What are the temporal and physical characteristics of locally applied vibration that modulate balance in older adults? - A systematic review of the literature.

BACKGROUND: Compromised balance is known to contribute to falls, which are associated with increased morbidity and mortality for older adults. Evidence suggests that the application of local vibration to the lower limbs of older adults has the potential to modulate balance. RESEARCH QUESTION: To identify the temporal and mechanical parameters of vibration applied locally to the lower limbs of older adults that modulate measures of balance, and to define the short- and long-term effects of vibration on balance in this population. METHODS: The PRISMA 2020 guidelines were used to conduct a systematic search including the PUBMED, EMBASE, and Scopus databases to identify peer-reviewed literature where vibration was applied to the lower limbs of older adults to modulate balance. Data was extracted using a study-specific data extraction form and risk of bias assessed. Where possible, effect sizes were calculated. RESULTS: Of 7777 records screened, ten randomised controlled trials and 43 prospective laboratory-based studies met the inclusion criteria. Vibration frequencies ranged from 1 to 272 Hz, most studies (n=41) used ≤100 Hz. Amplitude ranged from 0.2 to 3.0 mm, most studies (n=28) used ≤1 mm. Effects of short-term vibration (applied for seconds to hours) were measured during and/or immediately after application. Short-term suprathreshold perceived muscle/tendon vibration had a 'large' destabilising effect size on balance in healthy older adults, but little or no effect on older fallers. Short-term subthreshold vibration to the soles of the feet had a 'small' stabilising effect size. Suprathreshold muscle, tendon or sole vibration applied for 10-30 min over days to weeks improved balance measures, but most (8 of 10) had increased risk of bias. SIGNIFICANCE: The heterogeneity of methodology, populations, and vibration and balance parameters precluded conclusions about the relative effects of lower limb vibration in older adults. However, these results suggest that the application of local vibration to the lower limbs of older adults can modulate balance in the short- and long-term.

Cell constriction requires processive septal peptidoglycan synthase movement independent of FtsZ treadmilling in Staphylococcus aureus.

Bacterial cell division requires recruitment of peptidoglycan (PG) synthases to the division site by the tubulin homologue, FtsZ. Septal PG synthases promote septum growth. FtsZ treadmilling is proposed to drive the processive movement of septal PG synthases and septal constriction in some bacteria; however, the precise mechanisms spatio-temporally regulating PG synthase movement and activity and FtsZ treadmilling are poorly understood. Here using single-molecule imaging of division proteins in the Gram-positive pathogen Staphylococcus aureus, we showed that the septal PG synthase complex FtsW/PBP1 and its putative activator protein, DivIB, move with similar velocity around the division site. Impairing FtsZ treadmilling did not affect FtsW or DivIB velocities or septum constriction rates. Contrarily, PG synthesis inhibition decelerated or stopped directional movement of FtsW and DivIB, and septum constriction. Our findings suggest that a single population of processively moving FtsW/PBP1 associated with DivIB drives cell constriction independently of FtsZ treadmilling in S. aureus.

Avian architects: Technology, domestication, and animal minds in urban America.

In the mid-nineteenth century, the house sparrow (Passer domesticus) was introduced to the United States, quickly spreading across the country. For a brief period in the late nineteenth and early twentieth centuries, the observation of sparrow behavior was something of an urban pastime. Traits such as intelligence, reason, persistence, and craftsmanship were conferred onto sparrows by American urbanites. This paper argues that sparrow intelligence was often conflated with domestication: the ability of the birds to adapt to living alongside humans. Praise for the ingenuity of sparrows generally revolved around their nest building, particularly when such structures overcame the challenges posed by urban infrastructure and technology. Sparrows were far less praiseworthy when they caused electricity outages or contaminated water supplies. The sparrow in the United States demonstrates how the relationship between these anecdotes and their implications for animal minds was mediated by the technology and infrastructure of cities. Admirers of sparrows were not measuring the birds' mental capacity, but rather their ability to adapt to human habitations. Sparrows were only granted intelligence once they had demonstrated their ability to become domesticated.

Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy.

