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The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

Single-cell RNA sequencing allows us to model cellular state dynamics and fate decisions using expression similarity or RNA velocity to reconstruct state-change trajectories; however, trajectory inference does not incorporate valuable time point information or utilize additional modalities, whereas methods that address these different data views cannot be combined or do not scale. Here we present CellRank 2, a versatile and scalable framework to study cellular fate using multiview single-cell data of up to millions of cells in a unified fashion. CellRank 2 consistently recovers terminal states and fate probabilities across data modalities in human hematopoiesis and endodermal development. Our framework also allows combining transitions within and across experimental time points, a feature we use to recover genes promoting medullary thymic epithelial cell formation during pharyngeal endoderm development. Moreover, we enable estimating cell-specific transcription and degradation rates from metabolic-labeling data, which we apply to an intestinal organoid system to delineate differentiation trajectories and pinpoint regulatory strategies.

We sought to determine the association between intrauterine device (IUD) malposition and previous cesarean delivery (CD) and related uterine anatomical changes. A retrospective cohort of all persons with an IUD presenting for two‐ and three‐dimensional pelvic ultrasonography over 2 years, for any gynecologic indication, was compiled. IUD malposition was defined as IUD partially or completely positioned outside the endometrial cavity. Uterine position, uterine flexion, and cesarean scar defect (CSD) size were assessed. Patient characteristics and sonographic findings were compared between those with normally positioned and malpositioned IUD. Primary outcome was the rate of IUD malposition in persons with and without a history of CD. Logistic regression analysis was used to control for potential confounders. Two hundred ninety‐six persons with an IUD had a pelvic ultrasound, 240 (81.1%) had a normally positioned IUD, and 56 (18.9%) had a malpositioned IUD. The most common location of IUD malposition was low uterine segment and cervix (67.9%). Malpositioned IUD was associated with referral for evaluation of pelvic pain (P= .001). Prior CD was significantly associated with a malpositioned IUD, after adjusting for confounders (aOR 3.50, 95% CI 1.31–9.35, P= .01). Among persons with prior CD, uterine retroflexion and a large CSD were independent risk factors for IUD malposition (aOR 4.1, 95% CI 1.1–15.9, P= .04 and aOR 5.4, 95% CI 1.4–20.9, P= .01, respectively). Prior CD is associated with significantly increased risk of IUD malposition. Among persons with previous CD, those with a retroflexed uterus and a large CSD are more likely to have a malpositioned IUD.

Global agri-food systems couple sustainability challenges in producing countries to consumption behavior and regulations in destination markets. We assume that trade relations can be prioritized according to (1) the relevance (share of imports) and (2) leverage (share of domestic production for destination market). This study analyzes the relevance and leverage of the EU’s crop imports in monetary values, footprints, and deforestation. Our results identify high relevance and leverage values in trade relations with specific partner countries, particularly palm oil and rubber specialists in East Asia and soy-producing MERCOSUR countries. High leverage values in imports from African-Caribbean-Pacific small sugar specialists and other small countries highlight the EU’s potential to establish sustainability criteria. We suggest that the EU revises incoherent foreign and domestic policies and proactively engages with trading partners to include sustainability safeguards in the whole value chain with particular focus on trade relations with high relevance and leverage values.

As cancers progress, they become increasingly aggressive—metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3–5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1licenses non-canonical reprogramming.

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR–CLCN6, WNT3A, NPR3, PGRand RGL3), including two loci (PLCE1and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.

