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Zoos and aquariums are cultural institutions that rely on a steady stream of paying visitors, whose patronage comes in the form of admission fees or product sales, for their financial health, a condition that is vital to their continued delivery on the modern zoological mission, one that includes not only recreation but also conservation, education, and research [...]

We used the COVID-19 pandemic closure at the Saint Louis Zoo to examine visitor effects on space use and glucocorticoid levels in banteng, grizzly bears, polar bears, and western lowland gorillas. The study was divided into four six-week phases: closure in spring 2020, reopening in summer 2020, fall 2020, and spring 2021 as a seasonal comparison. Space use data were collected using video, and fecal samples were assayed for glucocorticoids. Generalized linear models were used to examine differences in zone occupancy and glucocorticoids between phases. The banteng spent more time near visitors, and glucocorticoids were only temporarily elevated in two of five animals when visitors returned. The grizzly bears spent more time in their habitat than in the den, and the polar bear spent more time near viewing areas after visitors returned. Glucocorticoids did not differ significantly between the closure and reopening for any bears. The gorillas spent less time close to visitors immediately after reopening but this effect waned by fall; glucocorticoid data were not available. Overall, based on space use and glucocorticoid levels, we suggest visitor effects on the gorillas are neutral, on the grizzly bears are neutral or positive, and are positive on the banteng and polar bear.

Clostridioides difficile infection (CDI) causes substantial morbidity and mortality worldwide with limited antibiotic treatment options. Ridinilazole is a precision bisbenzimidazole antibiotic being developed to treat CDI and reduce unacceptably high rates of infection recurrence in patients.

Globally, the anaerobic bacterium Clostridium perfringens causes severe disease in a wide array of hosts; however, C. perfringens strains are also carried asymptomatically. Accessory genes are responsible for much of the observed phenotypic variation and virulence within this species, with toxins frequently encoded on conjugative plasmids and many isolates carrying up to 10 plasmids. Despite this unusual biology, current genomic analyses have largely excluded isolates from healthy hosts or environmental sources. Accessory genomes, including plasmids, also have often been excluded from broader scale phylogenetic investigations. Here we interrogate a comprehensive collection of 464 C . perfringens genomes and identify the first putative non-conjugative enterotoxin (CPE)-encoding plasmids and a putative novel conjugative locus (Bcp) with sequence similarity to a locus reported from Clostridium botulinum . We sequenced and archived 102 new C. perfringens genomes, including those from rarely sequenced toxinotype B, C, D and E isolates. Long-read sequencing of 11 C . perfringens strains representing all toxinotypes (A–G) identified 55 plasmids from nine distinct plasmid groups. Interrogation of the 464 genomes in this collection identified 1045 plasmid-like contigs from the nine plasmid families, with a wide distribution across the C. perfringens isolates. Plasmids and plasmid diversity play an essential role in C. perfringens pathogenicity and broader biology. We have expanded the C. perfringens genome collection to include temporal, spatial and phenotypically diverse isolates including those carried asymptomatically in the gastrointestinal microbiome. This analysis has resulted in the identification of novel C. perfringens plasmids whilst providing a comprehensive understanding of species diversity.

BackgroundGenome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in non-coding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association, and identifying the phenotype it mediates, is a major challenge in the interpretation and translation of GWAS.ResultsHere, we show that pooled CRISPR screens are highly effective at identifying GWAS target genes and defining the cancer phenotypes they mediate. Following CRISPR mediated gene activation or suppression, we measure proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We perform 60 CRISPR screens and identify 20 genes predicted with high confidence to be GWAS targets that promote cancer by driving proliferation or modulating the DNA damage response in breast cells. We validate the regulation of a subset of these genes by breast cancer risk variants.ConclusionsWe demonstrate that phenotypic CRISPR screens can accurately pinpoint the gene target of a risk locus. In addition to defining gene targets of risk loci associated with increased breast cancer risk, we provide a platform for identifying gene targets and phenotypes mediated by risk variants.

