An optoacoustic field-programmable perceptron for recurrent neural networks.

Recurrent neural networks (RNNs) can process contextual information such as time series signals and language. But their tracking of internal states is a limiting factor, motivating research on analog implementations in photonics. While photonic unidirectional feedforward neural networks (NNs) have demonstrated big leaps, bi-directional optical RNNs present a challenge: the need for a short-term memory that (i) programmable and coherently computes optical inputs, (ii) minimizes added noise, and (iii) allows scalability. Here, we experimentally demonstrate an optoacoustic recurrent operator (OREO) which meets (i, ii, iii). OREO contextualizes the information of an optical pulse sequence via acoustic waves. The acoustic waves link different optical pulses, capturing their information and using it to manipulate subsequent operations. OREO's all-optical control on a pulse-by-pulse basis offers simple reconfigurability and is used to implement a recurrent drop-out and pattern recognition of 27 optical pulse patterns. Finally, we introduce OREO as bi-directional perceptron for new classes of optical NNs.

The NEI Audacious Goals Initiative: Advancing the Frontier of Regenerative Medicine.

Eight years since the launch of the National Eye Institute Audacious Goals Initiative for Regenerative Medicine, real progress has been made in the effort to restore vision by replacing retinal neurons. Although challenges remain, the infrastructure, tools, and preclinical models to support clinical studies in humans are being prepared. Building on the pioneering trials that are replacing the retinal pigment epithelium, it is expected that by the end of this decade first-in-human trials for the replacement of retinal neurons will be initiated.

Highly Strained Nanoscale Bicyclophane Monolayers Entering the Third Dimension: A Combined Synthetic and Scanning Tunneling Microscopy Investigation.

Invited for this month's cover are the collaborating groups of Prof. Dr. Sigurd Höger and Dr. Stefan-S. Jester from Rheinische Friedrich-Wilhelms-Universität Bonn, Germany. The cover picture shows a bicyclophane that forms a two-dimensional supramolecular nanopattern on graphite at the solid/liquid interface. After adsorption, the central unit points towards the volume phase. Read the full text of the article at 10.1002/cplu.202000711.

Update on the Status and Impact of the National Eye Institute Audacious Goals Initiative for Regenerative Medicine.

Purpose: This update will highlight a few of the projects funded by the National Eye Institute (NEI) Audacious Goals Initiative for Regenerative Medicine (AGI) and show their potential to advance regenerative medicine strategies and increase our understanding of the pathobiology of retinal disease. Methods: We summarize the recent updates from a talk given to the scientific community about the progress of various AGI-funded projects. Results: NEI is catalyzing the translation of ocular stem cell therapies with its AGI program. Since 2015, NEI has organized 3 consortia to catalyze stem cell-based therapies. The first focuses on developing functional imaging technologies that can enable noninvasive in vivo monitoring of activity of individual retinal neurons. The second consortium is identifying novel neural regeneration factors in the visual system. The third, funded in September of 2018, aims to generate translation-enabling models that mimic human eye disease and will evaluate the survival and integration of regenerated neurons in the visual system. Conclusions: To date, 3 AGI consortia have catalyzed research in areas that will enable clinical trials for novel regenerative medicine approaches. With the first of the 3 consortia entering the final year of funding, some of these AGI-funded projects stand ready for deployment in the scientific and medical communities.

NEI-Supported Age-Related Macular Degeneration Research: Past, Present, and Future.

Purpose: To review past and current National Eye Institute (NEI)-supported age-related macular degeneration (AMD) activities and initiatives and preview upcoming coordinated efforts for studying AMD. Methods: We conducted and summarized a portfolio analysis and literature review of NEI intramural and extramural AMD activities. Results: The NEI supports a broad range of AMD research, both by individual independent investigators as well as through networks and consortia. The International AMD Genomics Consortium, Age-Related Eye Disease Study, Age-Related Eye Disease Study 2 (AREDS2), and Comparison of AMD Treatments Trial legacy work probed the complex genetics, clinical presentation, and standards of patient care, respectively. The NEI AMD Pathobiology Working Group identified gaps and opportunities for future research efforts. The AMD Ryan Initiative Study and clinical trials testing the efficacies of minocycline to modulate retinal microglia activity and induced pluripotent stem cells-derived retinal pigmented epithelium (RPE) patch implants to rescue photoreceptor cell death are among the future directions for NEI-supported AMD research. Finally, NEI commissioned the creation of AREDS2 participant-derived induced pluripotent stem cell (iPSC) lines linked to their associated genomic and phenotypic datasets. These datasets will also be linked to the data obtained using their associated iPSC-derived cells (RPE, retina, choroid) and made publicly available. Conclusions: Investments by NEI for AMD research will continue to provide invaluable resources to investigators committed to addressing this complex blinding disease and other retinal degenerative diseases. Translational Relevance: NEI now stands poised to expand the resources available to clinical investigators to uncover disease mechanisms and move experimental therapies into clinical trials.

Highly Strained Nanoscale Bicyclophane Monolayers Entering the Third Dimension: A Combined Synthetic and Scanning Tunneling Microscopy Investigation.

Tetrabromo aromatics can be synthesized by the Fischer-Zimmermann condensation of appropriate pyrylium salts with arylene dicarboxylic acid salts. Their cyclization by intramolecular Yamamoto coupling yields strained bicyclophanes with adjustable sizes and different intraannular bridges. All compounds adsorb at the solid/liquid interface on highly oriented pyrolytic graphite (HOPG) and are investigated by scanning tunneling microscopy (STM) with submolecular resolution. The observed two-dimensional (2D) supramolecular nanopatterns depend only on the sizes and alkoxy periphery of the cyclophanes and are independent of the specific structures of the intraannular bridges. Since the central arylene moieties of the smaller species are oriented perpendicular to the planes of the bicyclophanes, their substituents protrude from the surface by up to 1.6 nm after adsorption. Therefore, these molecules are attractive platforms for addressing the volume phase above the graphite surface.

Improved Ocular Tissue Models and Eye-On-A-Chip Technologies Will Facilitate Ophthalmic Drug Development.

In this study, we describe efforts by the National Eye Institute (NEI) and National Center for Advancing Translational Science (NCATS) to catalyze advances in 3-dimensional (3-D) ocular organoid and microphysiological systems (MPS). We reviewed the recent literature regarding ocular organoids and tissue chips. Animal models, 2-dimensional cell culture models, and postmortem human tissue samples provide the vision research community with insights critical to understanding pathophysiology and therapeutic development. The advent of induced pluripotent stem cell technologies provide researchers with enticing new approaches and tools that augment study in more traditional models to provide the scientific community with insights that have previously been impossible to obtain. Efforts by the National Institutes of Health (NIH) have already accelerated the pace of scientific discovery, and recent advances in ocular organoid and MPS modeling approaches have opened new avenues of investigation. In addition to more closely recapitulating the morphologies and physiological responses of in vivo human tissue, key breakthroughs have been made in the past year to resolve long-standing scientific questions regarding tissue development, molecular signaling, and pathophysiological mechanisms that promise to provide advances critical to therapeutic development and patient care. 3-D tissue culture modeling and MPS offer platforms for future high-throughput testing of therapeutic candidates and studies of gene interactions to improve models of complex genetic diseases with no well-defined etiology, such as age-related macular degeneration and Fuchs' dystrophy.

3-D retina organoids: Building platforms for therapies of the future.

Across scientific disciplines, 3-D organoid culture systems offer platforms to integrate basic research findings with clinical care. The National Eye Institute mounted a $1.1 million 3-D Retina Organoid Challenge. Organoids developed through the Challenge will be valuable resources for drug screening, disease modeling, and precision and regenerative medicine.

Canonical and noncanonical g-protein signaling helps coordinate actin dynamics to promote macrophage phagocytosis of zymosan.