Although cell-free DNA (cfDNA) prenatal screening is widely used and has high sensitivity and specificity, there are circumstances in which the screening does not provide an interpretable result. Although this is relatively uncommon, it happens enough that clinical implications and potential reasons for follow-up should be studied and assessed. This study was designed to evaluate outcomes for pregnancies with nonreportable results on cfDNA screening tests.This study was a secondary analysis of the data from a multicenter prospective observational study of cfDNA screening for aneuploidy and 22q11.2 deletion syndrome. All patients were tested for trisomies 13, 18, and 21, as well as the 22q11.2 deletion syndrome, and all patients had confirmatory testing on the newborns in addition to collecting obstetric and perinatal outcomes. Inclusion criteria were women older than 18 years and at greater than 9 weeks of gestation with a singleton pregnancy. Exclusion criteria were having received cfDNA screening results before enrollment, organ transplant, ovum donation, vanishing twin, or being unwilling to provide a newborn sample. The primary outcome was the rate of adverse obstetrical and perinatal outcomes, including aneuploidy; preterm birth at less than 28, 34, or 37 weeks' gestation; preeclampsia; small for gestational age birth; and a composite outcome that included preterm birth before 37 weeks, preeclampsia, stillbirth at greater than 20 weeks, and small for gestational age.Final analyses included 17,851 individuals who had cfDNA screening, confirmatory genetic testing on the newborn, and obstetrical and perinatal outcomes recorded. Nonreportable results were found in 602 individuals (3.4%) after the first draw, with 32.2% of these due to low fetal fraction. Another third of the cohort had patterns where the risk of aneuploidy was uninterpretable but with an adequate fetal fraction, and in the final third, the fetal fraction could not be measured. Of the original 602 cases of nonreportable findings, 427 had a second draw, with 112 of these (26.2%) again having nonreportable results. There were no significant differences in baseline characteristics of age and parity for those with successful versus nonreportable test results; gestational age was significantly higher in individuals with nonreportable results (14.4 vs 13.4 weeks, P< 0.001), as was body mass index (26.2 vs 31.3), and the rate of chronic hypertension (4.0% vs 9.7%).In this cohort, there were 133 genetically confirmed trisomies, with 100 fetuses with trisomy 21, 18 individuals with trisomy 18, and 15 individuals with trisomy 13. Overall, the rate of aneuploidy was 1.7% in individuals with nonreportable results, versus 0.7% in those with reported results (P= 0.013; adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI], 1.1–4.0). Rates of preterm birth were also higher in those with nonreportable test results, with delivery at less than 34 weeks at 1.5% in those with a test result, 4.6% in those with one nonreportable test result and 6.9% in those with a second nonreportable test result (aOR, 2.2 and 2.7; 95% CI, 1.4–3.4 and 1.2–6.0, respectively). Preeclampsia showed a similar trend, with rates climbing from 3.9% in those with a reported result to 9.4% with 1 nonreportable result and 16.8% with 2 (aOR, 1.4 and 2.0; 95% CI, 1.0–1.9 and 1.1–3.7, respectively). Chances of live birth were significantly reduced in pregnancies with a nonreportable results (aOR, 0.20; 95% CI, 0.13–0.30), with the chances decreasing more after a second nonreportable test result (aOR, 0.11; 95% CI, 0.06–0.23).The study found that nonreportable cfDNA screening results are associated with an increased risk for aneuploidy, preterm birth, and preeclampsia, with a gradient of increased risk with a second failed test. This adds to literature with conflicting findings surrounding obstetrical complications in those with altered cfDNA levels and with most studies largely focused on characteristics that may be predictive of a nonreportable result rather than outcomes associated with nonreportable results. These results can inform clinicians who have patients with nonreportable test results in a way that may help them provide better care; future research should focus on more fully understanding the adverse outcomes associated with nonreportable tests to maximize this ability for clinicians in the future. Further research should also focus on specific populations or diagnoses to understand if there are fundamental differences in different groups of individuals.

Broad area laser diodes are attractive for the high optical power they can produce. Unfortunately, this high power normally comes at the cost of severely reduced spatial coherence since the wide area of the diode wave-guide is inherently spatially multi-mode along the slow axis. We demonstrate a method to significantly improve the spatial coherence of a high-power broad-area diode by placing it in an external cavity that is mode selective. We design the cavity, such that the diode aperture acts as its own spatial filter, obviating the need for an intra-cavity slit-filter, and optimally utilizing the entire gain medium. We demonstrate this soft filtering method using wide diodes of $200 \rm {\mu m}$ and $300 \rm {\mu m}$ widths and compare its power-efficiency to the standard approach of hard-filtering with a slit. We obtain high-gain operation in a pure single-mode, demonstrating up to 1.5 W CW power at 1064 nm with excellent beam quality ( $M^{2}=1.3$ at 90% power).