Scientific research has long been recognized as one of the four pillars of the zoo or aquarium mission, alongside recreation, conservation, and education. This study sought to quantify a sample of zoos’ participation in scientific research via the provision of biomaterials from animals to outside scientists and the associated training of undergraduate and graduate students that resulted from these projects. A convenience sample of zoos provided data on their participation in biomaterials-related projects and a focused analysis of biomaterials-related research facilitated by the Saint Louis Zoo was conducted. In addition, the Association of Zoos & Aquariums’ conservation & science database was queried to uncover what research projects AZA members engaged in over the last five years that likely involved biomaterials research and training of students. Results demonstrate that zoos are making significant contributions to science by agreeing to participate in large numbers of biomaterials-related projects across different areas of focus involving a variety of animal species annually, with results applicable to human and non-human animals. Support of such research often involves student thesis projects, thus contributing to the education of future scientists.

Animals use specific behaviors and skills to overcome challenges and access resources. Environmental enrichment is provided to animals in human care to both promote species-appropriate behaviors and reduce undesired behaviors. Feather pecking in birds is an undesired behavior without a clear cause. The Saint Louis Zoo houses three pairs of young Bali mynas (Leucopsar rothschildi) who pluck neck feathers from conspecifics. To reduce this behavior, animal care staff presented the birds with seven enrichment items from four categories, presenting each item twice. The enrichment included a modifiable, progressively challenging bamboo tube device at multiple levels of difficulty. While plucking was not affected by any enrichment item, we observed significant increases in locomotion and decreases in autopreening, allogrooming, and head bobbing. Leafy greens produced the greatest changes when compared to other enrichment types. Overall engagement with the progressively challenging enrichment increased with the change from the first to the second level of difficulty, and interaction with the device was highest for the third and most difficult version. These increases suggest that no habituation to the progressively challenging device occurred, while a possible neophobic effect declined with multiple uses and increased familiarity.

We report the characterization of an achromatic focusing metasurface at oblique incident angles. We show that in addition to the inherent off-axis aberrations that occurs due to the hyperbolic phase profile of the metasurface, the focusing performance is significantly degraded due to the meta-atoms' angular dispersion. To obtain insights into how the angular and spectral bandwidth of meta-atoms relate to the metasurface focusing performance, point-dipole models are used which incorporate different aspect's of the meta-atoms' angular response. It is emphasized that despite the meta-atoms being designed under the assumption that they support a single dipolar resonance, other resonances exist within the meta-atom geometry and become stronger at oblique incidence. These resonances disturb the designed phase and amplitude responses, resulting in lower focusing efficiency at higher incident angles. The modelling of higher order modes leads to good agreement with the experimental measurements, confirming that angular dispersion of the meta-atoms is the dominant mechanism in determining off-axis aberrations.

Background: Down syndrome (DS) is associated with increased risk for Alzheimer’s disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38–61 years). Results: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. Conclusion: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

Mutations in SFRP4 cause Pyle’s bone disease with wide metaphyses and increased skeletal fragility. The WNT signaling pathway plays important roles in determining skeletal architecture and SFRP4 is a secreted Frizzled decoy receptor that inhibits WNT signaling. Seven cohorts of male and female Sfrp4 gene knockout mice, examined through 2 years of age, had a normal lifespan but showed cortical and trabecular bone phenotypes. Mimicking human Erlenmeyer flask deformities, bone cross-sectional areas were elevated 2-fold in the distal femur and proximal tibia but only 30% in femur and tibia shafts. Reduced cortical bone thickness was observed in the vertebral body, midshaft femur and distal tibia. Elevated trabecular bone mass and numbers were observed in the vertebral body, distal femur metaphysis and proximal tibia metaphysis. Midshaft femurs retained extensive trabecular bone through 2 years of age. Vertebral bodies had increased compressive strength, but femur shafts had reduced bending strength. Trabecular, but not cortical, bone parameters in heterozygous Sfrp4 mice were modestly affected. Ovariectomy resulted in similar declines in both cortical and trabecular bone mass in wild-type and Sfrp4 KO mice. SFRP4 is critical for metaphyseal bone modeling involved in determining bone width. Sfrp4 KO mice show similar skeletal architecture and bone fragility deficits observed in patients with Pyle’s disease with SFRP4 mutations.

Long-term evaluations of whether modern zoological exhibits help to maintain variation in the behavior of zoo animals are lacking despite the hope that animals avoid falling into monotonous patterns of behavior or boredom. This study evaluated changes in behavior and habitat use over multi-year periods in nine individuals of five bear species at two zoological facilities. Behavioral data gathered over months to years were analyzed graphically for trends in the direction of change. The habitat use dynamics were assessed graphically by looking for trends in the entropy values over time. We found that the activity budgets remained diverse and were dynamic over time, more so in younger compared to older bears. Changes in behavior suggesting positive welfare were observed, while changes that may reflect declining welfare seemed more likely to be due to age or seasonality. The observed behavioral changes suggest that the bears did not become bored with their habitats; there was likely one to several hours of daily variation in behavior, and stereotypy was rare. The diversity in the habitat use decreased over time as the animals settled into patterns of use reflecting preferences for certain areas of their habitats.

