Expansion of anthropogenic noise and night lighting across our planet
is of increasing conservation concern
. Despite growing knowledge of physiological and behavioural responses to these stimuli ...from single-species and local-scale studies, whether these pollutants affect fitness is less clear, as is how and why species vary in their sensitivity to these anthropic stressors. Here we leverage a large citizen science dataset paired with high-resolution noise and light data from across the contiguous United States to assess how these stimuli affect reproductive success in 142 bird species. We find responses to both sensory pollutants linked to the functional traits and habitat affiliations of species. For example, overall nest success was negatively correlated with noise among birds in closed environments. Species-specific changes in reproductive timing and hatching success in response to noise exposure were explained by vocalization frequency, nesting location and diet. Additionally, increased light-gathering ability of species' eyes was associated with stronger advancements in reproductive timing in response to light exposure, potentially creating phenological mismatches
. Unexpectedly, better light-gathering ability was linked to reduced clutch failure and increased overall nest success in response to light exposure, raising important questions about how responses to sensory pollutants counteract or exacerbate responses to other aspects of global change, such as climate warming. These findings demonstrate that anthropogenic noise and light can substantially affect breeding bird phenology and fitness, and underscore the need to consider sensory pollutants alongside traditional dimensions of the environment that typically inform biodiversity conservation.
Neurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded ...across the mouse visual system, we use two-photon imaging to measure receptive fields (RFs) and size-tuning in primary visual cortex (V1) and three downstream higher visual areas (HVAs: LM (lateromedial), AL (anterolateral), and PM (posteromedial)) in mice of both sexes. Neurons in PM, compared with V1 or the other HVAs, have significantly larger RF sizes and less surround suppression, independent of stimulus eccentricity or contrast. To understand how this specialization of RFs arises in the HVAs, we measured the spatial properties of V1 inputs to each area. Spatial integration of V1 axons was remarkably similar across areas and significantly different from the tuning of neurons in their target HVAs. Thus, unlike other visual features studied in this system, specialization of spatial integration in PM cannot be explained by specific projections from V1 to the HVAs. Further, the differences in RF properties could not be explained by differences in convergence of V1 inputs to the HVAs. Instead, our data suggest that distinct inputs from other areas or connectivity within PM may support the area's unique ability to encode global features of the visual scene, whereas V1, LM, and AL may be more specialized for processing local features.
Surround suppression is a common feature of visual processing whereby large stimuli are less effective at driving neuronal responses than smaller stimuli. This is thought to enhance efficiency in the population code and enable higher-order processing of visual information, such as figure-ground segregation. However, this comes at the expense of global computations. Here we find that surround suppression is not equally represented across mouse visual areas: primary visual cortex has substantially more surround suppression than higher visual areas, and one higher area has significantly less suppression than two others examined, suggesting that these areas have distinct functional roles. Thus, we have identified a novel dimension of specialization in the mouse visual cortex that may enable both local and global computations.
The extent of artificial night light and anthropogenic noise (i.e., “light” and “noise”) impacts is global and has the capacity to threaten species across diverse ecosystems. Existing research ...involving impacts of light or noise has primarily focused on noise or light alone and single species; however, these stimuli often co‐occur and little is known about how co‐exposure influences wildlife and if and why species may vary in their responses. Here, we had three aims: (1) to investigate species‐specific responses to light, noise, and the interaction between the two using a spatially explicit approach to model changes in abundance of 140 prevalent bird species across North America, (2) to investigate responses to the interaction between light exposure and night length, and (3) to identify functional traits and habitat affiliations that explain variation in species‐specific responses to these sensory stimuli with phylogenetically informed models. We found species that responded to noise exposure generally decreased in abundance, and the additional presence of light interacted synergistically with noise to exacerbate its negative effects. Moreover, the interaction revealed negative emergent responses for several species that only reacted when light and noise co‐occurred. Additionally, an interaction between light and night length revealed 47 species increased in abundance with light exposure during longer nights. In addition to modifying behavior with optimal temperature and potential foraging opportunities, birds might be attracted to light, yet suffer inadvertent physiological consequences. The trait that most strongly related to avian response to light and noise was habitat affiliation. Specifically, species that occupy closed habitat were less tolerant of both sensory stressors compared to those that occupy open habitat. Further quantifying the contexts and intrinsic traits that explain how species respond to noise and light will be fundamental to understanding the ecological consequences of a world that is ever louder and brighter.
