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Dimeric calpains constitute a promising therapeutic target for many diseases such as cardiovascular, neurodegenerative and ischaemic disease. The discovery of selective calpain inhibitors, however, has been extremely challenging. Previously, allosteric inhibitors of calpains, such as PD150606, which included a specific α-mercaptoacrylic acid sub-structure, were reported to bind to the penta-EF hand calcium binding domain, PEF(S) of calpain. Although these are selective to calpains over other cysteine proteases, their mode of action has remained elusive due to their ability to inhibit the active site domain with and without the presence of PEF(S), with similar potency. These findings have led to the question of whether the inhibitory response can be attributed to an allosteric mode of action or alternatively to inhibition at the active site. In order to address this problem, we report a structure-based virtual screening protocol as a novel approach for the discovery of PEF(S) binders that populate a novel chemical space. We have identified compound 1, Vidupiprant, which is shown to bind to the PEF(S) domain by the TNS displacement method, and it exhibited specificity in its allosteric mode of inhibition. Compound 1 inhibited the full-length calpain-1 complex with a higher potency (IC 50  = 7.5 μM) than the selective, cell-permeable non-peptide calpain inhibitor, PD150606 (IC 50  = 19.3 μM), where the latter also inhibited the active site domain in the absence of PEF(S) (IC 50  = 17.8 μM). Hence the method presented here has identified known compounds with a novel allosteric mechanism for the inhibition of calpain-1. We show for the first time that the inhibition of enzyme activity can be attributed to an allosteric mode of action, which may offer improved selectivity and a reduced side-effects profile., (Copyright © 2018. Published by Elsevier Masson SAS.)

Terpene synthases catalyse the first step in the conversion of prenyl diphosphates to terpenoids. They act as templates for their substrates to generate a reactive conformation, from which a Mg 2+ -dependent reaction creates a carbocation-PP i ion pair that undergoes a series of rearrangements and (de)protonations to give the final terpene product. This tight conformational control was exploited for the (R)-germacrene A synthase- and germacradien-4-ol synthase-catalysed formation of a medium-sized cyclic terpenoid ether from substrates containing nucleophilic functional groups. Farnesyl diphosphate analogues with a 10,11-epoxide or an allylic alcohol were efficiently converted to a 11-membered cyclic terpenoid ether that was characterised by HRMS and NMR spectroscopic analyses. Further experiments showed that other sesquiterpene synthases, including aristolochene synthase, δ-cadinene synthase and amorphadiene synthase, yielded this novel terpenoid from the same substrate analogues. This work illustrates the potential of terpene synthases for the efficient generation of structurally and functionally novel medium-sized terpene ethers., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Estimation of a generating partition is critical for symbolization of measurements from discrete-time dynamical systems, where a sequence of symbols from a (finite-cardinality) alphabet may uniquely specify the underlying time series. Such symbolization is useful for computing measures (e.g., Kolmogorov-Sinai entropy) to identify or characterize the (possibly unknown) dynamical system. It is also useful for time series classification and anomaly detection. The seminal work of Hirata, Judd, and Kilminster ( 2004 ) derives a novel objective function, akin to a clustering objective, that measures the discrepancy between a set of reconstruction values and the points from the time series. They cast estimation of a generating partition via the minimization of their objective function. Unfortunately, their proposed algorithm is nonconvergent, with no guarantee of finding even locally optimal solutions with respect to their objective. The difficulty is a heuristic nearest neighbor symbol assignment step. Alternatively, we develop a novel, locally optimal algorithm for their objective. We apply iterative nearest-neighbor symbol assignments with guaranteed discrepancy descent, by which joint, locally optimal symbolization of the entire time series is achieved. While most previous approaches frame generating partition estimation as a state-space partitioning problem, we recognize that minimizing the Hirata et al. ( 2004 ) objective function does not induce an explicit partitioning of the state space, but rather the space consisting of the entire time series (effectively, clustering in a (countably) infinite-dimensional space). Our approach also amounts to a novel type of sliding block lossy source coding. Improvement, with respect to several measures, is demonstrated over popular methods for symbolizing chaotic maps. We also apply our approach to time-series anomaly detection, considering both chaotic maps and failure application in a polycrystalline alloy material.

While non-negative blind source separation (nBSS) has found many successful applications in science and engineering, model order selection, determining the number of sources, remains a critical yet unresolved problem. Various model order selection methods have been proposed and applied to real-world data sets but with limited success, with both order over- and under-estimation reported. By studying existing schemes, we have found that the unsatisfactory results are mainly due to invalid assumptions, model oversimplification, subjective thresholding, and/or to assumptions made solely for mathematical convenience. Building on our earlier work that reformulated model order selection for nBSS with more realistic assumptions and models, we report a newly and formally revised model order selection criterion rooted in the minimum description length (MDL) principle. Adopting widely invoked assumptions for achieving a unique nBSS solution, we consider the mixing matrix as consisting of deterministic unknowns, with the source signals following a multivariate Dirichlet distribution. We derive a computationally efficient, stochastic algorithm to obtain approximate maximum-likelihood estimates of model parameters and apply Monte Carlo integration to determine the description length. Our modeling and estimation strategy exploits the characteristic geometry of the data simplex in nBSS. We validate our nBSS-MDL criterion through extensive simulation studies and on four real-world data sets, demonstrating its strong performance and general applicability to nBSS. The proposed nBSS-MDL criterion consistently detects the true number of sources, in all of our case studies.

[This corrects the article DOI: 10.1038/s42003-018-0098-3.].

REV1 is a DNA damage tolerance protein and encodes two ubiquitin-binding motifs (UBM1 and UBM2) that are essential for REV1 functions in cell survival under DNA-damaging stress. Here we report the first solution and X-ray crystal structures of REV1 UBM2 and its complex with ubiquitin, respectively. Furthermore, we have identified the first small-molecule compound, MLAF50, that directly binds to REV1 UBM2. In the heteronuclear single quantum coherence NMR experiments, peaks of UBM2 but not of UBM1 are significantly shifted by the addition of ubiquitin, which agrees to the observation that REV1 UBM2 but not UBM1 is required for DNA damage tolerance. REV1 UBM2 interacts with hydrophobic residues of ubiquitin such as L8 and L73. NMR data suggest that MLAF50 binds to the same residues of REV1 UBM2 that interact with ubiquitin, indicating that MLAF50 can compete with the REV1 UBM2-ubiquitin interaction orthosterically. Indeed, MLAF50 inhibited the interaction of REV1 UBM2 with ubiquitin and prevented chromatin localization of REV1 induced by cisplatin in U2OS cells. Our results structurally validate REV1 UBM2 as a target of a small-molecule inhibitor and demonstrate a new avenue to targeting ubiquitination-mediated protein interactions with a chemical tool., (Published by Elsevier Ltd.)

Background: Firearm-associated injuries are the second leading cause of death in children in the United States. Fractures are common comorbid injuries in young patients with firearm-associated injuries. The purpose of this study was to define the burden of firearm-associated fractures (FAFs) in children and adolescents in the United States., Methods: We analyzed the 2003-2012 Kids' Inpatient Database. Patients were grouped into 4 age groups: 0 to 4, 5 to 9, 10 to 14, and 15 to 20 years old. Sample observations with both an external cause of injury code indicating gunshot injury and a diagnosis code indicating orthopaedic fracture (extremity, pelvis, or spine) were identified as cases of FAF. Sex, age, race, cause of injury, and fracture-related operating room procedures were catalogued. Population-level incidence was calculated for each year studied., Results: From 2003 to 2012, the incidence of FAF in patients 20 years and below of age increased from 73 to 96 cases per 100,000 admissions (P=0.009). The 0 to 4 age group saw the largest increase in injury frequency (141%, P=0.08). There was a 4-fold increase in the rate of unintentional injury in this subgroup. The most common age group affected by FAFs was 15 to 20 year olds. Minorities and male individuals were disproportionately affected. Assault and unintentional causes were the most common reasons for injury., Conclusions: The frequency of FAF in patients 20 years and below of age increased over the study period, with almost 1 case per 1000 admissions in 2012. The finding that certain subpopulations are disproportionately affected reflects the complex sociologic factors influencing gun violence in the United States., Level of Evidence: Level III-retrospective cohort study.

Symbiosis between dinoflagellates of the genus Symbiodinium and reef-building corals forms the trophic foundation of the world's coral reef ecosystems. Here we present the first draft genome of Symbiodinium goreaui (Clade C, type C1: 1.03 Gbp), one of the most ubiquitous endosymbionts associated with corals, and an improved draft genome of Symbiodinium kawagutii (Clade F, strain CS-156: 1.05 Gbp) to further elucidate genomic signatures of this symbiosis. Comparative analysis of four available Symbiodinium genomes against other dinoflagellate genomes led to the identification of 2460 nuclear gene families (containing 5% of Symbiodinium genes) that show evidence of positive selection, including genes involved in photosynthesis, transmembrane ion transport, synthesis and modification of amino acids and glycoproteins, and stress response. Further, we identify extensive sets of genes for meiosis and response to light stress. These draft genomes provide a foundational resource for advancing our understanding of  Symbiodinium biology and the coral-algal symbiosis., Competing Interests: The authors declare no competing interests.

Millions or billions of sperm are deposited by artificial insemination or natural mating into the cow reproductive tract but only a few arrive at the site of fertilization and only one fertilizes an oocyte. The remarkable journey that successful sperm take to reach an oocyte is long and tortuous, and includes movement through viscous fluid, avoiding dead ends and hostile immune cells. The privileged collection of sperm that complete this journey must pass selection steps in the vagina, cervix, uterus, utero-tubal junction and oviduct. In many locations in the female reproductive tract, sperm interact with the epithelium and the luminal fluid, which can affect sperm motility and function. Sperm must also be tolerated by the immune system of the female for an adequate time to allow fertilization to occur. This review emphasizes literature about cattle but also includes work in other species that emphasizes critical broad concepts. Although all parts of the female reproductive tract are reviewed, particular attention is given to the sperm destination, the oviduct.

The validity of a commercially available wearable device for measuring total sleep time was examined in a sample of well-trained young athletes during night-time sleep periods and daytime naps. Participants wore a FitBit HR Charge on their non-dominant wrist and had electrodes attached to their face and scalp to enable polysomnographic recordings of sleep in the laboratory. The FitBit automatically detected 24/30 night-time sleep periods but only 6/20 daytime naps. Compared with polysomnography, the FitBit overestimated total sleep time by an average of 52 ± 152 min for night-time sleep periods, and by 4 ± 8 min for daytime naps. It is important for athletes and practitioners to be aware of the limitations of wearable devices that automatically detect sleep duration.

This study examined the difference between athletes' self-reported and objective sleep durations during two nap opportunities. Twelve well-trained male soccer players' sleep durations were assessed using polysomnography and a self-report question during a 60- and 120-min nap opportunity. Participants underestimated sleep compared to objective sleep assessments for both the 60-min nap opportunity (p = 0.004) and 120-min nap opportunity (p = 0.001). Soccer players underestimated their sleep duration by approximately 10 min per hour of nap opportunity. It is yet to be determined if athletes are likely to underestimate sleep duration during their main nighttime sleep period.

This study examined the efficacy of daytime napping to supplement night-time sleep in athletes. Twelve well-trained male soccer players completed three conditions in a randomised, counterbalanced order: 9 h in bed overnight with no daytime nap (9 h + 0 h); 8 h in bed overnight with a 1-h daytime nap (8 h + 1 h); and 7 h in bed overnight with a 2-h daytime nap (7 h + 2 h). Sleep was assessed using polysomnography. The total amount of sleep obtained in the three conditions was similar, i.e. 8.1 h (9 h + 0 h), 8.2 h (8 h + 1 h), and 8.0 h (7 h + 2 h). Daytime napping may be an effective strategy to supplement athletes' night-time sleep.

The San Joaquin Valley (SJV) of California experiences high concentrations of particulate matter NH 4 NO 3 during episodes of meteorological stagnation in winter. A rich data set of observations related to NH 4 NO 3 formation was acquired during multiple periods of elevated NH 4 NO 3 during the Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality (DISCOVER-AQ) field campaign in SJV in January and February 2013. Here NH 4 NO 3 is simulated during the SJV DISCOVER-AQ study period with the Community Multiscale Air Quality (CMAQ) model, diagnostic model evaluation is performed using the DISCOVER-AQ data set, and integrated reaction rate analysis is used to quantify HNO 3 production rates. Simulated NO 3 - generally agrees well with routine monitoring of 24-hr average NO 3 - , but comparisons with hourly average NO 3 - measurements in Fresno revealed differences at higher time resolution. Predictions of gas-particle partitioning of total nitrate (HNO 3 + NO 3 - ) and NHx (NH 3 + NH 4 + ) generally agree well with measurements in Fresno, although partitioning of total nitrate to HNO 3 is sometimes overestimated at low relative humidity in afternoon. Gas-particle partitioning results indicate that NH 4 NO 3 formation is limited by HNO 3 availability in both the model and ambient. NH 3 mixing ratios are underestimated, particularly in areas with large agricultural activity, and additional work on the spatial allocation of NH 3 emissions is warranted. During a period of elevated NH 4 NO 3 , the model predicted that the OH + NO 2 pathway contributed 46% to total HNO 3 production in SJV and the N 2 O 5 heterogeneous hydrolysis pathway contributed 54%. The relative importance of the OH + NO 2 pathway for HNO 3 production is predicted to increase as NOx emissions decrease.

