One-dimensional proximity superconductivity in the quantum Hall regime.

Extensive efforts have been undertaken to combine superconductivity and the quantum Hall effect so that Cooper-pair transport between superconducting electrodes in Josephson junctions is mediated by one-dimensional edge states1-6. This interest has been motivated by prospects of finding new physics, including topologically protected quasiparticles7-9, but also extends into metrology and device applications10-13. So far it has proven challenging to achieve detectable supercurrents through quantum Hall conductors2,3,6. Here we show that domain walls in minimally twisted bilayer graphene14-18 support exceptionally robust proximity superconductivity in the quantum Hall regime, allowing Josephson junctions to operate in fields close to the upper critical field of superconducting electrodes. The critical current is found to be non-oscillatory and practically unchanging over the entire range of quantizing fields, with its value being limited by the quantum conductance of ballistic, strictly one-dimensional, electronic channels residing within the domain walls. The system described is unique in its ability to support Andreev bound states at quantizing fields and offers many interesting directions for further exploration.

The nutrient-improvement bacteria selected by Agave lechuguilla T. and their role in the rhizosphere community.

Agave lechuguilla has one of the widest distributions among other agave species in the Chihuahuan Desert. Their capacity to grow in poorly developed soils and harsh conditions has been related to their association with plant growth-promoting rhizobacteria. In this work, we explored how soil properties and plant growth stage influence the composition of the rhizobacterial communities, their interactions, and the enzymatic activity and abundance of nitrogen-fixing bacteria and organic phosphorus-mineralizing bacteria in two subregions of the Chihuahuan Desert. We found that mature plants of lechuguilla stimulated the activity and abundance of nutrient-improvement rhizobacteria, and these soil samples had a higher content of total organic carbon, ammonium (NH4) and nitrite + nitrate (NO2+NO3). Nutrient availability seems to be an essential driver of the bacterial community's structure since the genera with more connections (hubs) were those with known mechanisms related to the availability of nutrients, such as env. OPS17 (Bacteroidetes), Gemmatimonadaceae uncultured, S0134terrestrial group, BD211terrestrial group (Gemmatimonadetes), Chthoniobacteracea and Candidatus Udaeobacter (Verrucomicrobia). This work shows that the late growth stages of lechuguilla recruit beneficial bacteria that favor its establishment and tolerance to harsh conditions of the arid lands.

Embryo blastulation and quality between days 5 and 6 of extended embryo culture.

PURPOSE: This study aims to know what proportion of culture day 5 pre-blastocyst-stage embryos develop into blastocysts by culture day 6 and what patient and cycle characteristics are associated with delayed blastocyst formation. METHODS: A retrospective observational cohort analysis was performed including a total of 9886 embryos from 1008 IVF cycles in 835 patients, who underwent treatment between January 1, 2016, and December 31, 2018. Autologous fresh in vitro fertilization (IVF) cycles at a single academic center were included in the analysis. Embryos were group-cultured using single-step culture media. Blastulation was defined as the presence of a new blastocyst. Usable blastulation was defined as the presence of a new good or excellent quality, expanded, hatching, or hatched blastocysts. RESULTS: The mean blastulation rate between days 5 and 6 of extended embryo culture was 30.9%. The mean percentage of embryos developing into usable blastocyst-stage embryos was 19.8%. The factors associated with blastulation on day 6 included the total number of embryos and the number of pre-blastocysts on day 5, as well as the use of ICSI. Age, the number of total embryos, those remained in culture and pre-blastocysts, as well as the blastulation rate on day 5 were associated with usable blastulation. CONCLUSION: It is important to know the usable blastocyst development rate between culture days 5 and 6 in order to adequately counsel patients debating whether to proceed with fresh ET on day 5 or forego ET with the expectation that embryos will be biopsied for PGT and/or cryopreserved on culture day 6. Our findings provide evidence to help guide patients in this difficult decision.

Bacterial Diversity and Interaction Networks of Agave lechuguilla Rhizosphere Differ Significantly From Bulk Soil in the Oligotrophic Basin of Cuatro Cienegas.

