Helical van der Waals crystals with discretized Eshelby twist.

The ability to manipulate the twisting topology of van der Waals structures offers a new degree of freedom through which to tailor their electrical and optical properties. The twist angle strongly affects the electronic states, excitons and phonons of the twisted structures through interlayer coupling, giving rise to exotic optical, electric and spintronic behaviours1-5. In twisted bilayer graphene, at certain twist angles, long-range periodicity associated with moiré patterns introduces flat electronic bands and highly localized electronic states, resulting in Mott insulating behaviour and superconductivity3,4. Theoretical studies suggest that these twist-induced phenomena are common to layered materials such as transition-metal dichalcogenides and black phosphorus6,7. Twisted van der Waals structures are usually created using a transfer-stacking method, but this method cannot be used for materials with relatively strong interlayer binding. Facile bottom-up growth methods could provide an alternative means to create twisted van der Waals structures. Here we demonstrate that the Eshelby twist, which is associated with a screw dislocation (a chiral topological defect), can drive the formation of such structures on scales ranging from the nanoscale to the mesoscale. In the synthesis, axial screw dislocations are first introduced into nanowires growing along the stacking direction, yielding van der Waals nanostructures with continuous twisting in which the total twist rates are defined by the radii of the nanowires. Further radial growth of those twisted nanowires that are attached to the substrate leads to an increase in elastic energy, as the total twist rate is fixed by the substrate. The stored elastic energy can be reduced by accommodating the fixed twist rate in a series of discrete jumps. This yields mesoscale twisting structures consisting of a helical assembly of nanoplates demarcated by atomically sharp interfaces with a range of twist angles. We further show that the twisting topology can be tailored by controlling the radial size of the structure.

A Monometallic Bis(cyaphido) Complex.

The first example of a bis(cyaphido) complex, trans-[Ru(dppe)2(C≡P)2], is described, unequivocally demonstrating the synthetic accessibility and stability of complexes that feature more than one cyaphido ligand. Synthesis is achieved from the precedent cation [Ru(dppe)2(C≡P)]+ via sequential coordination and desilylation of the phosphaalkyne Me3SiC≡P. The heteroleptic analogue trans-[Ru(dppe)2(C≡N)(C≡P)] is also prepared from the same cation and NaCN; both cyaphido complexes are structurally characterized, enabling the first direct comparison of cyaphide with cyanide, its isoelectronic and isolobal counterpart. This demonstrates an enhanced π-acidity for -C≡P over -C≡N, while computational studies reveal also a higher π-donor character for the cyaphido ligand.

Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Genome characterization of the novel lytic phage vB_AbaAut_ChT04 and the antimicrobial activity of its lysin peptide against Acinetobacter baumannii isolates from different time periods.

Acinetobacter baumannii is an important opportunistic pathogen, usually associated with immunocompromised individuals with a prolonged period of stay in a hospital. Currently, the incidence of multi-drug resistant A. baumannii (MDR-AB) and extensively drug-resistant A. baumannii (XDR-AB) is increasing rapidly in Thailand, mirroring the trend worldwide. Novel therapeutic approaches for the treatment of A. baumannii infection using bacteriophages are being evaluated, and the use of phage-derived peptides is being tested as alternative approach to fighting infection. In this study, we isolated and determined the biological features of a lytic A. baumannii phage called vB_AbaAut_ChT04 (vChT04). The vChT04 phage was classified as a member of the family Autographiviridae of the class Caudoviricetes. It showed a short latent period (10 min) and a large burst size (280 PFU cell-1), and it was able to infect 52 out of 150 clinical MDR-AB strains tested (34.67%). Most of the phage-sensitive strains were A. baumannii strains that had been isolated during the same year that the phage was isolated. The phage showed activity across a broad pH (pH 5.0-8.0) and temperature (4-37°C) range. Whole-genome analysis revealed that the vChT04 genome comprises 41,158 bp with a 39.3% GC content and contains 48 open reading frames (ORFs), 28 of which were assigned putative functions based on homology to previously identified phage genes. Comparative genomic analysis demonstrated that vChT04 had the highest similarity to phage vB_AbaP_WU2001, which was isolated in the southern part of Thailand. An endolysin gene found in the vChT04 genome was used to synthesize an antimicrobial peptide (designated as PLysChT04) and its antimicrobial activity was evaluated using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. The MIC and MBC values of peptide PLysChT04 against MDR-AB and XDR-AB were 312.5-625 µg/mL, and it was able to inhibit both phage-susceptible and phage-resistant isolates collected over different time periods. PLysChT04 showed good efficacy in killing drug-resistant A. baumannii and other bacterial strains, and it is a promising candidate for development as an alternative therapeutic agent targeting A. baumannii infections.