While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Tregcell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Tregcell ‘connectivity’ to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Tregcell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Tregcell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Tregcell deprivation in either setting, as well as in Tregcell-poor versus Tregcell-rich human lung adenocarcinomas. Accordingly, punctual Tregcell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.

Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1–6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STINGpromoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner—these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.

Haws syndrome is a relatively common yet poorly understood disorder in cats. Ten cats with acute haws syndrome underwent ophthalmic and physical examinations, bloodwork, faecal analysis and pharmacological testing with 1% phenylephrine. The cats were discharged with broad‐spectrum deworming (with or without metronidazole) as well as topical tetrahydrozoline. Cats were 17.6 ± 9.1 (2‒36) months old. All eyes had bilateral third eyelid protrusion and ptosis but no miosis or other ocular abnormalities. Diarrhoea was noted in four of 10 cats; otherwise, the cats were systemically healthy. A newly adopted kitten with haws syndrome and diarrhoea caused the condition to develop in the other three cats (from the same multicat household) within 4‒11 days. All cats tested negative for feline immunodeficiency virus and feline leukaemia virus. Serum amyloid A levels were elevated in two of eight tested cats. Tests for the presence of Giardiawere positive in four of nine tested cats. Clinical signs transiently resolved within 20 minutes of the application of topical phenylephrine or tetrahydrozoline. Haws syndrome resolved in nine of the 10 cats within 37.7 ± 23 (12‒95) days but recurred in three of the nine cats 156‒182 days later. The small sample size limits the conclusions that can be drawn. Haws syndrome occurs in generally healthy cats, with or without diarrhoea, and is characterised by a sympathetic neuropathy causing bilateral third eyelid protrusion and ptosis. Clinical signs are possibly triggered by contagious gastrointestinal pathogen(s) that presumably affect(s) the gut microbiota and influence(s) the gut‒brain axis.

Upon antigenic stimulation, naïve CD4+ T cells can give rise to phenotypically distinct effector T helper cells and long-lived memory T cells. We computationally reconstructed the in vivo trajectory of CD4+ T cell differentiation during a type I inflammatory immune response and identified two distinct differentiation paths for effector and precursor central memory T cells arising directly from naïve CD4+ T cells. Unexpectedly, our studies revealed heterogeneity among naïve CD4+ T cells, which are typically considered homogeneous save for their diverse T cell receptor usage. Specifically, a previously unappreciated population of naïve CD4+ T cells sensing environmental type I IFN exhibited distinct activation thresholds, suggesting that naïve CD4+ T cell differentiation potential may be influenced by environmental cues. This population was expanded in human viral infection and type I IFN response-lined autoimmunity. Understanding the relevance of naïve T cell heterogeneity to beneficial and maladaptive T cell responses may have therapeutic implications for adoptive T cell therapies in cancer immunotherapy and vaccination.

Substance use disorder, and particularly cocaine use disorder, is a complex disease that affects societal, economic, and psychological factors. Endogenous β-endorphin released after prolonged cocaine withdrawal has been reported to activate the accumbal delta-opioid receptor (DOR), leading to attenuated cocaine seeking.However, using DOR β-endorphin activation to treat cocaine use disorder is impractical since β-endorphin does not cross the blood-brain barrier. Also, only activation of the sub-group DOR1 efficiently attenuates craving, as activation of DOR2 yields an opposite effect. Here, we isolated a specific peptide, PEP1, from a phage display peptide library with similar biological properties to β–endorphin, demonstrating specificity for DOR1 and functioning as full receptor agonists. Our pharmacodynamic results showed fast trafficking incorporation of DOR into the cell membrane, interpreted as superior rehabilitation of the receptor and its bioavailability compared to commercial agonists. We administered PEP1, either intrabrain or intranasal, to rats trained to self-administer cocaine. PEP1 induced a significant decrease in cocaine-craving behavior and reinstatement in three different animal models of addiction. Also, PEP1 did not exhibit rewarding properties and did not interfere with the natural reward system. ICP-OES analysis revealed that at least one hour post-administration, PEP1 was retained in the brain rather than in peripheral organs. These findings render PEP1 a potential novel regulator of cocaine craving, especially for being non-addictive. Hence, PEP1 should be further examined as a possible new therapy for substance use disorder.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jbusvent.2007.02.002 Byline: Aviad Pe'er (a), Ilan Vertinsky (b) Keywords: Exit; Entry; Agglomeration; Local renewal Abstract: This study posits that a local process of creative destruction provides an impetus to regional industrial renewal. We argue that exits of older firms release resources that stimulate local entry. New entrants add value to these resources by redeploying them in more productive uses. We test our hypotheses with a unique longitudinal database encompassing the entry and exit of Canadian manufacturing enterprises. We find that exits of old firms increase entry and that on average new entrants are more productive. Persistent high local rates of exit, however, deter entry. Author Affiliation: (a) Tuck School of Business at Dartmouth, 100 Tuck Hall, Hanover, NH 03755, USA (b) Sauder School of Business, University of British Columbia, 2053 Main Mall, Vancouver, B.C., Canada V6T 1Z2 Article History: Received 1 October 2004; Revised 1 January 2007; Accepted 1 February 2007

The imminent release of tissue atlases combining multichannel microscopy with single-cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards to guide data deposition, curation and release. We describe a Minimum Information about Highly Multiplexed Tissue Imaging (MITI) standard that applies best practices developed for genomics and for other microscopy data to highly multiplexed tissue images and traditional histology.

Computational trajectory inference enables the reconstruction of cell state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank (https://cellrank.org) for single-cell fate mapping in diverse scenarios, including regeneration, reprogramming and disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, taking into account the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in velocity vectors. On pancreas development data, CellRank automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. Applied to lineage-traced cellular reprogramming data, predicted fate probabilities correctly recover reprogramming outcomes. CellRank also predicts a new dedifferentiation trajectory during postinjury lung regeneration, including previously unknown intermediate cell states, which we confirm experimentally.

Patterns of sequencing coverage along a bacterial genome—summarized by a peak-to-trough ratio (PTR)—have been shown to accurately reflect microbial growth rates, revealing a new facet of microbial dynamics and host–microbe interactions. Here, we introduce Compute PTR (CoPTR): a tool for computing PTRs from complete reference genomes and assemblies. Using simulations and data from growth experiments in simple and complex communities, we show that CoPTR is more accurate than the current state of the art while also providing more PTR estimates overall. We further develop a theory formalizing a biological interpretation for PTRs. Using a reference database of 2935 species, we applied CoPTR to a case-control study of 1304 metagenomic samples from 106 individuals with inflammatory bowel disease. We show that growth rates are personalized, are only loosely correlated with relative abundances, and are associated with disease status. We conclude by showing how PTRs can be combined with relative abundances and metabolomics to investigate their effect on the microbiome.

