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.

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.

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.

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.

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder.

ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.

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.

The Magnitude of Rapid Weight Loss and Rapid Weight Gain in Combat Sport Athletes Preparing for Competition: A Systematic Review.

Combat sport athletes typically engage in a process called making weight, characterized by rapid weight loss (RWL) and subsequent rapid weight gain (RWG) in the days preceding competition. These practices differ across each sport, but no systematic comparison of the size of the changes in body mass exists. The aim was to determine the magnitude of RWL and RWG in combat sport athletes preparing for competition. The review protocol was preregistered with PROSPERO (CRD42017055279). In eligible studies, athletes prepared habitually with a RWL period ≤7 days preceding competition. An electronic search of EBSCOhost (CINAHL Plus, MEDLINE, and SPORTDiscus) and PubMed Central was performed up to July 2018. Sixteen full-text studies (total 4,432 participants; 156 females and 4,276 males) were included, providing data from five combat sports (boxing, judo, mixed martial arts, taekwondo, and wrestling). Three studies reported RWL and 14 studies reported RWG. Duration permitted for RWG ranged 3-32 hr. The largest changes in body mass occurred in two separate mixed martial arts cohorts (RWL: 7.4 ± 1.1 kg [∼10%] and RWG: 7.4 ± 2.8 kg [11.7% ± 4.7%]). The magnitude of RWG appears to be influenced by the type of sport, competition structure, and recovery duration permitted. A cause for concern is the lack of objective data quantifying the magnitude of RWL. There is insufficient evidence to substantiate the use of RWG as a proxy for RWL, and little data are available in females. By engaging in RWG, athletes are able to exploit the rules to compete up to three weight categories higher than at the official weigh-in.

Robust and accurate decoding of motoneuron behaviour and prediction of the resulting force output.

KEY POINTS: The spinal alpha motoneuron is the only cell in the human CNS whose discharge can be routinely recorded in humans. We have reengineered motor unit collection and decomposition approaches, originally developed in humans, to measure the neural drive to muscle and estimate muscle force generation in the in vivo cat model. Experimental, computational, and predictive approaches are used to demonstrate the validity of this approach across a wide range of modes to activate the motor pool. The utility of this approach is shown through the ability to track individual motor units across trials, allowing for better predictions of muscle force than the electromyography signal, and providing insights in to the stereotypical discharge characteristics in response to synaptic activation of the motor pool. This approach now allows for a direct link between the intracellular data of single motoneurons, the discharge properties of motoneuron populations, and muscle force generation in the same preparation. ABSTRACT: The discharge of a spinal alpha motoneuron and the resulting contraction of its muscle fibres represents the functional quantum of the motor system. Recent advances in the recording and decomposition of the electromyographic signal allow for the identification of several tens of concurrently active motor units. These detailed population data provide the potential to achieve deep insights into the synaptic organization of motor commands. Yet most of our understanding of the synaptic input to motoneurons is derived from intracellular recordings in animal preparations. Thus, it is necessary to extend the new electrode and decomposition methods to recording of motor unit populations in these same preparations. To achieve this goal, we use high-density electrode arrays and decomposition techniques, analogous to those developed for humans, to record and decompose the activity of tens of concurrently active motor units in a hindlimb muscle in the in vivo cat. Our results showed that the decomposition method in this animal preparation was highly accurate, with conventional two-source validation providing rates of agreement equal to or superior to those found in humans. Multidimensional reconstruction of the motor unit action potential provides the ability to accurately track the same motor unit across multiple contractions. Additionally, correlational analyses demonstrate that the composite spike train provides better estimates of whole muscle force than conventional estimates obtained from the electromyographic signal. Lastly, stark differences are observed between the modes of activation, in particular tendon vibration produced quantal interspike intervals at integer multiples of the vibration period.

Interactions of staphyloxanthin and enterobactin with myeloperoxidase and reactive chlorine species.

When neutrophils engulf bacteria, myeloperoxidase converts hydrogen peroxide to hypochlorous acid, which is toxic to all micro-organisms. It has been suggested that some pathogens have virulence factors that target myeloperoxidase to dampen the oxidative reactions of neutrophils. These virulence factors include staphyloxanthin, the golden pigment of Staphylococcus aureus, and enterobactin - a siderophore released by gram-negative bacteria. We investigated the potential of staphyloxanthin and enterobactin to shield bacteria from hypochlorous acid and related chloramines. Clinical strains of S. aureus with high levels of staphyloxanthin and related carotenoids were in general more resistant to low doses of hypochlorous acid than non-pigmented bacteria. But some non-pigmented strains were also resistant to the oxidant. Doses of reactive chlorine species that killed bacteria also bleached their carotenoids. Hypochlorous acid, NH2Cl, and NHCl2 bleached purified staphyloxanthin. When S. aureus were phagocytosed by neutrophils there was no discernible loss of staphyloxanthin. These data suggest that staphyloxanthin is capable of protecting bacteria from low doses of reactive chlorine species formed inside phagosomes. Enterobactin was not an inhibitor of myeloperoxidase. We conclude that staphyloxanthin may protect some bacterial strains against oxidative killing by neutrophils, but enterobactin will not inhibit the production of hypochlorous acid.

The Sparrow Question: Social and Scientific Accord in Britain, 1850-1900.

During the latter-half of the nineteenth century, the utility of the house sparrow (Passer domesticus) to humankind was a contentious topic. In Britain, numerous actors from various backgrounds including natural history, acclimatisation, agriculture and economic ornithology converged on the bird, as contemporaries sought to calculate its economic cost and benefit to growers. Periodicals and newspapers provided an accessible and anonymous means of expression, through which the debate raged for over 50 years. By the end of the century, sparrows had been cast as detrimental to agriculture. Yet consensus was not achieved through new scientific methods, instruments, or changes in practice. This study instead argues that the rise and fall of scientific disciplines and movements paved the way for consensus on "the sparrow question." The decline of natural history and acclimatisation stifled a raging debate, while the rising science of economic ornithology sought to align itself with agricultural interests: the latter overwhelmingly hostile to sparrows.

Changing techniques in crop plant classification: molecularization at the National Institute of Agricultural Botany during the 1980s.

Modern methods of analysing biological materials, including protein and DNA sequencing, are increasingly the objects of historical study. Yet twentieth-century taxonomic techniques have been overlooked in one of their most important contexts: agricultural botany. This paper addresses this omission by harnessing unexamined archival material from the National Institute of Agricultural Botany (NIAB), a British plant science organization. During the 1980s the NIAB carried out three overlapping research programmes in crop identification and analysis: electrophoresis, near infrared spectroscopy (NIRS) and machine vision systems. For each of these three programmes, contemporary economic, statutory and scientific factors behind their uptake by the NIAB are discussed. This approach reveals significant links between taxonomic practice at the NIAB and historical questions around agricultural research, intellectual property and scientific values. Such links are of further importance given that the techniques developed by researchers at the NIAB during the 1980s remain part of crop classification guidelines issued by international bodies today.

Force steadiness during a co-contraction task can be improved with practice, but only by young adults and not by middle-aged or old adults.

NEW FINDINGS: What is the central question of this study? Does the capacity to modulate afferent input to spinal motor neurons during steady submaximal contractions change with advancing age? What is the main finding and its importance? After practising a co-contraction task involving lower leg muscles, young subjects improved force steadiness by reducing the amount of Ia presynaptic inhibition as indexed by D1 inhibition. Middle-aged and old adults both found the task challenging, and force steadiness even worsened for old adults after practising the co-contraction task. Despite similar muscle strength for young and middle-aged adults, the capacity to modulate a spinal reflex pathway was reduced in middle-aged adults. This study compared the changes in steadiness and the modulation of presynaptic inhibition of soleus Ia afferents in young, middle-aged and old adults before and after a single session of practising a task that involved concurrent contraction of dorsiflexor and plantarflexor muscles. The hypothesis was that young subjects would be able to improve steadiness with practice by modulating Ia afferent feedback as indicated by changes in a measure of presynaptic inhibition (D1 inhibition), but that middle-aged and older subjects would exhibit a lesser ability to augment steadiness. There were no differences in steadiness between groups during an initial co-contraction trial (P = 0.713). Maximal voluntary contraction force for the plantarflexors was not significantly different between young and middle-aged subjects (P > 0.05), but it was significantly less in old subjects (P < 0.05). The main finding of the study was that young adults were able to improve steadiness by ∼19% (P < 0.001) during a co-contraction task after 50 min of practice, whereas there was no change for the middle-aged adults, and old adults became less steady by ∼15% (P < 0.05). The improvement in steadiness by young adults was accompanied by a significant reduction in the amount of Ia presynaptic inhibition as indexed by D1 inhibition (P < 0.01). Conversely, neither of the other two groups exhibited any change in D1 inhibition after practising the co-contraction task. In contrast to young subjects, middle-aged and old adults found the co-contraction task challenging and were not able to improve steadiness after practising the low-force isometric contraction.

Acceptability of financial incentives for breastfeeding: thematic analysis of readers' comments to UK online news reports.