Addendum: Immune clearance of highly pathogenic SIV infection.

This corrects the article DOI: 10.1038/nature12519.

Renewable electricity storage using electrolysis.

Electrolysis converts electrical energy into chemical energy by storing electrons in the form of stable chemical bonds. The chemical energy can be used as a fuel or converted back to electricity when needed. Water electrolysis to hydrogen and oxygen is a well-established technology, whereas fundamental advances in CO2 electrolysis are still needed to enable short-term and seasonal energy storage in the form of liquid fuels. This paper discusses the electrolytic reactions that can potentially enable renewable energy storage, including water, CO2 and N2 electrolysis. Recent progress and major obstacles associated with electrocatalysis and mass transfer management at a system level are reviewed. We conclude that knowledge and strategies are transferable between these different electrochemical technologies, although there are also unique complications that arise from the specifics of the reactions involved.

Gut microbiota of wild fish as reporters of compromised aquatic environments sleuthed through machine learning.

Human-generated negative impacts on aquatic environments are rising. Despite wild fish playing a key role in aquatic ecologies and comprising a major global food source, physiological consequences of these impacts on them are poorly understood. Here we address the issue through the lens of interrelationship between wild fish and their gut microbiota, hypothesizing that fish microbiota are reporters of the aquatic environs. Two geographically separate teleost wild-fish species were studied (Lake Erie, Ohio, and Caribbean Sea, US Virgin Islands). At each geolocation, fresh fecal samples were collected from fish in areas of presence or absence of known aquatic compromise. Gut microbiota was assessed via microbial 16S-rRNA gene sequencing and represents the first complete report for both fish species. Despite marked differences in geography, climate, water type, fish species, habitat, diet, and gut microbial compositions, the pattern of shifts in microbiota shared by both fish species was nearly identical due to aquatic compromise. Next, these data were subjected to machine learning (ML) to examine reliability of using the fish-gut microbiota as an ecomarker for anthropogenic aquatic impacts. Independent of geolocation, ML predicted aquatic compromise with remarkable accuracy (>90%). Overall, this study represents the first multispecies stress-related comparison of its kind and demonstrates the potential of artificial intelligence via ML as a tool for biomonitoring and detecting compromised aquatic conditions.

Long-term survival and toxicity in patients with neuroendocrine tumors treated with 177 Lu-octreotate peptide radionuclide therapy.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) has shown favorable results in neuroendocrine tumors (NETs). Long-term safety and efficacy data for 177 Lu-octreotate PRRT, particularly in combination with chemotherapy, is lacking. METHODS: The authors conducted a retrospective review of the long-term toxicity and survival outcomes of 104 patients with advanced NETs treated on 4 phase 2 clinical trials with Lutetium-177-octreotate (177 Lu-octreotate) PRRT, mostly in combination with chemotherapy. Median follow-up was 68 months, which represents the longest follow-up study of 177 Lu-octreotate PRRT for NETs to date. RESULTS: Median progression-free survival (PFS) was 37 months, and median overall survival (OS) was 71 months. Five- and 10-year OS were 62% and 29%, and 5- and 10-year PFS were 36% and 21%, respectively, demonstrating 177 Lu-octreotate can provide durable responses. PRRT was well tolerated with 1.9% of patients developing chronic renal impairment and 1% of patients developing long-term thrombocytopenia. Interestingly, there was a relatively high rate of myelodysplasia (MDS)/leukemia (6.7%), possibly attributable to the longer follow-up (with all except 1 case occurring more than 4 years after PRRT treatment) or to the addition of concurrent chemotherapy. CONCLUSIONS: Lutetium-177-Octreotate PRRT remains an efficacious and well tolerated treatment in long-term follow-up. For clinicians deciding on the timing of PRRT for individual patients, the 6.7% long-term risk of MDS/leukemia needs to be balanced against the 21% PFS at 10 years.

Adaptive strategies of sponges to deoxygenated oceans.

Ocean deoxygenation is one of the major consequences of climate change. In coastal waters, this process can be exacerbated by eutrophication, which is contributing to an alarming increase in the so-called 'dead zones' globally. Despite its severity, the effect of reduced dissolved oxygen has only been studied for a very limited number of organisms, compared to other climate change impacts such as ocean acidification and warming. Here, we experimentally assessed the response of sponges to moderate and severe simulated hypoxic events. We ran three laboratory experiments on four species from two different temperate oceans (NE Atlantic and SW Pacific). Sponges were exposed to a total of five hypoxic treatments, with increasing severity (3.3, 1.6, 0.5, 0.4 and 0.13 mg O2  L-1 , over 7-12-days). We found that sponges are generally very tolerant of hypoxia. All the sponges survived in the experimental conditions, except Polymastia crocea, which showed significant mortality at the lowest oxygen concentration (0.13 mg O2  L-1 , lethal median time: 286 h). In all species except Suberites carnosus, hypoxic conditions do not significantly affect respiration rate down to 0.4 mg O2  L-1 , showing that sponges can uptake oxygen at very low concentrations in the surrounding environment. Importantly, sponges displayed species-specific phenotypic modifications in response to the hypoxic treatments, including physiological, morphological and behavioural changes. This phenotypic plasticity likely represents an adaptive strategy to live in reduced or low oxygen water. Our results also show that a single sponge species (i.e., Suberites australiensis) can display different strategies at different oxygen concentrations. Compared to other sessile organisms, sponges generally showed higher tolerance to hypoxia, suggesting that sponges could be favoured and survive in future deoxygenated oceans.

Absence of 21st century warming on Antarctic Peninsula consistent with natural variability.

Since the 1950s, research stations on the Antarctic Peninsula have recorded some of the largest increases in near-surface air temperature in the Southern Hemisphere. This warming has contributed to the regional retreat of glaciers, disintegration of floating ice shelves and a 'greening' through the expansion in range of various flora. Several interlinked processes have been suggested as contributing to the warming, including stratospheric ozone depletion, local sea-ice loss, an increase in westerly winds, and changes in the strength and location of low-high-latitude atmospheric teleconnections. Here we use a stacked temperature record to show an absence of regional warming since the late 1990s. The annual mean temperature has decreased at a statistically significant rate, with the most rapid cooling during the Austral summer. Temperatures have decreased as a consequence of a greater frequency of cold, east-to-southeasterly winds, resulting from more cyclonic conditions in the northern Weddell Sea associated with a strengthening mid-latitude jet. These circulation changes have also increased the advection of sea ice towards the east coast of the peninsula, amplifying their effects. Our findings cover only 1% of the Antarctic continent and emphasize that decadal temperature changes in this region are not primarily associated with the drivers of global temperature change but, rather, reflect the extreme natural internal variability of the regional atmospheric circulation.

piNET: a versatile web platform for downstream analysis and visualization of proteomics data.