Background: All organisms employ biological clocks to anticipate physical changes in the environment; however, the integration of biological clocks in symbiotic systems has received limited attention. In corals, the interpretation of rhythmic behaviours is complicated by the daily oscillations in tissue oxygen tension resulting from the photosynthetic and respiratory activities of the associated algal endosymbiont Symbiodinium. In order to better understand the integration of biological clocks in cnidarian hosts of Symbiodinium, daily rhythms of behaviour and gene expression were studied in symbiotic and aposymbiotic morphs of the sea-anemone Aiptasia diaphana., Results: The results showed that whereas circatidal (approx. 12-h) cycles of activity and gene expression predominated in aposymbiotic morphs, circadian (approx. 24-h) patterns were the more common in symbiotic morphs, where the expression of a significant number of genes shifted from a 12- to 24-h rhythm. The behavioural experiments on symbiotic A. diaphana displayed diel (24-h) rhythmicity in body and tentacle contraction under the light/dark cycles, whereas aposymbiotic morphs showed approximately 12-h (circatidal) rhythmicity. Reinfection experiments represent an important step in understanding the hierarchy of endogenous clocks in symbiotic associations, where the aposymbiotic Aiptasia morphs returned to a 24-h behavioural rhythm after repopulation with algae., Conclusion: Whilst some modification of host metabolism is to be expected, the extent to which the presence of the algae modified host endogenous behavioural and transcriptional rhythms implies that it is the symbionts that influence the pace. Our results clearly demonstrate the importance of the endosymbiotic algae in determining the timing and the duration of the extension and contraction of the body and tentacles and temporal gene expression.

Purpose: Feeding difficulties are common among patients with cerebral palsy (CP) and neuromuscular (NM) scoliosis. We theorize that posterior spinal fusion (PSF) reduces intra-abdominal pressure, resulting in improved feeding and subsequent weight gain. We hypothesized that, among nonambulatory patients with CP and NM scoliosis, we would observe significant gain in weight following PSF., Methods: Fifty subjects with nonambulatory CP who underwent PSF for NM scoliosis were included. Age and weight were recorded for the preoperative year; on the day of surgery; and at 6-month, 1-year, and 2-year follow-up. Weights were converted to weight percentiles using CP-specific growth charts. The weight percentile distributions were compared between time points using descriptive statistics as well as regression analysis., Results: The average change in weight from the day of surgery to 2-year follow-up was +3.4 percentiles. Patients who started out under the 50th percentile gained an average of 17.3 percentiles in the first year after PSF ( p = 0.009). Regression analysis showed that patients with baseline weight <50th percentile tended to gain in weight percentile over the first postoperative year ( β = 1.990, p = 0.001). No trend was present among this group prior to surgery ( p = 0.692) or during the second postoperative year ( p = 0.945). No trends were noted prior to or after surgery for patients with baseline weights ≥50th percentile. No significant association was observed between curve severity (measured by preoperative Cobb angle) and weight change., Conclusions: This series is the first to document significant weight gain after PSF for NM scoliosis, supporting the theory that spinal correction improves digestive function., Level of Evidence: Prognostic level II.

As the depth increases and the light fades in oceanic cold seeps, a variety of chemosynthetic-based benthic communities arise. Previous assessments reported polychaete annelids belonging to the family Siboglinidae as part of the fauna at cold seeps, with the 'Vestimentifera' clade containing specialists that depend on microbial chemosynthetic endosymbionts for nutrition. Little information exists concerning the microbiota of the external portion of the vestimentiferan trunk wall. We employed 16S rDNA-based metabarcoding to describe the external microbiota of the chitin tubes from the vestimentiferan Escarpia collected from a chemosynthetic community in a cold seep area at the southwestern Atlantic Ocean. The most abundant operational taxonomic unit (OTU) belonged to the family Pirellulaceae (phylum Planctomycetes), and the second most abundant OTU belonged to the order Methylococcales (phylum Proteobacteria), composing an average of 21.1 and 15.4% of the total reads on tubes, respectively. These frequencies contrasted with those from the surrounding environment (sediment and water), where they represent no more than 0.1% of the total reads each. Moreover, some taxa with lower abundances were detected only in Escarpia tube walls. These data constitute on the first report of an epibiont microbial community found in close association with external surface of a cold-seep metazoan, Escarpia sp., from a chemosynthetic community in the southwestern Atlantic Ocean.

Neuromuscular electrical stimulation (NMES) is used to produce contractions to restore movement and reduce secondary complications for individuals experiencing motor impairment. NMES is conventionally delivered through a single pair of electrodes over a muscle belly or nerve trunk using short pulse durations and frequencies between 20 and 40Hz (conventional NMES). Unfortunately, the benefits and widespread use of conventional NMES are limited by contraction fatigability, which is in large part because of the nonphysiological way that contractions are generated. This review provides a summary of approaches designed to reduce fatigability during NMES, by using physiological principles that help minimize fatigability of voluntary contractions. First, relevant principles of the recruitment and discharge of motor units (MUs) inherent to voluntary contractions and conventional NMES are introduced, and the main mechanisms of fatigability for each contraction type are briefly discussed. A variety of NMES approaches are then described that were designed to reduce fatigability by generating contractions that more closely mimic voluntary contractions. These approaches include altering stimulation parameters, to recruit MUs in their physiological order, and stimulating through multiple electrodes, to reduce MU discharge rates. Although each approach has unique advantages and disadvantages, approaches that minimize MU discharge rates hold the most promise for imminent translation into rehabilitation practice. The way that NMES is currently delivered limits its utility as a rehabilitative tool. Reducing fatigability by delivering NMES in ways that better mimic voluntary contractions holds promise for optimizing the benefits and widespread use of NMES-based programs., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Nursing ensures lactocrine delivery of maternally derived, milk-borne bioactive factors to offspring, which affects postnatal development of female reproductive tract tissues. Disruption of lactocrine communication for two days from birth (postnatal day (PND) 0) by feeding milk replacer in lieu of nursing or consumption of colostrum alters porcine uterine gene expression globally by PND 2 and inhibits uterine gland genesis by PND 14. Here, objectives were to determine effects of: (1) nursing or milk replacer feeding from birth; (2) a single dose of colostrum or milk replacer and method of feeding and (3) a single feeding of colostrum or milk replacer, with or without oral supplementation of IGF1, administered at birth on aspects of porcine uterine development at 12-h postnatally. Results indicate nursing for 12 h from birth supports rapid establishment of a uterine developmental program, illustrated by patterns of endometrial cell proliferation, expression of genes associated with uterine wall development and entry into mitosis and establishment of a uterine MMP9/TIMP1 system. A single feeding of colostrum at birth increased endometrial cell proliferation at 12 h, regardless of method of feeding. Oral supplementation of IGF1 was sufficient to support endometrial cell proliferation at 12 h in replacer-fed gilts, and supplementation of colostrum with IGF1 further increased endometrial cell proliferation. Results indicate that lactocrine regulation of postnatal uterine development is initiated with the first ingestion of colostrum. Further, results suggest IGF1 may be lactocrine-active and support a 12-h bioassay, which can be used to identify uterotrophic lactocrine activity., (© 2018 Society for Reproduction and Fertility.)