Due to the environmental conditions presented in arid zones, it is expected to have a high influence of deterministic processes over the community assemblages. Symbiotic interactions with microorganisms could increase colonization and survival of plants in difficult conditions, independent of the plants physiological and morphological characteristics. In this context, the microbial communities associated to plants that inhabit these types of areas can be a good model to understand the community assembly processes. We investigated the influence of stochastic and deterministic processes in the assemblage of rhizosphere microbial communities of Agave lechuguilla and bulk soil on the Cuatro Cienegas Basin, a site known for its oligotrophic conditions. We hypothesize that rhizospheric microbial communities of A. lechuguilla differ from those of bulk soil as they differ in physicochemical properties of soil and biotic interactions, including not only the plant, but also their microbial co-occurrence networks, it is expected that microbial species usually critical for plant growth and health are more common in the rhizosphere, whereas in the bulk soil microbial species related to the resistance to abiotic stress are more abundant. In order to confirm this hypothesis, 16S rRNA gene was sequenced by Illumina from rhizospheric and bulk soil samples in two seasons, also the physicochemical properties of the soil were determined. Our results showed differences in bacterial diversity, community composition, potential functions, and interaction networks between the rhizosphere samples and the ones from bulk soil. Although community structure arises from a complex interplay between deterministic and stochastic forces, our results suggest that A. lechuguilla recruits specific rhizospheric microbes with functional traits that benefits the plant through growth promotion and nutrition. This selection follows principally a deterministic process that shapes the rhizospheric microbial communities, directed by the plant modifications around the roots but also subjected to the influence of other environmental variables, such as seasonality and soil properties. Interestingly, keystone taxa in the interactions networks, not necessarily belong to the most abundant taxonomic groups, but they have an important role by their functional traits and keeping the connections on the community network.

Humic Substances Mediate Anaerobic Methane Oxidation Linked to Nitrous Oxide Reduction in Wetland Sediments.

Humic substances are redox-active organic molecules, which play pivotal roles in several biogeochemical cycles due to their electron-transferring capacity involving multiple abiotic and microbial transformations. Based on the redox properties of humic substances, and the metabolic capabilities of microorganisms to reduce and oxidize them, we hypothesized that they could mediate the anaerobic oxidation of methane (AOM) coupled to the reduction of nitrous oxide (N2O) in wetland sediments. This study provides several lines of evidence indicating the coupling between AOM and the reduction of N2O through an extracellular electron transfer mechanism mediated by the redox active functional groups in humic substances (e.g., quinones). We found that the microbiota of a sediment collected from the Sisal wetland (Yucatán Peninsula, southeastern Mexico) was able to reduce N2O (4.6 ± 0.5 µmol N2O g sed. -1 day-1) when reduced humic substances were provided as electron donor in a close stoichiometric relationship. Furthermore, a microbial enrichment derived from the wetland sediment achieved simultaneous 13CH4 oxidation (1.3 ± 0.1 µmol 13CO2 g sed. -1 day-1) and N2O reduction (25.2 ± 0.5 µmol N2O g sed. -1 day-1), which was significantly dependent on the presence of humic substances as an extracellular electron shuttle. Taxonomic characterization based on 16S rRNA gene sequencing revealed Acinetobacter (a É£-proteobacterium), the Rice Cluster I from the Methanocellaceae and an uncultured archaeon from the Methanomicrobiaceae family as the microbes potentially involved in AOM linked to N2O reduction mediated by humic substances. The findings reported here suggest that humic substances might play an important role to prevent the emission of greenhouse gases (CH4 and N2O) from wetland sediments. Further efforts to evaluate the feasibility of this novel mechanism under the natural conditions prevailing in ecosystems must be considered in future studies.

Dissolution and final fate of arsenic associated with gypsum, calcite, and ferrihydrite: Influence of microbial reduction of As(V), sulfate, and Fe(III).

Several studies have demonstrated that gypsum (CaSO4·2H2O) and calcite (CaCO3) can be important hosts of arsenic in contaminated hydrogeological systems. However, the extent to which microbial reducing processes contribute to the dissolution and transformation of carbonate and sulfate minerals and, thereby, to arsenic mobilization is poorly understood. These processes are likely to have a strong impact on arsenic mobility in iron-poor environments and in reducing aquifers where iron oxyhydroxides become unstable. Anoxic batch bioassays with arsenate (As(V)) coprecipitated with calcite, gypsum, or ferrihydrite (Fe(OH)3) were conducted in the presence of sulfate or molybdate to examine the impact of bioprocesses (i.e. As(V), sulfate, and Fe(III)-reduction) on arsenic dissolution, speciation, and eventual remineralization. Microbial reduction of As(V)-bearing calcite caused an important dissolution of arsenite, As(III), which remained in solution up to the end of the experiment (30 days). The reduction of As(V) from gypsum-As(V) also led to the release of As(III), which was subsequently remineralized, possibly as arsenic sulfides. The presence of sulfate triggered arsenic dissolution in the bioassays with ferrihydrite-As(V). This study showed that although gypsum and calcite have a lower capacity to bind arsenic, compared to iron oxides, they can play a critical role in the biogeochemical cycle of arsenic in natural calcareous and gypsiferous systems depleted of iron since they can be a source of electron acceptors for reducing bioprocesses.