Based on over 3.4 million observations of birds at feeders from across the contiguous USA, this study documents influences of noise and light pollution, plus their interaction, on 140 bird species. Birds tend to decline in abundance with noise exposure and exposure to light pollution accentuates the negative effect of noise. Still, interactions with noise and light were diverse, spanning across antagonistic, synergistic, and emergent responses. Additionally, many species tended to increase in abundance with elevated light pollution when nights were longer. In general, birds that live in forests were more sensitive to noise and light than those in more open habitats.
Reports of the use of whole-exome sequencing in clinical practice are limited. We report our experience with whole-exome sequencing in 115 patients in a single center and evaluate its feasibility and ...clinical usefulness in clinical care.
Whole-exome sequencing was utilized based on the judgment of three clinical geneticists. We describe age, gender, ethnicity, consanguinity, indication for testing, family history, insurance, laboratory results, clinician interpretation of results, and impact on patient care.
Most patients were children (78.9%). The most common indications for testing were birth defects (24.3%) and developmental delay (25.2%). We identified four new candidate human disease genes and possibly expanded the disease phenotypes associated with five different genes. Establishing a diagnosis led to discontinuation of additional planned testing in all patients, screening for additional manifestations in eight, altered management in fourteen, novel therapy in two, identification of other familial mutation carriers in five, and reproductive planning in six.
Our results show that whole-exome sequencing is feasible, has clinical usefulness, and allows timely medical interventions, informed reproductive choices, and avoidance of additional testing. Our results also suggest phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods.
Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed ...B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.
This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1.
Metastatic breast cancer is incurable. In order to improve patient survival, it is critical to develop a better understanding of the molecular mechanisms that regulate metastasis and the underlying ...process of cell motility. Here, we focus on the role of the adaptor molecule Breast Cancer Antiestrogen Resistance 3 (BCAR3) in cellular processes that contribute to cell motility, including protrusion, adhesion remodeling, and contractility. Previous work from our group showed that elevated BCAR3 protein levels enhance cell migration, while depletion of BCAR3 reduces the migratory and invasive capacities of breast cancer cells. In the current study, we show that BCAR3 is necessary for membrane protrusiveness, Rac1 activity, and adhesion disassembly in invasive breast cancer cells. We further demonstrate that, in the absence of BCAR3, RhoA-dependent signaling pathways appear to predominate, as evidenced by an increase in RhoA activity, ROCK-mediated phosphorylation of myosin light chain II, and large ROCK/mDia1-dependent focal adhesions. Taken together, these data establish that BCAR3 functions as a positive regulator of cytoskeletal remodeling and adhesion turnover in invasive breast cancer cells through its ability to influence the balance between Rac1 and RhoA signaling. Considering that BCAR3 protein levels are elevated in advanced breast cancer cell lines and enhance breast cancer cell motility, we propose that BCAR3 functions in the transition to advanced disease by triggering intracellular signaling events that are essential to the metastatic process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fluoride/proton antiporters of the CLC
family combat F
toxicity in bacteria by exporting this halide from the cytoplasm. These transporters belong to the widespread CLC superfamily but display ...transport properties different from those of the well-studied Cl
/H
antiporters. Here, we report a structural and functional investigation of these F
-transport proteins. Crystal structures of a CLC
homolog from Enterococcus casseliflavus are captured in two conformations with simultaneous accessibility of F
and H
ions via separate pathways on opposite sides of the membrane. Manipulation of a key glutamate residue critical for H
and F
transport reverses the anion selectivity of transport; replacement of the glutamate with glutamine or alanine completely inhibits F
and H
transport while allowing for rapid uncoupled flux of Cl
. The structural and functional results lead to a 'windmill' model of CLC antiport wherein F
and H
simultaneously move through separate ion-specific pathways that switch sidedness during the transport cycle.
Six Sigma and Lean methodologies are effective quality improvement tools in many health care settings. We applied the DMAIC methodology (define, measure, analyze, improve, control) to address ...deficiencies in our pediatric anesthesia supply chain. We defined supply chain problems by mapping existing processes and soliciting comments from those involved. We used daily distance walked by anesthesia technicians and number of callouts for missing supplies as measurements that we analyzed before and after implementing improvements (anesthesia cart redesign). We showed improvement in the metrics after those interventions were implemented, and those improvements were sustained and thus controlled 1 year after implementation.
Synopsis
Artificial light at night (ALAN) functions as a novel environmental stimulus that has the potential to disrupt interactions among species. Despite recent efforts to explain nocturnal ...pollinators’ responses to this stimulus, the likelihood and associated mechanisms of attraction toward artificial light and potential consequences on fitness for diurnal pollinators are still largely unclear. Here, we took advantage of the obligate mutualism between yucca moths (Tegeticula maculata maculata) and yucca plants (Hesperoyucca whipplei) to understand how direct light exposure and skyglow can influence a pairwise plant–pollinator interaction. To surmise whether adult moths exhibit positive phototaxis, we deployed a set of field-placed light towers during the peak of yucca flowering and compared the number of moths caught in traps between dark-controlled and light-treated trials. Adult moth abundance was much higher when light was present, which suggests that ALAN may alter this diurnal moth’s activity patterns to expand their temporal niche into the night. To evaluate ALAN effects on yucca fruit set and moth larva recruitment, we measured skyglow exposure above yucca plants and direct light intensity from a second set of light towers. Both larva and fruit recruitment increased with skyglow, and fruit set also increased with direct lighting, but the relationship was weaker. Contrarily, larva recruitment did not change when exposed to a gradient of direct light, which may instead reflect effects of ALAN on moth physiology, such as disrupted female oviposition, or misdirecting behaviors essential to oviposition activity. Our results suggest that ALAN can positively influence the fitness of both plants and moths in this tightly co-evolved mutualism, but the benefits to each species may depend on whether night lighting is direct or indirect. Whether such effects and mechanisms could relate to susceptibility to the presence of ALAN on this or other plant–pollinator relationships will remain an important focus of future research.
Immune effector cell (IEC) therapies have revolutionized our approach to relapsed B-cell malignancies, and interest in the investigational use of IECs is rapidly expanding into other diseases. ...Current challenges in the analysis of IEC therapies include small sample sizes, limited access to clinical trials and a paucity of predictive biomarkers of efficacy and toxicity associated with IEC therapies. Retrospective and prospective multi-center cell therapy trials can assist in overcoming these barriers through harmonization of clinical endpoints and correlative assays for immune monitoring, allowing additional cross-trial analysis to identify biomarkers of failure and success. The Consortium for Pediatric Cellular Immunotherapy (CPCI) offers a unique platform to address the aforementioned challenges by delivering cutting-edge cell and gene therapies for children through multi-center clinical trials. Here the authors discuss some of the important pre-analytic variables, such as biospecimen collection and initial processing procedures, that affect biomarker assays commonly used in IEC trials across participating CPCI sites. The authors review the recent literature and provide data to support recommendations for alignment and standardization of practices that can affect flow cytometry assays measuring immune effector function as well as interpretation of cytokine/chemokine data. The authors also identify critical gaps that often make parallel comparisons between trials difficult or impossible.
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