Pioglitazone, an FDA-approved compound, has been shown to target the novel mitochondrial protein mitoNEET and produce short-term neuroprotection and functional benefits following traumatic brain injury. To expand on these findings, we now investigate the dose- and time-dependent effects of pioglitazone administration on mitochondrial function after experimental traumatic brain injury. We then hypothesize that optimal pioglitazone dosing will lead to ongoing neuroprotection and cognitive benefits that are dependent on pioglitazone-mitoNEET signalling pathways. We show that delayed intervention is significantly more effective than early intervention at improving acute mitochondrial bioenergetics in the brain after traumatic brain injury. In corroboration, we demonstrate that mitoNEET is more heavily expressed, especially near the cortical contusion, in the 18 h following traumatic brain injury. To explore whether these findings relate to ongoing pathological and behavioural outcomes, mice received controlled cortical impact followed by initiation of pioglitazone treatment at either 3 or 18 h post-injury. Mice with treatment initiation at 18 h post-injury exhibited significantly improved behaviour and tissue sparing compared to mice with pioglitazone initiated at 3 h post-injury. Further using mitoNEET knockout mice, we show that this therapeutic effect is dependent on mitoNEET. Finally, we demonstrate that delayed pioglitazone treatment improves serial motor and cognitive performance in conjunction with attenuated brain atrophy after traumatic brain injury. This study illustrates that mitoNEET is the critical target for delayed pioglitazone intervention after traumatic brain injury, mitochondrial-targeting is highly time-dependent after injury and there is an extended therapeutic window to effectively treat mitochondrial dysfunction after brain injury., Hubbard et al. show that delayed mitochondrial-targeted therapy with pioglitazone improves functional outcomes following experimental traumatic brain injury. Pioglitazone interacts with the mitochondrial protein mitoNEET to elevate acute bioenergetics and attenuate ongoing cognitive deficits and MRI-assessed brain atrophy.

Multipotent mesenchymal stromal cells (MSCs) ameliorate a wide range of diseases in preclinical models, but the lack of clarity around their mechanisms of action has impeded their clinical utility. The therapeutic effects of MSCs are often attributed to bioactive molecules secreted by viable MSCs. However, we found that MSCs underwent apoptosis in the lung after intravenous administration, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevented MSC death and attenuated their immunosuppressive effects in disease models used to define MSC potency. Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies., Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.

Fecal glucocorticoid metabolite (FGM) concentrations, activity, and personality were assessed for 35 fennec foxes (Vulpes zerda) to determine whether animals managed as ambassadors differed from ex...

A factor in our inability to meet the challenge of clinical antibiotic resistance has been the low productivity of research and development (RD) efforts, with only incremental improvements on existing broad-spectrum classes coming into clinical use recently. The disappointing returns from this approach have focussed attention on narrower-spectrum antibiotics; such new agents are directed against the pathogen of relevance with the additional benefit of preserving the human microbiome(s). Our knowledge of the gut microbiome and its contribution to health homeostasis increases yearly and suggests that broad-spectrum treatments incur health costs beyond the initial infection. Improved diagnostics, antibiotic stewardship, and the crucial role of the gut microbiome in health indicate targeted agents as a more viable approach for future antibiotic RD.

The motion of small objects in acoustophoresis depends on the acoustic radiation force and torque. These are nonlinear phenomena originating from wave scattering, and consist of primary and secondary components. The primary radiation force is the force acting on an object due to the incident field, in the absence of other objects. The secondary component, known as acoustic interaction force, accounts for the interaction among objects, and contributes to the clustering patterns of objects, as commonly observed in experiments. In this tutorial, the theory of acoustic interaction forces is presented using the force potential and partial-wave expansion approaches, and the distinguishing features of these forces such as rotational coupling and non-reciprocity are described. Theoretical results are compared to experimental measurements of interaction forces using a glass micro-capillary setup to explain the practical challenges. Finally, the phenomenon of clustering patterns induced by the close-range interaction of objects is demonstrated to point out the considerations about multiple collision and the predicted clustering patterns entirely due to the interaction force. Understanding the principles of acoustic interaction enables us to develop novel acoustofluidic applications beyond the typical processing of large populations of particles and with focus on the controlled manipulation of small clusters.

In this work we investigate a periodic structure in the frequency range from 20 Hz to 5500 Hz designed for broadband noise insulation. The considered unit cell consists of a simple structure: a pair of polymer pipes with slits carved along the axes, representing two coupled Helmholtz resonators. In order to develop a design with a broad band gap, we analyze the eigenmodes of the infinite two-dimensional structure considering their symmetry and interaction. This analysis is supported by parametric optimization of the resonator geometry. The obtained band diagram is compared with numerically determined transmission coefficient of a finite structure based on the same unit cell. The number of unit cells of the finite structure is chosen to be sufficient for demonstration of insulating properties and stop band formation. Furthermore, we analyze how the transmission coefficient is linked to the pressure field distribution inside the resonators. Owing to the simplicity of the geometry, the obtained results may become a basis for development of budget-friendly passive systems for broadband noise insulation within the audible range of frequencies.

The development of mouse models that replicate the genetic and pathological features of human disease is important in preclinical research because these types of models enable the completion of meaningful pharmacokinetic, safety, and efficacy studies. Numerous relevant mouse models of human disease have been discovered in high-throughput screening programs, but there are important specific phenotypes revealed by histopathology that are not reliably detected by any other physiological or behavioral screening tests. As part of comprehensive phenotypic analyses of over 4000 knockout (KO) mice, histopathology identified 12 lines of KO mice with lesions indicative of an autosomal recessive myopathy. This report includes a brief summary of histological and other findings in these 12 lines. Notably, the inverted screen test detected muscle weakness in only 4 of these 12 lines ( Scyl1, Plpp7, Chkb, and Asnsd1), all 4 of which have been previously recognized and published. In contrast, 6 of 8 KO lines showing negative or inconclusive findings on the inverted screen test ( Plppr2, Pnpla7, Tenm1, Srpk3, Sidt2, Yif1b, Mrs2, and Pnpla2) had not been previously identified as having myopathies. These findings support the need to include histopathology in phenotype screening protocols in order to identify novel genetic myopathies that are not clinically evident or not detected by the inverted screen test.

Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (Ksr2) locus develop severe early-onset obesity and type 2 diabetes (T2D). Both conditions are phenocopied in mice with Ksr2 deleted, but whether this affects bone health remains unknown. Here we studied the bones of global Ksr2 null mice and found that Ksr2 negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, Ksr1, was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with Ksr2’s known role as a regulator of feeding by its function in the hypothalamus, pair feeding and osteoblast-specific conditional deletion of Ksr2 reveals that Ksr2 can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in absence of Ksr2, bone strength, as well as fracture healing response remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how Ksr2, an adiposity and diabetic gene, regulates bone metabolism.

Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (KSR2) locus develop severe early-onset obesity and type 2 diabetes. Both conditions are phenocopied in mice withOur bones are living tissues which constantly reshape and renew themselves. This ability relies on stem cells present in the marrow cavity, which can mature into the various types of cells needed to produce new bone material, marrow fat, or other components. Obesity and associated conditions such as type 2 diabetes are often linked to harmful changes in the skeleton. In particular, these metabolic conditions are associated with weight-bearing bones becoming more prone to facture and healing poorly. Mice genetically modified to model obesity and diabetes could help researchers to study exactly how these conditions – and the genetic changes that underlie them – impact bone health. Gomez et al. aimed to address this question by focusing on

OBJECTIVE Inhibiting sodium–glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters. RESEARCH DESIGN AND METHODS Using a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h. RESULTS Changes from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed. CONCLUSIONS Changes from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069).

Lupus Nephritis (LN) is the leading cause of morbidity and mortality from Systemic Lupus Erythematosus (SLE) and enhanced activation of the transcription regulator nuclear factor kappa B (NF-κB) is implicated as a central player in the development and progression of LN. SLE and LN are proposed to develop through a "two-hit" process of genetic mutation or variants providing susceptibility to disease provoking molecular events in response to environmental triggers (viral infection, medication, etc.). Many of the susceptibility genes identified in association with LN are involved in NF-κB regulation and loss of function of some of the protein products in animal's results in protection from or development of SLE and LN phenotypes. This short commentary will discuss these factors and implications in precision treatment of LN.