The UVS9 Gene of Chlamydomonas Encodes an XPG Homolog with a New Conserved Domain

Publication date: Available online 19 November 2015
Source:DNA Repair
Author(s): Erin Deitsch, Erin M. Hibbard, Jason L. Petersen
Nucleotide excision repair (NER) is a key pathway for removing DNA damage that destabilizes the DNA double helix. During NER a protein complex coordinates to cleave the damaged DNA strand on both sides of the damage. The resulting lesion-containing oligonucleotide is displaced from the DNA and a replacement strand is synthesized using the undamaged strand as template. Ultraviolet (UV) light is known to induce two primary forms of DNA damage, the cyclobutane pyrimidine dimer and the 6-4 photoproduct, both of which destabilize the DNA double helix. The uvs9 strain of Chlamydomonas reinhardtii was isolated based on its sensitivity to UV light and was subsequently shown to have a defect in NER. In this work, the UVS9 gene was cloned through molecular mapping and shown to encode a homolog of XPG, the structure-specific nuclease responsible for cleaving damaged DNA strands 3′ to sites of damage during NER. 3′ RACE revealed that the UVS9 transcript is alternatively polyadenylated. The predicted UVS9 protein is nearly twice as long as other XPG homologs, primarily due to an unusually long spacer region. Despite this difference, amino acid sequence alignment of UVS9p with XPG homologs revealed a new conserved domain involved in TFIIH interaction.



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Development of 68Ga-Labeled Multivalent Nitroimidazole Derivatives for Hypoxia Imaging

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Sudhakara Reddy Seelam, Ji Youn Lee, Yun-Sang Lee, Mi Kyung Hong, Young Joo Kim, Vinay Kumar Banka, Dong Soo Lee, June-Key Chung, Jae Min Jeong
Radiolabeled nitroimidazole (NI) derivatives have been extensively studied for imaging hypoxia. To increase the hypoxic tissue uptake, we developed ⁶⁸Ga-labeled agents based on mono-, bis-, and trisnitroimidazole conjugates with the chelating agent 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP). All the three agents showed high radiolabeling yields (>96%) and were found to be stable up to 4 h in prepared medium at room temperature and in human serum at 37 °C. The trivalent agent showed a significant increase in hypoxic to normoxic uptake ratio (p < 0.005) according to the in vitro cell uptake experiments. Immunohistochemical analysis confirmed the presence of hypoxia in xenografted CT26 tumor tissue. The trivalent derivative (⁶⁸Ga-3: 0.17 ± 0.04, ⁶⁸Ga-4: 0.33 ± 0.04, ⁶⁸Ga-5: 0.45 ± 0.09, and ⁶⁸Ga-6: 0.47 ± 0.05% ID/g) showed the highest uptake by tumor cells according to the biodistribution studies in CT-26 xenografted mice. All the nitroimidazole derivatives showed significantly higher uptake by tumor cells than the control agent (p < 0.05) at 1 h post-injection. The trivalent derivative (⁶⁸Ga-3: 0.10 ± 0.06; ⁶⁸Ga-4: 0.20 ± 0.06; ⁶⁸Ga-5: 0.33 ± 0.08; ⁶⁸Ga-6: 0.59 ± 0.09) also showed the highest standard uptake value for tumor cells at 1 h post-injection in animal PET studies using CT-26 xenografted mice. In conclusion, we successfully synthesized multivalent ⁶⁸Ga-labeled NI derivatives for imaging hypoxia. Among them, the trivalent agent showed the highest tumor uptake in biodistribution and animal PET studies.

Graphical abstract

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Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Hao Zhang, Min-Hang Xin, Xiao-Xiao Xie, Shuai Mao, Sai-Jie Zuo, She-Min Lu, San-Qi Zhang
In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one- 6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially against PI3Kα. In addition, compound (S)-C5 can efficaciously inhibit tumor growth in a mice S-180 model. These findings suggest that our designed compounds can serve as potent PI3K inhibitors and effective anticancer agents.

