LIM Kinase Regulation of Cytoskeletal Dynamics is Required for Salivary Gland Branching Morphogenesis

Coordinated actin microfilament and microtubule dynamics is required for salivary gland development, although the mechanisms by which they contribute to branching morphogenesis are not defined. Because LIM kinase (LIMK) regulates both actin and microtubule organization, we investigated the role of LIMK signaling in mouse embryonic submandibular salivary glands using ex vivo organ cultures. Both LIMK 1 and 2 were necessary for branching morphogenesis and functioned to promote epithelial early- and late-stage cleft progression through regulation of both microfilaments and microtubules. LIMK-dependent regulation of these cytoskeletal systems was required to control focal adhesion protein– dependent fibronectin assembly and integrin β1 activation, involving the LIMK effectors cofilin and TPPP/p25, for assembly of the actin- and tubulin-based cytoskeletal systems, respectively. We demonstrate that LIMK regulates the early stages of cleft formation—cleft initiation, stabilization, and progression—via establishment of actin stability. Further, we reveal a novel role for the microtubule assembly factor p25 in regulating stabilization and elongation of late-stage progressing clefts. This study demonstrates the existence of multiple actin- and microtubule-dependent stabilization steps that are controlled by LIMK and are required in cleft progression during branching morphogenesis

Multiplatform Analysis of Intratumoral PTEN Heterogeneity in Melanoma

Loss of protein expression of the tumor suppressor PTEN is associated with increased cancer aggressiveness, decreased tumor immune infiltration, and resistance to immune and targeted therapies in melanoma. We assessed a unique cohort of eight melanoma samples with focal loss of PTEN protein expression to understand the features and mechanisms of PTEN loss in this disease. We compared the PTEN-negative (PTEN[-]) areas to their adjacent PTEN-positive (PTEN[+]) areas using DNA sequencing, DNA methylation, RNA expression, digital spatial profiling, and immunohistochemical platforms. Variations or homozygous deletions of PTEN were identified in PTEN(-) areas that were not detected in the adjacent PTEN(+) areas in three cases (37.5%), but no clear genomic or DNA methylation basis for loss was identified in the remaining PTEN(-) samples. RNA expression data from two independent platforms identified a consistent increase in chromosome segregation gene expression in PTEN(-) versus adjacent PTEN(+) areas. Proteomic analysis showed a relative paucity of tumor-infiltrating lymphocytes in PTEN(-) versus adjacent PTEN(+) areas. The findings add to our understanding of potential molecular intratumoral heterogeneity in melanoma and the features associated with the loss of PTEN protein in this disease

Myocardial Fat Imaging

The presence of intramyocardial fat may form a substrate for arrhythmias, and fibrofatty infiltration of the myocardium has been shown to be associated with sudden death. Therefore, noninvasive detection could have high prognostic value. Fat-water–separated imaging in the heart by MRI is a sensitive means of detecting intramyocardial fat and characterizing fibrofatty infiltration. It is also useful in characterizing fatty tumors and delineating epicardial and/or pericardial fat. Multi-echo methods for fat and water separation provide a sensitive means of detecting small concentrations of fat with positive contrast and have a number of advantages over conventional chemical-shift fat suppression. Furthermore, fat and water–separated imaging is useful in resolving artifacts that may arise due to the presence of fat. Examples of fat-water–separated imaging of the heart are presented for patients with ischemic and nonischemic cardiomyopathies, as well as general tissue classification

The relationships between biotic uniqueness and abiotic uniqueness are context dependent across drainage basins worldwide

