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Behavioral larval zebrafish screens leverage a high-throughput small molecule discovery format to find neuroactive molecules relevant to mammalian physiology. We screen a library of 650 central nervous system active compounds in high replicate to train deep metric learning models on zebrafish behavioral profiles. The machine learning initially exploited subtle artifacts in the phenotypic screen, necessitating a complete experimental re-run with rigorous physical well-wise randomization. These large matched phenotypic screening datasets (initial and well-randomized) provide a unique opportunity to quantify and understand shortcut learning in a full-scale, real-world drug discovery dataset. The final deep metric learning model substantially outperforms correlation distance–the canonical way of computing distances between profiles–and generalizes to an orthogonal dataset of diverse drug-like compounds. We validate predictions by prospective in vitro radio-ligand binding assays against human protein targets, achieving a hit rate of 58% despite crossing species and chemical scaffold boundaries. These neuroactive compounds exhibit diverse chemical scaffolds, demonstrating that zebrafish phenotypic screens combined with metric learning achieve robust scaffold hopping capabilities. The authors used deep metric learning to characterize 650 neuroactive compounds by zebrafish behavioral profiles. After redesigning a large screen to overcome AI/ML shortcut learning, zebrafish behavioral similarity found compounds acting on the same human receptors as structurally dissimilar drugs. [ABSTRACT FROM AUTHOR]

Natural disasters trigger complex chains of events within human societies1. Immediate deaths and damage are directly observed after a disaster and are widely studied, but delayed downstream outcomes, indirectly caused by the disaster, are difficult to trace back to the initial event1,2. Tropical cyclones (TCs)—that is, hurricanes and tropical storms—are widespread globally and have lasting economic impacts3–5, but their full health impact remains unknown. Here we conduct a large-scale evaluation of long-term effects of TCs on human mortality in the contiguous United States (CONUS) for all TCs between 1930 and 2015. We observe a robust increase in excess mortality that persists for 15 years after each geophysical event. We estimate that the average TC generates 7,000–11,000 excess deaths, exceeding the average of 24 immediate deaths reported in government statistics6,7. Tracking the effects of 501 historical storms, we compute that the TC climate of CONUS imposes an undocumented mortality burden that explains a substantial fraction of the higher mortality rates along the Atlantic coast and is equal to roughly 3.2–5.1% of all deaths. These findings suggest that the TC climate, previously thought to be unimportant for broader public health outcomes, is a meaningful underlying driver for the distribution of mortality risk in CONUS, especially among infants (less than 1 year of age), people 1–44 years of age, and the Black population. Understanding why TCs induce this excess mortality is likely to yield substantial health benefits.A large-scale evaluation of the long-term effects of tropical cyclones on human mortality in the contiguous United States estimates that the average tropical cyclone results in 7,000–11,000 excess deaths, far exceeding previous estimates. [ABSTRACT FROM AUTHOR]

There is information redundancy in both spatial and spectral aspects of hyperspectral images. Considering a fixed proportion in sequential forward method may not find the optimal bands, we modify a band selection (BS) method by introducing a parameter to adjust the proportion of standard deviation to correlation, which may select key bands quickly and accurately. In addition, slant Haar type orthogonal transforms (SHTOT) have slant base vectors suitable to express the image brightness with gradual change. However, SHTOT have attracted little attention of scholars'. This paper introduces SHTOT with fast algorithm and varied parameters to the further compression of band images from a space point of view. Comparative experiments were performed with other BS strategies and state-of-the-art orthogonal transforms, such as DCT, DWT, Walsh, slant transform, Haar type orthogonal transforms. Final experimental results achieved on the commonly used data sets validate that the proposed approach has a faster speed, high compression ratio and good image quality. Additionally, it is more appropriate to choose different SHTOT for the specific application. The sparse SHTOT generated by certain parameter values are more suitable for the high requirement in image quality, but the compression ratio isn't very high, while dense SHTOT produced by another parameter values are fitter for the opposite cases. [ABSTRACT FROM AUTHOR]

Globalization and the expansion of essential services over continuous 24 h cycles have necessitated the adaptation of the human workforce to shift‐based schedules. Night shift work (NSW) causes a state of desynchrony between the internal circadian machinery and external environmental cues, which can impact inflammatory and metabolic pathways. The discovery of clock genes in the lung has shed light on potential mechanisms of circadian misalignment in chronic pulmonary disease. Here, the current knowledge of circadian clock disruption caused by NSW and its impact on lung inflammation and associated pathophysiology in chronic lung diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and COVID‐19, is reviewed. Furthermore, the limitations of the current understanding of circadian disruption and potential future chronotherapeutic advances are discussed. [ABSTRACT FROM AUTHOR]