This study examined the hypothesis that flow sorting sperm by sex chromosomes affects oviduct cell binding which would influence formation of the sperm reservoir in the oviduct. The sperm-rich fraction from boars (n = 5) was collected, sperm were stained with Hoechst 33342 and sorted. Sperm were sorted based on the presence of either an X or Y chromosome and placed into the following treatments: 1) sperm selected for the Y chromosome, 2) selected for the X, 3) an equal mixture of sorted X and Y, and 4) a control of non-sorted sperm from the same collection. Samples were tested for oviduct cell binding within 12 h of sorting. Additionally, sperm were analyzed for motility characteristics, acrosome status, and binding to the two oviduct glycan motifs that bind porcine sperm, biantennary 6-sialylated N-acetyllactosamine on a mannose core (bi-SiaLN) and sulfated Le X trisaccharide (suLe X ). The disaccharide found within both glycan motifs, N-acetyllactosamine (LacNAc), was used as a control. Sperm binding to oviduct cells was reduced by more than half in the three sorted samples when compared to the control sperm that were not sorted. The percentage of sperm that were motile 24 h after sorting was also decreased significantly in each of the sorted sample groups when compared to the unsorted control. In contrast, sorting did not decrease the percentage of sperm that bound purified soluble glycans or the location on sperm to which they bound. There was also no difference in sperm acrosome status among the four groups. In summary, sorting reduced sperm binding to the complex matrix around oviductal cell aggregates but sperm binding to purified soluble oviduct glycans was not affected. The requirement for higher affinity and motility to bind glycans immobilized on oviduct cells may explain this difference. The reduction in sperm fertility observed following sex-sorting may be explained partially by a reduced or altered ability to bind to the oviduct epithelium., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Since the discovery of Chromera velia as a novel coral-associated microalga, this organism has attracted interest because of its unique evolutionary position between the photosynthetic dinoflagellates and the parasitic apicomplexans. The nature of the relationship between Chromera and its coral host is controversial. Is it a mutualism, from which both participants benefit, a parasitic relationship, or a chance association? To better understand the interaction, larvae of the common Indo-Pacific reef-building coral Acropora digitifera were experimentally infected with Chromera, and the impact on the host transcriptome was assessed at 4, 12, and 48 h post-infection using Illumina RNA-Seq technology. The transcriptomic response of the coral to Chromera was complex and implies that host immunity is strongly suppressed, and both phagosome maturation and the apoptotic machinery is modified. These responses differ markedly from those described for infection with a competent strain of the coral mutualist Symbiodinium, instead resembling those of vertebrate hosts to parasites and/or pathogens such as Mycobacterium tuberculosis. Consistent with ecological studies suggesting that the association may be accidental, the transcriptional response of A. digitifera larvae leads us to conclude that Chromera could be a coral parasite, commensal, or accidental bystander, but certainly not a beneficial mutualist.

Anthozoans (e.g., corals, anemones) are an ecologically important and diverse group of marine metazoans that occur from shallow to deep waters worldwide. However, our understanding of the evolutionary relationships among the ~7,500 species within this class is hindered by the lack of phylogenetically informative markers that can be reliably sequenced across a diversity of taxa. We designed and tested 16,306 RNA baits to capture 720 ultraconserved element loci and 1,071 exon loci. Library preparation and target enrichment were performed on 33 taxa from all orders within the class Anthozoa. Following Illumina sequencing and Trinity assembly, we recovered 1,774 of 1,791 targeted loci. The mean number of loci recovered from each species was 638 ± 222, with more loci recovered from octocorals (783 ± 138 loci) than hexacorals (475 ± 187 loci). Parsimony informative sites ranged from 26 to 49% for alignments at differing hierarchical taxonomic levels (e.g., Anthozoa, Octocorallia, Hexacorallia). The per cent of variable sites within each of three genera (Acropora, Alcyonium, and Sinularia) for which multiple species were sequenced ranged from 4.7% to 30%. Maximum-likelihood analyses recovered highly resolved trees with topologies matching those supported by other studies, including the monophyly of the order Scleractinia. Our results demonstrate the utility of this target-enrichment approach to resolve phylogenetic relationships from relatively old to recent divergences. Redesigning the baits with improved affinities to capture loci within each subclass will provide a valuable toolset to address systematic questions, further our understanding of the timing of diversifications and help resolve long-standing controversial relationships in the class Anthozoa., (© 2017 John Wiley & Sons Ltd.)

Despite recent research and improvements in spinal implants, complications remain frequent in patients who undergo pediatric spinal deformity surgery. Although the rate of neurologic injury after pediatric spinal deformity surgery is low, the rate of surgical site infection after pediatric spinal deformity surgery is high, particularly in patients who have neuromuscular scoliosis. Although symptomatic implant complications that require revision surgery are rare with the use of modern spinal fusion constructs, they are common in patients who have early-onset scoliosis. Patients who have perioperative respiratory or gastrointestinal complications benefit from early recognition and supportive treatment. The cause of perioperative complications in patients who undergo pediatric spinal deformity surgery often is multifactorial; therefore, surgeons should understand the numerous risk factors for and strategies for the prevention of pediatric spinal deformity surgery complications.

