Using evolutionary algorithms and machine learning to explore sequence space for the discovery of antimicrobial peptides

We present a proof-of-concept methodology for efficiently optimizing a chemical trait by using an artificial evolutionary workflow. We demonstrate this by optimizing the efficacy of antimicrobial peptides (AMPs). In particular, we used a closed-loop approach that combines a genetic algorithm, machine learning, and in vitro evaluation to improve the antimicrobial activity of peptides against Escherichia coli. Starting with a 13-mer natural AMP, we identified 44 highly potent peptides, achieving up to a ca. 160-fold increase in antimicrobial activity within just three rounds of experiments. During these experiments, the conformation of the peptides selected was changed from a random coil to an α-helical form. This strategy not only establishes the potential of in vitro molecule evolution using an algorithmic genetic system but also accelerates the discovery of antimicrobial peptides and other functional molecules within a relatively small number of experiments, allowing the exploration of broad sequence and structural space

Seagrass ecosystem contributions to people's quality of life in the Pacific Island Countries and Territories

Seagrass ecosystems provide critical contributions (goods and perceived benefits or detriments) for the livelihoods and wellbeing of Pacific Islander peoples. Through in-depth examination of the contributions provided by seagrass ecosystems across the Pacific Island Countries and Territories (PICTs), we find a greater quantity in the Near Oceania (New Guinea, the Bismarck Archipelago and the Solomon Islands) and western Micronesian (Palau and Northern Marianas) regions; indicating a stronger coupling between human society and seagrass ecosystems. We also find many non-material contributions historically have been overlooked and under-appreciated by decision-makers. Closer cultural connections likely motivate guardianship of seagrass ecosystems by Pacific communities to mitigate local anthropogenic pressures. Regional comparisons also shed light on general and specific aspects of the importance of seagrass ecosystems to Pacific Islanders, which are critical for forming evidence-based policy and management to ensure the long-term resilience of seagrass ecosystems and the contributions they provide

Seagrass ecosystems of the Pacific Island countries and territories: a global bright spot

Seagrass ecosystems exist throughout Pacific Island Countries and Territories (PICTs). Despite this area covering nearly 8% of the global ocean, information on seagrass distribution, biogeography, and status remains largely absent from the scientific literature. We confirm 16 seagrass species occur across 17 of the 22 PICTs with the highest number in Melanesia, followed by Micronesia and Polynesia respectively. The greatest diversity of seagrass occurs in Papua New Guinea (13 species), and attenuates eastward across the Pacific to two species in French Polynesia. We conservatively estimate seagrass extent to be 1446.2 km2, with the greatest extent (84%) in Melanesia. We find seagrass condition in 65% of PICTs increasing or displaying no discernible trend since records began. Marine conservation across the region overwhelmingly focuses on coral reefs, with seagrass ecosystems marginalised in conservation legislation and policy. Traditional knowledge is playing a greater role in managing local seagrass resources and these approaches are having greater success than contemporary conservation approaches. In a world where the future of seagrass ecosystems is looking progressively dire, the Pacific Islands appears as a global bright spot, where pressures remain relatively low and seagrass more resilient

Identification and Characterization of RBM44 as a Novel Intercellular Bridge Protein

Intercellular bridges are evolutionarily conserved structures that connect differentiating germ cells. We previously reported the identification of TEX14 as the first essential intercellular bridge protein, the demonstration that intercellular bridges are required for male fertility, and the finding that intercellular bridges utilize components of the cytokinesis machinery to form. Herein, we report the identification of RNA binding motif protein 44 (RBM44) as a novel germ cell intercellular bridge protein. RBM44 was identified by proteomic analysis after intercellular bridge enrichment using TEX14 as a marker protein. RBM44 is highly conserved between mouse and human and contains an RNA recognition motif of unknown function. RBM44 mRNA is enriched in testis, and immunofluorescence confirms that RBM44 is an intercellular bridge component. However, RBM44 only partially localizes to TEX14-positive intercellular bridges. RBM44 is expressed most highly in pachytene and secondary spermatocytes, but disappears abruptly in spermatids. We discovered that RBM44 interacts with itself and TEX14 using yeast two-hybrid, mammalian two-hybrid, and immunoprecipitation. To define the in vivo function of RBM44, we generated a targeted deletion of Rbm44 in mice. Rbm44 null male mice produce somewhat increased sperm, and show enhanced fertility of unknown etiology. Thus, although RBM44 localizes to intercellular bridges during meiosis, RBM44 is not required for fertility in contrast to TEX14

Microglial activation and chronic neurodegeneration

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurode-generative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson’s disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype

First M87 Event Horizon Telescope Results. III. Data Processing and Calibration

We present the calibration and reduction of Event Horizon Telescope (EHT) 1.3 mm radio wavelength observations of the supermassive black hole candidate at the center of the radio galaxy M87 and the quasar 3C 279, taken during the 2017 April 5-11 observing campaign. These global very long baseline interferometric observations include for the first time the highly sensitive Atacama Large Millimeter/submillimeter Array (ALMA); reaching an angular resolution of 25 μas, with characteristic sensitivity limits of ∼1 mJy on baselines to ALMA and ∼10 mJy on other baselines. The observations present challenges for existing data processing tools, arising from the rapid atmospheric phase fluctuations, wide recording bandwidth, and highly heterogeneous array. In response, we developed three independent pipelines for phase calibration and fringe detection, each tailored to the specific needs of the EHT. The final data products include calibrated total intensity amplitude and phase information. They are validated through a series of quality assurance tests that show consistency across pipelines and set limits on baseline systematic errors of 2% in amplitude and 1° in phase. The M87 data reveal the presence of two nulls in correlated flux density at ∼3.4 and ∼8.3 Gλ and temporal evolution in closure quantities, indicating intrinsic variability of compact structure on a timescale of days, or several light-crossing times for a few billion solar-mass black hole. These measurements provide the first opportunity to image horizon-scale structure in M87

First M87 Event Horizon Telescope Results. V. Physical Origin of the Asymmetric Ring

The Event Horizon Telescope (EHT) has mapped the central compact radio source of the elliptical galaxy M87 at 1.3 mm with unprecedented angular resolution. Here we consider the physical implications of the asymmetric ring seen in the 2017 EHT data. To this end, we construct a large library of models based on general relativistic magnetohydrodynamic (GRMHD) simulations and synthetic images produced by general relativistic ray tracing. We compare the observed visibilities with this library and confirm that the asymmetric ring is consistent with earlier predictions of strong gravitational lensing of synchrotron emission from a hot plasma orbiting near the black hole event horizon. The ring radius and ring asymmetry depend on black hole mass and spin, respectively, and both are therefore expected to be stable when observed in future EHT campaigns. Overall, the observed image is consistent with expectations for the shadow of a spinning Kerr black hole as predicted by general relativity. If the black hole spin and M87's large scale jet are aligned, then the black hole spin vector is pointed away from Earth. Models in our library of non-spinning black holes are inconsistent with the observations as they do not produce sufficiently powerful jets. At the same time, in those models that produce a sufficiently powerful jet, the latter is powered by extraction of black hole spin energy through mechanisms akin to the Blandford-Znajek process. We briefly consider alternatives to a black hole for the central compact object. Analysis of existing EHT polarization data and data taken simultaneously at other wavelengths will soon enable new tests of the GRMHD models, as will future EHT campaigns at 230 and 345 GHz