Graphical abstract

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SAR Studies Directed Toward the Pyridine Moiety of the Sap-Feeding Insecticide Sulfoxaflor (Isoclast™ active)

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Michael R. Loso, Zoltan Benko, Ann Buysse, Timothy C. Johnson, Benjamin M. Nugent, Richard B. Rogers, Thomas C. Sparks, Nick X. Wang, Gerald B. Watson, Yuanming Zhu
Sap-feeding insect pests constitute a major insect pest complex that includes a range of aphids, whiteflies, planthoppers and other insect species. Sulfoxaflor (Isoclast™ active), a new sulfoximine class insecticide, targets sap-feeding insect pests including those resistant to many other classes of insecticides. A structure activity relationship (SAR) investigation of the sulfoximines insecticides revealed the importance of a 3-pyridyl ring and a methyl substituent on the methylene bridge linking the pyridine and the sulfoximine moiety to achieving strong Myzus persicae activity. A more in depth QSAR investigation of pyridine ring substituents revealed a strong correlation with the calculated log octanol/water partition coefficient (SLogP). Model development resulted in a highly predictive model for a set of 18 sufoximines including sulfoxaflor. The model is consistent with and helps explain the highly optimized pyridine substitution pattern for sulfoxaflor.

Graphical abstract

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Synthesis of tetravalent LacNAc-glycoclusters as high-affinity cross-linker against Erythrina cristagalli agglutinin

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Makoto Ogata, Yasushi Chuma, Yoshinori Yasumoto, Takashi Onoda, Myco Umemura, Taichi Usui, Enoch Y. Park
Four kinds of tetravalent double-headed glycoclusters [(LacNAc)4-DHGs] were designed with linkers of varying lengths consisting of alkanedionic carboxyamido groups (C6, C12, C18 and C24) between two bi-antennary LacNAc-glycosides. These glycoclusters served as high-affinity cross-linking ligands for the LacNAc-binding lectin Erythrina cristagalli agglutinin (ECA). The binding activity and cross-linking between each ligand and ECA were characterized by a hemagglutination inhibition (HI) assay, isothermal titration calorimetry (ITC), a quantitative precipitation assay and dynamic light scattering (DLS). For the precipitation assay and DLS measurement, the synthesized (LacNAc)4-DHGs were found to be capable of binding and precipitating the ECA as multivalent ligands. ITC analysis indicated the binding of (LacNAc)4-DHGs was driven by a favorable enthalpy change. Furthermore, the entropy penalty from binding (LacNAc)4-DHGs clearly decreased in a spacer length-dependent manner. The binding affinities of flexible (LacNAc)4-DHGs (C18 and C24) with long spacers were found to be more favorable than those of the clusters having short spacers (C6 and C12). These results were supported by molecular dynamics simulations with explicit water molecules for the tetravalent glycoclusters with ECA. We concluded that the subtle modification in the epitope-presenting scaffolds exerts the significant effect in the recognition efficiency involved in the LacNAc moieties by ECA.

Graphical abstract

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Characterization of Childhood Obesity and Behavioral Factors

Childhood obesity is a major public health threat in the United States. Recent data indicate that 34.2% of children ages 6 to 11 years are overweight or obese. The purpose of this study is to describe childhood obesity levels and identify risk behaviors in two school-based health centers in Michigan, one urban and one rural.

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Use of a Pediatric Bleeding Questionnaire in the Screening of Von Willebrand Disease in Young Females at Menarche in the Primary Care Setting

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by deficiency or dysfunction in von Willebrand factor. Assessment of hemorrhagic symptoms is essential for early diagnosis, although bleeding histories are taken in a nonstandardized manner. Validated bleeding assessment tools provide objectivity in evaluating bleeding patterns of females at menarche and may improve provider confidence in screening for VWD. Utilizing a pretest/posttest design, in this project we implemented and evaluated the use of a pediatric bleeding questionnaire in eight pediatric primary care clinics for 3 months.

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Fossil hominin radii from the Sima de los Huesos Middle Pleistocene site (Sierra de Atapuerca, Spain)

Publication date: January 2016
Source:Journal of Human Evolution, Volume 90
Author(s): Laura Rodríguez, José Miguel Carretero, Rebeca García-González, Carlos Lorenzo, Asier Gómez-Olivencia, Rolf Quam, Ignacio Martínez, Ana Gracia-Téllez, Juan Luis Arsuaga
Complete radii in the fossil record preceding recent humans and Neandertals are very scarce. Here we introduce the radial remains recovered from the Sima de los Huesos (SH) site in the Sierra de Atapuerca between 1976 and 2011 and which have been dated in excess of 430 ky (thousands of years) ago. The sample comprises 89 specimens, 49 of which are attributed to adults representing a minimum of seven individuals. All elements are described anatomically and metrically, and compared with other fossil hominins and recent humans in order to examine the phylogenetic polarity of certain radial features. Radial remains from SH have some traits that differentiate them from those of recent humans and make them more similar to Neandertals, including strongly curved shafts, anteroposterior expanded radial heads and both absolutely and relatively long necks. In contrast, the SH sample differs from Neandertals in showing a high overall gracility as well as a high frequency (80%) of an anteriorly oriented radial tuberosity. Thus, like the cranial and dental remains from the SH site, characteristic Neandertal radial morphology is not present fully in the SH radii. We also analyzed the cross-sectional properties of the SH radial sample at two different levels: mid-shaft and at the midpoint of the neck length. When standardized by shaft length, no difference in the mid-shaft cross-sectional properties were found between the SH hominins, Neandertals and recent humans. Nevertheless, due to their long neck length, the SH hominins show a higher lever efficiency than either Neandertals or recent humans. Functionally, the SH radial morphology is consistent with more efficient pronation-supination and flexion-extension movements. The particular trait composition in the SH sample and Neandertals resembles more closely morphology evident in recent human males.



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The larger mammal fauna from the Lower Paleolithic Schöningen Spear site and its contribution to hominin subsistence

Publication date: Available online 19 November 2015
Source:Journal of Human Evolution
Author(s): Thijs van Kolfschoten, Elfi Buhrs, Ivo Verheijen
The locality Schöningen (Germany) is an important source of knowledge about Lower Paleolithic hominin subsistence. The locality includes a series of sites dated to the late Middle Pleistocene with a Holsteinian (MIS 11) and Reinsdorf Interglacial (MIS 9) age. One of the youngest sites is Schöningen 13 II-4, the Spear Horizon site also known as the Horse Butchery site. The organic remains excavated here are exceptionally well-preserved as they were embedded in anaerobic, waterlogged sediments in an area where the groundwater is rich in calcium carbonate. The fossil assemblage is ideal for the study of patterns in hominin interference with the mammalian species encountered at the site.The vertebrate record is extensive and very diverse. The fossil larger carnivore guild of the Spear Horizon faunal assemblage includes saber-toothed cat, fox, and wolf. Herbivores are represented by an elephant species, two equid species, two rhinoceros species, two cervid species, and two large bovid species.Evidence of hominin interference presents itself as either marks on skeletal remains related to the use of bones as knapping tools or hammers, or as marks that indicate butchering activities such as skinning, dismembering, defleshing, filleting, and marrow extraction. The humerus of the saber-toothed cat clearly shows that the bone has been used as a knapping tool. The fossil remains of the other larger carnivores do not show any signs of hominin interference or exploitation. This also applies to the limited number of elephant and rhinoceros remains found at the site. The large horse Equus mosbachensis dominates the larger mammal record and played a major role in hominin subsistence. Marks on the horse bones indicate that a large number of carcasses have been butchered. Traces on the fossil remains of both red deer (Cervus elaphus) and the large bovids also indicate exploitation by Lower Paleolithic hominins.



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Cochlear labyrinth volume in Krapina Neandertals

Publication date: Available online 19 November 2015
Source:Journal of Human Evolution
Author(s): Michaela E. Beals, David W. Frayer, Jakov Radovčić, Cheryl A. Hill
Research with extant primate taxa suggests that cochlear labyrinth volume is functionally related to the range of audible frequencies. Specifically, cochlear volume is negatively correlated with both the high and low frequency limits of hearing so that the smaller the cochlea, the higher the normal range of audible frequencies. The close anatomical relationship between the membranous cochlea and the bony cochlear labyrinth allows for the determination of cochlear size from fossil specimens. This study compares Krapina Neandertal cochlear volumes to extant taxa cochlear volumes. Cochlear volumes were acquired from high-resolution computed tomography scans of temporal bones of Krapina Neandertals, chimpanzees, gorillas, and modern humans. We find that Krapina Neandertals' cochlear volumes are similar to modern Homo sapiens and are significantly larger than chimpanzee and gorilla cochlear volumes. The measured cochlear volume in Krapina Neandertals suggests they had a range of audible frequencies similar to the modern human range.



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In vitro antibacterial and antibiotic-potentiation activities of the methanol extracts from Beilschmiedia acuta, Clausena anisata, Newbouldia laevis and Polyscias fulva against multidrug-resistant Gram-negative bacteria

Background: The present study was designed to investigate the antibacterial activities of the methanol extracts from different parts of Beilschmedia acuta Kosterm (Lauraceae), Clausena anisata (Willd) Hook (Rutaceae), Newbouldia laevis Seem (Bignoniaceae) and Polyscias fulva (Hiern) Harms (Araliaceae) as well as their synergistic effects with antibiotics against a panel of Gram-negative bacteria, including multi-drug resistant (MDR) phenotypes expressing active efflux pumps. Methods: Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) of the extracts, as well as those of antibiotics in association with the most active ones, B. acuta, N. laevis and P. fulva. Results: MIC values obtained indicate that extracts from the bark of B. acuta were active on all the 26 tested Gram-negative bacteria, with MICs ranging from values below 8 to 256 μg/mL. Other samples displayed selective activities, their inhibitory effects being observed on 9 (34.62 %) of the 26 bacterial strains for N. laevis leaves extract, 6 (23.10 %) for both C. anisata leaves and roots extracts, 7 (26.9 %) and 4 (15.4 %) for leaves and roots extracts of P. fulva respectively. Extract from B. actua bark displayed the best antibacterial activity with MIC values below 100 μg/mL against 16 (61.5 %) of the 26 tested microorganisms. The lowest MIC values (below 8 μg/mL) were obtained with this extract against Escherichia coli W3110 and Klebsiella pneumoniae ATCC11296. The MIC values of this extract were lower than those of ciprofloxacin against E. coli W3110, Enterobacter aerogenes ATCC13048, CM64 and Providencia stuartii NAE16. At MIC/2, the best percentages of synergistic effects (100 %), were obtained with B. acuta bark extract and tetracycline (TET) as well as with P. fulva leaves extract and TET and kanamycin (KAN). Conclusion: The overall results of the present study provide information for the possible use of the studied plants and mostly Beilschmedia acuta in the control of bacterial infections including MDR phenotypes.

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Psychiatrist Tinnitus

Tinnitus is a medical condition that is usually describing as a "ringing" sensation in the ears. Many patients report that the experience can range from a mild sort of buzzing to a constant static or ringing sound. The aspect that makes the condition so difficult is the fact that there is no sure medical cure for it, and once a person suffers from tinnitus, it can be a constant presence that never shuts off. The constant sound and the inability to really sit and experience silence can be seriously debilitating, stressful and very depressing.
There are many causes for tinnitus, but the most usual reason for the condition is a trauma to the ear that results in damage to the tiny cochlear receptors inside. These receptors send electric signal to the brain, but when they are damaged, (from loud noise from a gunshot or a from being too close to the speakers at a very loud rock concert, for example) they may misfire and send out a perception of sound to the brain, even when there isn't any sound being produced.

