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The sequestration of organic carbon in seafloor sediments plays a key role in regulating global climate; however, human activities can disturb previously-sequestered carbon stocks, potentially reducing the capacity of the ocean to store CO 2 . Recent studies revealed profound seafloor impacts and sedimentary carbon loss due to fishing and shipping, yet most other human activities in the ocean have been overlooked. Here, we present an assessment of organic carbon disturbance related to the globally-extensive subsea telecommunications cable network. Up to 2.82–11.26 Mt of organic carbon worldwide has been disturbed as a result of cable burial, in water depths of up to 2000 m. While orders of magnitude lower than that disturbed by bottom fishing, it is a non-trivial amount that is absent from global budgets. Future offshore developments that disturb the seafloor should consider the safeguarding of carbon stocks, across the full spectrum of Blue Economy industries. The sequestration of organic carbon in seafloor sediments plays a key role in regulating global climate. Here, the authors present an assessment of organic carbon disturbance related to the globally-extensive subsea telecommunications cable network.

During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor-ligand interactions occur in the following sequence with the following cellular morphologies; 1) an early heparin-blockable interaction which weakly deforms the erythrocyte, 2) EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite's actin-myosin motor, 3) a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4) an AMA1-RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine.

Low-cost mass-produced sensors and optics have recently made it feasible to build telescope arrays which observe the entire accessible sky simultaneously. In this article, we discuss the scientific motivation for these telescopes, including exoplanets, stellar variability, and extragalactic transients. To provide a concrete example we detail the goals and expectations for the Evryscope, an under-construction 780 MPix telescope which covers 8660 sq. deg. in each 2-minute exposure; each night, 18,400 sq. deg. will be continuously observed for an average of ≈6 hr. Despite its small 61 mm aperture, the system's large field of view provides an étendue which is ∼10% of LSST. The Evryscope, which places 27 separate individual telescopes into a common mount which tracks the entire accessible sky with only one moving part, will return 1%-precision, many-year-length, high-cadence light curves for every accessible star brighter than ∼16th magnitude. The camera readout times are short enough to provide near-continuous observing, with a 97% survey time efficiency. The array telescope will be capable of detecting transiting exoplanets around every solar-type star brighter than mV = 12, providing at least few-millimagnitude photometric precision in long-term light curves. It will be capable of searching for transiting giant planets around the brightest and most nearby stars, where the planets are much easier to characterize; it will also search for small planets nearby M-dwarfs, for planetary occultations of white dwarfs, and will perform comprehensive nearby microlensing and eclipse-timing searches for exoplanets inaccessible to other planet-finding methods. The Evryscope will also provide comprehensive monitoring of outbursting young stars, white dwarf activity, and stellar activity of all types, along with finding a large sample of very-long-period M-dwarf eclipsing binaries. When relatively rare transients events occur, such as gamma-ray bursts (GRBs), nearby supernovae, or even gravitational wave detections from the Advanced LIGO/Virgo network, the array will return minute-by-minute light curves without needing pointing toward the event as it occurs. By coadding images, the system will reach V ∼ 19 in 1-hr integrations, enabling the monitoring of faint objects. Finally, by recording all data, the Evryscope will be able to provide pre-event imaging at 2-minute cadence for bright transients and variable objects, enabling the first high-cadence searches for optical variability before, during and after all-sky events.

Radio pulsars with millisecond spin periods are thought to have been spun up by the transfer of matter and angular momentum from a low-mass companion star during an x-ray-emitting phase. The spin periods of the neutron stars in several such low-mass x-ray binary (LMXB) systems have been shown to be in the millisecond regime, but no radio pulsations have been detected. Here we report on detection and follow-up observations of a nearby radio millisecond pulsar (MSP) in a circular binary orbit with an optically identified companion star. Optical observations indicate that an accretion disk was present in this system within the past decade. Our optical data show no evidence that one exists today, suggesting that the radio MSP has turned on after a recent LMXB phase.

Background People with Parkinson’s disease (PD) have a high fall rate and many falls are associated with turns. Despite this, there is minimal research on effects of rehabilitation on the quality of turns. Further, quantifying turns in the home may have broader implications since rehabilitation of turns would ideally improve turning in real world mobility. Methods Sixty people with PD and a history of falls will be randomized to receive either a novel TURNing InTervention (TURN-IT) or no intervention (control group). The TURN-IT group will be seen for 6 weeks (18 visits) for an individualized, progressive program that is based on the specific constraints of turning in PD. Wearable sensors will be used to measure 7 days of mobility, including turns, before and after intervention or control period. In addition, blinded assessments of gait, mobility and turns will occur before and after intervention for both groups and falls will be monitored for twelve months post intervention with bimonthly email questionnaires. Discussion This study has the potential to change how we rehabilitate and assess turning in people with PD and falls. There are several novel aspects to our study including a comprehensive turning-focused intervention that is tailored to the underlying constraints that impair turning in people with PD. Further, our outcome measure of turning quality during 7 days of daily life is novel and has implications for determining real-life changes after rehabilitation. The ultimate goal of this rehabilitation intervention is to improve how patients turn in daily life and to reduce falls. Trials registration This protocol is registered at clinicaltrials.gov; #NCT04897256; https://clinicaltrials.gov/ct2/show/NCT04897256?term=Horak&cond=Parkinson+Disease&draw=2&rank=4 .

Plasmodium falciparum is responsible for the most severe form of malaria disease in humans, causing more than 1 million deaths each year. As an obligate intracellular parasite, P. falciparum's ability to invade erythrocytes is essential for its survival within the human host. P. falciparum invades erythrocytes using multiple host receptor—parasite ligand interactions known as invasion pathways. Here we show that CR1 is the host erythrocyte receptor for PfRh4, a major P. falciparum ligand essential for sialic acid—independent invasion. PfRh4 and CR1 interact directly, with a K d of 2.9 μM. PfRh4 binding is strongly correlated with the CR1 level on the erythrocyte surface. Parasite invasion via sialic acid—independent pathways is reduced in low-CR1 erythrocytes due to limited availability of this receptor on the surface. Furthermore, soluble CR1 can competitively block binding of PfRh4 to the erythrocyte surface and specifically inhibit sialic acid—independent parasite invasion. These results demonstrate that CR1 is an erythrocyte receptor used by the parasite ligand PfRh4 for P. falciparum invasion.

Complement factor H (FH) binds complement 3b and promotes the stepwise degradation of C3b to C3d, protecting self cells from being mistakenly recognized as foreign. A previous structure showed how CCP modules 1–4 of FH bind C3b; this study now shows the interaction of CCP modules 19–20 with C3d and builds a model for the interaction of the complete FH molecule with C3b. Complement factor H (FH) attenuates C3b molecules tethered by their thioester domains to self surfaces and thereby protects host tissues. Factor H is a cofactor for initial C3b proteolysis that ultimately yields a surface-attached fragment (C3d) corresponding to the thioester domain. We used NMR and X-ray crystallography to study the C3d–FH19–20 complex in atomic detail and identify glycosaminoglycan-binding residues in factor H module 20 of the C3d–FH19–20 complex. Mutagenesis justified the merging of the C3d–FH19–20 structure with an existing C3b–FH1–4 crystal structure. We concatenated the merged structure with the available FH6–8 crystal structure and new SAXS-derived FH1–4, FH8–15 and FH15–19 envelopes. The combined data are consistent with a bent-back factor H molecule that binds through its termini to two sites on one C3b molecule and simultaneously to adjacent polyanionic host-surface markers.