[EN] Context: Global change, including land-use change and habitat degradation, has led to a decline in biodiversity, more so in freshwater than in terrestrial ecosystems. However, the research on freshwaters lags behind terrestrial and marine studies, highlighting the need for innovative approaches to comprehend freshwater biodiversity. Objectives: We investigated patterns in the relationships between biotic uniqueness and abiotic environmental uniqueness in drainage basins worldwide. Methods: We compiled high-quality data on aquatic insects (mayflies, stoneflies, and caddisflies at genus-level) from 42 drainage basins spanning four continents. Within each basin we calculated biotic uniqueness (local contribution to beta diversity, LCBD) of aquatic insect assemblages, and four types of abiotic uniqueness (local contribution to environmental heterogeneity, LCEH), categorized into upstream land cover, chemical soil properties, stream site landscape position, and climate. A mixed-effects meta-regression was performed across basins to examine variations in the strength of the LCBD-LCEH relationship in terms of latitude, human footprint, and major continental regions (the Americas versus Eurasia). Results: On average, relationships between LCBD and LCEH were weak. However, the strength and direction of the relationship varied among the drainage basins. Latitude, human footprint index, or continental location did not explain significant variation in the strength of the LCBD-LCEH relationship. Conclusions: We detected strong context dependence in the LCBD-LCEH relationship across the drainage basins. Varying environmental conditions and gradient lengths across drainage basins, land-use change, historical contingencies, and stochastic factors may explain these findings. This context dependence underscores the need for basin-specific management practices to protect the biodiversity of riverine systemsSIOpen Access funding provided by University of Oulu (including Oulu University Hospital). The work for this article was supported by the Academy of Finland’s grant to JHeino for the project GloBioTrends (Grant No. 331957). JGG was funded by the European Union Next Generation EU/PRTR (Grant No. AG325). Work by LMB has been continuously supported by the National Council for Scientifc & Technological Development (CNPq) and Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) (grants 308974/2020–4 and 465610/2014–5). PB and ZC were fnancially supported by the National Research Development and Innovation Ofce (NKFIH FK 135 136), and PB was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences BO-00106–21. LB thanks the National Council for Scientifc and Technological Development (CNPq) for the Scientifc Initiation Fellowship for JVASS and the productivity fellowship in research to LSB (process nº. 305929/2022–4). MC was awarded National Council for Scientifc & Technological Development (CNPq) research productivity grant 304060/2020–8 and received grants (PPM 00104–18, APQ-00261–22) from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais. SD and JRGM acknowledge funding by the Leibniz Competition (Grant No. J45/2018) and the German Federal Ministry of Education and Research (BMBF grant agreement number no. 033W034A). DRM was supported by National Council for Scientifc & Technological Development (CNPq) (Grant No. PQ-309763–2020-7). DMPC received a postdoctoral scholarship from P&D Aneel- Cemig GT-611. PH was partially funded by the eLTER PLUS project (Grant Agreement No. 871128). LJ is grateful to 33 Forest, CIKEL Ltd. and Instituto de Floresta Tropical (IFT), Biodiversity Research Consortium Brazil-Norway (BRC), and Norsk Hydro for the fnancial and logistical support for sampling. Brazilian National Council for Scientifc and Technological Development (CNPq) is acknowledged for fnancing the projects and for granting a research productivity fellowship to LJ (304710/2019–9). APJF was supported by Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq, Brazil, process no. 449315/2014–2 and 481015/2011–6). RL also received a research productivity fellowship from CNPq (grant # 312531/2021–4). MSL received a postdoctoral scholarship from ANEEL/CEMIG (Project GT-599). Part of feld sampling and aquatic insects processing were funded by Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq; 403758/2021–1); Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM; Programa Biodiversa) and INCT ADAPTA II – (CNPq: 465540/2014–7; FAPEAM: 062.1187/2017). NH (308970/2019–5) received productivity fellowships from CNPq. RTM received a fellowship from Biodiversa/FAPEAM (01.02.016301.03271/2021–93). KLM acknowledges fnancial support from the Swiss Federal Ofce for the Environment to undertake data collection. Funding for the Segura River basin project was provided by the Seneca Foundation and the European Fund of Regional Development (PLP10/FS/97). FOR was supported by CNPq research grant. TS was partially funded by grant 13/50424–1 and 21/00619–7 from the São Paulo Research Foundation (FAPESP), and by grant 309496/2021–7 from the Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq). FVN was supported by grant #2021/13299–0, São Paulo Research Foundation (FAPESP). ALA acknowledges Brazilian National Council for Scientifc and Technological Development (CNPq, Brazil) for granting a postdoctoral scholarship to her (process number: 167873/2022–9

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection