Soft Spots Research Articles

Predicting plasticity with soft vibrational modes: from dislocations to glasses.

We show that quasilocalized low-frequency modes in the vibrational spectrum can be used to construct soft spots, or regions vulnerable to rearrangement, which serve as a universal tool for the identification of flow defects in solids. We show that soft spots not only encode spatial information, via their location, but also directional information, via directors for particles within each soft spot. Single crystals with isolated dislocations exhibit low-frequency phonon modes that localize at the core, and their polarization pattern predicts the motion of atoms during elementary dislocation glide in two and three dimensions in exquisite detail. Even in polycrystals and disordered solids, we find that the directors associated with particles in soft spots are highly correlated with the direction of particle displacements in rearrangements.

Use of Wicking Fabric to Help Prevent Frost Boils in Alaskan Pavements

AbstractBeaver Slide is on the Dalton Highway near 177.8 km (110.5 mi), and it is downhill when heading north. The road gradient is approximately 11% and the road prism is on a side hill. Each year, there are soft spots that usually appear in late April and remain all summer, which are also called “frost boils” by engineers at the Alaska Department of Transportation and Public Facilities (AKDOT&PF). The frost boils have resulted in extremely unsafe driving conditions and frequent accidents. Past repair efforts indicate conventional road construction methods do not work. A new type of geosynthetic wicking fabric has been recently developed that has a high specific surface area (consequently high wettability and high capillary action) and high directional permittivity. Preliminary laboratory tests indicate it has great promise as a cost-effective means to solve the frost heave-related problems on northern road systems. This study verifies the effectiveness of the wicking fabric to mitigate frost boils in Al...

Podosomes of dendritic cells facilitate antigen sampling

Dendritic cells sample the environment for antigens and play an important role in establishing the link between innate and acquired immunity. Dendritic cells contain mechanosensitive adhesive structures called podosomes that consist of an actin-rich core surrounded by integrins, adaptor proteins and actin network filaments. They facilitate cell migration via localized degradation of extracellular matrix. Here, we show that podosomes of human dendritic cells locate to spots of low physical resistance in the substrate (soft spots) where they can evolve into protrusive structures. Pathogen recognition receptors locate to these protrusive structures where they can trigger localized antigen uptake, processing and presentation to activate T-cells. Our data demonstrate a novel role in antigen sampling for the podosomes of dendritic cells.

Policy advocacy experiences of Saskatchewan nonprofit organizations: Caught between rocks and hard places with multiple constituents?

In Canada, nonprofit, social service, community‐based organizations (CBOs) play an important role in advocating for social policies intended to positively influence people's lives. This article explores the challenges and opportunities that exist within the dynamic relations among social service CBOs, the marginalized communities they serve, and governments, as these CBOs attempt to influence social policy development. Qualitative data were collected from CBOs from 18 communities throughout the province of Saskatchewan and these data show how CBOs find themselves having to juggle and negotiate with multiple constituents and their myriad perspectives, often resulting in feelings of being caught between rocks and hard places. Nonetheless, analysis of the data also indicates these CBOs manoeuvre themselves around these precarious circumstances to find soft spots for progressive change. In my conclusion, I focus on the multiple constituent perspectives with which CBOs must contend, the potential salience of constituents in advocacy theory, the possible role of geographic and spatial variables in advocacy theory, iterative decision‐making loops that may better characterize advocacy than decisions made in serial fashion, and finally, advocacy chill and advocacy warmth.

Metabolite identification of crude extract from Ganoderma lucidum in rats using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry

The metabolism of traditional Chinese medicine is very complicated and has been a great challenge. In the present paper, a new strategy was established to study the metabolism of crude extract from Ganoderma lucidum using the highly separative and sensitive ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. Based on the investigation of the metabolism of five representative single compounds (ganoderic acid), a total of 90 metabolites were identified from the bile sample after oral administration of the crude extract. Among them, 21 compounds were identified by comparison with the reference standards, the other unknown metabolites were tentatively characterized by interpretation of the high resolution low collision energy and high collision energy mass spectra using the fragmentation rules. The metabolic characteristics and "soft spots" of the ganoderic acids were revealed. After being absorbed, the ganoderic acids from the extract could undergo extensive phases I and II metabolism in rat before excreted into the bile. The main ganoderic acids could transform from one to another through reduction, oxidation, deacetylation and desaturation reactions. Other metabolic transformation included hydroxylation, sulfation and glucuronidation. The total tendency was that the low polar ganoderic acids were transformed into the high polar metabolites to eliminate from the organism. The metabolic "soft spots" of the ganoderic acids were 3,7,15,23-carbonyl groups (or hydroxyl groups), angular methyl groups, 20(22)-double bond, 12-acetoxyl group and 26-carboxylic acid moiety. These results are considered to be important for the further investigation of G. lucidum.

First Report of Penicillium expansum Causing Postharvest Blue Mold of Fresh Date Palm Fruit (Phoenix dactylifera) in Spain.

A survey of postharvest losses of commercially handled and cold-stored fruit of fresh date palm (Phoenix dactylifera L.), cvs. Medjool and Hayani, was conducted in the 2009 and 2010 seasons in the grove of Elx (Alacant Province, Southeast Spain). Disease symptoms consisting of circular, light brown, soft spots located in any part of the fruit skin were observed in 2 to 5% of the fruit. At room temperature, the lesions expanded rapidly and blue mold symptoms were apparent. The potential causal agent (isolate IVIA NiAA-2) was transferred to PDA and incubated at 25°C. The identification was performed at the Spanish Type Culture Collection (CECT, University of Valencia, Spain) based on colony morphology of the isolate grown on Czapeck yeast extract agar (CYA) and malt extract agar (MEA) at 26°C. Colonies were circular (average diameter of 40 mm at 7 days), radially sulcate, with dense velvety white mycelium, and very abundant, bluish green conidia. The underside of the plates showed light brown and pale green colonies on CYA and MEA, respectively. On CYA, but not on MEA, a light yellow exudate was produced and a brownish pigment diffused into the medium. At 5 and 37°C on CYA, white microcolonies and no colonies were observed, respectively. Conidia were ellipsoidal to subglobose, smooth and thin walled, measuring 3.0 to 3.5 × 2.5 to 3.0 μm (n = 50) (4). Based on these morphological characteristics, the isolate IVIA NiAA-2 was tentatively identified as Penicillium expansum L. To confirm the identity, we amplified and sequenced the rDNA internal transcribed spacer (ITS) region with primers ITS1 and ITS4 (GenBank Accession No. KC169942). A BLAST search showed 99% identity and 100% query coverage with P. expansum strain NRRL 6069 (DQ339562) (2). Selected healthy dates cv. Medjool were surface disinfected by dipping in 0.5% sodium hypochlorite for 2 min followed by thorough rinsing in deionized water. Pathogenicity was tested by pipetting 20 μl of a spore suspension (1 × 106 spores per ml), prepared from 7-day PDA cultures, onto fresh skin wounds, which were made on disinfected fruit using a sterile, stainless steel rod with a probe tip 1 mm in width × 2 mm in length (one wound on each of nine dates, incubated in one humid chamber). Disinfected, wounded, and non-inoculated dates were used as controls. The procedure was repeated three times. Disease symptoms were observed on all inoculated fruit (average lesion size of 6, 15, and 22 mm after 4, 7, and 10 days of incubation at 20°C, respectively) and P. expansum was consistently reisolated, thereby fulfilling Koch's postulates. No decay was observed on any of the non-inoculated fruit. Unidentified species of Penicillium have been reported to cause date palm fruit rot (1,3). To our knowledge, this is the first report of P. expansum causing postharvest decay of date palm fruit in Spain.

Metabolism‐Directed Structure Optimization of Benzimidazole‐Based F. Tularensis Enoyl‐Reductase (FabI) Inhibitors

FabI is an attractive antibiotic target against F. Tularensis, a Category A biowarfare agent of high risk to public health. Our previous study identified a novel class of benzimidazole analogs possessing excellent FabI inhibitory activity but unknown metabolic stability. The objective of this study was to characterize structure‐metabolism relationships (SMR) for this series to guide chemical modification. To this end, hepatic microsomal stability and bioactivity data were obtained for 22 lead compounds. Methyl, methoxy, or methylenedioxy substitution at the core structure was found unfavorable to the metabolic stability. Metabolite identification studies on 4 model compounds revealed hydroxylation of the benzimidazole ring as the major metabolic route. Introduction of methyl groups on this moiety provided additional metabolic soft spots. Cyclic modification strategy was then proposed, and 9 cyclopentane and oxacyclopentane derivatives were newly synthesized, which showed 4–13‐fold increases in t1/2 without impaired bioactivity. Subsequently, quantitative SMR models were successfully constructed using genetic algorithm variable selection, multi‐linear regression and artificial neural network techniques. Collectively, SMR for the FabI inhibitors were systematically analyzed, and the results should help product optimization for optimal pharmacokinetic properties.

The impact of surgical complexities

This issue is a humdinger, by far the best our 1-year-old journal has produced. There are sparkling gems and intense controversies. The article on the perceptions of the impact of fellowship training on residency education at the University of Toronto is fascinating. Like any good research it raises more questions than it answers. Dr. Ethan Grober and colleagues report that many residents believe there are too many fellows. The implication is that their surgical experience has been diluted. The increase in urologists doing postresidency training has been dramatic. The most important driver of this trend is that acquiring expertise in urology has become more challenging. Routine bread-and-butter procedures like TURP and open ureterolithotomy, which could be learned relatively quickly and performed successfully by most practitioners (thus the mantra see one, do one, teach one), have been replaced by more technically challenging procedures. The success and morbidity of these procedures are a function of clinical volume and experience. The shift to minimal access surgery has augmented this dramatically. The number of these complex procedures that a resident performs in his training may not be sufficient to confer expertise. Thus it is natural that residents completing their training seek to polish their skills. Fellowships offer an opportunity to work with colleagues who have different perspectives and approaches, to focus on a particular area of interest, to acquire research skills in preparation for an academic career and to see the world. Fellows can augment a resident's experience, but the downside is that they enter a surgical arena where residents are hungering for cases. This has the potential to create conflict. For example, Dr. Grober and colleagues suggest that residents must continue to take an “active role in complex cases.” Does this mean that a resident is entitled to elbow a fellow aside during a postchemo retroperitoneal lymph node dissection, a laparoscopic redo pyeloplasty or other procedures that a general urologist likely would not perform, in the interests of resident training? There is a widening consensus by health policy makers that complex procedures should be performed by practitioners with a large volume of those cases, reflecting the volume–quality outcome relationship. In England this has become formalized. Hospitals that perform fewer than 50 major pelvic surgeries per year lose the funding for those procedures. Recognizing this trend, many residents in British training programs are trained from the start to be nonsurgical urologists. We have not gone that route in Canada, thankfully. But we must grapple with the realities of increasing surgical complexity and what this means for surgical training. Fellowship training is likely to increase, and the impact on residency training must be managed carefully and thoughtfully. The Point / Counterpoint debate on the use of androgen replacement therapy for “andropause” is exactly the kind of writing that we hoped for in this section. It is a must-read. Both sides of the debate are informed and deeply considered. Dr. Morales presents a compelling and authoritative case for TRT; Dr. Casey, with characteristic wit, probes the soft spots in his arguments. It is the “weird” cases in medicine that often provide clues to disease biology. The 3 cases of penile cancer in neonatally circumcised men are interesting. All 3 men had a history of HPV infection. Perhaps, analogous to HIV, circumcision provides protection against penile cancer by reducing the likelihood or severity of HPV infection in men. This is a research question which has been largely neglected.

Calorimetric glass transition explained by hierarchical dynamic facilitation

The glass transition refers to the nonequilibrium process by which an equilibrium liquid is transformed to a nonequilibrium disordered solid, or vice versa. Associated response functions, such as heat capacities, are markedly different on cooling than on heating, and the response to melting a glass depends markedly on the cooling protocol by which the glass was formed. This paper shows how this irreversible behavior can be interpreted quantitatively in terms of an East-model picture of localized excitations (or soft spots) in which molecules can move with a specific direction, and from which excitations with the same directionality of motion can appear or disappear in adjacent regions. As a result of these facilitated dynamics, excitations become correlated in a hierarchical fashion. These correlations are manifested in the dynamic heterogeneity of the supercooled liquid phase. Although equilibrium thermodynamics is virtually featureless, a nonequilibrium glass phase emerges when the model is driven out of equilibrium with a finite cooling rate. The correlation length of this emergent phase is large and increases with decreasing cooling rate. A spatially and temporally resolved fictive temperature encodes memory of its preparation. Parameters characterizing the model can be determined from reversible transport data, and with these parameters, predictions of the model agree well with irreversible differential scanning calorimetry.