Background Komagataella phaffii (Pichia pastoris ) is a methylotrophic commercially important non-conventional species of yeast that grows in a fermentor to exceptionally high densities on simple media and secretes recombinant proteins efficiently. Genetic engineering strategies are being explored in this organism to facilitate cost-effective biomanufacturing. Small, stable artificial chromosomes in K. phaffii could offer unique advantages by accommodating multiple integrations of extraneous genes and their promoters without accumulating perturbations of native chromosomes or exhausting the availability of selection markers. Results Here, we describe a linear “nano”chromosome (of 15–25 kb) that, according to whole-genome sequencing, persists in K. phaffii over many generations with a copy number per cell of one, provided non-homologous end joining is compromised (by KU70 -knockout). The nanochromosome includes a copy of the centromere from K. phaffii chromosome 3, a K. phaffii -derived autonomously replicating sequence on either side of the centromere, and a pair of K. phaffii -like telomeres. It contains, within its q arm, a landing zone in which genes of interest alternate with long (approx. 1-kb) non-coding DNA chosen to facilitate homologous recombination and serve as spacers. The landing zone can be extended along the nanochromosome, in an inch-worming mode of sequential gene integrations, accompanied by recycling of just two antibiotic-resistance markers. The nanochromosome was used to express PDI , a gene encoding protein disulfide isomerase. Co-expression with PDI allowed the production, from a genomically integrated gene, of secreted murine complement factor H, a plasma protein containing 40 disulfide bonds. As further proof-of-principle, we co-expressed, from a nanochromosome, both PDI and a gene for GFP-tagged human complement factor H under the control of P AOX1 and demonstrated that the secreted protein was active as a regulator of the complement system. Conclusions We have added K. phaffii to the list of organisms that can produce human proteins from genes carried on a stable, linear, artificial chromosome. We envisage using nanochromosomes as repositories for numerous extraneous genes, allowing intensive engineering of K. phaffii without compromising its genome or weakening the resulting strain.

The selectivity and affinity of numerous protein–protein interactions depends upon the folding of intrinsically disordered regions (IDRs) that accompanies complexation. Here we investigate how folding-on-binding of a protein IDR by small molecules is facilitated by synergestic exploitation of interactions with a folded protein region. To this end, the molecular driving forces that underpin ordering of the N-terminal intrinsically disordered ‘lid’ region of the oncoprotein MDM2 by the small molecule AM-7209 were elucidated by a combination of molecular dynamics simulations, calorimetry and NMR measurements. Strikingly, mutations of lid residues distant from the ligand-binding site modulate potency by up to three orders of magnitude. A key requirement for conversion of this IDR into an ordered motif is collective stabilisation of a network of non-polar contacts between a chlorophenyl moiety of AM-7209 and the lid residue I19 to overcome conformational entropy loss associated with folding of the IDR. Our findings underscore the crucial role that protein IDRs can play in drug-resistance mechanisms and expand strategies available to medicinal chemists for ligand optimisation endeavours. Protein–protein interactions often rely on the folding of intrinsically disordered regions (IDRs) during complexation. Here, the authors reveal how small molecule AM-7209 induces folding of the MDM2 oncoprotein’s IDR through non-polar interactions, by combining molecular dynamics simulations, calorimetry and NMR measurements.

Despite sharing 92% sequence identity, paralogous human translation elongation factor 1 alpha-1 (eEF1A1) and elongation factor 1 alpha-2 (eEF1A2) have different but overlapping functional profiles. This may reflect the differential requirements of the cell-types in which they are expressed and is consistent with complex roles for these proteins that extend beyond delivery of tRNA to the ribosome. To investigate the structural basis of these functional differences, we created and validated comparative three-dimensional (3-D) models of eEF1A1 and eEF1A2 on the basis of the crystal structure of homologous eEF1A from yeast. The spatial location of amino acid residues that vary between the two proteins was thereby pinpointed, and their surface electrostatic and lipophilic properties were compared. None of the variations amongst buried amino acid residues are judged likely to have a major structural effect on the protein fold, or to affect domain-domain interactions. Nearly all the variant surface-exposed amino acid residues lie on one face of the protein, in two proximal but distinct sub-clusters. The result of previously performed mutagenesis in yeast may be interpreted as confirming the importance of one of these clusters in actin-bundling and filament disorganization. Interestingly, some variant residues lie in close proximity to, and in a few cases show differences in interactions with, residues previously inferred to be directly involved in binding GTP/GDP, eEF1Balpha and aminoacyl-tRNA. Additional sequence-based predictions, in conjunction with the 3-D models, reveal likely differences in phosphorylation sites that could reconcile some of the functional differences between the two proteins. The revelation and putative functional assignment of two distinct sub-clusters on the surface of the protein models should enable rational site-directed mutagenesis, including homologous reverse-substitution experiments, to map surface binding patches onto these proteins. The predicted variant-specific phosphorylation sites also provide a basis for experimental verification by mutagenesis. The models provide a structural framework for interpretation of the resulting functional analysis.