Axis formation and related spatial patterning are initiated by symmetry breaking during development. A geometrically confined culture of human pluripotent stem cells (hPSCs) mimics symmetry breaking and cell patterning. Using this, polarized spinal cord organoids (pSCOs) with a self‐organized dorsoventral (DV) organization are generated. The application of caudalization signals promoted regionalized cell differentiation along the radial axis and protrusion morphogenesis in confined hPSC colonies. These detached colonies grew into extended spinal cord‐like organoids, which established self‐ordered DV patterning along the long axis through the spontaneous expression of polarized DV patterning morphogens. The proportions of dorsal/ventral domains in the pSCOs can be controlled by the changes in the initial size of micropatterns, which altered the ratio of center‐edge cells in 2D. In mature pSCOs, highly synchronized neural activity is separately detected in the dorsal and ventral side, indicating functional as well as structural patterning established in the organoids. This study provides a simple and precisely controllable method to generate spatially ordered organoids for the understanding of the biological principles of cell patterning and axis formation during neural development. [ABSTRACT FROM AUTHOR]

Blood flow reflects the eye's health and is disrupted in many diseases. Many pathological processes take place at the cellular level like as microcirculation of blood in vessels, and the processing of medical images is a difficult recognition task. Existing techniques for measuring blood flow are limited due to the complex assumptions, equipment and calculations requirements. In this paper, we propose a method for determining the blood flow characteristics in eye conjunctiva vessels, such as linear and volumetric blood speed and topological characteristics of the vascular net. The method preprocesses the video to improve the conditions of analysis and then builds an integral optical flow for definition of flow dynamical characteristic of eye vessels. These characteristics make it possible to determine changes in blood flow in eye vessels. We show the efficiency of our method in natural eye vessel scenes. The research provides valuable insights to novices with limited experience in the diagnosis and can serve as a valuable tool for experienced medical professionals. [ABSTRACT FROM AUTHOR]

A physicochemical description and a mathematical model are created for the formation of an oxygen flame during the interaction of an oxygen jet with the converter atmosphere. Software package Oxygen Flame, which can be used to predict the chemical composition, temperature, velocity, and diameter of the oxygen flame reaching the bath in a real converter process, has been developed. The Oxygen Flame software package is verified using experimental data. An adequate estimation of the state variables of the flame, including its geometric characteristics, is an important problem in creating control systems for the basic oxygen process. The most important aspect is the possibility of modeling the flame formed by lances with a various number of nozzles, various location, and configuration. The presented model makes it possible to analyze all possible configurations of the converter flame for a multinozzle lance depending on the chosen blowing conditions and the characteristics of an oxygen lance (number and geometric characteristics of its nozzles), the unit size, the blowing intensity conditions, and the location of the oxygen lance above the melt. The main calculation results are as follows: the image and geometric characteristics of the oxygen flame surface, which can be used to estimate the reaction zone size and the chemical composition, velocity, and temperature of the flame reaching a metal. [ABSTRACT FROM AUTHOR]

Nitroarenes are readily available compounds that are commonly utilized in reductive processes to form C–NAr bonds via reactive nitrogen intermediates. Recent advances in the development of reductive reactions of nitroarenes using organomagnesium, organozinc, and single-electron transfer reagents are discussed within this short review. 1 Introduction 2 Organomagnesium-Mediated Reductive Reactions of Nitroarenes 3 Organozinc- and Zinc-Mediated Reductive Reactions of Nitroarenes 4 Iodine-Catalyzed Redox Cyclizations of Nitroarenes 5 Titanium(III)-Mediated Reductive Cyclizations 6 Sulfur-Mediated Reductive Reactions of Nitroarenes 7 Alkoxide-Mediated Reductive Reactions of Nitroarenes 8 4,4′-Bipyridine-Mediated Reductive Reactions of Nitroarenes 9 Visible-Light-Driven Reductive Amination Reactions 10 Electrochemical Reductive Reactions 11 Conclusion [ABSTRACT FROM AUTHOR]

Background and Purpose: Bradykinin (BK‐(1–9)) is an endogenous nonapeptide involved in multiple physiological and pathological processes. Peptide fragments of bradykinin are believed to be biologically inactive. We have now tested the two major peptide fragments of bradykinin in human and animals. Experimental Approach BK peptides were quantified by MS in male rats. NO release was quantified from human, mouse and rat cells loaded with DAF‐FM. Rat aortic rings were used to measure vascular reactivity. Changes in BP and HR were measured in conscious male rats. To evaluate pro‐inflammatory effects both vascular permeability and nociception were measured in adult mice. Key Results: BK‐(1–7) and BK‐(1–5) are produced in vivo from BK‐(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK‐(1–9), NO production elicited by BK‐(1–7) or BK‐(1–5) was not inhibited by B1 or B2 receptor antagonists. BK‐(1–7) and BK‐(1–5) induced concentration‐dependent vasorelaxation of aortic rings, without involvement of B1 or B2 receptors. Intravenous or intra‐arterial administration of BK‐(1–7) or BK‐(1–5) induced similar hypotensive response in vivo. Nociceptive responses of BK‐(1–7) and BK‐(1–5) were reduced compared to BK‐(1–9), and no increase in vascular permeability was observed for BK‐(1–9) fragments. Conclusions and Implications: BK‐(1–7) and BK‐(1–5) are endogenous peptides present in plasma. BK‐related peptide fragments show biological activity, not mediated by B1 or B2 receptors. These BK fragments could constitute new, active components of the kallikrein–kinin system. [ABSTRACT FROM AUTHOR]

Ever since the first biologically active chemokines were discovered in the late 1980s, these messenger proteins and their receptors have been the target for a plethora of drug discovery efforts in the pharmaceutical industry, as well as in academia. Owing to the publication of several chemokine receptor X-ray crystal structures, a highly druggable, intracellular, allosteric binding site which partially overlaps with the G protein binding site was discovered. This intriguing, new approach for chemokine receptor antagonism has captured researchers around the world, pushing the exploration of this intracellular binding site and new antagonists thereof. In this review, we have highlighted the past two decades of research on small-molecule chemokine receptor antagonists that modulate receptor function at the intracellular binding site. [ABSTRACT FROM AUTHOR]

Background and Purpose: Bradykinin (BK-(1-9)) is an endogenous nonapeptide involved in multiple physiological and pathological processes. Peptide fragments of bradykinin are believed to be biologically inactive. We have now tested the two major peptide fragments of bradykinin in human and animals., Experimental Approach: BK peptides were quantified by MS in male rats. NO release was quantified from human, mouse and rat cells loaded with DAF-FM. Rat aortic rings were used to measure vascular reactivity. Changes in BP and HR were measured in conscious male rats. To evaluate pro-inflammatory effects both vascular permeability and nociception were measured in adult mice., Key Results: BK-(1-7) and BK-(1-5) are produced in vivo from BK-(1-9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1-9), NO production elicited by BK-(1-7) or BK-(1-5) was not inhibited by B 1 or B 2 receptor antagonists. BK-(1-7) and BK-(1-5) induced concentration-dependent vasorelaxation of aortic rings, without involvement of B 1 or B 2 receptors. Intravenous or intra-arterial administration of BK-(1-7) or BK-(1-5) induced similar hypotensive response in vivo. Nociceptive responses of BK-(1-7) and BK-(1-5) were reduced compared to BK-(1-9), and no increase in vascular permeability was observed for BK-(1-9) fragments., Conclusions and Implications: BK-(1-7) and BK-(1-5) are endogenous peptides present in plasma. BK-related peptide fragments show biological activity, not mediated by B 1 or B 2 receptors. These BK fragments could constitute new, active components of the kallikrein-kinin system., (© 2022 The British Pharmacological Society.)

Staphylococcus aureus frequently causes infections that are challenging to treat, leading to high rates of persistent and relapsing infection. Here, to understand how the host environment influences treatment outcomes, we study the impact of human serum on staphylococcal antibiotic susceptibility. We show that serum triggers a high degree of tolerance to the lipopeptide antibiotic daptomycin and several other classes of antibiotic. Serum-induced daptomycin tolerance is due to two independent mechanisms. Firstly, the host defence peptide LL-37 induces tolerance by triggering the staphylococcal GraRS two-component system, leading to increased peptidoglycan accumulation. Secondly, GraRS-independent increases in membrane cardiolipin abundance are required for full tolerance. When both mechanisms are blocked, S. aureus incubated in serum is as susceptible to daptomycin as when grown in laboratory media. Our work demonstrates that host factors can significantly modulate antibiotic susceptibility via diverse mechanisms, and combination therapy may provide a way to mitigate this., (© 2022. The Author(s).)