BACKGROUND: Whilst it is recommended that babies are breastfed exclusively for the first six months, many mothers do not maintain breastfeeding for this length of time. Previous research confirms that women and midwives value financial incentives for breastfeeding, but limited research has explored the wider acceptability of these interventions to the general public. This paper examines opinion towards financial incentives for breastfeeding using reader responses to UK on-line media coverage of a study undertaken in this area. METHODS: This study used netnography to undertake a thematic analysis of 3,373 reader comments posted in response to thirteen articles, published in November 2013, which reported findings from a feasibility study of financial incentives for breastfeeding. All articles were published on one of six UK news websites that achieved a monthly audience of at least five million viewers across laptop and desktop computers and mobile devices during April-May 2013. RESULTS: Nine analytical themes were identified, with a majority view that financial incentives for breastfeeding are unacceptable. These themes cover a range of opinions: from negligent parents unable to take responsibility for their own actions; through to psychologically vulnerable members of society who should be protected from coercion and manipulation; to capable and responsible women who can, and should be allowed to, make their own decisions. Many views focused on the immediate costs of the intervention, concluding that this was something that was currently unaffordable to fund (e.g. by the NHS). Others contrasted the value of the incentive against other 'costs' of breastfeeding. There was some consideration of the issue of cost-effectiveness and cost-saving, where the potential future benefit from initial investment was identified. Many commenters identified that financial incentives do not address the many structural and cultural barriers to breastfeeding. CONCLUSIONS: Overall, those commenting on the on-line UK news articles viewed financial incentives for breastfeeding as unacceptable and that alternative, structural, interventions were likely to be more effective. Further consideration of how best to conduct internet-based qualitative research to elicit opinion towards public health issues is required.

Reliability of nerve function assessments for people with peripheral neuropathy.

Examining degenerative sensory and reflexive activity among people with peripheral neuropathy (PN) is important for clinical examinations and understanding relevant neural impairments. However, other than the test of presynaptic inhibition, the reliability of other related tests is largely unknown. The purpose of this project was to examine the test-retest reliability of lower extremity sensory and reflexive measures in people with PN. Twelve participants (8 women, 4 men, age = 72.5 ± 9.2 years) diagnosed with PN were assessed on two occasions at least 7 d apart. Plantar sensitivity, H-reflex and active and passive ankle proprioception (AAP and PAP) were tested. Paired student's t-test and Intraclass correlation coefficients (ICC) were used for statistical analysis. Significant difference was observed in AAP at 0º position (p = 0.04). No other significant differences were observed. Moderate to high reliability was observed at measures of Plantar sensitivity (0.92), peak to peak H (0.71) and M (0.84) waves, latency between H and M (0.78), H-Index (0.85), AAP (0.62) and PAP index (0.60). Low reliability was observed of other parameters. The measures of Hmax, Mmax, latency, H-Index, plantar sensitivity and AAP & PAP indices of proprioception tests can be measured reliably for further study in this population.

Discharge characteristics of motor units during long-duration contractions.

The purpose of the study was to determine how long humans could sustain the discharge of single motor units during a voluntary contraction. The discharge of motor units in first dorsal interosseus of subjects (27.8 ± 8.1 years old) was recorded for as long as possible. The task was terminated when the isolated motor unit stopped discharging action potentials, despite the ability of the individual to sustain the abduction force. Twenty-three single motor units were recorded. Task duration was 21.4 ± 17.8 min. When analysed across discharge duration, mean discharge rate (10.6 ± 1.8 pulses s(-1)) and mean abduction force (5.5 ± 2.8% maximum) did not change significantly (discharge rate, P = 0.119; and abduction force, P = 0.235). In contrast, the coefficient of variation for interspike interval during the initial 30 s of the task was 22.2 ± 6.0% and increased to 31.9 ± 7.0% during the final 30 s (P < 0.001). All motor units were recruited again after 60 s of rest. Although subjects were able to sustain a relatively constant discharge rate, the cessation of discharge was preceded by a gradual increase in discharge variability. The findings also showed that the maximal duration of human motor unit discharge exceeds that previously reported for the discharge elicited in motor neurons by intracellular current injection in vitro.

Sex differences in time to task failure during early pubertal development.

INTRODUCTION: We compared fatigability and activation of elbow flexor muscles in children at 3 pubertal stages during a sustained submaximal contraction. METHODS: In 72 healthy children (39 boys) aged 11 ± 3 years (range, 8-14 years), differences in fatigability (time to task failure) and muscle activation were compared at 3 Tanner stages (T1-T3). RESULTS: Time to task failure and muscle activation were similar between boys and girls at prepubertal Tanner stage 1. Time to task failure was briefer for girls than boys at Tanner stages 2 and 3 and was predicted by the coactivation indices and percent body fat in girls. Muscle torque was the only predictor for the time to task failure in boys. CONCLUSIONS: Differences in fatigability and muscle coactivation were evident during the initial pubertal stages (T2 and T3), but not before the onset of puberty (T1).

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.