Anaerobic ammonium oxidation linked to sulfate and ferric iron reduction fuels nitrogen loss in marine sediments.

Availability of fixed nitrogen is a pivotal driver on primary productivity in the oceans, thus the identification of key processes triggering nitrogen losses from these ecosystems is of major importance as they affect ecosystems function and consequently global biogeochemical cycles. Denitrification and anaerobic ammonium oxidation coupled to nitrite reduction (Anammox) are the only identified marine sinks for fixed nitrogen. The present study provides evidence indicating that anaerobic ammonium oxidation coupled to the reduction of sulfate, the most abundant electron acceptor present in the oceans, prevails in marine sediments. Tracer analysis with 15N-ammonium revealed that this microbial process, here introduced as Sulfammox, accounts for up to 5 µg 15N2 produced g-1 day-1 in sediments collected from the eastern tropical North Pacific coast. Raman and X-ray diffraction spectroscopies revealed that elemental sulfur and sphalerite (ZnFeS) were produced, besides free sulfide, during the course of Sulfammox. Anaerobic ammonium oxidation linked to Fe(III) reduction (Feammox) was also observed in the same marine sediments accounting for up to 2 µg 15N2 produced g-1 day-1. Taxonomic characterization, based on 16S rRNA gene sequencing, of marine sediments performing the Sulfammox and Feammox processes revealed the microbial members potentially involved. These novel nitrogen sinks may significantly fuel nitrogen loss in marine environments. These findings suggest that the interconnections among the oceanic biogeochemical cycles of N, S and Fe are much more complex than previously considered.

Low rates of osteoporosis treatment after hospitalization for hip fracture in Hawaii.

We evaluated osteoporosis treatment and DEXA utilization rates of patients who were admitted for hip fracture in a single healthcare system in Hawaii from 2015 to 2016. We found that osteoporosis treatment and DEXA utilization rates were low, highlighting a critical gap in osteoporosis care after admission for hip fracture. INTRODUCTION: The objective of this study was to evaluate osteoporosis care after an admission for hip fracture at three community hospitals within a single healthcare system in Hawaii. METHODS: A retrospective chart review was conducted (n = 428) of patients ≥ 50 years and hospitalized for hip fractures between January 1, 2015, and May 31, 2016, at three major hospitals within Hawaii Pacific Health, a large healthcare system in Hawaii. Basic demographics were collected, and medications prescribed were quantified and described within 1 year of hip fracture. Logistic regression was used to evaluate the association between collected variables and the odds of osteoporosis treatment. RESULTS: Only 115 (26.9%) patients were prescribed a medication for osteoporosis as a secondary prevention within a year of hospitalization for hip fracture. DEXA scans were performed in 137 (32.0%) patients. Most of the treated patients were prescribed oral bisphosphonates. Treatment facility, female gender, and higher BMI were found to be predictive factors for osteoporosis treatment. CONCLUSION: The use of osteoporosis medication for secondary prevention after admission for hip fracture in Hawaii is low. Efforts need to be made to improve treatment rates, especially among males.

Clinical prediction rules for mortality in patients with pulmonary embolism and cancer to guide outpatient management: a meta-analysis.

Essentials Clinical prediction rules (CPRs) can stratify patients with pulmonary embolism (PE) and cancer. A meta-analysis was done to assess prognostic accuracy in CPRs for mortality in these patients. Eight studies evaluating ten CPRs were included in this study. CPRs should continue to be used with other patient factors for mortality risk stratification. SUMMARY: Background Cancer treatment is commonly complicated by pulmonary embolism (PE), which remains a leading cause of morbidity and mortality in these patients. Some guidelines recommend the use of clinical prediction rules (CPRs) to help clinicians identify patients at low risk of mortality and therefore guide care. Objective To determine and compare the accuracy of available CPRs for identifying cancer patients with PE at low risk of mortality. Methods A literature search of Medline and Scopus (January 2000 to August 2017) was performed. Studies deriving/validating ≥ 1 CPR for early post-PE all-cause mortality were included. A bivariate, random-effects model was used to pool sensitivity and specificity estimates for each CPR. Traditional random-effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low risk of early mortality, mortality in low risk patients and odds ratios for death compared with higher-risk patients. Results Eight studies evaluating 10 CPRs were included. The highest sensitivities were observed with Hestia (98.1%, 95% confidence interval [CI] = 75.6-99.9%) and the EPIPHANY index (97.4%, 95% CI = 93.2-99.0%); sensitivities of remaining rules ranged from 59.9 to 96.6%. Of the six CPRs with sensitivities ≥ 95%, none had specificities > 33%. Random-effects meta-analysis suggested that 6.6-51.6% of cancer patients with PE were at low risk of mortality, 0-14.3% of low-risk patients died and low-risk patients had a 43-94% lower odds of death compared with those at higher risk. Conclusions Because of the limited total body of evidence regarding CPRs, their results, in conjunction with other pertinent patient-specific clinical factors, should continue to be used in identifying appropriate management for PE in patients with cancer.

Methanogenic and Sulfate-Reducing Activities in a Hypersaline Microbial Mat and Associated Microbial Diversity.

Methanogenesis and sulfate reduction are important microbial processes in hypersaline environments. However, key aspects determining substrate competition between these microbial processes have not been well documented. We evaluated competitive and non-competitive substrates for stimulation of both processes through microcosm experiments of hypersaline microbial mat samples from Guerrero Negro, Baja California Sur, Mexico, and we assessed the effect of these substrates on the microbial community composition. Methylotrophic methanogenesis evidenced by sequences belonging to methanogens of the family Methanosarcinaceae was found as the dominant methanogenic pathway in the studied hypersaline microbial mat. Nevertheless, our results showed that incubations supplemented with acetate and lactate, performed in absence of sulfate, also produced methane after 40 days of incubation, apparently driven by hydrogenotrophic methanogens affiliated to the family Methanomicrobiaceae. Sulfate reduction was mainly stimulated by addition of acetate and lactate; however, after 40 days of incubation, an increase of the H2S concentrations in microcosms amended with trimethylamine and methanol was also observed, suggesting that these substrates are putatively used for sulfate reduction. Moreover, 16S rRNA gene sequencing analysis showed remarkable differences in the microbial community composition among experimental treatments. In the analyzed sample amended with acetate, sulfate-reducing bacteria (SRB) belonging to the family Desulfobacteraceae were dominant, while members of Desulfohalobiaceae, Desulfomicrobiaceae, and Desulfovibrionaceae were found in the incubation with lactate. Additionally, we detected an unexpected high abundance of unclassified Hydrogenedentes (near 25%) in almost all the experimental treatments. This study contributes to better understand methanogenic and sulfate-reducing activities, which play an important role in the functioning of hypersaline environments.

Denitrifying bacterial communities display different temporal fluctuation patterns across Dutch agricultural soils.

Considering the great agronomic and environmental importance of denitrification, the aim of the present study was to study the temporal and spatial factors controlling the abundance and activity of denitrifying bacterial communities in a range of eight agricultural soils over 2 years. Abundance was quantified by qPCR of the nirS, nirK and nosZ genes, and the potential denitrification enzyme activity (DEA) was estimated. Our data showed a significant temporal variation considerably high for the abundance of nirK-harboring communities, followed by nosZ and nirS communities. Regarding soil parameters, the abundances of nosZ, nirS and nirK were mostly influenced by organic material, pH, and slightly by NO3-, respectively. Soil texture was the most important factor regulating DEA, which could not be explained by the abundance of denitrifiers. Analyses of general patterns across lands to understand the soil functioning is not an easy task because the multiple factors influencing processes such as denitrification can skew the data. Careful analysis of atypical sites are necessary to classify the soils according to trait similarity and in this way reach a better predictability of the denitrifiers dynamics.

The impact of appointment-based medication synchronization on medication taking behaviour and health outcomes: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Proactive synchronization of medication refills through an appointment-based model (ABM) is a community pharmacy-based intervention targeting adherence to medications. We aimed to systematically review evidence on the impact of the ABM on medication taking behaviour, health resource utilization, clinical outcomes and the preferences of patients and providers. METHODS: We conducted a systematic literature search of MEDLINE and Scopus from database inception through 6 February 2017. Studies were included if they were original investigations evaluating the impact of the ABM on at least one outcome of interest and published in the peer-reviewed literature as a full-text manuscript in the English language. Outcomes included medication taking behaviour, clinical and economic outcomes, health resource utilization, and patient or provider satisfaction. Data were synthesized qualitatively. RESULTS: Five studies, mostly observational in design and with low risk of bias, were included. Objective measures of medication taking behaviour were consistently improved in patients enrolled in an ABM vs control, indicating an association between appointment-based medication synchronization with improved adherence and decreased likelihood of non-persistence. A single decision analysis indicates a cost savings over 1 year associated with the appointment-based medication synchronization programme modelled, for hypertension, diabetes and hyperlipidaemia. Limited data regarding health resource utilization and clinical outcomes and patient or provider satisfaction exist and are currently inconclusive. WHAT IS NEW AND CONCLUSION: The ABM provides a unique, patient-centred service to improve medication adherence amongst patients taking chronic medications while demonstrating a positive financial return on investment. Future research is needed to determine the impact of the ABM on final health outcomes.

Up-flow anaerobic sediment trapped (UAST) reactor as a new configuration for the enrichment of anammox bacteria from marine sediments.

A novel reactor configuration for the enrichment of anammox bacteria from marine sediments was developed. Marine sediments were successfully kept inside the bioreactors during the enrichment process by strategically installing traps at different depths to prevent the wash-out of sediments. Three up-flow anaerobic sediment trapped (UAST) reactors were set up (α, ß and ω supplied with 50, 150 and 300mgCa2+/L, respectively). Nitrogen removal rates (NRR) of up to 3.5gN/L-d and removal efficiencies of >95% were reached. Calcium enhanced biomass production as evidenced by increased volatile suspended solids and extracellular polymeric substances. After the long-term operation, dominant families detected were Rhodobacteracea, Flavobacteracea, and Alteromonadacea, while the main anammox genera detected in the three reactors were Candidatus Kuenenia and Candidatus Anammoximicrobium. The UAST reactor is proposed as suitable technology for the enrichment of anammox bacteria applicable for the treatment of saline industrial wastewaters with high nitrogen content.

Anaerobic Methane Oxidation Driven by Microbial Reduction of Natural Organic Matter in a Tropical Wetland.

Wetlands constitute the main natural source of methane on Earth due to their high content of natural organic matter (NOM), but key drivers, such as electron acceptors, supporting methanotrophic activities in these habitats are poorly understood. We performed anoxic incubations using freshly collected sediment, along with water samples harvested from a tropical wetland, amended with 13C-methane (0.67 atm) to test the capacity of its microbial community to perform anaerobic oxidation of methane (AOM) linked to the reduction of the humic fraction of its NOM. Collected evidence demonstrates that electron-accepting functional groups (e.g., quinones) present in NOM fueled AOM by serving as a terminal electron acceptor. Indeed, while sulfate reduction was the predominant process, accounting for up to 42.5% of the AOM activities, the microbial reduction of NOM concomitantly occurred. Furthermore, enrichment of wetland sediment with external NOM provided a complementary electron-accepting capacity, of which reduction accounted for ∼100 nmol 13CH4 oxidized · cm-3 · day-1 Spectroscopic evidence showed that quinone moieties were heterogeneously distributed in the wetland sediment, and their reduction occurred during the course of AOM. Moreover, an enrichment derived from wetland sediments performing AOM linked to NOM reduction stoichiometrically oxidized methane coupled to the reduction of the humic analogue anthraquinone-2,6-disulfonate. Microbial populations potentially involved in AOM coupled to microbial reduction of NOM were dominated by divergent biota from putative AOM-associated archaea. We estimate that this microbial process potentially contributes to the suppression of up to 114 teragrams (Tg) of CH4 · year-1 in coastal wetlands and more than 1,300 Tg · year-1, considering the global wetland area.IMPORTANCE The identification of key processes governing methane emissions from natural systems is of major importance considering the global warming effects triggered by this greenhouse gas. Anaerobic oxidation of methane (AOM) coupled to the microbial reduction of distinct electron acceptors plays a pivotal role in mitigating methane emissions from ecosystems. Given their high organic content, wetlands constitute the largest natural source of atmospheric methane. Nevertheless, processes controlling methane emissions in these environments are poorly understood. Here, we provide tracer analysis with 13CH4 and spectroscopic evidence revealing that AOM linked to the microbial reduction of redox functional groups in natural organic matter (NOM) prevails in a tropical wetland. We suggest that microbial reduction of NOM may largely contribute to the suppression of methane emissions from tropical wetlands. This is a novel avenue within the carbon cycle in which slowly decaying NOM (e.g., humic fraction) in organotrophic environments fuels AOM by serving as a terminal electron acceptor.

Reduction in surgical fog with a warm humidified gas management protocol significantly shortens procedure time in pediatric robot-assisted laparoscopic procedures.

INTRODUCTION: The adoption of robot-assisted laparoscopic (RAL) procedures in the field of urology has occurred rapidly, but is, to date, without pediatric-specific instrumentation. Surgical fog is a significant barrier to safe and efficient laparoscopy. This appears to be a significant challenge when adapting three-dimensional 8.5-mm scopes to use in pediatric RAL surgery. The objective of the present study was to compare matched controls from a prospectively collected database to procedures that were performed utilizing special equipment and a protocol to minimize surgical fog in pediatric RAL procedures. METHODS: A prospectively collected database of all patients who underwent RAL pediatric urology procedures was used to compare: procedure, age, sex, American Society of Anesthesiologists score, weight, console time, number of times the camera was removed to clean the lens during a procedure, length of hospital stay, and morphine equivalents required in the postoperative period. A uniquely developed protocol was used, it consisted of humidified (95% relative humidity) and warmed CO2 gas (95 °F) insufflation via Insuflow® on a working trocar, with active smoke evacuation via PneuVIEW®XE on the opposite working trocar with a gas pass through of 3.5-5 l/min. The outcomes were compared with matched controls (Summary Fig). RESULTS: The novel gas protocol was utilized in 13 procedures (five pyeloplasties, two revision pyeloplasties, three ureteroureterostomies (UU), three nephrectomies) and compared with 13 procedures (six pyeloplasties, one revision pyeloplasty, three UU, three nephrectomies) prior to the protocol development. There was no statistical difference in age (P = 0.78), sex (P = 0.11), ASA score (P = 1.00) or weight (P = 0.69). There were no open conversions, ≥Grade 2 Clavien complications, or readmissions within 30 days in either group. CONCLUSIONS: This novel gas protocol yielded a statistically significant reduction in procedure time, by decreasing the number of times the camera was required to be pulled during the case by more than five occurrences, and saved approximately 35 min on average per case.

Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

WHAT IS KNOWN AND OBJECTIVE: Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid-associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach - peripherally restricted kappa-opioid receptor (KOR) agonists (pKORAs). METHODS: Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa-opioid receptor agonists. Each source was summarized, reviewed and assessed. RESULTS: The historical development of pKORAs can be traced from the design of increasingly KOR-selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood-brain barrier. Novel compounds are under development and have progressed to clinical trials. WHAT IS NEW AND CONCLUSIONS: The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile.

The influence of intramolecular sulfur-lone pair interactions on small-molecule drug design and receptor binding.

Sulfur-lone pair interactions are important conformational control elements in sulfur-containing heterocycles that abound in pharmaceuticals, natural products, agrochemicals, polymers and other important classes of organic molecules. Nonetheless, the role of intramolecular sulfur-lone pair interactions in the binding of small molecules to receptors is often overlooked. Here we analyze the magnitudes and origins of these interactions for a variety of biologically relevant small molecules using quantum chemical and automated docking calculations. In most cases examined in this study, the lowest energy conformation of the small molecule displays a sulfur-lone pair close contact. However, docking studies, both published and new, often predict that conformations without sulfur-lone pair contacts have the best binding affinity for their respective receptors. This is a serious problem. Since many of these predicted bound conformations are not actually energetically accessible, pursuing design (e.g., drug design) around these binding modes necessarily will lead, serendipity aside, to dead end designs. Our results constitute a caution that one best not neglect these interactions when predicting the binding affinities of potential ligands (drugs or not) for hosts (enzymes, receptors, DNA, RNA, synthetic hosts). Moreover, a better understanding and awareness of sulfur-lone pair interactions should facilitate the rational modulation of host-guest interactions involving sulfur-containing molecules.