ABSTRACT: Patients with multiple myeloma (MM) treated with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells usually relapse with BCMA+ disease, indicative of CAR T-cell suppression. CD200 is an immune checkpoint that is overexpressed on aberrant plasma cells (aPCs) in MM and is an independent negative prognostic factor for survival. However, CD200 is not present on MM cell lines, a potential limitation of current preclinical models. We engineered MM cell lines to express CD200 at levels equivalent to those found on aPCs in MM and show that these are sufficient to suppress clinical-stage CAR T-cells targeting BCMA or the Tn glycoform of mucin 1 (TnMUC1), costimulated by 4-1BB and CD2, respectively. To prevent CD200-mediated suppression of CAR T cells, we compared CRISPR-Cas9-mediated knockout of the CD200 receptor (CD200RKO), to coexpression of versions of the CD200 receptor that were nonsignaling, that is, dominant negative (CD200RDN), or that leveraged the CD200 signal to provide CD28 costimulation (CD200R-CD28 switch). We found that the CD200R-CD28 switch potently enhanced the polyfunctionality of CAR T cells, and improved cytotoxicity, proliferative capacity, CAR T-cell metabolism, and performance in a chronic antigen exposure assay. CD200RDN provided modest benefits, but surprisingly, the CD200RKO was detrimental to CAR T-cell activity, adversely affecting CAR T-cell metabolism. These patterns held up in murine xenograft models of plasmacytoma, and disseminated bone marrow predominant disease. Our findings underscore the importance of CD200-mediated immune suppression in CAR T-cell therapy of MM, and highlight a promising approach to enhance such therapies by leveraging CD200 expression on aPCs to provide costimulation via a CD200R-CD28 switch.

MELLODDY: Cross-pharma Federated Learning at Unprecedented Scale Unlocks Benefits in QSAR without Compromising Proprietary Information.

Federated multipartner machine learning has been touted as an appealing and efficient method to increase the effective training data volume and thereby the predictivity of models, particularly when the generation of training data is resource-intensive. In the landmark MELLODDY project, indeed, each of ten pharmaceutical companies realized aggregated improvements on its own classification or regression models through federated learning. To this end, they leveraged a novel implementation extending multitask learning across partners, on a platform audited for privacy and security. The experiments involved an unprecedented cross-pharma data set of 2.6+ billion confidential experimental activity data points, documenting 21+ million physical small molecules and 40+ thousand assays in on-target and secondary pharmacodynamics and pharmacokinetics. Appropriate complementary metrics were developed to evaluate the predictive performance in the federated setting. In addition to predictive performance increases in labeled space, the results point toward an extended applicability domain in federated learning. Increases in collective training data volume, including by means of auxiliary data resulting from single concentration high-throughput and imaging assays, continued to boost predictive performance, albeit with a saturating return. Markedly higher improvements were observed for the pharmacokinetics and safety panel assay-based task subsets.

The impact of COVID-19 prevention measures on surgical wound infection rates post-cardiac surgery.

The COVID-19 pandemic had a huge impact on medical services. Several measures have been implemented to reduce the risk of viral transmission. In this paper, we assessed the impact of these measures on surgical wound infection rates in patients post-cardiac surgery. Hypothesis testing was used to compare post-cardiac operation infection rates between the year prior to the COVID-19 pandemic being declared and the first 13 months of the pandemic. The infection rates in 969 patients with operations between 01/03/2019 and 29/02/2020 were compared to those of 925 patients with cardiac surgery between 01/03/2020 and 31/03/2021. Infection rates for various operative urgencies and infection types were analysed. To compare infection rates, a two-tailed pooled z-test using the difference in infection proportions was performed. A 5% significance level was used and only categories with at least 10 patients in both the pre-covid and covid populations were tested. For leg infections, only operations involving coronary artery bypass grafting were included. To ensure that any differences in outcomes were not due to differences in patient demographics resulting in unequal operative risks, Euroscore II values, a measure of cardiac operative risk, were compared between the pre-covid and post-covid cohorts. The Mann-Whitney U-test was used to determine whether the distributions of Euroscore II values were likely to be drawn from the same population. A significance level of 5% was used. A total of 1901 patients (932 during the COVID-19 pandemic) were included in this study. Significant reduction in post-operative infections for all patients undergoing cardiac surgery from 4.3% of patients before COVID to 1.5% during the pandemic. During the pandemic, fewer elective and more urgent operations were performed. This study suggests a significant role of iatrogenic causes in wound infections prior to the pandemic. The implementation of COVID-19 prevention measures in healthcare providers can reduce surgical infection rates. As COVID-19-related restrictions have been eased, we suggest maintaining them in healthcare providers to reduce the incidence of surgical wound infections.

A plague of weasels and ticks: animal introduction, ecological disaster, and the balance of nature in Jamaica, 1870-1900.

Towards the end of the nineteenth century, British colonists in Jamaica became increasingly exasperated by the damage caused to their sugar plantations by rats. In 1872, a British planter attempted to solve this problem by introducing the small Indian mongoose (Urva auropunctata). The animals, however, turned on Jamaica's insectivorous birds and reptiles, leading to an explosion in the tick population. This paper situates the mongoose catastrophe as a closing chapter in the history of the nineteenth-century acclimatization movement. While foreign observers saw the introduction of the mongoose as a cautionary tale, caricaturing British Jamaica as overrun by a plague of weasels and ticks, British colonists, administrators and naturalists - identifying a gradual decline of both populations - argued that the 'balance of nature' would eventually reassert itself. As this paper argues, through this dubious claim they were attempting to retrospectively rationalize or justify the introductions and their disastrous aftermath. This strategy enabled them to gloss over the lasting ecological damage caused by the mongoose, and allowed its adherents to continue their uncritical support of both the Jamaican plantation economy and animal introductions in the British Empire.

Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function.

Natural killer (NK) cells are frequently expanded for the clinic using irradiated, engineered K562 feeder cells expressing a core transgene set of membrane-bound (mb) IL15 and/or mbIL21 together with 41BBL. Prior comparisons of mbIL15 to mbIL21 for NK expansion lack comparisons of key attributes of the resulting NK cells, including their high-dimensional phenotype, polyfunctionality, the breadth and potency of cytotoxicity, cellular metabolism, and activity in xenograft tumor models. Moreover, despite multiple rounds of K562 stimulation, studies of sequential use of mbIL15- and mbIL21-based feeder cells are absent. We addressed these gaps and found that using mbIL15- versus mbIL21-based feeder cells drove distinct phenotypic and functional profiles. Feeder cells expressing mbIL15 alone drove superior functionality by nearly all measures, whereas those expressing mbIL21 alone drove superior yield. In combination, most attributes resembled those imparted by mbIL21, whereas in sequence, NK yield approximated that imparted by the first cytokine, and the phenotype, transcriptome, and function resembled that driven by the second cytokine, highlighting the plasticity of NK cell differentiation. The sequence mbIL21 followed by mbIL15 was advantageous in achieving significant yields of highly functional NK cells that demonstrated equivalent in vivo activity to those expanded by mbIL15 alone in two of three xenograft models. Our findings define the impact of mbIL15 versus mbIL21 during NK expansion and reveal a previously underappreciated tradeoff between NK yield and function for which sequential use of mbIL21-based followed by mbIL15-based feeder cells may be the optimal approach in many settings.

Effect of passive and active ventilation on malaria mosquito house entry and human comfort: an experimental study in rural Gambia.

Rural houses in sub-Saharan Africa are typically hot and allow malaria mosquitoes inside. We assessed whether passive or active ventilation can reduce house entry of malaria mosquitoes and cool a bedroom at night in rural Gambia. Two identical experimental houses were used: one ventilated and one unventilated (control). We evaluated the impact of (i) passive ventilation (solar chimney) and (ii) active ventilation (ceiling fan) on the number of mosquitoes collected indoors and environmental parameters (temperature, humidity, CO2, evaporation). Although the solar chimney did not reduce entry of Anopheles gambiae sensu lato, the ceiling fan reduced house entry by 91% compared with the control house. There were no differences in indoor nightly temperature, humidity or CO2 between intervention and control houses in either experiment. The solar chimney did not improve human comfort assessed using psychrometric analysis. While the ceiling fan improved human comfort pre-midnight, in the morning it was too cool compared with the control house, although this could be remedied through provision of blankets. Further improvements to the design of the solar chimney are needed. High air velocity in the ceiling fan house probably reduced mosquito house entry by preventing mosquito flight. Improved ventilation in houses may reduce malaria transmission.

Efficacy of coxsackievirus A21 against drug-resistant neoplastic B cells.

Primary drug resistance and minimal residual disease are major challenges in the treatment of B cell neoplasms. Therefore, this study aimed to identify a novel treatment capable of eradicating malignant B cells and drug-resistant disease. Oncolytic viruses eradicate malignant cells by direct oncolysis and activation of anti-tumor immunity, have proven anti-cancer efficacy, and are safe and well tolerated in clinical use. Here, we demonstrate that the oncolytic virus coxsackievirus A21 can kill a range of B cell neoplasms, irrespective of an anti-viral interferon response. Moreover, CVA21 retained its capacity to kill drug-resistant B cell neoplasms, where drug resistance was induced by co-culture with tumor microenvironment support. In some cases, CVA21 efficacy was actually enhanced, in accordance with increased expression of the viral entry receptor ICAM-1. Importantly, the data confirmed preferential killing of malignant B cells and CVA21 dependence on oncogenic B cell signaling pathways. Significantly, CVA21 also activated natural killer (NK) cells to kill neoplastic B cells and drug-resistant B cells remained susceptible to NK cell-mediated lysis. Overall, these data reveal a dual mode of action of CVA21 against drug-resistant B cells and support the development of CVA21 for the treatment of B cell neoplasms.

Administration of ß-lactam antibiotics to patients with reported penicillin allergy in the emergency department.

BACKGROUND: ß-lactam antibiotics are amongst the most commonly prescribed medications in the Emergency Department (ED) due to their role in empiric sepsis therapy; however, inferior therapeutic options are often utilized due to a reported allergy; penicillin (PCN) being most frequent. In the United States, 10% of the population endorses an allergic reaction to PCN while <1% experience IgE-mediated reactions. This study aimed to evaluate the frequency and outcome of patients in the ED whose PCN allergies were challenged with ß-lactam antibiotics. METHODS: We conducted a retrospective chart review of patients in the ED at an academic medical center aged ≥18, and who received a ß-lactam despite a reported PCN allergy between January 2015 and December 2019. Patients who did not receive a ß-lactam or did not report a PCN allergy prior to administration were excluded. The primary outcome was the frequency of IgE-mediated reactions in response to ß-lactam administration. A secondary outcome assessed the frequency of continuation of ß-lactams upon admission from the ED. RESULTS: 819 patients were included (66% female) with prior reported PCN reactions: hives (22.5%), rash (15.4%), swelling (6.2%), anaphylaxis (3.5%), other (12.1%), or undocumented on medical electronic record (40.3%). No patients experienced an IgE-mediated reaction to the ß-lactam administered in the ED. Previously reported allergies had no effect on the continuation of ß-lactams when admitted or discharged (OR: 1, 95% CI: 0.7-1.44). Patients who had a history of an IgE-mediated penicillin allergy were frequently continued (77%) on a ß-lactam after leaving the ED via admission or discharge. CONCLUSION: ß-lactam administration in patients with previously reported PCN allergies did not result in any IgE-mediated reactions nor in an increase in adverse reactions. Our data contributes to the body of evidence that supports the administration of ß-lactams to patients with documented PCN allergies.

Long-term voluntary wheel running effects on markers of long interspersed nuclear element-1 in skeletal muscle, liver, and brain tissue of female rats.

We sought to determine the effects of long-term voluntary wheel running on markers of long interspersed nuclear element-1 (L1) in skeletal muscle, liver, and the hippocampus of female rats. In addition, markers of the cGAS-STING DNA-sensing pathway that results in inflammation were interrogated. Female Lewis rats (n = 34) were separated into one of three groups including a 6-mo-old group to serve as a young comparator group (CTL, n = 10), a group that had access to a running wheel for voluntary wheel running (EX, n = 12), and an age-matched group that did not (SED, n = 12). Both SED and EX groups were carried out from 6 mo to 15 mo of age. There were no significant differences in L1 mRNA expression for any of the tissues between groups. Methylation of the L1 promoter in the soleus and hippocampus was significantly higher in SED and EX than in CTL group (P < 0.05). ORF1p expression was higher in older SED and EX rats than in CTL rats for every tissue (P < 0.05). There were no differences between groups for L1 mRNA or cGAS-STING pathway markers. Our results suggest there is an increased ORF1 protein expression across tissues with aging that is not mitigated by voluntary wheel running. In addition, although previous data imply that L1 methylation changes may play a role in acute exercise for L1 RNA expression, this does not seem to occur during extended periods of voluntary wheel running.

Outcome measures for technique survival reported in peritoneal dialysis: A systematic review.

BACKGROUND: Peritoneal dialysis (PD) technique survival is an important outcome for patients, caregivers and health professionals, however, the definition and measures used for technique survival vary. We aimed to assess the scope and consistency of definitions and measures used for technique survival in studies of patients receiving PD. METHOD: MEDLINE, EMBASE and CENTRAL databases were searched for randomised controlled studies (RCTs) conducted in patients receiving PD reporting technique survival as an outcome between database inception and December 2019. The definition and measures used were extracted and independently assessed by two reviewers. RESULTS: We included 25 RCTs with a total of 3645 participants (41-371 per trial) and follow up ranging from 6 weeks to 4 years. Terminology used included 'technique survival' (10 studies), 'transfer to haemodialysis (HD)' (8 studies) and 'technique failure' (7 studies) with 17 different definitions. In seven studies, it was unclear whether the definition included transfer to HD, death or transplantation and eight studies reported 'transfer to HD' without further definition regarding duration or other events. Of those remaining, five studies included death in their definition of a technique event, whereas death was censored in the other five. The duration of HD necessary to qualify as an event was reported in only four (16%) studies. Of the 14 studies reporting causes of an event, all used a different list of causes. CONCLUSION: There is substantial heterogeneity in how PD technique survival is defined and measured, likely contributing to considerable variability in reported rates. Standardised measures for reporting technique survival in PD studies are required to improve comparability.

Don't Overweight Weights: Evaluation of Weighting Strategies for Multi-Task Bioactivity Classification Models.

Machine learning models predicting the bioactivity of chemical compounds belong nowadays to the standard tools of cheminformaticians and computational medicinal chemists. Multi-task and federated learning are promising machine learning approaches that allow privacy-preserving usage of large amounts of data from diverse sources, which is crucial for achieving good generalization and high-performance results. Using large, real world data sets from six pharmaceutical companies, here we investigate different strategies for averaging weighted task loss functions to train multi-task bioactivity classification models. The weighting strategies shall be suitable for federated learning and ensure that learning efforts are well distributed even if data are diverse. Comparing several approaches using weights that depend on the number of sub-tasks per assay, task size, and class balance, respectively, we find that a simple sub-task weighting approach leads to robust model performance for all investigated data sets and is especially suited for federated learning.

Single-molecule imaging reveals that Z-ring condensation is essential for cell division in Bacillus subtilis.

Although many components of the cell division machinery in bacteria have been identified1,2, the mechanisms by which they work together to divide the cell remain poorly understood. Key among these components is the tubulin FtsZ, which forms a Z ring at the midcell. FtsZ recruits the other cell division proteins, collectively called the divisome, and the Z ring constricts as the cell divides. We applied live-cell single-molecule imaging to describe the dynamics of the divisome in detail, and to evaluate the individual roles of FtsZ-binding proteins (ZBPs), specifically FtsA and the ZBPs EzrA, SepF and ZapA, in cytokinesis. We show that the divisome comprises two subcomplexes that move differently: stationary ZBPs that transiently bind to treadmilling FtsZ filaments, and a moving complex that includes cell wall synthases. Our imaging analyses reveal that ZBPs bundle FtsZ filaments together and condense them into Z rings, and that this condensation is necessary for cytokinesis.

Analysis of Ignition Sites for the Explosives 3,3'-Diamino-4,4'-azoxyfurazan (DAAF) and 1,3,5,7-Tetranitro-1,3,5,7-tetrazoctane (HMX) Using Crush Gun Impact Testing.

The handling safety characteristics of energetic materials must be measured in order to ensure the safe transport and use of explosives. Drop-weight impact sensitivity measurements are one of the first standardized tests performed for energetics. They utilize a small amount of the explosive sample and a standard weight, which is dropped on the material from various heights to determine its sensitivity. While multiple laboratories have used the impact sensitivity test as an initial screening tool for explosive sensitivity for the past 60 years, variability exists due to the use of different instruments, different methods to determine the initiation, and the scatter commonly associated with less-sensitive explosives. For example, standard explosives such as 1,3,5,7-tetranitro-1,3,5,7-tetrazoctane (HMX) initiate reliably and consistently on the drop-weight impact test, whereas insensitive explosives such as 3,3'-diamino-4,4'-azoxyfurazan (DAAF) exhibit variability in sound levels and the expended material. Herein we investigate the impact sensitivity of DAAF and HMX along with a more detailed investigation of ignition sites using a novel "crush gun" apparatus: a pneumatically powered drop-weight tower with advanced diagnostics, including high-speed visual and infrared cameras. Using this crush gun assembly, the ignition sites in HMX and DAAF were analyzed with respect to the effects of particle size and the presence of a source of grit. The formation of ignition sites was observed in both explosives; however, only HMX showed ignition sites that propagated to a deflagration at lower firing speeds. Finally, the presence of grit particles was shown to increase the occurrence of ignition sites in DAAF at lower firing speeds, though propagation to a full reaction was not observed on the time scale of the test. These results enable a better understanding of how ignition and propagation occurs during the impact testing of DAAF.

Combination and processing keratin with lignin as biocomposite materials for additive manufacturing technology.

Additive manufacturing using Nature's resources is a desirable goal. In this work we examine how the inherent macromolecular properties of keratin and lignin can be utilised and developed using green chemistry principles to form 4D functional materials. A new methodology utilising protein complexation by lignin was applied to form copolymers and reinforce keratin cross-linking networks on aqueous and solid state processing. Solubility, chemical and processing characteristics found a favoured 4:1 ratio of keratin to lignin was most desired for effective further processing as 3D printed paste forms. Thermally processing keratin-lignin with plasticisers and processing aids demonstrated extruded FDM filaments could be formed at temperatures >130°C, but degradation of keratin-lignin materials was observed. Employing paste printing strategies, keratin-lignin hydrogels could successfully print 3D skirt outlines. This was achieved with aqueous hydrogels prepared at 30-40% solids content with and without plasticizers over a defined processing timeframe. Mechanical response to moisture stimuli was successfully demonstrated for the 4:1 keratin-lignin printed material on water soaking, realising the ability of these keratin-lignin biocomposite materials to introduce a 4th dimensional response after 3D printing. STATEMENT OF SIGNIFICANCE: In this paper we describe new perspectives for how biopolymers can be used and processed to develop (co)polymers as 3D & 4D printed responsive materials without the need for synthetic chemical modifications. We utilise a novel methodology employing bioconjugation to synthesise and develop co-polymer materials from keratin and lignin and demonstrate this can be achieved in both water and solid state. We manipulate the inherent chemical attributes of both biopolymers to develop these new functional materials under green chemistry processing conditions. This is a practical example how the chemical coupling of two biopolymers at molecular-scale can be leveraged to give co-polymer materials which retain their inherent macromolecular properties to behave as functional, 4D responsive biomaterials.

Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21.

BACKGROUND: The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible. METHODS: This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment. RESULTS: An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response. CONCLUSION: This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.

Imitating nature: Analogy and experiment in D'Arcy Thompson's Science of Form.

D'Arcy Wentworth Thompson's "Science of Form" - the explanation of biological development and morphology through physical forces and mathematical laws - has traditionally been viewed as an idiosyncratic, even heretical, episode in the history of evolutionary biology. Yet recent scholarship has sought to overturn this view by demonstrating that Thompson was active in contemporary scientific networks. This paper argues that a key influence upon Thompson's seminal work, On Growth and Form (1917), may be far more practical, and lie closer to home, than previously realised: experimental demonstrations of basic concepts in physics. Harnessing previously unpublished archival sources, this paper traces Thompson's correspondence with Charles Darling, Arthur Worthington and Cecil Warburton. In these exchanges, Thompson described his own experiments, or requested that experiments be conducted on his behalf. This correspondence, and its subsequent inclusion in the first edition of On Growth and Form, revises our current picture of Thompson from that of an abstract thinker to keen experimentalist. Moreover, his contact with physicists indicates that simple experiments enabled extensive crosstalk between early twentieth century physics and biology.