Objectives: To investigate the risk of developing central nervous system (CNS) lymphoma in patients with vitreoretinal lymphoma (VRL) presenting with unilateral versus (vs.) bilateral ocular involvement. Methods: Retrospective, multicentre cohort study from January 1, 1984 to December 31, 2020. Results: There were 218 eyes of 127 patients with isolated VRL of the confirmed or presumed diffuse large B-cell subtype in the absence of known CNS or systemic lymphoma. Overall, mean patient age at presentation was 67 years (median 68, range 22–93 years), with 52 (40%) male, and 118 (90%) Caucasian. By univariate Cox regression analysis, two factors were predictive of decreased risk for development of CNS lymphoma, including initial presentation with unilateral VRL (versus bilateral VRL) (HR 0.5 [0.2–0.9], p= 0.02) and use of systemic chemotherapy for initial treatment of isolated ocular disease (HR 0.2 [0.1–0.6], p= 0.002). Both factors remained significant on multivariate and competing risk analyses. Progression from unilateral to bilateral VRL, patient age at presentation, and ocular structures involved (vitreous, subretinal space, subretinal pigment epithelial space) were not significantly associated with CNS lymphoma risk. Conclusion: Initial presentation with unilateral VRL and treatment of isolated VRL with systemic chemotherapy were associated with lower risk of developing CNS lymphoma. Further study is required to determine whether select patients with isolated VRL might benefit from systemic chemotherapy in the prevention of CNS lymphoma.

Byline: Jacob. Pe'er The eyelids are composed of four layers: skin and subcutaneous tissue including its adnexa, striated muscle, tarsus with the meibomian glands, and the palpebral conjunctiva. Benign and [...]

The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.

Ophthalmoscopy is a valuable tool in clinical practice. We report the use of a novel smartphone‐based handheld device for visualisation and photo‐documentation of the ocular fundus in veterinary medicine. Selected veterinary patients of a referral ophthalmology service were included if one or both eyes had clear ocular media, allowing for examination of the fundus. Following pharmacological mydriasis, fundic images were obtained with a handheld fundus camera (Volk VistaView). For comparison, the fundus of a subset of animals was also imaged with a veterinary‐specific fundus camera (Optomed Smartscope VET2). The large field of view achieved by the Volk VistaView allowed for rapid and thorough observation of the ocular fundus in animals, providing a tool to visualise and record common pathologies of the posterior segment. Captured fundic images were sometimes overexposed, with the tapetal fundus artificially appearing hyperreflective when using the Volk VistaView camera, a finding that was less frequent when activating a ‘veterinary mode’ that reduced the sensitivity of the camera's sensor. The Volk VistaView compared well with the Optomed Smartscope VET2. The main study limitation was the small sample size. The Volk VistaView camera was easy to use and provided good‐quality fundic images in veterinary patients with healthy or diseased eyes, offering a wide field of view that was ideal for screening purposes.

Passive mode-locking relies critically on a saturable loss mechanism to form ultrashort pulses. However, in Kerr-lens mode-locking (KLM), no actual absorption takes place, but rather losses appear due to diffraction, and actual light must escape the cavity. The Kerr-lens effect works to generate through diffraction an effective instantaneous saturable absorber that depends delicately on the interplay between the spatial and temporal profiles of the pulse. Despite the importance of KLM as a technique for generating ultrafast pulses and the fundamental role of diffraction losses in its operation, these losses have never been observed directly. Here, we measure the light that leaks out due to diffraction losses in a hard-aperture Kerr-lens mode-locked Ti:sapphire laser, and compare the measured results with a numerical theory that explicitly calculates the spatiotemporal behavior of the pulse.

We propose and fully analyze the simplest technique to date (to our knowledge) for generating light-based universal quantum computing resources, namely, 2D, 3D, and n-hypercubic cluster states in general. The technique uses two standard optical components: first, a single optical parametric oscillator pumped below threshold by a monochromatic field, which generates Einstein–Podolsky–Rosen entangled states, a.k.a. two-mode squeezed states, over the quantum optical frequency comb; second, phase modulation at frequencies that are multiples of the comb spacing (via RF or optical means). The compactness of this technique paves the way to implementing quantum computing on chip using quantum nanophotonics.

Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Krasoncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Krasmutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an ‘acinar-to-neoplasia’ chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Krasto unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene–environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure1–4, but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases of 14 lung samples from donors who died of COVID-19. Integrated computational analysis uncovered substantial remodelling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of fibroblasts and putative TP63+intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells, which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in heart tissue from donors with COVID-19, and mapped cell types and genes implicated with disease severity based on COVID-19 genome-wide association studies. Our foundational dataset elucidates the biological effect of severe SARS-CoV-2 infection across the body, a key step towards new treatments.