The Link to Insomnia

Many people who have tinnitus have trouble sleeping because of the constant perception of noise. The ensuing insomnia also brings on stress and depression, with the result that patients with tinnitus can become inconsolable. Since there is no surefire treatment for the problem, many doctors approach it in various ways in hopes of finding something that will relieve the symptoms.

Psychiatrist Tinnitus

Studies that have come out in the last few decades are finding more and more of a psychiatrist tinnitus link. In the past tinnitus was always viewed as a medical condition that could lead to depression, but today more and more experts are seeing psychiatrist tinnitus treatment as a real solution to this difficult condition.

Many medical experts now believe that tinnitus and depression are very linked together, so both need to be treated in order for a patient to have relief. Some doctors are now finding that prescribing sleeping pills for the insomnia brings relief, as well as antidepressants for the linked depression. Once these two elements are relieved, the tinnitus often begins to fade.

Today, many medical professionals and psychiatrists are very relieved to see that the link between depression and tinnitus is leading the way to sound treatment for patients who have been suffering for years with this condition.

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Intrinsic medial temporal lobe connectivity relates to individual differences in episodic autobiographical remembering

Publication date: Available online 19 November 2015
Source:Cortex
Author(s): Signy Sheldon, Norman Farb, Daniela J. Palombo, Brian Levine
People vary in how they remember the past: some recall richly detailed episodes; others more readily access the semantic features of events. The neural correlates of such trait-like differences in episodic and semantic remembering are unknown. We found that self-reported individual differences in how one recalls the past were related to predictable intrinsic connectivity patterns of the medial temporal lobe (MTL) memory system. A pattern of MTL connectivity to posterior brain regions supporting visual-perceptual processing (occipital/parietal cortices) was related to the endorsement of episodic memory-based remembering (recalling spatiotemporal event information), whereas MTL connectivity to inferior and middle prefrontal cortical regions was related to the endorsement of semantic memory-based remembering (recalling facts). These findings suggest that the tendency to engage in episodic autobiographical remembering is associated with accessing and constructing detailed images of a past event in memory, while the tendency to engage in semantic autobiographical remembering is associated with organizing and integrating higher-order conceptual information. More broadly, these findings suggest that differences in how people naturally use memory are instantiated though distinct patterns of MTL functional connectivity.



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Protocols for Analyzing the Role of Paneth Cells in Regenerating the Murine Intestine using Conditional Cre-lox Mouse Models

Intestinal epithelial stem cells (ISCs) are intermingled with Paneth cells. These cells are differentiated progeny of the ISC, which support the ISCs and provide antibacterial protection. Here we demonstrate how we used transgenic conditional mouse models to establish that Paneth cells play a crucial role in maintaining the intestinal epithelia.

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Feasibilty study on the use of methylation-specific MLPA for the 11p15 region on prenatal samples

What's already known about this topic?

• A few publications describing prenatal diagnosis of BWS are known.
• However, the methylation status of the 11p15 imprinted region in normal prenatal samples is not known. Such information is important for determining if regions or specific nucleotides are suitable for prenatal diagnosis.

What does this study add?

• In postnatal diagnosis, methylation-specific MLPA is the most frequently used method for thediagnosis of Beckwith-Wiedemann and Silver-Russell syndrome. In the work presented here, the feasibility of such a ms-MLPA on prenatal samples from normal pregnancies is studied.

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A CO2 Concentration Gradient Facility for Testing CO2 Enrichment and Soil Effects on Grassland Ecosystem Function

The Lysimeter Carbon Dioxide Gradient Facility creates a 250 to 500 µl L-1 linear carbon dioxide gradient in temperature-controlled chambers housing grassland plant communities on clay, silty clay, and sandy soil monoliths. The facility is used to determine how past and future carbon dioxide levels affect grassland carbon cycling.

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