17 research outputs found
FIGURE 2 in A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China
No full textFIGURE 2. Bayesian phylogram of Leptolalax inferred from a 511 bp fragment of the 16S mtDNA gene. "*" denotes high support by Bayesian posterior probabilities (BPP> 95%), and bootstrap support values (BS> 70%); "-" represents low support values. The scale bar represents 0.06 nucleotide substitutions per site.Published as part of Yuan, Zhiyong, Sun, Ruida, Chen, Jinmin, Rowley, Jodi J. L., Wu, Zhengjun, Hou, Shaobing, Wang, Shaoneng & Che, Jing, 2017, A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China, pp. 551-570 in Zootaxa 4300 (4) on page 554, DOI: 10.11646/zootaxa.4300.4.5, http://zenodo.org/record/84014
FIGURE 3 in A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China
No full textFIGURE 3. (A) Dorsal view, (B) lateral view, (C) Ventral view, (D) dorsolateral view, (E) dorsal view of thighs and (F) posterioventral view of thighs in the holotype (KIZ046696) of Leptolalax maoershanensis sp. nov. in life.Published as part of Yuan, Zhiyong, Sun, Ruida, Chen, Jinmin, Rowley, Jodi J. L., Wu, Zhengjun, Hou, Shaobing, Wang, Shaoneng & Che, Jing, 2017, A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China, pp. 551-570 in Zootaxa 4300 (4) on page 558, DOI: 10.11646/zootaxa.4300.4.5, http://zenodo.org/record/84014
Targeting Prostaglandin E2 Receptor EP2 for Treatment of High-Risk Neuroblastoma
No full textProstaglandin E2 (PGE2) is a predominant proinflammatory regulator that plays pivotal roles in regulating tumor cell proliferation, migration, and invasion. It fosters an inflammation-enriched microenvironment that facilitates angiogenesis and immune evasion. Neuroblastoma (NB) is a lethal pediatric malignancy. PGE2 has been reported to promote high-risk NB proliferation and progression. However, the PGE2 receptor subtype (EP1-EP4) which potentially contributed to NB growth remained elusive. In this research, at first, we demonstrated that EP2 receptor was highly correlated with NB aggressiveness, and acted as a predominant Gαs-coupled receptor mediating PGE2-initiated cyclic AMP (cAMP) signaling in NB cells with high-risk factors, including chromosome 11q deletion and MYCN amplification. CRISPR/Cas9 induced EP2 knockout blocked the development of NB xenografts in athymic nude mice. Additionally, EP2 conditional knockdown prevented established tumors from progressing in vivo. Pharmacological inhibition of EP2 by our recently developed antagonist TG6-129 substantially suppressed the NB tumor growth in both nude mice and syngeneic immunocompetent hosts, with the observable anti-inflammatory, anti-angiogenic, and apoptotic effects. Next, based on the scaffold of TG6-129, we developed, and identified a novel robust EP2 antagonizing compound GLL-618. GLL-618 demonstrated enhanced EP2 binding potency. Meanwhile, it also showed advanced pharmacokinetic features such as prolonged plasma half-life and im-proved bioavailability. Applied as a single treatment reagent, GLL-618 could significantly inhibited high-risk NB neuro-spheres development and suppressed high-risk NB xenograft tumors growth by 50%. Subsequently, we combined GLL-618 with vincristine, a prevalently used chemotherapy drug for the treatment of high-risk NB. GLL-618 could synergistically increase the anti-tumor effect of vincristine, which was evidenced by an overall 70% tumor weight reduction at the treatment endpoint in an immunocompetent allograft model, accompanied with quenched proinflammatory signaling within the tumor microenvironment and elevated expression of apoptotic markers. In conclusion, this study suggested that the PGE2/EP2 signaling pathway might contribute to NB development and progression. EP2 inhibition with our drug-like compounds could be potentially applied as an alternative, and adjunctive treatment strategy for this deadly pediatric cancer
Leptolalax maoershanensis Yuan & Sun & Chen & Rowley & Wu & Hou & Wang & Che 2017, sp. nov.
No full textLeptolalax maoershanensis sp. nov. Yuan, Sun, Chen, Rowley & Che (Fig. 2–6) Holotype. KIZ 046696, adult male from Antangping, Maoershan Nature Reserve, Ziyuan, Guangxi, China (25.9116°N, 110.4652°E, elevation 1575 m. a.s.l.; Fig. 1), collected by Zhiyong Yuan on 4 April 2016. Paratypes. KIZ019385–86 (two adult males), KIZ045758 (adult male), KIZ046698–700 (three adult males), KIZ027229 (adult female) from the type locality collected by Jinmin Chen on 5 June 2015; KIZ019384 (adult male), KIZ027230–41 (11 adult males), KIZ046643 (adult male) and KIZ027234 (adult female) from the type locality collected by Zhiyong Yuan during April 2016. Diagnosis. The new species is assigned to the genus Leptolalax on the basis of the following characters: medium size, rounded finger tips, presence of an elevated inner palmar tubercle not continuous to the thumb, presence of supra–axillary, femoral and ventrolateral glands, vomerine teeth absent, tubercles on eyelids, and pale vertical bar present on anterior tip of snout (Dubois 1980, 1983; Ohler et al. 2011, Rowley & Cao 2009, Rowley et al. 2013). Leptolalax maoershanensis sp. nov. is distinguished from its congeners by a combination of (1) medium size (SVL 25.2 mm – 30.4 mm in eight adult males and 29.1 mm in a one adult female), (2) head longer than wide, (3) externally distinct tympanum, (4) distinct black supratympanic line present, (5) dorsal skin shagreened with small tubercles and longitudinal folds, (6) distinct dark spots on the flank, (7) creamy-white chest and belly with irregular black spots, (8) grey-pinkish to dark brownish-violet ventral skin of limbs with numerous whitish speckles, (9) distinct ventrolateral glands, forming a distinct white line, (10) finger webbing and fringes absent, (11) toe webbing rudimentary and lateral fringes narrow, (12) longitudinal ridges indistinct under toes and not interrupted at the articulations, (13) a distinctly bicolored iris, typically bright orange-red in upper half, fading to silver in lower half. Description of the holotype. SVL 28.8 mm; head slightly longer than wide (HDL/HDW = 1.25), triangular in dorsal view; snout rounded in both ventral view and lateral view, protruding slightly beyond lower jaw (Fig. 3); nostril oval-shaped located closer to tip of snout than to eye; loreal region oblique; canthus rostralis distinct; eyes large (EYE/HDL = 0.33), eye diameter slightly smaller than snout length (EYE/SNT = 0.77), notably protuberant in both dorsal and lateral view, pupil vertical; tympanum distinct, rounded, diameter smaller than that of the eye (TMP /EYE = 0.47); tympanic annulus notably elevated relative to supratympanic line; vomerine teeth absent; pineal ocellus absent; vocal sac openings slit-like, located posteriolaterally on floor of mouth; tongue long and moderate width, with a shallow notch at posterior tip; supratympanic ridge distinct, running from eye towards axillary with raised tubercles. Forelimb long and slender, fingers long and slender, without webbing and lateral fringes (Fig. 4); relative length of fingers II<I<IV <III; tips of fingers rounded and slightly swollen; nuptial pad absent; subarticular tubercles absent in fingers, inner metacarpal tubercle large and rounded, separated from small, laterally compressed and much smaller outer metacarpal. Hindlimb relatively long, tibia less than half of snoutvent length (TIB/SVL = 0.41); tibiotarsal articulation of adpressed limb reaching snout, but not beyond snout tip, posterior edge of tibiotarsal articulation reaches well beyond anterior margin of eye; relative toe length I<II<V<III<IV; toe tips rounded and thickened; greatly reduced basal webbing present between all five toes; narrow lateral fringes present on all toes, hardly discernible; subarticular tubercles distinct under toes II and III; distinct dermal ridges present under toes I, V and IV; large, oval inner metatarsal tubercle distinct, outer metatarsal tubercle absent; dorsal skin rough with small tubercles and irregular pustules; ventral skin smooth; oval supra– axillary gland distinct at forelimb basis on ventral surface of axillary region; oval femoral glands distinct on posteroventral surface of thigh, closer to knee than to vent; ventrolateral glands forming a distinct line on flanks. Skin on dorsum mostly rough with tiny and raised tubercles; ventral skin smooth; pectoral gland small, oval; femoral gland small, oval, on posteroventral surface of thigh, closer to knee than to vent; supra-axillary gland oval, raised. Ventrolateral glands forming distinct lines. Color of holotype. In life, dorsal surface of head and trunk olive brown with large, dark brown, irregularly shaped markings; large reverse-triangle dark brown markings between eyes, connected to the W-shaped marking between axillae; faint transverse dark brown bars on dorsal surface of fingers and toes, lower arms, tarsus, thighs and tibia (Fig. 3); upper lip barred with dark and light brown; one dark blotch between nostril and eyes on loreal region; black band along canthus rostralis, through eye, and continuing along supratympanic ridge, encompassing most of tympanum, terminating above axilla; supratympanic ridge present, elbow to upper arm is reddish in color; five large, irregularly-shaped black blotches on flanks from the groin to axilla; fine, distinct reddish tubercles scattered on upper eyelids, snout, dorsal surfaces of head, body and limbs. Ventral surface of throat, chest and belly creamy white with irregular black spots; ventral surfaces of lip, limbs, covered with irregular white speckles; ventral surface of thighs grey-brown with white spots. Supra-axillary gland, ventrolateral glands and femoral glands white. Iris bicolored: copper in upper half, silver in lower third, with black reticulations throughout. In preservative, dorsal surface dark grey-brown with slightly paler limbs (Fig. 5); ventral surface of throat, chest, belly and interior portions of arms fade to yellowish- whitish, ventral surface of thighs dark brown with white spots; bars and blotches on dorsum and limbs are more pronounced. Morphological variation. Variation in size and body proportions of the type series are shown in Table 2. Representative photographs of paratypes in life are shown in Fig. 6. In life, the dorsal surface of the head and trunk varies from olive brown to reddish in color. Individuals vary in the number and size of tubercles, pustules, black ventrolateral blotches, and dorsal bars on the dorsum or dorsal surface of arms and legs. The W-shaped marking between axillae indistinct in some individuals (KIZ04663, 019384–86, 0 45758, 0 46699, 027232). The ventral surface of the throat is near immaculate creamy-white white in eight individuals (KIZ046700, KIZ046698, KIZ019385, 0 46643, 0 19384, 0 45768, 0 27230, 045771). The white speckles vary in number and size on the ventral surfaces of the lip and limbs. Etymology. The specific epithet, “ maoershanensis ”, is in reference to the type locality, Maoershan Nature Reserve. Molecular relationships. A total of 511 base pairs (bp) alignment for the16S gene were obtained. The five sequences belonging to the newly acquired specimens (GenBank accession numbers: KY986930 – KY986934) share a same haplotype. The observed interspecific uncorrected p -distances between the new population from Maoershan and all species in the subgenus for which comparable sequences were available varied from 6.6% (L. liui) to 19.5% (L. gracilis). The smallest genetic distance was observed between L. bourreti and L. eos (4.6%). The individuals from Maoershan formed a monophyletic group with L. liui and L. laui, with high support in both analyses (Fig. 2), but the relationships among these three species were not resolved. In combination with morphological differences (see below), we conclude that the newly collected Maoershan specimens represent a distinct species, and we describe it herein. TABLE]. List of voucher specimens anđ GenBank accession numbers for all DNA sequences incluđeđ in this stuđy. Natural history. All specimens were collected at night in small bamboo forest in Maoershan Nature Reserve at about 1550 m elevation (Fig. 7). Calling males were found along the stream, perching on large rocks, rocky crevices or under deadwood. Insect-like calls could be heard during April and June. The breeding season of this species is likely to encompass April to July as females collected during these months were gravid, and males were heard calling only from April to the beginning of July (observed by Shaobing Hou, who conducted fieldworks in Maoershan each month from 2015 to 2016). During both surveys, the number of males observed was much greater than females (males: females = 5: 1 in June 2015 and 14: 1 in April 2016). The new species occurs in syntopy with Pachytriton inexpectatus Nishikawa, Jiang, Matsui, & Mo, Megophrys sp., Quasipaa boulengeri Günther, during the same seasons. Distribution. The species is currently only known from Maoershan Nature Reserve, Ziyuan, Guangxi, China. Comparisons. Leptolalax maoershanensis sp. nov. can be differentiated from all Leptolalax species south of the Isthmus of Kra currently assigned in the subgenus Leptolalax (L. arayai, L. dringi, L. fritinniens, L. gracilis, L. hamidi, L. heteropus, L. kajangensis, L. kecil, L. marmoratus, L. maurus, L. pictus, L. platycephalus, L. sabahmontanus and L. solus) in having supra-axillary and ventrolateral glands (vs. supra-axillary and ventrolateral glands absent). Leptolalax maoershanensis sp. nov. differs from all known Leptolalax species distributed north of the Isthmus of Kra by a combination of male body size, presence of a distinct black supratympanic line, externally distinct tympanum, and black spots on the flank, plus ventral colouration, degree of webbing and fringing on the toes, iris coloration and dorsal skin texture (Table 3, Appendix II). Leptolalax maoershanensis sp. nov.. can be further differentiated from the two most morphologically and molecularly similar species, L. laui and L. liui, from China, by having longitudinal ridges indistinct under the toes and not interrupted at the articulations (vs. distinct longitudinal ridges interrupted at the articulations in L. liui), dorsal skin with irregular pustules or glandular folds (vs. absence in L. laui) and ³6.6% divergence at the 16S gene fragment examined. From L. alpinus, a morphologically similar species from China for which no comparable molecular data is available, the new species differs by having narrow lateral fringes on the toes (vs. wide lateral fringes), a smooth to finely shagreened dorsum with small tubercles and irregular pustules (vs. smooth dorsum without irregular pustules), head slightly longer than wide (vs. head width approximately equal to head length), and hindlimbs relatively long, with the tibiotarsal articulation of adpressed limbs reaching the snout (vs. tibiotarsal articulation of adpressed limb reaching anterior margin of eye).Published as part of Yuan, Zhiyong, Sun, Ruida, Chen, Jinmin, Rowley, Jodi J. L., Wu, Zhengjun, Hou, Shaobing, Wang, Shaoneng & Che, Jing, 2017, A new species of the genus Leptolalax (Anura: Megophryidae) from Guangxi, China, pp. 551-570 in Zootaxa 4300 (4) on pages 553-559, DOI: 10.11646/zootaxa.4300.4.5, http://zenodo.org/record/84014
Identification of a Novel UT-B Urea Transporter in Human Urothelial Cancer
No full textThe urea transporter UT-B is widely expressed and has been studied in erythrocyte, kidney, brain and intestines. Interestingly, UT-B gene has been found more abundant in bladder than any other tissue. Recently, gene analyses demonstrate that SLC14A1 (UT-B) gene mutations are associated with bladder cancer, suggesting that urea transporter UT-B may play an important role in bladder carcinogenesis. In this study, we examined UT-B expression in bladder cancer with human primary bladder cancer tissues and cancer derived cell lines. Human UT-B has two isoforms. We found that normal bladder expresses long form of UT-B2 but was lost in 8 of 24 (33%) or significantly downregulated in 16 of 24 (67%) of primary bladder cancer patients. In contrast, the short form of UT-B1 lacking exon 3 was detected in 20 bladder cancer samples. Surprisingly, a 24-nt in-frame deletion in exon 4 in UT-B1 (UT-B1 1 24) was identified in 11 of 20 (55%) bladder tumors. This deletion caused a functional defect of UT-B1. Immunohistochemistry revealed that UT-B protein levels were significantly decreased in bladder cancers. Western blot analysis showed a weak UT-B band of 40 kDa in some tumors, consistent with UT-B1 gene expression detected by RT-PCR. Interestingly, bladder cancer associate UT-B1 1 24 was barely sialylated, reflecting impaired glycosylation of UT-B1 in bladder tumors. In conclusion, SLC14A1 gene and UT-B protein expression are significantly changed in bladder cancers. The aberrant UT-B expression may promote bladder cancer development or facilitate carcinogenesis induced by other carcinogens.Emory URC grant; NIH [R01-DK087838, R01-DK89828, R01-DK41707]; China Scholarship Council (CSC) under the State Scholarship FundSCI(E)ARTICLE
Identification of a Novel UT-B Urea Transporter in Human Urothelial Cancer
No full textThe urea transporter UT-B is widely expressed and has been studied in erythrocyte, kidney, brain and intestines. Interestingly, UT-B gene has been found more abundant in bladder than any other tissue. Recently, gene analyses demonstrate that SLC14A1 (UT-B) gene mutations are associated with bladder cancer, suggesting that urea transporter UT-B may play an important role in bladder carcinogenesis. In this study, we examined UT-B expression in bladder cancer with human primary bladder cancer tissues and cancer derived cell lines. Human UT-B has two isoforms. We found that normal bladder expresses long form of UT-B2 but was lost in 8 of 24 (33%) or significantly downregulated in 16 of 24 (67%) of primary bladder cancer patients. In contrast, the short form of UT-B1 lacking exon 3 was detected in 20 bladder cancer samples. Surprisingly, a 24-nt in-frame deletion in exon 4 in UT-B1 (UT-B1Δ24) was identified in 11 of 20 (55%) bladder tumors. This deletion caused a functional defect of UT-B1. Immunohistochemistry revealed that UT-B protein levels were significantly decreased in bladder cancers. Western blot analysis showed a weak UT-B band of 40 kDa in some tumors, consistent with UT-B1 gene expression detected by RT-PCR. Interestingly, bladder cancer associate UT-B1Δ24 was barely sialylated, reflecting impaired glycosylation of UT-B1 in bladder tumors. In conclusion, SLC14A1 gene and UT-B protein expression are significantly changed in bladder cancers. The aberrant UT-B expression may promote bladder cancer development or facilitate carcinogenesis induced by other carcinogens
LmbU, a Cluster-Situated Regulator for Lincomycin, Consists of a DNA-Binding Domain, an Auto-Inhibitory Domain, and Forms Homodimer
No full textFew studies were reported about the regulatory mechanism of lincomycin biosynthesis since it was found in 1962. Although we have proved that a cluster-situated regulator (CSR) LmbU (GenBank Accession No. ABX00623.1) positively modulates lincomycin biosynthesis in Streptomyces lincolnensis NRRL 2936, the molecular mechanism of LmbU regulation is still unclear. In this study, we demonstrated that LmbU binds to the target lmbAp by a central DNA-binding domain (DBD), which interacts with the binding sites through the helix-turn-helix (HTH) motif. N-terminal of LmbU includes an auto-inhibitory domain (AID), inhibiting the DNA-binding activity of LmbU. Without the AID, LmbU variant can bind to its own promoter. Interestingly, compared to other LmbU homologs, the homologs within the biosynthetic gene clusters (BGCs) of known antibiotics generally contain N-terminal AIDs, which offer them the abilities to play complex regulatory functions. In addition, cysteine 12 (C12) has been proved to be mainly responsible for LmbU homodimer formation in vitro. In conclusion, LmbU homologs naturally exist in hundreds of actinomycetes, and belong to a new regulatory family, LmbU family. The present study reveals the DBD, AID and dimerization of LmbU, and sheds new light on the regulatory mechanism of LmbU and its homologs
Bootstrapping over Free -Module
No full textBootstrapping, introduced by Gentry at STOC 2009, remains the only known method for realizing fully homomorphic encryption (FHE). Since Alperin-Sheriff and Peikert’s 2014 breakthrough on symmetric group accumulator (ACC) based bootstrapping, algebraic ACC designs have offered the lowest bootstrapping latency. The work of Ducas and Micciancio further advanced this paradigm by embedding into the multiplicative subgroup of the cyclotomic ring and exploiting FFT/NTT for fast computation, leading to the milestone constructions FHEW and TFHE. Despite their efficiency, these ring-based schemes face a fundamental limitation: correctness requires , rigidly coupling precision, performance, and key size to the polynomial dimension.
We address this limitation by introducing a new accumulator structure - a free -module . This generalization decouples and through a tunable factor , with the classical ring-based construction recovered as the special case . The computation over resulting -algebra enables efficient computation over can be effectively reduced to the base ring . Based on this structure, we design a bootstrapping scheme that achieves asymptotic improvements in precision, performance, and key size. Experimental results further demonstrate significant concrete gains, confirming the practicality of our approach
