EVs were surface-labeled to high radiochemical purity and specific activity with 89Zirconium deferoxamine ([89Zr]Zr-DFO) and/or cy7-scrambled antisense oligonucleotide (Cy7-ExoASOscr), or luminally loaded with GFP for in vivo tracking in rodents and non-human primates (NHPs). Positron Emission Tomography (PET) and subsequent immunohistochemistry (IHC) and autoradiography (ARG) cross-validation enabled assessment of the anatomical and cellular distribution of labeled EVs both spatially and temporally. RESULTS: Over time, systemic administration of engineered EVs distributed preferentially to the liver and spleen (Intravenous, IV), gastrointestinal tract and lymph nodes (Intraperitoneal, IP) and local/regional lymph nodes (Subcutaneous, SC). Immunostaining of dissected organs displaying PET signal revealed co-localization of an EV marker (PTGFRN) with a subset of macrophage markers (CD206, F4/80, IBA1). Compartmental dosing into NHP cerebrospinal fluid (CSF) resulted in a heterogenous distribution of labeled EVs depending upon whether the route was intrathecal (ITH), intracisterna magna (ICM) or intracerebroventricular (ICV), compared to the homogeneous distribution observed in rodents. Thus anatomically, ITH administration in NHP revealed meningeal distribution along the neuraxis to the base of the skull. In contrast ICM and ICV dosing resulted in meningeal distribution around the skull and to the cervical and thoracic spinal column. Further characterization using IHC shows uptake in a subset of meningeal macrophages. CONCLUSIONS: The present studies provide a comprehensive assessment of the fate of robustly and reproducibly labeled engineered EVs across several mammalian species. The in vivo distribution was observed to be both spatially and temporally dependent upon the route of administration providing insight into potential targeting opportunities for engineered EVs carrying a therapeutic payload.

Exosome-mediated genetic reprogramming of tumor-associated macrophages by exoASO-STAT6 leads to potent monotherapy antitumor activity.

Effectiveness of checkpoint immunotherapy in cancer can be undermined by immunosuppressive tumor-associated macrophages (TAMs) with an M2 phenotype. Reprogramming TAMs toward a proinflammatory M1 phenotype is a novel approach to induce antitumor immunity. The M2 phenotype is controlled by key transcription factors such as signal transducer and activator of transcription 6 (STAT6), which have been "undruggable" selectively in TAMs. We describe an engineered exosome therapeutic candidate delivering an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6), which selectively silences STAT6 expression in TAMs. In syngeneic models of colorectal cancer and hepatocellular carcinoma, exoASO-STAT6 monotherapy results in >90% tumor growth inhibition and 50 to 80% complete remissions. Administration of exoASO-STAT6 leads to induction of nitric oxide synthase 2 (NOS2), an M1 macrophage marker, resulting in remodeling of the tumor microenvironment and generation of a CD8 T cell-mediated adaptive immune response. Collectively, exoASO-STAT6 represents the first platform targeting transcription factors in TAMs in a highly selective manner.

Absolute pitch correlates with high performance on interval naming tasks.

Absolute pitch, the rare ability to identify or produce a musical tone without a reference tone, has been shown to be advantageous in some musical tasks; however, its relevance in musical contexts primarily involving relative pitch has been questioned. To explore this issue, 36 trained musicians-18 absolute pitch possessors and 18 non-possessors with equivalent age of onset and duration of musical training-were tested on interval naming tasks requiring only relative pitch. The intervals to be named were either ascending or descending with separation ranging from 1 to 12 semitones and equally involved all 12 pitch classes. Three different conditions were employed; these used brief sine waves, piano tones, and piano tones preceded by a V7-I chord cadence so as to establish a tonal context. The possession of absolute pitch was strongly correlated with enhanced performance on all these tests of relative pitch. Furthermore, no evidence was found that this absolute pitch avantage depended on key, interval size, or musical context.

Exosome Surface Display of IL12 Results in Tumor-Retained Pharmacology with Superior Potency and Limited Systemic Exposure Compared with Recombinant IL12.

The promise of IL12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL12, a novel, engineered exosome therapeutic that displays functional IL12 on the surface of an exosome. IL12 exosomal surface expression was achieved via fusion to the abundant exosomal surface protein PTGFRN resulting in equivalent potency in vitro to recombinant IL12 (rIL12) as demonstrated by IFNγ production. Following intratumoral injection, exoIL12 exhibited prolonged tumor retention and greater antitumor activity than rIL12. Moreover, exoIL12 was significantly more potent than rIL12 in tumor growth inhibition. In the MC38 model, complete responses were observed in 63% of mice treated with exoIL12; in contrast, rIL12 resulted in 0% complete responses at an equivalent IL12 dose. This correlated with dose-dependent increases in tumor antigen-specific CD8+ T cells. Rechallenge studies of exoIL12 complete responder mice showed no tumor regrowth, and depletion of CD8+ T cells completely abrogated antitumor activity of exoIL12. Following intratumoral administration, exoIL12 exhibited 10-fold higher intratumoral exposure than rIL12 and prolonged IFNγ production up to 48 hours. Retained local pharmacology of exoIL12 was further confirmed using subcutaneous injections in nonhuman primates. This work demonstrates that tumor-restricted pharmacology of exoIL12 results in superior in vivo efficacy and immune memory without systemic IL12 exposure and related toxicity. ExoIL12 is a novel cancer therapeutic candidate that overcomes key limitations of rIL12 and thereby creates a therapeutic window for this potent cytokine.

ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance.

Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, enhances the potency of CDN and preferentially activates antigen presenting cells in the TME. Following intratumoral injection, exoSTING was retained within the tumor, enhanced local Th1 responses and recruitment of CD8+ T cells, and generated systemic anti-tumor immunity to the tumor. ExoSTING at therapeutically active doses did not induce systemic inflammatory cytokines, resulting in an enhanced therapeutic window. ExoSTING is a novel, differentiated therapeutic candidate that leverages the natural biology of EVs to enhance the activity of CDNs.

Absolute pitch correlates with high performance on musical dictation.

Absolute pitch (AP)--the ability to name a musical note in the absence of a reference note--is a rare ability whose relevance to musical proficiency has so far been unclear. Sixty trained musicians--thirty who self-reported AP and thirty with equivalent age of onset and duration of musical training--were administered a test for AP and also a musical dictation test not requiring AP. Performance on both types of test were highly correlated (r=.81, p<.001). When subjects were divided into three groups based on their performance on the AP test, highly significant differences between the groups emerged. Those who clearly possessed AP showed remarkably high performance on the musical dictation test, the scores of those without AP varied widely, and the performance of the intermediate group of borderline AP possessors fell between that of clear AP possessors and clear nonpossessors. The findings support the hypothesis that AP is associated with proficiency in performing other musical tasks, and run counter to the claim that it confers a disadvantage in the processing of relative pitch.

A cross-sectional study of hand function in inclusion body myositis: Implications for functional rating scale.

Inclusion body myositis (IBM) is a slowly progressive and heterogeneous disorder that is a challenge for measuring clinical trial efficacy. The current methods of measuring progression of the disease utilizes the Inclusion Body Myositis Functional Rating Scale, grip strength by dynamometer, and finger flexor strength. One of the hallmarks of the disease is selective deep finger flexor weakness. To date, no adequate data has been available to determine how well the Functional Rating Scale relates to this hallmark physical exam deficit. Our study is the first to investigate the degree of correlation between items pertaining to hand function in the Functional Rating Scale with measured grip and finger flexor strength in IBM patients. We have found a lower than expected correlation with finger flexor strength and even lower with grip strength. The current Functional Rating Scale will benefit from optimization to measure clinical progression more accurately.

Absolute pitch among students in an American music conservatory: association with tone language fluency.

Absolute pitch (AP), the ability to name a musical note in the absence of a reference note, is extremely rare in the U.S. and Europe, and its genesis is unclear. The prevalence of AP was examined among students in an American music conservatory as a function of age of onset of musical training, ethnicity, and fluency in speaking a tone language. Taking those of East Asian ethnicity, the performance level on a test of AP was significantly higher among those who spoke a tone language very fluently compared with those who spoke a tone language fairly fluently and also compared with those who were not fluent in speaking a tone language. The performance level of this last group did not differ significantly from that of Caucasian students who spoke only nontone language. Early onset of musical training was associated with enhanced performance, but this did not interact with the effect of language. Further analyses showed that the results could not be explained by country of early music education. The findings support the hypothesis that the acquisition of AP by tone language speakers involves the same process as occurs in the acquisition of a second tone language.

Restoring function and aesthetics in a patient previously treated for amelogenesis imperfecta.

A 26-year-old male patient presented with generalised gingival recession related to the margins of crowns fitted between the ages of 12 and 15 years. The patient, previously treated for Amelogenesis Imperfecta, suffered a mandibular fracture at the age of 22 years. He had an anterior open bite and in the retruded contact position the 28 and 38 were the only teeth in contact. This case demonstrates the management of compromised fixed prosthodontic care following further growth and trauma. On completion of treatment a good functional and aesthetic result was achieved.

The butterfly effect of the "butterfly effect".

The "Butterfly Effect" metaphor states with variance that the flap of a butterfly's wings in Brazil can cause a tornado in Texas. This metaphor has become part of the common vernacular of Western culture. In this paper I discuss the origins of the metaphor, examine its current usage within popular culture, and present an argument as to why it is popular. I propose that the metaphor is a type of semantic attractor, a narrative device with invariant meaning but audience-specific contextualization. Finally I address whether the Butterfly Effect metaphor is a good example of itself.

Pitch circularity from tones comprising full harmonic series.

This paper describes an algorithm for producing pitch circularity using tones that each comprise a full harmonic series, and reports an experiment that demonstrates such circularity. Banks of 12 tones (i.e., scales) were created, with F0 varying in semitone steps. For each scale, as F0 descended, the amplitudes of the odd-numbered harmonics were reduced relative to the even-numbered ones by 3.5 dB for each semitone step. In consequence, the tone with the lowest F0 was heard as though displaced up an octave. In an experiment employing two such scales, all possible ordered tone pairs from each scale were presented, making 132 ordered tone pairs for each scale. Sixteen subjects judged for each tone pair whether the second tone was higher or lower than the first. The data derived from these pairwise comparisons were subjected to Kruskal's nonmetric multidimensional scaling, and excellent circularities were obtained. Individual differences in the subjects' judgments were also explored. The findings support the argument that musical pitch should be characterized as varying along two dimensions: the monotonic dimension of pitch height and the circular dimension of pitch class.