Both chemotaxis and phagocytosis depend upon actin-driven cell protrusions and cell membrane remodeling. While chemoattractant receptors rely upon canonical G-protein signaling to activate downstream effectors, whether such signaling pathways affect phagocytosis is contentious. Here, we report that Gαi nucleotide exchange and signaling helps macrophages coordinate the recognition, capture, and engulfment of zymosan bioparticles. We show that zymosan exposure recruits F-actin, Gαi proteins, and Elmo1 to phagocytic cups and early phagosomes. Zymosan triggered an increase in intracellular Ca(2+) that was partially sensitive to Gαi nucleotide exchange inhibition and expression of GTP-bound Gαi recruited Elmo1 to the plasma membrane. Reducing GDP-Gαi nucleotide exchange, decreasing Gαi expression, pharmacologically interrupting Gßγ signaling, or reducing Elmo1 expression all impaired phagocytosis, while favoring the duration that Gαi remained GTP bound promoted it. Our studies demonstrate that targeting heterotrimeric G-protein signaling offers opportunities to enhance or retard macrophage engulfment of phagocytic targets such as zymosan.

Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by studying multiple areas of the same liver from patients with HCC. METHODS: We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes along with the intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center from individual livers of 11 patients with HCC and on selected LCM samples. HBV markers in liver and serum were determined by real-time polymerase chain reaction (PCR) and confocal immunofluorescence. RESULTS: Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HB surface antigen (HBsAg). The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipids and fatty acids, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARα/RXRα nuclear receptors, comprising PGC-1α and FOXO1, two key regulators critically involved not only in the metabolic functions of the liver but also in the life cycle of HBV, acting as essential transcription factors for viral gene expression. These findings were confirmed by gene expression of microdissected hepatocytes. Moreover, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen genes, NUF2 and TTK. CONCLUSIONS: Integrated gene expression profiling of whole liver tissue with that of microdissected hepatocytes demonstrated that HBV-associated HCC is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis, opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets.

Characterizing and Diminishing Autofluorescence in Formalin-fixed Paraffin-embedded Human Respiratory Tissue.

Tissue autofluorescence frequently hampers visualization of immunofluorescent markers in formalin-fixed paraffin-embedded respiratory tissues. We assessed nine treatments reported to have efficacy in reducing autofluorescence in other tissue types. The three most efficacious were Eriochrome black T, Sudan black B and sodium borohydride, as measured using white light laser confocal Λ2 (multi-lambda) analysis. We also assessed the impact of steam antigen retrieval and serum application on human tracheal tissue autofluorescence. Functionally fitting this Λ2 data to 2-dimensional Gaussian surfaces revealed that steam antigen retrieval and serum application contribute minimally to autofluorescence and that the three treatments are disparately efficacious. Together, these studies provide a set of guidelines for diminishing autofluorescence in formalin-fixed paraffin-embedded human respiratory tissue. Additionally, these characterization techniques are transferable to similar questions in other tissue types, as demonstrated on frozen human liver tissue and paraffin-embedded mouse lung tissue fixed in different fixatives.

Root traits contributing to plant productivity under drought.

Geneticists and breeders are positioned to breed plants with root traits that improve productivity under drought. However, a better understanding of root functional traits and how traits are related to whole plant strategies to increase crop productivity under different drought conditions is needed. Root traits associated with maintaining plant productivity under drought include small fine root diameters, long specific root length, and considerable root length density, especially at depths in soil with available water. In environments with late season water deficits, small xylem diameters in targeted seminal roots save soil water deep in the soil profile for use during crop maturation and result in improved yields. Capacity for deep root growth and large xylem diameters in deep roots may also improve root acquisition of water when ample water at depth is available. Xylem pit anatomy that makes xylem less "leaky" and prone to cavitation warrants further exploration holding promise that such traits may improve plant productivity in water-limited environments without negatively impacting yield under adequate water conditions. Rapid resumption of root growth following soil rewetting may improve plant productivity under episodic drought. Genetic control of many of these traits through breeding appears feasible. Several recent reviews have covered methods for screening root traits but an appreciation for the complexity of root systems (e.g., functional differences between fine and coarse roots) needs to be paired with these methods to successfully identify relevant traits for crop improvement. Screening of root traits at early stages in plant development can proxy traits at mature stages but verification is needed on a case by case basis that traits are linked to increased crop productivity under drought. Examples in lesquerella (Physaria) and rice (Oryza) show approaches to phenotyping of root traits and current understanding of root trait genetics for breeding.

The Fukushima Dai-ichi accident: additional lessons from a radiological emergency assistance mission.

In response to the March 2011 earthquake-tsunami disaster and the Fukushima Dai-ichi nuclear accident, a special nongovernmental Radiological Emergency Assistance Mission flew to Japan from the United States. Invited by one of Japan's largest hospital and healthcare groups and facilitated by a New York-based international disaster relief organization, the mission included an emergency physician, a health physicist, and a disaster management specialist. During the 10 d mission, team members conducted fieldwork in areas affected by the earthquake, tsunami, and nuclear accident; went to cities and towns in the 20-30 km Emergency Evacuation Preparation Zone around the damaged nuclear plant; visited other communities affected by the nuclear accident; went to evacuation shelters; met with mayors and other local officials; met with central government officials; exchanged observations, experiences, and information with Japanese medical, emergency response, and disaster management colleagues; and provided radiological information and training to more than 1,100 Japanese hospital and healthcare personnel and first responders. The mission produced many insights with potential relevance for radiological/nuclear emergency preparedness and response. The first "lessons learned" were published in December 2011. Since that time, additional broad insights from the mission and mission followup have been identified. Five of these new lessons, which focus primarily on community impacts and responses and public communication issues, are presented and discussed in this article.

Learning from the 2011 Great East Japan Disaster: insights from a special radiological emergency assistance mission.

On March 11, 2011, the eastern portion of Japan was struck by a massive earthquake and tsunami that killed more than 15,700 people, left thousands of others hurt or missing, and caused widespread destruction. In addition, the Great East Japan Disaster seriously damaged the Fukushima Dai-ichi nuclear power station, knocking out power, severely affecting communications, and causing a loss of cooling to some reactor cores. Significant quantities of radioactive materials were released, a "no go" zone was created around the crippled reactors, and thousands of people were evacuated. With concern about the radiological emergency growing, one of Japan's largest hospital and healthcare groups issued a request for assistance to a U.S.-based international disaster relief organization. After consultations with the Japanese, a special Radiological Emergency Assistance Mission was assembled. The mission, which traveled to Japan in April 2011, had several aims: (1) to rapidly assess the situation on the ground, (2) to exchange information, experiences, and insights with Japanese colleagues, and (3) to provide radiological information and practical refresher training to Japanese healthcare professionals and first responders. In addition to achieving these aims and laying the groundwork for future cooperation, the mission produced dozens of insights and lessons. These have potential relevance not only for future large-scale radiation accidents, but also for radiological and nuclear terrorism situations. They also have more general relevance for emergency planning, preparedness, and response. In this article, several of the most salient insights and lessons are highlighted.

Risk communication and radiological/nuclear terrorism: a strategic view.

It is now widely recognized that effective communication is a crucial element in radiological/nuclear terrorism preparedness. Whereas in the past, communication and information issues were sometimes viewed as secondary in comparison with technical concerns, today the need to improve risk communication, public information, and emergency messaging is seen as a high priority. The process of improving radiological/nuclear terrorism risk communication can be conceptualized as occurring in four overlapping phases. The first phase involves the recognition that communication and information issues will be pivotal in shaping how a radiological/nuclear terrorism incident unfolds and in determining its outcome. This recognition has helped shape the second phase, in which various research initiatives have been undertaken to provide an empirical basis for improved communication. In the third and most recent phase, government agencies, professional organizations and others have worked to translate research findings into better messages and informational materials. Like the first and second phases, the third phase is still unfolding. The fourth phase in risk communication for radiological/nuclear terrorism-a mature phase-is only now just beginning. Central to this phase is a developing understanding that for radiological/nuclear terrorism risk communication to be fully effective, it must go beyond crafting better messages and materials (as essential as that may be). This emerging fourth phase seeks to anchor radiological/nuclear communication in a broader approach: one that actively engages and partners with the public. In this article, each of the four stages is discussed, and future directions for improving radiological/nuclear terrorism risk communication are explored.

Social, psychological, and behavioral responses to a nuclear detonation in a US city: implications for health care planning and delivery.

A nuclear detonation in a US city would have profound psychological, social, and behavioral effects. This article reviews the scientific literature on human responses to radiation incidents and disasters in general, and examines potential behavioral health care provider (BHCP) contributions in the hours and days after a nuclear detonation. In the area directly affected by the blast, the immediate overarching goal of BHCP interventions is the support of lifesaving activities and the prevention of additional casualties from fallout. These interventions include 6 broad categories: promoting appropriate protective actions, discouraging dangerous behaviors, managing patient/survivor flow to facilitate the best use of scarce resources, supporting first responders, assisting with triage, and delivering palliative care when appropriate. At more distant sites, BHCP should work with medical providers to support hospitalized survivors of the detonation. Recommendations are also made on BHCP interventions later in the response phase and during recovery.

Anthropocene streams and base-level controls from historic dams in the unglaciated mid-Atlantic region, USA.

Recently, widespread valley-bottom damming for water power was identified as a primary control on valley sedimentation in the mid-Atlantic US during the late seventeenth to early twentieth century. The timing of damming coincided with that of accelerated upland erosion during post-European settlement land-use change. In this paper, we examine the impact of local drops in base level on incision into historic reservoir sediment as thousands of ageing dams breach. Analysis of lidar and field data indicates that historic milldam building led to local base-level rises of 2-5 m (typical milldam height) and reduced valley slopes by half. Subsequent base-level fall with dam breaching led to an approximate doubling in slope, a significant base-level forcing. Case studies in forested, rural as well as agricultural and urban areas demonstrate that a breached dam can lead to stream incision, bank erosion and increased loads of suspended sediment, even with no change in land use. After dam breaching, key predictors of stream bank erosion include number of years since dam breach, proximity to a dam and dam height. One implication of this work is that conceptual models linking channel condition and sediment yield exclusively with modern upland land use are incomplete for valleys impacted by milldams. With no equivalent in the Holocene or late Pleistocene sedimentary record, modern incised stream-channel forms in the mid-Atlantic region represent a transient response to both base-level forcing and major changes in land use beginning centuries ago. Similar channel forms might also exist in other locales where historic milling was prevalent.

Exercise enhances angiogenesis during bone defect healing in mice.

The aim of the present study was to investigate the effect of exercise on angiogenesis during bone defect healing in mice. We evaluated angiogenesis during cranial bone defect healing by intravital fluorescence microscopy (IVM) at days 0-21. To characterize the type of bone repair, we performed additional histomorphometric analyses at days 3-15. IVM was conducted in mice, which were housed in cages supplied with running wheels (exercise group; n=7) and compared to IVM results of mice, which were housed in cages without running wheels (controls; n=7). In the exercise group, we additionally performed correlation analyses between results of the IVM and the running distance. IVM showed an accelerated decrease of bone defect area in the exercise group compared to the control group. This was associated with a significantly higher blood vessel diameter in animals undergoing exercise at days 9 and 12 and a significant correlation between running distance and blood vessel density at day 9 (r = 0.74). Histomorphometry showed osseous bridging of the defect at day 9. The newly woven bone was covered by a neo-periosteum containing those blood vessels, which were visible by IVM. We conclude that exercise accelerates bone defect healing and stimulates angiogenesis during bore repair.