Aberrant inflammation in the CNS has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a new approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular cross-talk along the neuroinflammatory axis in vitro. We used the tri-culture system to model neuroinflammation in Alzheimer’s disease with hPSCs harboring the APPSWE+/+ mutation and their isogenic control. We found that complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated in tri-culture and further enhanced in APPSWE+/+ tri-cultures due to microglia initiating reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in Alzheimer’s disease and presents a broadly applicable platform to study neuroinflammation in human disease.

Despite conservation commitments, most countries still lack large-scale biodiversity monitoring programs to track progress toward agreed targets. Monitoring program design is frequently approached from a top-down, data-centric perspective that ignores the socio-cultural context of data collection. A rich landscape of people and organizations, with a diversity of motivations and expertise, independently engages in biodiversity monitoring. This diversity often leads to complementarity in activities across places, time periods, and taxa. In this Perspective, we propose a framework for aligning different efforts to realize large-scale biodiversity monitoring through a networked design of stakeholders, data, and biodiversity schemes. We emphasize the value of integrating independent biodiversity observations in conjunction with a backbone of structured core monitoring, thereby fostering broad ownership and resilience due to a strong partnership of science, society, policy, and individuals. Furthermore, we identify stakeholder-specific barriers and incentives to foster joint collaboration toward effective large-scale biodiversity monitoring.

Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer — the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives — was initially described in lung cancers harbouring an EGFRmutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.

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.

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.

Immune checkpoint therapy with anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types1,2. Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73himacrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73−/−mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2010.06.006 Byline: Pe'er Dar, Juliana Gebb, Laura Reimers, Peter S. Bernstein, Cynthia Chazotte, Irwin R. Merkatz Keywords: 3-dimensional power Doppler; preeclampsia; screening tool; uteroplacental circulation space Abstract: The objective of the study was to compare 3-dimensional power Doppler (3DPD) of the uteroplacental circulation space (UPCS) in the first trimester between women who develop preeclampsia (PEC) and those who do not and to assess the 3DPD method as a screening tool for PEC. Author Affiliation: Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY Article History: Received 26 July 2009; Revised 2 November 2009; Accepted 7 June 2010 Article Note: (footnote) This study was supported in part by a grant from the Federico Foundation., Cite this article as: Dar P, Gebb J, Reimers L, et al. First-trimester 3-dimensional power Doppler of the uteroplacental circulation space: a potential screening method for preeclampsia. Am J Obstet Gynecol 2010;203:238.e1-7.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajo.2007.12.004 Byline: Anita Panda (a), Jacob Pe'er (a)(b), Anand Aggarwal (a), Hrishikesh Das (a)(c), Abhiyan Kumar (a), Shalini Mohan (a) Abstract: To evaluate patients with ocular surface squamous neoplasia (OSSN) on treatment with topical mitomycin C (MMC) with regard to changes in corneal thickness and endothelial count. Author Affiliation: (a) Cornea, Ocular Surface Disease, and Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India (b) Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (c) Department of Ophthalmology, B P Koirala Institute of Ophthalmology, Dharan, Nepal. Article History: Accepted 1 December 2007

EGFR-mutant lung cancers are clinically and genomically heterogeneous with concurrent RB transcriptional corepressor 1 (RB1)/tumor protein p53 (TP53) alterations identifying a subset at increased risk for small cell transformation. The genomic alterations that induce lineage plasticity are unknown.

A major challenge of analyzing the compositional structure of microbiome data is identifying its potential origins. Here, we introduce fast expectation-maximization microbial source tracking (FEAST), a ready-to-use scalable framework that can simultaneously estimate the contribution of thousands of potential source environments in a timely manner, thereby helping unravel the origins of complex microbial communities (https://github.com/cozygene/FEAST). The information gained from FEAST may provide insight into quantifying contamination, tracking the formation of developing microbial communities, as well as distinguishing and characterizing bacteria-related health conditions.