δ-Cadinene synthase is a sesquiterpene cyclase that utilises the universal achiral precursor farnesyl diphosphate (FDP) to generate predominantly the bicyclic sesquiterpene δ-cadinene and about 2 % germacradien-4-ol, which is also generated from FDP by the cyclase germacradien-4-ol synthase. Herein, the mechanism by which sesquiterpene synthases discriminate between deprotonation and reaction with a nucleophilic water molecule was investigated by site-directed mutagenesis of δ-cadinene synthase. If W279 in δ-cadinene synthase was replaced with various smaller amino acids, the ratio of alcohol versus hydrocarbon product was directly proportional to the van der Waals volume of the amino acid side chain. DCS-W279A is a catalytically highly efficient germacradien-4-ol synthase (k cat /K M =1.4×10 -3  μm s -1 ) that produces predominantly germacradien-4-ol in addition to 11 % δ-cadinene. Water capture is not achieved through strategic positioning of a water molecule in the active site, but through a coordinated series of loop movements that allow bulk water access to the final carbocation in the active site prior to product release., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

In this systematic review of randomized controlled trials, we aimed to assess the effects of different surgical treatments for olecranon fractures in adults, especially the rate of metalwork prominence. We searched the Cochrane Bone, Joint, and Muscle Trauma Group's Specialized Register (2018), the Cochrane Central Register of Controlled Trials (CENTRAL, 2018, Issue 1), Ovid MEDLINE (1946-2018), and Embase (1980-2018). We also searched ISRCTN registry, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry platform for ongoing and recently completed trials (2018). Data were extracted using a pretested form. Risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. For binary outcomes, we expressed the treatment effects as risk ratios with 95% confidence intervals; for continuous outcomes, we expressed treatment effects as mean differences. We included eight trials involving 399 patients (220 men and 179 women); there were six RCTs and two quasi-RCTs. In seven trials, standard-tension band-wiring technique (TBW) was the control group. We compared it against the modified plate fixation or modified techniques of TBW. For trials comparing TBW versus modified-TBW (five trials), similar outcomes were reported, but with a higher rate of metalwork prominence with standard TBW. Two trials compared plate fixation with TBW and reported higher metalwork prominence with TBW but more serious complications with plate fixation. One trial compared locking plate with memory connector plate fixation with no significant differences. Tension band wiring remains the gold standard technique for olecranon fractures with high rate of symptomatic metalwork prominence.

Outpatient surgery refers to a surgical procedure that is performed without an overnight stay in a hospital. Outpatient surgery is associated with decreased individual and societal costs while achieving equivalent health outcomes and excellent patient satisfaction. Successful outpatient pediatric surgery is predicated on appropriate patient selection, adequate pain control, thorough preoperative education, and close clinical follow-up. Continuous research in quality, value, and patient safety are needed to ensure that this practice continues in as safe and efficient a manner as possible., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Iliac crest apophyseal avulsion fractures are rare injuries caused mainly through forceful contraction of attached muscles during high level sporting activities. We present the first case of a spontaneous iliac crest apophyseal avulsion insufficiency fracture in a patient with severe atopic eczema on oral steroids and review the relevant literature.

Sesquiterpene synthases catalyze the conversion of farnesyl diphosphate to more than 300 different hydrocarbon and alcohol natural products which often contain multiple fused rings and stereocenters. Recent work has taken advantage of the exquisite stereospecificity of these enzymes to synthesize complex novel sesquiterpenoids using nonnatural substrates. In this chapter, we describe the expression, purification, and use of one such synthase to convert a nonnatural substrate to a novel cyclic ether, thereby expanding the terpenome., (© 2018 Elsevier Inc. All rights reserved.)

Atomic motion at grain boundaries is essential to microstructure development, growth and stability of catalysts and other nanostructured materials. However, boundary atomic motion is often too fast to observe in a conventional transmission electron microscope (TEM) and too slow for ultrafast electron microscopy. Here, we report on the entire transformation process of strained Pt icosahedral nanoparticles (ICNPs) into larger FCC crystals, captured at 2.5 ms time resolution using a fast electron camera. Results show slow diffusive dislocation motion at nm/s inside ICNPs and fast surface transformation at μm/s. By characterizing nanoparticle strain, we show that the fast transformation is driven by inhomogeneous surface stress. And interaction with pre-existing defects led to the slowdown of the transformation front inside the nanoparticles. Particle coalescence, assisted by oxygen-induced surface migration at T ≥ 300 °C, also played a critical role. Thus by studying transformation in the Pt ICNPs at high time and spatial resolution, we obtain critical insights into the transformation mechanisms in strained Pt nanoparticles.

The Cas family scaffolding protein p130Cas is a Src substrate localized in focal adhesions (FAs) and functions in integrin signaling to promote cell motility, invasion, proliferation, and survival. p130Cas targeting to FAs is essential for its tyrosine phosphorylation and downstream signaling. Although the N-terminal SH3 domain is important for p130Cas localization, it has also been reported that the C-terminal region is involved in p130Cas FA targeting. The C-terminal region of p130Cas or Cas family homology domain (CCHD) has been reported to adopt a structure similar to that of the focal adhesion kinase C-terminal focal adhesion-targeting domain. The mechanism by which the CCHD promotes FA targeting of p130Cas, however, remains unclear. In this study, using a calorimetry approach, we identified the first LD motif (LD1) of the FA-associated protein paxillin as the binding partner of the p130Cas CCHD (in a 1:1 stoichiometry with a K d ∼4.2 μm) and elucidated the structure of the p130Cas CCHD in complex with the paxillin LD1 motif by X-ray crystallography. Of note, a comparison of the CCHD/LD1 complex with a previously solved structure of CCHD in complex with the SH2-containing protein NSP3 revealed that LD1 had almost identical positioning of key hydrophobic and acidic residues relative to NSP3. Because paxillin is one of the key scaffold molecules in FAs, we propose that the interaction between the p130Cas CCHD and the LD1 motif of paxillin plays an important role in p130Cas FA targeting., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.

Because of their enhanced kinetic properties, nanocrystallites have received much attention as potential electrode materials for energy storage. However, because of the large specific surface areas of nanocrystallites, they usually suffer from decreased energy density, cycling stability, and effective electrode capacity. In this work, we report a size-dependent excess capacity beyond theoretical value (170 mA h g -1 ) by introducing extra lithium storage at the reconstructed surface in nanosized LiFePO 4 (LFP) cathode materials (186 and 207 mA h g -1 in samples with mean particle sizes of 83 and 42 nm, respectively). Moreover, this LFP composite also shows excellent cycling stability and high rate performance. Our multimodal experimental characterizations and ab initio calculations reveal that the surface extra lithium storage is mainly attributed to the charge passivation of Fe by the surface C-O-Fe bonds, which can enhance binding energy for surface lithium by compensating surface Fe truncated symmetry to create two types of extra positions for Li-ion storage at the reconstructed surfaces. Such surface reconstruction nanotechnology for excess Li-ion storage makes full use of the large specific surface area of the nanocrystallites, which can maintain the fast Li-ion transport and greatly enhance the capacity. This discovery and nanotechnology can be used for the design of high-capacity and efficient lithium ion batteries.

The lactocrine hypothesis for maternal programming of female reproductive tract development is based on the idea that non-nutritive, milk-borne bioactive factors (MbFs), delivered from mother to offspring during nursing, play a role in determining the trajectory of development with long-term consequences in the adult. Porcine female reproductive tract development is completed postnatally, and the period during which maternal support of neonatal growth derives exclusively from colostrum/milk defines a window of opportunity for lactocrine programming of reproductive tissues. Beyond nutrition, milk serves as a delivery system for a variety of bioactive factors. Porcine relaxin is a prototypical MbF. Present in colostrum at highest concentrations at birth, relaxin is transmitted into the circulation of nursing piglets where it can act on Relaxin receptors found in neonatal female reproductive tract tissues. This process is facilitated by the physiology of the maternal-neonatal dyad and the fact that the neonatal gastrointestinal tract is open to absorb macromolecules for a period of time postnatally. Age at first nursing and duration of nursing from birth are also important for porcine female reproductive tract development. These parameters affect both the quality and quantity of colostrum consumed. Disruption of lactocrine signaling by feeding milk replacer from birth altered porcine uterine, cervical, and testicular development by postnatal Day 2. Moreover, insufficient colostrum consumption in nursing piglets can impair uterine capacity to support viable litters of optimal size in adulthood. In the pig, lactocrine signaling supports neonatal organizational events associated with normal reproductive development and may program adult uterine capacity., (© 2017 The Authors. Molecular Reproduction and Development Published by Wiley Periodicals, Inc.)

Diamond owes its unique mechanical, thermal, optical, electrical, chemical, and biocompatible materials properties to its complete sp 3 -carbon network bonding. Crystallinity is another major controlling factor for materials properties. Although other Group-14 elements silicon and germanium have complementary crystalline and amorphous forms consisting of purely sp 3 bonds, purely sp 3 -bonded tetrahedral amorphous carbon has not yet been obtained. In this letter, we combine high pressure and in situ laser heating techniques to convert glassy carbon into "quenchable amorphous diamond", and recover it to ambient conditions. Our X-ray diffraction, high-resolution transmission electron microscopy and electron energy-loss spectroscopy experiments on the recovered sample and computer simulations confirm its tetrahedral amorphous structure and complete sp 3 bonding. This transparent quenchable amorphous diamond has, to our knowledge, the highest density among amorphous carbon materials, and shows incompressibility comparable to crystalline diamond.Diamond's properties are dictated by its crystalline, fully tetrahedrally bonded structure. Here authors synthesize a bulk sp 3 -bonded amorphous form of carbon under high pressure and temperature, show that it has bulk modulus comparable to crystalline diamond and that it can be recovered under ambient conditions.

Background: Dimethylsulfoniopropionate (DMSP) is a small sulphur compound which is produced in prodigious amounts in the oceans and plays a pivotal role in the marine sulfur cycle. Until recently, DMSP was believed to be synthesized exclusively by photosynthetic organisms; however we now know that corals and specific bacteria can also produce this compound. Corals are major sources of DMSP, but the molecular basis for its biosynthesis is unknown in these organisms., Results: Here we used salinity stress, which is known to trigger DMSP production in other organisms, in conjunction with transcriptomics to identify coral genes likely to be involved in DMSP biosynthesis. We focused specifically on both adults and juveniles of the coral Acropora millepora: after 24 h of exposure to hyposaline conditions, DMSP concentrations increased significantly by 2.6 fold in adult corals and 1.2 fold in juveniles. Concomitantly, candidate genes enabling each of the necessary steps leading to DMSP production were up-regulated., Conclusions: The data presented strongly suggest that corals use an algal-like pathway to generate DMSP from methionine, and are able to rapidly change expression of the corresponding genes in response to environmental stress. However, our data also indicate that DMSP is unlikely to function primarily as an osmolyte in corals, instead potentially serving as a scavenger of ROS and as a molecular sink for excess methionine produced as a consequence of proteolysis and osmolyte catabolism in corals under hypo-osmotic conditions.

Background: Perioperative care pathways are tools used in high-volume clinical settings to standardize care, reduce variability, and improve outcomes. However, the mechanism by which the information is transmitted to other caregivers is often inconsistent and error-prone. At our institution, we developed an online, user-editable ("wiki") database to communicate post-operative protocols. The purpose of this study is to evaluate the hypothesis that implementation of the wiki would improve protocol adherence and reduce unintentional deviations inpatient care., Methods: We conducted a retrospective review of patients who underwent primary lower extremity arthroplasty at our institution during three 6-month time periods including immediately before, 6 months after, and 2 years following introduction of the wiki. Adherence to defined perioperative care pathways (laboratory studies, post-operative imaging, perioperative antibiotics, and inpatient pain medications) was compared between the groups., Results: After wiki implementation, adherence to protocols improved significantly for laboratory orders (P < .0001), imaging (P < .001), pain control regimen (P = .03), and overall protocol adherence (P < .001). Improvements were seen in some areas almost immediately, while others did not show improvements until 2 years after implementation. Costs associated with unnecessary testing were reduced by 82%., Conclusion: Development of an online wiki for tracking post-operative protocols improves care pathway adherence and reduces variability in care while lowering costs associated with unnecessary testing, although some benefits may not be immediately realized. Several practical barriers to implementing the wiki are also discussed, along with proposed solutions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent discoveries that astrocytes exert proactive regulatory effects on neural information processing and that they are deeply involved in normal brain development and disease pathology have stimulated broad interest in understanding astrocyte functional roles in brain circuit. Measuring astrocyte functional status is now technically feasible, due to recent advances in modern microscopy and ultrasensitive cell-type specific genetically encoded Ca 2+ indicators for chronic imaging. However, there is a big gap between the capability of generating large dataset via calcium imaging and the availability of sophisticated analytical tools for decoding the astrocyte function. Current practice is essentially manual, which not only limits analysis throughput but also risks introducing bias and missing important information latent in complex, dynamic big data. Here, we report a suite of computational tools, called Functional AStrocyte Phenotyping (FASP), for automatically quantifying the functional status of astrocytes. Considering the complex nature of Ca 2+ signaling in astrocytes and low signal to noise ratio, FASP is designed with data-driven and probabilistic principles, to flexibly account for various patterns and to perform robustly with noisy data. In particular, FASP explicitly models signal propagation, which rules out the applicability of tools designed for other types of data. We demonstrate the effectiveness of FASP using extensive synthetic and real data sets. The findings by FASP were verified by manual inspection. FASP also detected signals that were missed by purely manual analysis but could be confirmed by more careful manual examination under the guidance of automatic analysis. All algorithms and the analysis pipeline are packaged into a plugin for Fiji (ImageJ), with the source code freely available online at https://github.com/VTcbil/FASP.

RING-between-RING (RBR) E3s contain RING1 domains that are structurally similar yet mechanistically distinct from canonical RING domains. Both types of E3 bind E2∼ubiquitin (E2∼Ub) via their RINGs but canonical RING E3s promote closed E2∼Ub conformations required for direct Ub transfer from the E2 to substrate, while RBR RING1s promote open E2∼Ub to favor Ub transfer to the E3 active site. This different RING/E2∼Ub conformation determines its direct target, which for canonical RING E3s is typically a substrate or substrate-linked Ub, but is the E3 active-site cysteine in the case of RBR-type E3s. Here we show that a short extension of HHARI RING1, namely Zn 2+ -loop II, not present in any RING E3s, acts as a steric wedge to disrupt closed E2∼Ub, providing a structural explanation for the distinctive RING1-dependent conformational restriction mechanism utilized by RBR E3s., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

For the promotion of lithium-oxygen batteries available for practical applications, the development of advanced cathode catalysts with low-cost, high activity, and stable structural properties is demanded. Such development is rooted on certain intelligent catalyst-electrode design that fundamentally facilitates electronic and ionic transport and improves oxygen diffusivity in a porous environment. Here we design a biphasic nitrogen-doped cobalt@graphene multiple-capsule heterostructure, combined with a flexible, stable porous electrode architecture, and apply it as promising cathodes for lithium-oxygen cells. The biphasic nitrogen-doping feature improves the electric conductivity and catalytic activity; the multiple-nanocapsule configuration makes high/uniform electroactive zones possible; furthermore, the colander-like porous electrode facilitates the oxygen diffusion, catalytic reaction, and stable deposition of discharge products. As a result, the electrode exhibits much improved electrocatalytic properties associated with unique morphologies of electrochemically grown lithium peroxides.

Yaoyang Chuang, Marcelo Kitahara, Hironobu Fukami, Dianne Tracey, David J. Miller, and Chaolun Allen Chen (2017) Group I introns encoding a homing endonuclease gene (HEG) that is potentially capable of sponsoring mobility are present in the cytochrome oxidase subunit 1 ( cox1 ) gene of some Hexacorallia, including a number of scleractinians assigned to the "robust" coral clade. In an e ort to infer the evolutionary history of this cox1 group I intron, DNA sequences were determined for 12 representative "basal" and "complex" corals and for 11 members of the Corallimorpharia, a sister order of the Scleractinia. Comparisons of insertion sites, secondary structures, and amino acid sequences of the HEG implied a common origin for cox1 introns of corallimorpharians, and basal and complex corals, but cox1 introns of robust corals were highly divergent, most likely reflecting independent acquisition. Phylogenetic analyses with a calibrated molecular clock suggested that cox1 introns of scleractinians and corallimorpharians have persisted at the same insertion site as that in the common ancestor 552 million years ago (mya). This ancestral intron was probably lost in complex corals around 213 to 190 mya at the junction between the Trassic and Jurassic. The coral cox1 gene remained intronless until new introns, probably from sponges or fungi, reinvaded different positions of the cox1 gene in robust corals around 135 mya in the Cretaceous, and then it subsequently began to lose them around 65.5 mya in some robust coral lineages coincident with the later Maastrichtian extinction at the Cretaceous-Tertiary boundary.

Bacteria associated with marine invertebrates are thought to have a range of important roles that benefit the host including production of compounds that may exclude pathogenic microorganisms and recycling of essential nutrients. This study characterised the microbiome of a gonochoric octocoral, Lobophytum pauciflorum, and investigated whether either sex or environmental stresses influenced the diversity of the associated microbiome through amplicon profiling of the bacterial 16S rRNA gene. Sequences affiliated to Spirochaetaceae and Endozoicimonaceae dominated the microbiome of L. pauciflorum, representing 43% and 21% of the community, respectively. Among the dominant class affiliations, no sex-specific differences were detected, though unassigned sequences were at a 2-fold higher relative abundance in samples from female individuals than from males. These potentially novel sequences contributed to observed differences between sexes as detected by a multivariate analysis at the OTU level. Exposing L. pauciflorum fragments to increased temperature (31°C), decreased pH (7.9) or both stressors simultaneously for 12 days did not significantly alter the microbial community, indicating that the soft coral microbiome is relatively resilient to short-term environmental stress., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A recent study has demonstrated that porcine spermatozoa recognize with high affinity carbohydrate structures containing Lewis X motifs. Sperm adhesion to Lewis X is proposed to mediate sperm binding to the oviduct epithelium to form a reservoir. The objective of this study was to identify Lewis X-binding proteins from porcine spermatozoa as candidate receptors for oviduct glycans. To identify low-abundance proteins typically masked by proteins originating from seminal fluid, Lewis X candidate receptors were enriched from cauda epididymal boar spermatozoa. Plasma membrane preparations from cauda epididymal spermatozoa were subjected to RP-HPLC and glycan blotting assays to isolate and detect proteins that bind Lewis X. Following bottom-up LC-MS/MS analysis, among the two bands that bound sulfated Lewis X, ADAM5, which spermatozoa, was confidently identified. ADAM family members have been established as contributors to sperm entry into the oviduct. A second sulfated Lewis X-binding protein identified was the peripheral membrane protein lactadherin (also known as P47, SED1 and MFG-E8 in different species). The interaction between Lewis X and lactadherin was functionally important because competitive inhibition by soluble recombinant lactadherin reduced sperm binding to the oviduct epithelium. Furthermore, far-western blotting demonstrated that purified lactadherin could bind oviduct cells. In summary, these findings reveal that, in addition to the previously reported glycan affinity of accessory gland proteins that adhere to spermatozoa, multiple proteins intrinsic to spermatozoa have affinity for a specific oviduct glycan. Further, in addition to binding to the zona pellucida, lactadherin is now implicated in binding to oviduct glycans to promote formation of the sperm reservoir., (© 2017 American Society of Andrology and European Academy of Andrology.)

Maternal effects on development can program cell fate and dictate offspring phenotype. Such effects do not end at birth, but extend into postnatal life through signals communicated from mother to offspring in first milk (colostrum). Transmission of bioactive factors from mother to offspring as a specific consequence of nursing defines a lactocrine mechanism. The female reproductive tract is not fully formed at birth (postnatal day = PND 0). Data for ungulates and mice indicate that disruption of development during neonatal life can have lasting effects on the form and function of uterine tissues. Uterine growth and histogenesis proceed in an ovary-independent manner shortly after birth, suggesting that extra-ovarian inputs are important in this process. Data for the pig indicate that lactocrine signals communicated within 12 to 48 h from birth constitute one source of such uterotrophic support. Disruption of lactocrine signaling, either naturally, by limited colostrum consumption, or experimentally, by milk replacer feeding, alters neonatal porcine uterine development and can have negative consequences for reproductive performance in adults. Substantial differences in endometrial and uterine gene expression between colostrum- and replacer-fed gilts were evident by PND 2, when RNA sequencing revealed over 800 differentially expressed, lactocrine-sensitive genes. Lactocrine-sensitive biological processes identified through transcriptomic studies and integrated microRNA-mRNA pathway analyses included those associated with both cell-cell and ESR1 signaling, and tissue development. Evidence for the pig indicates that colostrum consumption and lactocrine signaling are required to establish a normal uterine developmental program and optimal uterine developmental trajectory.

Polymeric membranes are an energy-efficient means of purifying water, but they suffer from fouling during filtration. Modification of the membrane surface is one route to mitigating membrane fouling, as it helps to maintain high levels of water productivity. Here, a series of common techniques for modification of the membrane surface are reviewed, including surface coating, grafting, and various treatment techniques such as chemical treatment, UV irradiation, and plasma treatment. Historical background on membrane development and surface modification is also provided. Finally, polydopamine, an emerging material that can be easily deposited onto a wide variety of substrates, is discussed within the context of membrane modification. A brief summary of the chemistry of polydopamine, particularly as it may pertain to membrane development, is also described., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We investigate semisupervised learning (SL) and pool-based active learning (AL) of a classifier for domains with label-scarce (LS) and unknown categories, i.e., defined categories for which there are initially no labeled examples. This scenario manifests, e.g., when a category is rare, or expensive to label. There are several learning issues when there are unknown categories: 1) it is a priori unknown which subset of (possibly many) measured features are needed to discriminate unknown from common classes and 2) label scarcity suggests that overtraining is a concern. Our classifier exploits the inductive bias that an unknown class consists of the subset of the unlabeled pool's samples that are atypical (relative to the common classes) with respect to certain key (albeit a priori unknown) features and feature interactions. Accordingly, we treat negative log- p -values on raw features as nonnegatively weighted derived feature inputs to our class posterior, with zero weights identifying irrelevant features. Through a hierarchical class posterior, our model accommodates multiple common classes, multiple LS classes, and unknown classes. For learning, we propose a novel semisupervised objective customized for the LS/unknown category scenarios. While several works minimize class decision uncertainty on unlabeled samples, we instead preserve this uncertainty [maximum entropy (maxEnt)] to avoid overtraining. Our experiments on a variety of UCI Machine learning (ML) domains show: 1) the use of p -value features coupled with weight constraints leads to sparse solutions and gives significant improvement over the use of raw features and 2) for LS SL and AL, unlabeled samples are helpful, and should be used to preserve decision uncertainty (maxEnt), rather than to minimize it, especially during the early stages of AL. Our AL system, leveraging a novel sample-selection scheme, discovers unknown classes and discriminates LS classes from common ones, with sparing use of oracle labeling.

Many classification tasks require both labeling objects and determining label associations for parts of each object. Example applications include labeling segments of images or determining relevant parts of a text document when the training labels are available only at the image or document level. This task is usually referred to as multi-instance (MI) learning, where the learner typically receives a collection of labeled (or sometimes unlabeled) bags, each containing several segments (instances). We propose a semisupervised MI learning method for multilabel classification. Most MI learning methods treat instances in each bag as independent and identically distributed samples. However, in many practical applications, instances are related to each other and should not be considered independent. Our model discovers a latent low-dimensional space that captures structure within each bag. Further, unlike many other MI learning methods, which are primarily developed for binary classification, we model multiple classes jointly, thus also capturing possible dependencies between different classes. We develop our model within a semisupervised framework, which leverages both labeled and, typically, a larger set of unlabeled bags for training. We develop several efficient inference methods for our model. We first introduce a Markov chain Monte Carlo method for inference, which can handle arbitrary relations between bag labels and instance labels, including the standard hard-max MI assumption. We also develop an extension of our model that uses stochastic variational Bayes methods for inference, and thus scales better to massive data sets. Experiments show that our approach outperforms several MI learning and standard classification methods on both bag-level and instance-level label prediction. All code for replicating our experiments is available from https://github.com/hsoleimani/MLTM .

Objective: . Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller., Methods: . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images., Results: . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P  = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain., Conclusions: . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Ammoniated aerosols are important for urban air quality, but emissions of the key precursor NH 3 are not well quantified. Mobile laboratory observations are used to characterize fleet-integrated NH 3 emissions in six cities in the U.S. and China. Vehicle NH 3 :CO 2 emission ratios in the U.S. are similar between cities (0.33-0.40 ppbv/ppmv, 15% uncertainty) despite differences in fleet composition, climate, and fuel composition. While Beijing, China has a comparable emission ratio (0.36 ppbv/ppmv) to the U.S. cities, less developed Chinese cities show higher emission ratios (0.44 and 0.55 ppbv/ppmv). If the vehicle CO 2 inventories are accurate, NH 3 emissions from U.S. vehicles (0.26 ± 0.07 Tg/yr) are more than twice those of the National Emission Inventory (0.12 Tg/yr), while Chinese NH 3 vehicle emissions (0.09 ± 0.02 Tg/yr) are similar to a bottom-up inventory. Vehicle NH 3 emissions are greater than agricultural emissions in counties containing near half of the U.S. population and require reconsideration in urban air quality models due to their colocation with other aerosol precursors and the uncertainties regarding NH 3 losses from upwind agricultural sources. Ammonia emissions in developing cities are especially important because of their high emission ratios and rapid motorizations.

The nervous systems of cnidarians, pre-bilaterian animals that diverged close to the base of the metazoan radiation, are structurally simple and thus have great potential to reveal fundamental principles of neural circuits. Unfortunately, cnidarians have thus far been relatively intractable to electrophysiological and genetic techniques and consequently have been largely passed over by neurobiologists. However, recent advances in molecular and imaging methods are fueling a renaissance of interest in and research into cnidarians nervous systems. Here, we review current knowledge on the nervous systems of cnidarian species and propose that researchers should seize this opportunity and undertake the study of members of this phylum as strategic experimental systems with great basic and translational relevance for neuroscience., (Copyright © 2016 Elsevier Ltd. All rights reserved.)