Discovery and Mode-of-Action Characterization of a New Class of Acetolactate Synthase-Inhibiting Herbicides.

Herbicides are effective tools to manage weeds and enable food production and sustainable agriculture. Corteva Agriscience R&D has recently discovered new diphenyl-ether compounds displaying excellent postemergent efficacy on important weed species along with corn safety. Here, we describe the chemistry, biology, biochemistry, and computational modeling research that led to the discovery and elucidation of the primary mode of action for these compounds. The target protein was found to be acetolactate synthase (ALS), a key enzyme in the biosynthesis of branched chain amino acids (valine, leucine, and isoleucine). While weed resistance evolution to ALS herbicides is widespread, the molecular interaction of the diphenyl-ether compounds at the active site of the ALS enzyme differs significantly from that of some commercial ALS inhibitors. The unique biochemical profile of these molecules along with their excellent herbicidal activity and corn selectivity make them a noteworthy development in the pursuit of novel, safe, and sustainable weed control solutions.

A New Class of Diaryl Ether Herbicides: Structure-Activity Relationship Studies Enabled by a Rapid Scaffold Hopping Approach.

We report on the development of a novel class of diaryl ether herbicides. After the discovery of a phenoxybenzoic acid with modest herbicidal activity, optimization led to several molecules with improved control of broadleaf and grass weeds. To facilitate this process, we first employed a three-step combinatorial approach, then pivoted to a one-step Ullmann-type coupling that provided faster access to new analogs. After determining that the primary target site of our benchmark diaryl ethers was acetolactate synthase (ALS), we further leveraged this copper-catalyzed methodology to conduct a scaffold hopping campaign in the hope of uncovering an additional mode of action with fewer documented cases of resistance. Our comprehensive and systematic investigation revealed that while the herbicidal activity of this area seems to be exclusively linked to ALS inhibition, our molecules represent a structurally distinct class of Group 2 herbicides. The structure-activity relationships that led us to this conclusion are described herein.

Bioactive coatings for dental implants: A review of alternative strategies to prevent peri-implantitis induced by anaerobic bacteria.

Members of oral bacterial communities form biofilms not only on tooth surfaces but also on the surface of dental implants that replace natural teeth. Prolonged interaction of host cells with biofilm-forming anaerobes frequently elicits peri-implantitis, a destructive inflammatory disease accompanied by alveolar bone loss leading to implant failure. Here we wish to overview how the deposition of bioactive peptides to dental implant surfaces could potentially inhibit bacterial colonization and the development of peri-implantisis. One preventive strategy is based on natural antimicrobial peptides (AMPs) immobilized on titanium surfaces. AMPs are capable to destroy both Gram positive and Gram negative bacteria directly. An alternative strategy aims at coating implant surfaces - especially the transmucosal part - with peptides facilitating the attachment of gingival epithelial cells and connective tissue cells. These cells produce AMPs and may form a soft tissue seal that prevents oral bacteria from accessing the apical part of the osseointegrated implant. Because a wide variety of titanium-bound peptides were studied in vitro, we wish to concentrate on bioactive peptides of human origin and some of their derivatives. Furthermore, special attention will be given to peptides effective under in vivo test conditions.

Regional differences in the ependyma of the optic tectal ventricle of adult zebrafish with structures referring to brain hydrodynamics.

Classical electron microscopic morphological studies provide detailed ultrastructural information, which may lend insights into cellular functions. As a follow-up to our morphological investigation of the adult zebrafish (Danio rerio) optic tectum, in this study, we have analyzed the ependymal structures lining the surfaces of the tectal ventricle: the torus, tegmental surface of the valvula cerebelli and the periventricular gray zone of the optic tectal cortex. We used toluidine blue stained plastic (semithin) sections for light microscopy and scanning electron microscopy. Our morphological findings of gated entrances and/or egresses indicate that, at least in the adult zebrafish brain, there may be a bidirectional direct flow communication between the ventricular cerebrospinal fluid and the parenchymal interstitial fluid.

Adenoviruses across the animal kingdom: a walk in the zoo.

Adenoviruses (AdVs) infect representatives of numerous species from almost every major vertebrate class, albeit their incidence shows great variability. AdVs infecting birds, reptiles, and bats are the most common and diverse, whereas only one AdV has been so far isolated both from fish and amphibians. The family Adenoviridae is divided into five genera, each corresponding to an independent evolutionary lineage that supposedly coevolved with its respective vertebrate hosts. Members of genera Mastadenovirus and Aviadenovirus seem to infect exclusively mammals and birds, respectively. The genus Ichtadenovirus includes the single known AdV from fish. The majority of AdVs in the genus Atadenovirus originated from squamate reptiles (lizards and snakes), but also certain mammalian and avian AdVs are classified within this genus. The genus Siadenovirus contains the only AdV isolated from frog, along with numerous avian AdVs. In turtles, members of a sixth AdV lineage have been discovered, pending official recognition as an independent genus. The most likely scenario for AdV evolution includes long-term cospeciation with the hosts, as well as occasional switches between closely or, rarely, more distantly related hosts.

Spatial characterization of light beams analyzed by cylindrical-grating slit-less spectrometers.

In this work, we theoretically analyze the spatial information provided by cylindrical-grating slit-less spectrometers. We raise attention on the often not considered property that the spatial features acquired using these spectrometers are different from what can be obtained using a spectrometer with an entrance slit. In relation to this, we also highlight that they do not provide information directly on the real spatial beam profile. It is important to consider this fact in spatio-spectral analysis of extreme ultraviolet radiation, often carried out using cylindrical-grating slit-less spectrometers. Since the models used are based on the Fresnel diffraction integral and ideal optical systems, the results are valid also for other spectral regions.

Circum-Mediterranean phylogeography of a bat coupled with past environmental niche modeling: A new paradigm for the recolonization of Europe?

The isolation of populations in the Iberian, Italian and Balkan peninsulas during the ice ages define four main paradigms that explain much of the known distribution of intraspecific genetic diversity in Europe. In this study we investigated the phylogeography of a wide-spread bat species, the bent-winged bat, Miniopterus schreibersii around the Mediterranean basin and in the Caucasus. Environmental Niche Modeling (ENM) analysis was applied to predict both the current distribution of the species and its distribution during the last glacial maximum (LGM). The combination of genetics and ENM results suggest that the populations of M. schreibersii in Europe, the Caucasus and Anatolia went extinct during the LGM, and the refugium for the species was a relatively small area to the east of the Levantine Sea, corresponding to the Mediterranean coasts of present-day Syria, Lebanon, Israel, and northeastern and northwestern Egypt. Subsequently the species first repopulated Anatolia, diversified there, and afterwards expanded into the Caucasus, continental Europe and North Africa after the end of the LGM. The fossil record in Iberia and the ENM results indicate continuous presence of Miniopterus in this peninsula that most probably was related to the Maghrebian lineage during the LGM, which did not persist afterwards. Using our results combined with similar findings in previous studies, we propose a new paradigm explaining the general distribution of genetic diversity in Europe involving the recolonization of the continent, with the main contribution from refugial populations in Anatolia and the Middle East. The study shows how genetics and ENM approaches can complement each other in providing a more detailed picture of intraspecific evolution.

Epidemiological and biological determinants of Staphylococcus aureus clinical infection in New York State maximum security prisons.

BACKGROUND: Large outbreaks of Staphylococcus aureus (SA) infections have occurred in correctional facilities across the country. We aimed to define the epidemiological and microbiological determinants of SA infection in prisons to facilitate development of prevention strategies for this underserved population. METHODS: We conducted a case-control study of SA infection at 2 New York State maximum security prisons. SA-infected inmates were matched with 3 uninfected controls. Subjects had cultures taken from sites of infection and colonization (nose and throat) and were interviewed via structured questionnaire. SA isolates were characterized by spa typing. Bivariate and multivariable analyses were conducted using conditional logistic regression. RESULTS: Between March 2011 and January 2013, 82 cases were enrolled and matched with 246 controls. On bivariate analysis, the use of oral and topical antibiotics over the preceding 6 months was strongly associated with clinical infection (OR, 2.52; P < .001 and 4.38, P < .001, respectively). Inmates with clinical infection had 3.16 times the odds of being diabetic compared with inmates who did not have clinical infection (P < .001). Concurrent nasal and/or oropharyngeal colonization was also associated with an increased odds of infection (OR, 1.46; P = .002). Among colonized inmates, cases were significantly more likely to carry the SA clone spa t008 (usually representing the epidemic strain USA300) compared to controls (OR, 2.52; P = .01). CONCLUSIONS: Several inmate characteristics were strongly associated with SA infection in the prison setting. Although many of these factors were likely present prior to incarceration, they may help medical staff identify prisoners for targeted prevention strategies.

Carrier-envelope phase changes in the focal region: propagation effects measured by spectral interferometry.

Spectral interferometric measurements are presented that show how wave propagation affects the carrier-envelope phase (CEP) of an ultrashort pulse in the focal region and results in variations that are different from the Gouy phase shift. Wavelength-dependent properties of the input beam are investigated and are seen to influence how the CEP is altered. The measured CEP changes show characteristics similar to the variations predicted by theory.

Full genome sequence of a novel circo-like virus detected in an adult European eel Anguilla anguilla showing signs of cauliflower disease.

An adult European eel Anguilla anguilla, showing typical signs of the so-called cauliflower disease, was subjected to pathological and molecular virological examinations. Samples taken from internal organs and the polypoid proliferative tissue from the mouth were examined by PCR for the detection of several viruses. Positive results were obtained with a nested PCR targeting the rep gene of circoviruses. Analysis of the partial rep sequence indicated the presence of a putative novel circovirus, but attempts to isolate it remained unsuccessful. The missing part of the genome was acquired by an inverse nested PCR with 2 specific primer pairs, designed from the newly determined rep sequence, followed by genome walking. The circular full genome was found to consist of 1378 nt (GenBank accession no. KC469701). Two oppositely oriented open reading frames (ORFs) were present, of which one was unambiguously identified as a circoviral rep gene. However, the predicted product of the other ORF, though it is a clear positional counterpart of the cap genes, showed no obvious homology to any known circoviral capsid proteins. A stem-loop-like element in the intergenic region between the 5' ends of the ORFs was also found. Phylogenetic calculations indicated that the novel virus belongs to the genus Circovirus in the family Circoviridae. The relative amount of the viral DNA in the organ samples was estimated by quantitative real-time PCR. The results suggested that the examined fish was caught in an active viremic state, although the role of this circovirus in the etiology of the cauliflower diseases could not be ascertained.

Rotation of the polarization direction and reversal of helicity of ultrashort pulsed beams propagating in free space.

We unveil the origin of the recently revealed polarization-state changes of polarization-shaped few-cycle pulses induced by free-space beam propagation. Simple rules are formulated to show how the orientation and ellipticity of the instantaneous polarization ellipse of the source and propagated pulses relate to each other. We demonstrate our findings with examples that clearly display the relationships found and highlight their relevance. We show, for example, that pulses often used in high-harmonic generation or attosecond pulse production rotate as a whole during free-space beam propagation or upon focusing. A pulse that may reverse its ellipticity from right-handed to left-handed during propagation is also introduced. It is shown that these effects are independent of the beam size and/or focal length. We also present how these instantaneous polarization-state changes could be noticed in classical measurements of light polarization using polarizers, phase retarders, and time-integrating detectors.

Task demand influences relationships among sex, clustering strategy, and recall: 16-word versus 9-word list learning tests.

OBJECTIVE: We compared the relationships among sex, clustering strategy, and recall across different task demands using the 16-word California Verbal Learning Test-Second Edition (CVLT-II) and the 9-word Philadelphia (repeatable) Verbal Learning Test (PrVLT). BACKGROUND: Women generally score higher than men on verbal memory tasks, possibly because women tend to use semantic clustering. This sex difference has been established via word-list learning tests such as the CVLT-II. METHODS: In a retrospective between-group study, we compared how 2 separate groups of cognitively healthy older adults performed on a longer and a shorter verbal learning test. The group completing the CVLT-II had 36 women and 26 men; the group completing the PrVLT had 27 women and 21 men. RESULTS: Overall, multiple regression analyses revealed that semantic clustering was significantly associated with total recall on both tests' lists (P<0.001). Sex differences in recall and semantic clustering diminished with the shorter PrVLT word list. CONCLUSIONS: Semantic clustering uniquely influenced recall on both the longer and shorter word lists. However, serial clustering and sex influenced recall depending on the length of the word list (ie, the task demand). These findings suggest a complex nonlinear relationship among verbal memory, clustering strategies, and task demand.

Partial characterization of a new adenovirus lineage discovered in testudinoid turtles.

In the USA and in Hungary, almost simultaneously, adenoviruses of a putative novel lineage were detected by PCR and sequencing in turtles belonging to four different species (including two subspecies) of the superfamily Testudinoidea. In the USA, partial sequence of the adenoviral DNA-dependent DNA polymerase was obtained from samples of a captive pancake tortoise (Malacochersus tornieri), four eastern box turtles (Terrapene carolina carolina) and two red-eared sliders (Trachemys scripta elegans). In Hungary, several individuals of the latter subspecies as well as some yellow-bellied sliders (T. scripta scripta) were found to harbor identical, or closely related, putative new adenoviruses. From numerous attempts to amplify any other genomic fragment by PCR, only a nested method was successful, in which a 476-bp fragment of the hexon gene could be obtained from several samples. In phylogeny reconstructions, based on either DNA polymerase or hexon partial sequences, the putative new adenoviruses formed a clade distinct from the five accepted genera of the family Adenoviridae. Three viral sub-clades corresponding to the three host genera (Malacochersus, Terrapene, Trachemys) were observed. Attempts to isolate the new adenoviruses on turtle heart (TH-1) cells were unsuccessful. Targeted PCR screening of live and dead specimens revealed a prevalence of approximately 25% in small shelter colonies of red-eared and yellow-bellied sliders in Hungary. The potential pathology of these viruses needs further investigation; clinically healthy sliders were found to shed the viral DNA in detectable amounts. Based on the phylogenetic distance, the new adenovirus lineage seems to merit the rank of a novel genus.

Challenges and strategies for research in prisons.

In this article, we discuss some of the challenges encountered while conducting research in two maximum security prisons and approaches we found helpful to facilitate the research process through the development of collaborative relationships, the establishment of prison contacts, and the implementation of rigorous research methods. As a result of our experiences, we have been successful at maintaining a high rate of inmate participation (>80%) and a well-functioning multidisciplinary team. The approaches described may be useful to other investigators planning to conduct research in a challenging setting such as prisons.

Use of different morphological techniques to analyze the cellular composition of the adult zebrafish optic tectum.

Cellular composition of the adult zebrafish (Danio rerio) optic tectal cortex was examined in this study. Morphological techniques such as 1 µm thick serial plastic sections stained with osmium tetroxide and toluidine blue, modified rapid Golgi silver impregnation, GFAP immunohistochemistry, confocal microscopy, as well as scanning and transmission electron microscopy were used. Neuronal and glial components are described and the layers of the cortex are revisited. Specific neuronal arrangements as well as unique glial/ependymal cells are described. A three dimensional rendering of the astrocytic fiber arrangement in the marginal zone is presented and a composite drawing summarizes the cellular composition of the optic tectum.

Staphylococcus aureus oropharyngeal carriage in a prison population.

Throat carriage (42.7%) of Staphylococcus aureus exceeded nasal carriage (35.0%) in 2 New York prisons. Methicillin resistance, primarily due to USA300, was high at both sites; 25% of dually colonized inmates had different strains. Strategies to reduce S. aureus transmission will need to consider the high frequency of throat colonization.

Femoral insufficiency fractures associated with prolonged bisphosphonate therapy.

BACKGROUND: Emerging evidence has linked the long-term use of bisphosphonates with femoral insufficiency fractures. It has been suggested that the prolonged effect on bone remodeling leads to the accumulation of microfractures and weakening of bone. QUESTIONS/PURPOSES: We investigated the association between bisphosphonate use and femoral insufficiency fractures. METHODS: We evaluated 100 patients with low-energy femoral shaft fractures before and after bisphosphonates became available for use. Twenty-one consecutive patients who presented between January 1995 and February 1997 were compared with 79 consecutive patients who presented between January 2007 and February 2009. The radiographs of all 100 patients were examined for evidence of preexisting insufficiency fractures. We identified insufficiency fractures by a transverse fracture line on the tension side of the femur with lateral cortical thickening immediately adjacent to the fracture. Relevant details from the history were recorded. RESULTS: Forty-one patients had an underlying femoral insufficiency fracture, all of whom had been receiving bisphosphonate therapy. Among the 21 patients with low-energy femoral fractures before the availability of bisphosphonates, none had insufficiency fractures. Of the 41 patients with insufficiency fractures, 29 (71%) had prodromal pain and 18 (44%) had bilateral insufficiency fractures. Bisphosphonate use was associated (odds ratio greater than 1000) with insufficiency fracture. The mean duration of bisphosphonate use in patients with insufficiency fractures was longer than in patients without fractures (7.1 versus 3.2 years). CONCLUSION: Long-term bisphosphonate use is associated with insufficiency fractures of the femoral shaft, which commonly present with prodromal thigh pain and may be bilateral. These fractures were not seen before bisphosphonates became available for use.

Structural determination of a neutral exopolysaccharide produced by Lactobacillus delbrueckii ssp. bulgaricus LBB.B332.

The neutral exopolysaccharide produced by Lactobacillus delbrueckii ssp. bulgaricus LBB.B332 in skimmed milk was found to be composed of d-glucose, d-galactose, and l-rhamnose in a molar ratio of 1:2:2. Linkage analysis and 1D/2D NMR (1H and 13C) studies carried out on the native polysaccharide as well as on an oligosaccharide generated by a periodate oxidation protocol, showed the polysaccharide to consist of linear pentasaccharide repeating units with the following structure: -->3-alpha-D-Glcp-(1-->3)-alpha-D-Galp-(1-->3)-alpha-L-Rhap-(1-->2)-alpha-L-Rhap-(1-->2)-alpha-D-Galp-(1-->.

Structure of a neutral exopolysaccharide produced by Lactobacillus delbrueckii ssp. bulgaricus LBB.B26.

The neutral exopolysaccharide produced by Lactobacillus delbrueckii ssp. bulgaricus LBB.B26 in skimmed milk was found to be composed of d-glucose and d-galactose in a molar ratio of 2:3. Linkage analysis and 1D/2D NMR ((1)H and (13)C) studies performed on the native polysaccharide, and on an oligosaccharide obtained from a partial acid hydrolysate of the native polysaccharide, showed the polysaccharide to consist of branched pentasaccharide repeating units with the following structure. [structure: see text]