Buckling pathways in spherical shells with soft spots

Thin elastic spherical shells are known to exhibit a buckling instability at a finite external pressure. We study how this buckling is influenced by a weak region in an otherwise uniform shell, focusing on the case of a single small circular soft spot that is thinner than the rest of the shell. Using numerical simulations and theoretical arguments, we show that the soft region fundamentally alters the buckling behavior of the shell. The soft spot influences both the pressure at which the shell buckles, and the postbuckling shape of the shell. Depending on the properties of the soft spot, we find either a single buckling transition or two separate transitions as the external pressure is increased. We analyze the dependence of these buckling transitions on the size and thickness of the soft region. Besides contributing to our fundamental understanding of buckling transitions in inhomogeneous shells, our results can be applied to designing capsules with tunable shapes.

Low-energy non-linear excitations in sphere packings

We study theoretically and numerically how hard frictionless particles in random packings can rearrange. We demonstrate the existence of two distinct unstable non-linear modes of rearrangement, both associated with the opening and the closing of contacts. The first mode, whose density is characterized by some exponent θ′, corresponds to motions of particles extending throughout the entire system. The second mode, whose density is characterized by an exponent θ ≠ θ′, corresponds to the local buckling of a few particles. Extended modes are shown to yield at a much higher rate than local modes when a stress is applied. We show that the distribution of contact forces follows P(f) ∼ fmin(θ′,θ), and that imposing the restriction that the packing cannot be densified further leads to the bounds and , where γ characterizes the singularity of the pair distribution function g(r) at contact. These results extend the theoretical analysis of [Wyart, Phys. Rev. Lett., 2012, 109, 125502] where the existence of local modes was not considered. We perform numerics that support that these bounds are saturated with γ ≈ 0.38, θ ≈ 0.17 and θ′ ≈ 0.44. We measure systematically the stability of all such modes in packings, and confirm their marginal stability. The principle of marginal stability thus allows us to make clearcut predictions on the ensemble of configurations visited in these out-of-equilibrium systems, and on the contact forces and pair distribution functions. It also reveals the excitations that need to be included in a description of plasticity or flow near jamming, and suggests a new path to study two-level systems and soft spots in simple amorphous solids of repulsive particles.

Metabolism-guided drug design

Preclinical drug metabolism studies play a key role in the lead identification and optimization process in drug discovery. Characterization of the metabolic pathways of new chemical entities is an integral part of drug discovery not only in optimizing clearance properties but also in eliminating potential safety concerns associated with the formation of protein and/or DNA-reactive metabolites. Metabolism studies in early discovery have been used to identify metabolic soft spots leading to high metabolic instability, and also in the characterization of active metabolites. Availability of such information has aided in the rational design of compounds with increased resistance to metabolism and overall improvements in oral pharmacokinetics and dose size. Mechanistic drug metabolism studies have proven particularly invaluable in mitigating reactive metabolite risks, which can lead to mutagenicity, time-dependent inactivation of cytochrome P450 enzymes and/or idiosyncratic adverse drug reactions. Characterization of stable conjugates derived from bioactivation of small molecule drug candidates provides indirect information on the structure of the reactive metabolite species, thereby providing insight into the bioactivation mechanism and hence a rationale on which to base subsequent chemical intervention strategies. This review will showcase case studies of metabolism-guided drug design using literature and in-house examples.

Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor.

The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilino-aminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs.

Identification of Metabolites of Ganoderic Acid D by Ultra-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

Ganoderic acid D (GD) is the major active triterpenoid in Ganoderma lucidum, a medicinal fungus used daily. However, the metabolic fate of GD remains unknown. To know whether GD is extensively metabolized, we first investigated the metabolism of GD in vitro and in vivo. The metabolic profiles of the bile samples obtained from rats in vivo were almost the same as those obtained in vitro. Using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry, a total of 25 metabolites were identified from the bile sample. Few metabolites were found in the urine samples. These results indicated that biliary rather than renal clearance was the major route of excretion. The major metabolites were identified by comparison with the standard reference compounds. Metabolites at low concentrations were identified by interpreting the mass spectra. Both phase I and phase II metabolites were observed. The metabolic transformation included reduction, monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of GD were the 3-carbonyl group, angular methyl groups, the 7-hydroxy group, and the 26-carboxylic acid moiety. Overall, this study gives us an insight into the metabolism of GD, an active oxygenated tetracyclic triterpenoid.

Electrochemistry as an adjunct to mass spectrometry in drug development

Oxidation plays a number of critical roles in biology and drug metabolism. In addition to being the major process for generating energy in a living cell, it also is the major mechanism by which drugs are metabolized. Oxidation is a contributor to drug bioactivation and idiosyncratic toxicity, and is also involved in drug stability and degradation. Electrochemistry (EC) when used with HPLC has long been recognized as a sensitive and selective detection technique. Indeed more than 90% of pharmaceuticals in the market place are easily oxidized and can be detected using this technique. However, the inherent electrochemical nature of many drugs goes beyond simple analysis. This commonality of oxidation makes EC particularly well suited to studying the oxidative processes in pharmaceuticals – both in the formulation and by the organism. Presented here are techniques that combine EC and MS in a number of formats that can be used: a) to enhance ionization thereby extending the range of compounds measured by LC-MS; b) for the micro-synthesis and identification of drug metabolites; c) for the detection of reactive intermediates and their conjugates; d) identification of potentially problematic molecular “soft spots”; and e) to rapidly study drug stability and predict which antioxidant(s) should be included in formulations.

A Semi-Automated Method For The Integrated Evaluation of Half-Life And Metabolic Soft Spots of Discovery Compounds

An integrated method that provides rates of both parent disappearance and metabolite formation was developed. Buspirone, mirtazapine and verapamil were used as model compounds in developing the method. Incubations were carried out on a robotic platform. Qualitative analysis of metabolites in 30 µM samples was conducted by data-dependent HPLC-MS/MS on a high-resolution instrument. Quantitative analysis of the parent compound and metabolites in 0.5 µM samples was conducted by full-scan MS(2) with product ion extraction using an ion trap mass spectrometer. Data generated for the compounds included half-life and intrinsic clearance of the parent molecule, characterization of metabolites and relative rates of metabolite formation. A correction factor was used to convert MS responses of metabolites in 0.5 µM samples to UV areas in order to compare relative metabolite concentrations. The approach allows for the investigation of a set of six compounds simultaneously, with a turnaround time of 1 week or less.

Design and synthesis of 4-O-methylhonokiol analogs as inhibitors of cyclooxygenase-2 (COX-2) and PGF1 production

A series of novel 4-O-methylhonokiol analogs were synthesized in light of revealing structure–activity relationship for inhibitory effect of COX-2 enzyme. The key strategy of the molecular design was oriented towards modification of the potential metabolic soft spots (e.g., phenol and olefin) or by altering the polar surface area via incorporating heterocycles such as isoxazole and triazole. Most of all exhibited the inhibitory effects on COX-2 and PGF1 production but not macrophage NO production. Especially, aryl carbamates 10 and 11 exhibited more potent inhibitory activity against COX-2 and PGF1 production.

Vibrational Modes Identify Soft Spots in a Sheared Disordered Packing

We analyze low-frequency vibrational modes in a two-dimensional, zero-temperature, quasistatically sheared model glass to identify a population of structural "soft spots" where particle rearrangements are initiated. The population of spots evolves slowly compared to the interval between particle rearrangements, and the soft spots are structurally different from the rest of the system. Our results suggest that disordered solids flow via localized rearrangements that tend to occur at soft spots, which are analogous to dislocations in crystalline solids.

Field- and current-induced domain-wall motion in permalloy nanowires with magnetic soft spots

We study field- and current-induced domain-wall motion in permalloy nanowires containing a square-shaped magnetically softened region. Implantation of chromium ions is used to induce pinning sites via a local reduction in the saturation magnetization. Micromagnetic simulations, magnetic transmission soft x-ray microscopy, and electrical measurements are employed to characterize the pinning potential which significantly differs for transverse and vortex walls. Reliable domain-wall depinning from a so-called magnetic soft spot by single current pulses is observed. This demonstrates the suitability of these pinning sites for applications.

Bioactivation of Drugs: Risk and Drug Design

Bioactivation through drug metabolism is frequently suspected as an initiating event in many drug toxicities. The CYP450 and peroxidase enzyme systems are generally considered the most important groups of enzymes involved in bioactivation, producing either electrophilic or radical metabolites. Drug design efforts routinely consider these factors, and a number of structural alerts for bioactivation have been identified. Among the most frequently encountered structural alerts are aromatic systems with electron-donating substituents and some five-membered heterocycles. Metabolism of these groups can lead to chemically reactive electrophiles. Strategies that have been used to minimize the associated risk involve replacing the structural-alert moiety, blocking or making metabolism less favorable, and incorporating metabolic soft spots to facilitate metabolism away from the structural-alert substituent. The metabolism of drugs to radicals usually leads to cellular oxidative stress. The formation of radical metabolites can be minimized through the use of similar approaches but remains an area less frequently considered in drug design.