Rapid progress in proteomics and large-scale profiling of biological systems at the protein level necessitates the continued development of efficient computational tools for the analysis and interpretation of proteomics data. Here, we present the piNET server that facilitates integrated annotation, analysis and visualization of quantitative proteomics data, with emphasis on PTM networks and integration with the LINCS library of chemical and genetic perturbation signatures in order to provide further mechanistic and functional insights. The primary input for the server consists of a set of peptides or proteins, optionally with PTM sites, and their corresponding abundance values. Several interconnected workflows can be used to generate: (i) interactive graphs and tables providing comprehensive annotation and mapping between peptides and proteins with PTM sites; (ii) high resolution and interactive visualization for enzyme-substrate networks, including kinases and their phospho-peptide targets; (iii) mapping and visualization of LINCS signature connectivity for chemical inhibitors or genetic knockdown of enzymes upstream of their target PTM sites. piNET has been built using a modular Spring-Boot JAVA platform as a fast, versatile and easy to use tool. The Apache Lucene indexing is used for fast mapping of peptides into UniProt entries for the human, mouse and other commonly used model organism proteomes. PTM-centric network analyses combine PhosphoSitePlus, iPTMnet and SIGNOR databases of validated enzyme-substrate relationships, for kinase networks augmented by DeepPhos predictions and sequence-based mapping of PhosphoSitePlus consensus motifs. Concordant LINCS signatures are mapped using iLINCS. For each workflow, a RESTful API counterpart can be used to generate the results programmatically in the json format. The server is available at http://pinet-server.org, and it is free and open to all users without login requirement.

LINCS Data Portal 2.0: next generation access point for perturbation-response signatures.

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program with the goal of generating a large-scale and comprehensive catalogue of perturbation-response signatures by utilizing a diverse collection of perturbations across many model systems and assay types. The LINCS Data Portal (LDP) has been the primary access point for the compendium of LINCS data and has been widely utilized. Here, we report the first major update of LDP (http://lincsportal.ccs.miami.edu/signatures) with substantial changes in the data architecture and APIs, a completely redesigned user interface, and enhanced curated metadata annotations to support more advanced, intuitive and deeper querying, exploration and analysis capabilities. The cornerstone of this update has been the decision to reprocess all high-level LINCS datasets and make them accessible at the data point level enabling users to directly access and download any subset of signatures across the entire library independent from the originating source, project or assay. Access to the individual signatures also enables the newly implemented signature search functionality, which utilizes the iLINCS platform to identify conditions that mimic or reverse gene set queries. A newly designed query interface enables global metadata search with autosuggest across all annotations associated with perturbations, model systems, and signatures.

Sample Selection Bias Due to Differential Mortality: A Supplementary Measure of Old-Age Poverty.

Traditional "head count" measures of poverty at advanced older ages understate the risk of falling into poverty because of survivorship bias due to the income-mortality gradient, which indicates that people in poverty have higher mortality rates than people with higher income. Survivorship bias is a form of sample selection bias. This paper presents a supplementary measure for poverty at older ages, based on an adaption of a model for correcting survivorship bias in rate of return data for mutual funds. Using U.S. longitudinal data from the Health and Retirement Study (HRS) for 1996 and 2002-2012 for the same cohort, we develop a new estimate of poverty at older ages that suggests that traditional cross-sectional measures understate the risk of falling into poverty by roughly a quarter. This finding has important implications for social programs that relate to the causes and consequences of the selectivity bias.

Microscale Fluid Behavior during Cryo-EM Sample Blotting.

Blotting has been the standard technique for preparing aqueous samples for single-particle electron cryo-microscopy for over three decades. This technique removes the excess solution from a transmission electron microscope grid by pressing absorbent filter paper against the specimen before vitrification. However, this standard technique produces vitreous ice with inconsistent thickness from specimen to specimen and from region to region within the same specimen, the reasons for which are not understood. Here, high-speed interference contrast microscopy is used to demonstrate that the irregular pattern of fibers in the filter paper imposes tortuous, highly variable boundaries during the removal of excess liquid from a flat, hydrophilic surface. As a result, aqueous films of nonuniform thickness are formed while the filter paper is pressed against the substrate. This pattern of nonuniform liquid thickness changes again after the filter paper is pulled away, but the thickness still does not become completely uniform. We suggest that similar topographical features of the liquid film are produced during the standard technique used to blot EM grids and that these manifest in nonuniform ice after vitrification. These observations suggest that alternative thinning techniques, which do not rely on direct contact between the filter paper and the grid, may result in more repeatable and uniform sample thicknesses.

Exascale applications: skin in the game.

As noted in Wikipedia, skin in the game refers to having 'incurred risk by being involved in achieving a goal', where 'skin is a synecdoche for the person involved, and game is the metaphor for actions on the field of play under discussion'. For exascale applications under development in the US Department of Energy Exascale Computing Project, nothing could be more apt, with the skin being exascale applications and the game being delivering comprehensive science-based computational applications that effectively exploit exascale high-performance computing technologies to provide breakthrough modelling and simulation and data science solutions. These solutions will yield high-confidence insights and answers to the most critical problems and challenges for the USA in scientific discovery, national security, energy assurance, economic competitiveness and advanced healthcare. This article is part of a discussion meeting issue 'Numerical algorithms for high-performance computational science'.

Data Portal for the Library of Integrated Network-based Cellular Signatures (LINCS) program: integrated access to diverse large-scale cellular perturbation response data.

The Library of Integrated Network-based Cellular Signatures (LINCS) program is a national consortium funded by the NIH to generate a diverse and extensive reference library of cell-based perturbation-response signatures, along with novel data analytics tools to improve our understanding of human diseases at the systems level. In contrast to other large-scale data generation efforts, LINCS Data and Signature Generation Centers (DSGCs) employ a wide range of assay technologies cataloging diverse cellular responses. Integration of, and unified access to LINCS data has therefore been particularly challenging. The Big Data to Knowledge (BD2K) LINCS Data Coordination and Integration Center (DCIC) has developed data standards specifications, data processing pipelines, and a suite of end-user software tools to integrate and annotate LINCS-generated data, to make LINCS signatures searchable and usable for different types of users. Here, we describe the LINCS Data Portal (LDP) (http://lincsportal.ccs.miami.edu/), a unified web interface to access datasets generated by the LINCS DSGCs, and its underlying database, LINCS Data Registry (LDR). LINCS data served on the LDP contains extensive metadata and curated annotations. We highlight the features of the LDP user interface that is designed to enable search, browsing, exploration, download and analysis of LINCS data and related curated content.

Predictors of Dropout in Disordered Gamblers in UK Residential Treatment.

Within the cohort of individuals who seek treatment for disordered gambling, over half fail to complete treatment. The current study sought to identify predictors of treatment dropout in a sample of gamblers attending a residential treatment facility for disordered gamblers in the UK and to report differences in voluntary and enforced dropout. Data on 658 gamblers seeking residential treatment with the Gordon Moody Association (GMA) was analysed, collected between 2000 and 2015. Measurements included demographic data, self-reported gambling behavior, (including the Problem Gambling Severity Index), mental and physical health status, and a risk assessment. Binary logistic regression models were used to examine predictors of treatment termination. Results confirm a high percentage of treatment dropout among disordered gamblers (51.3%). Significant predictors of treatment dropout included older age of the client, higher levels of education, higher levels of debt, online gambling, gambling on poker, shorter duration of treatment, higher depression, experience of previous treatment programmes and medication, and adverse childhood experiences. Within non-completers, significant predictors of enforced dropout included lifetime homelessness, less debt, sports gambling, depression and lifetime smoking. Those who were on a longer treatment programme and had previously received gambling treatment or support were less likely to be asked to leave. Clinicians working in inpatient support need to be aware of the increased psychopathogical and psychosocial problems in those who are at risk of termination and make attempts to retain them in treatment and increase patient compliance.

Correction to: Predictors of Dropout in Disordered Gamblers in UK Residential Treatment.

The original version of this article contained errors in Table 1. The numbers (N) and percentages (%) in the 'completed treatment' column were incorrect. It is now corrected with this erratum.

Deprotection Strategies for Thioimidates during Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides.

Thioamides are important biophysical probes of peptide folding but are prone to α-C epimerization during Fmoc solid-phase peptide synthesis. The stereochemical integrity of thioamide-containing peptides can be dramatically improved by protecting the thioamide as a thioimidate during synthesis. A drawback of this approach, however, is that once synthesis of the peptide is complete, regeneration of the thioamide requires the toxic, corrosive, and flammable gas H2S. This work examines several approaches to supplant H2S as a deprotection reagent in favor of a safer and more convenient alternative. Ultimately, a new application of the 4-azidobenzyl protecting group to thioamides was found to provide the most suitable means of both protection of α-C stereochemistry and conversion back to thioamide.

Immune clearance of highly pathogenic SIV infection.

Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69-172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors.