Cities have come to play an important role in the global governance of climate change, and are increasingly recognized as a crucial component of the post-Paris climate regime. Based in part on their ...jurisdictional authority, shared commitment to action and disdain for negotiations, there is considerable optimism that cities can meaningfully contribute to the creation of an effective bottom-up global response. Focusing on the processes through which cities themselves are being steered towards particular actions and objectives, attention is directed towards the recent explosion of efforts to engender coordinated efforts and activities between cities through the conceptual lens of orchestration. The practice of orchestration is unpacked, and the importance of identifying who orchestrates, how, and in the service of which/whose objectives is highlighted. Thus, analysis is oriented towards the politics and power dynamics of orchestration, and a step is taken towards critically assessing the promise and potential of ongoing activities in the realm of global urban climate governance.
Chiral molecules exist as pairs of nonsuperimposable mirror images; a fundamental symmetry property vastly underexplored in organic electronic devices. Here, we show that organic field-effect ...transistors (OFETs) made from the helically chiral molecule 1-aza6helicene can display up to an 80-fold difference in hole mobility, together with differences in thin-film photophysics and morphology, solely depending on whether a single handedness or a 1:1 mixture of left- and right-handed molecules is employed under analogous fabrication conditions. As the molecular properties of either mirror image isomer are identical, these changes must be a result of the different bulk packing induced by chiral composition. Such underlying structures are investigated using crystal structure prediction, a computational methodology rarely applied to molecular materials, and linked to the difference in charge transport. These results illustrate that chirality may be used as a key tuning parameter in future device applications.
Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has ...increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors ...have been identified in mice
. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma
. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2-RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2-RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2-RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.
Metformin, the most commonly prescribed anti‐diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive ...function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti‐aging drug—the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose‐dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.
We monitored metformin impact in nine strains spanning three Caenorhabditis species that feature a nucleotide diversity greater than that between mouse and humans. We find that metformin promotes healthy aging across diverse genetic backgrounds, but that genetic background can determine whether metformin has a positive, neutral, or negative effect. Data demonstrate the potential broad reach of metformin but also underscore that individual genetics will underlie efficacy over a diverse test set.
The center of mass (CoM) is the location in a body where mass distribution is balanced. It has a fundamental role in balance and motion which has been poorly described in the dog. The objective of ...this study was to estimate the variance of the center of mass (CoM) in a heterogeneous population of client-owned dogs and to describe the relationship between CoM, subject morphometrics and an inertial measurement unit (IMU) box positioned ventrally on a neck collar. A single force platform and a reaction board were used to determine CoM in the transverse, sagittal and dorsal planes in thirty-one healthy adult dogs. A series of morphometric measurements were acquired with each dog standing, including distances relative to an IMU box positioned ventrally on a neck collar. Mean transverse plane CoM was 48% the distance from ischium to the IMU box, near the xiphoid process. Mean sagittal place CoM was 59% the width of the chest on the left side. Mean dorsal plane CoM was 41% the distance from the most dorsal to the most ventral aspect of the body. Dog length was the primary variable required to maximize the relationship between three-dimensional CoM and identifiable variables measured. A CoM based normalization procedure should be considered to normalize mass or motion based outcome measure output (e.g., ground reaction forces, vector acceleration) in a heterogeneous population of dogs. Future research will be needed to determine if CoM-based normalization procedures reduce variance in outcome measures affected by subject morphometrics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In social science and popular parlance, Black low-income fathers continue to be represented as largely absent, disengaged, and negligent. These negative representations belie emerging qualitative and ...quantitative empirical data that demonstrate Black fathers, across lines of class, are constructively and responsibly involved in the lives of their children. The present study used qualitative data from 2 focus groups (n = 6 and n = 5) and 9 individual interviews with low-income, urban-residing Black men who are coresiding caregivers to young children (Mchild age = 47.9 months, SD = 11.4) to clarify how these men conceive of and pursue positive parenting. Caregivers were recruited from 11 Head Start programs in New York City. Interviews lasted 90-120 min and were transcribed verbatim. Content and thematic analysis of verbatim transcripts yielded 23 thematic codes related to men's views of positive parenting. Themes revealed that fathers constructed positive parenting as a "generative" enterprise. However, generativity for these fathers reflected different concerns from generative parenting as conceived in extant literatures. In particular, our findings suggest the need to expand existing understandings of generative parenting by attending to challenges of emotional honesty, authenticity, dignity, and community.
Public Significance Statement
Over the past decade, more than $100 million in federal funding has been targeted to promoting positive fathering, particularly among low-income Black fathers. However, the success of such initiatives depends on leveraging how low-income Black men conceive of and enact positive parenting. This study contributes to the public good by offering evidence of men's conceptualizations and enactments of what it means to parent well.
Limiting the debilitating consequences of ageing is a major medical challenge of our time. Robust pharmacological interventions that promote healthy ageing across diverse genetic backgrounds may ...engage conserved longevity pathways. Here we report results from the Caenorhabditis Intervention Testing Program in assessing longevity variation across 22 Caenorhabditis strains spanning 3 species, using multiple replicates collected across three independent laboratories. Reproducibility between test sites is high, whereas individual trial reproducibility is relatively low. Of ten pro-longevity chemicals tested, six significantly extend lifespan in at least one strain. Three reported dietary restriction mimetics are mainly effective across C. elegans strains, indicating species and strain-specific responses. In contrast, the amyloid dye ThioflavinT is both potent and robust across the strains. Our results highlight promising pharmacological leads and demonstrate the importance of assessing lifespans of discrete cohorts across repeat studies to capture biological variation in the search for reproducible ageing interventions.
Small mammal species are declining across northern Australia. Predation by feral cats Felis sylvestris catus is one hypothesised cause. Most evidence of cat impacts on native prey comes from islands, ...where cat densities are often high, but cats typically occur at low densities on mainland Australia. We conducted a field experiment to measure the effect of predation by low‐density cat populations on the demography of a native small mammal. We established two 12·5‐ha enclosures in tropical savanna in the Northern Territory. Each enclosure was divided in half, with cats allowed access to one half but not the other. We introduced about 20 individuals of a native rodent, Rattus villosissimus, into each of the four compartments (two enclosures × two predator‐access treatments). We monitored rat demography by mark‐recapture analysis and radiotracking, and predator incursions by camera surveillance and track and scat searches. Rat populations persisted over the duration of the study (18 months) in the predator‐proof treatment, where we detected no predator incursions, but declined to extinction in both predator‐accessible compartments. In one case, cat incursions were frequently detected and the rat population was rapidly extirpated (<3 months); in the other, cat incursions were infrequent, and the population declined more gradually (c. 16 months) due to low recruitment. We detected no incursions by dingoes Canis dingo, the other mammalian predator in the area. Synthesis and applications. This is the first study to provide direct evidence that cats are capable of extirpating small mammals in a continental setting, in spite of their low population densities. This finding supports the hypothesis that predation by feral cats is contributing to declines of small mammals in northern Australia. The conservation management of native small mammals in northern Australia may require intensive control of cat populations, including large cat‐free enclosures.
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