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Our previous study demonstrated a close relationship between the NOTCH signaling pathway and salivary adenoid cystic carcinoma (SACC). Its receptor gene, NOTCH1, and its downstream gene, HES1, contribute to the proliferation, invasion and metastasis of SACC. Accumulating evidence supports HEY1 as another effector of the signaling pathway. The purpose of this study was to explore the effects of the NOTCH1-HEY1 pathway on the proliferation, invasion and metastasis of SACC cells. Our results verified that HEY1 is a specific molecular target of the NOTCH signaling pathway in SACC cells and that its expression in carcinoma is much higher than that in paracarcinoma tissues. The expression of NOTCH1 and HEY1 are positively correlated in the salivary adenoid cystic carcinoma tissues. NOTCH1 is significantly related to the activation of HEY1 in SACC, and that HEY1 reciprocally regulates NOTCH1 expression in SACC. HEY1 promotes cell proliferation and spheroid formation and inhibits cell apoptosis in vitro. In addition, HEY1 enhances the tumorigenicity of SACC in vivo. Furthermore, HEY1 increases cell invasion and metastasis by driving the expression of epithelial-mesenchymal transition (EMT)-related genes and MMPs. The results of this study indicate that the NOTCH1-HEY1 pathway is specifically upregulated in SACC and promotes cell proliferation, self-renewal, invasion, metastasis and the expression of EMT-related genes and MMPs. Our findings suggest that a NOTCH1-HEY1 pathway inhibitor might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.

Boulenophrys fengshunensis sp. nov. Wang, Zeng, Lyu & Wang Fengshun Horned Toad (in English) / Fēng Shùn Jiǎo Chán (丰NJDzdz in Chinese) Chresonymy: Megophrys sp 14 — Liu et al. 2018 Figures 7–8 Holotype. SYS a004744, adult male, collected by Jian Wang and Zhi-Tong Lyu on 13 May 2016 from Mt. Tongguzhang (24°10'31.12"N, 116°21'2.63"E; ca. 1500 m a.s.l.), Fengshun, Meizhou, Guangdong, China. Paratypes (N=7). Adult males, SYS a004724/ CIB118528, SYS a004725–4728, collected by Jian Wang and Zhi-Tong Lyu on 11 May 2016 from the same locality of the holotype. Adult females, SYS a005220–5221, collected by Jian Wang on 9 August 2016 from the same locality of the holotype. Etymology. The specific epithet “ fengshunensis ” refers to the type locality of the new species, the Fengshun County. Diagnosis. (1) Small body size, SVL 34.3–39.4 mm (36.9 ± 1.7, N = 6) in adult males and SVL 42.5–44.9 mm (N = 2) in adult females; (2) snout pointed in dorsal view; (3) tympanum moderate in size TD/ED 0.56–0.67, tubercles bearing spines on tips present on skin of temporal region including the tympanum; (4) vomerine ridge and vomerine teeth present; (5) margin of tongue rounded, not notched distally; (6) hindlimbs short, heels not meeting and tibio-tarsal articulation reaching forward to the region between tympanum and posterior corner of eye, TIB/SVL 0.37–0.43; (7) a subarticular tubercle present at the base of each fingers; (8) toes without lateral fringes and with rudiment of webbing; (9) distinct sparse enlarged tubercles on the surface of limbs, flanks, posterior part of belly and around the cloaca; (10) tips of the tubercles on ventral surface of thighs and around the cloaca bearing tiny spines; (11) single subgular vocal sac in males; (12) nuptial pads with well-developed villiform black nuptial spines on the dorsal surface of the first and second fingers in breeding males. Comparisons. Comparative data of Boulenophrys fengshunensis sp. nov. and the other recognized members of Boulenophrys are listed in Table 3. Boulenophrys fengshunensis sp. nov. can be distinguished from Boulenophrys puningensis sp. nov. and Boulenophrys hungtai sp. nov. having a tympanum with tubercles bearing spines on their tips (vs. tympanic region smooth without granules, tubercles or spines in Boulenophrys puningensis sp. nov. and Boulenophrys hungtai sp. nov.); the presence of both a vomerine ridge and vomerine teeth (vs. absence of vomerine ridge but with vomerine teeth present in Boulenophrys hungtai sp. nov.); tubercles on skin of the posterior part of belly without spines (vs. tubercles on skin of the posterior part of belly bearing spines on their tips in both Boulenophrys puningensis sp. nov. and Boulenophrys hungtai sp. nov.). With a smaller body size, SVL 34.3–39.4 mm in adult males and SVL 42.5–44.9 mm in adult females, Boulenophrys fengshunensis sp. nov. differs from the seven congeners whose SVL ≥ 50 mm in males or SVL ≥ 60 mm in females, including B. caudoprocta (81.3 mm in a single male), B. jingdongensis (53.0– 56.5 mm in males and 63.5 mm in a single female), B. liboensis (60.5–67.7 mm in males and 60.8–70.6 in females), B. mirabilis (55.8–61.4 mm in males and 68.5–74.8 mm in females), B. omeimontis (56.0– 59.5 mm in males and 68.0– 72.5 mm in females), B. sangzhiensis (54.7 mm in a single male), and B. shuichengensis (102.0– 118.3 mm in males and 99.8–115.6 mm in females). In having relatively shorter shanks with heels that do not meet when the flexed hind limbs are held at right angles to the body axis, Boulenophrys fengshunensis sp. nov. can be easily distinguished from the following 35 congeners, i.e. B. angka, B. anlongensis, B. baishanzuensis, B. baolongensis, B. binchuanensis, B. binlingensis, B. boettgeri, B. congjiangensis, B. cheni, B. chishuiensis, B. daiyunensis, B. jiangi, B. jinggangensis, B. jiulianensis, B. leishanensis, B. lini, B. minor, B. mufumontana, B. nanlingensis, B. palpebralespinosa, B. qianbeiensis, B. sanmingensis, B. shimentaina, B. shunhuangensis, B. spinata, B. tongboensis, B. tuberogranulatus, B. wuliangshanensis, B. wushanensis, B. xiangnanensis, B. xianjuensis, B. yaoshanensis, B.yangmingensis, B. yingdeensis and B. yunkaiensis, all of which have relatively longer shanks with the heels meeting or overlapping. By the presence of vomerine teeth, Boulenophrys fengshunensis sp. nov. differs from B. acuta, B. brachykolos, B. caobangensis, B. daoji, B. huangshanensis, B. kuatunensis, B. lishuiensis, B. lushuiensis, B. obesa, B. ombrophila, and B. wugongensis, all of which lack vomerine teeth. By having a rounded margin of the tongue that is not notched distally, Boulenophrys fengshunensis sp. nov. differs from B. hoanglienensis, B. insularis, which have a notched tongue. By the absence of lateral fringes on toes, Boulenophrys fengshunensis sp. nov. differs from B. rubrimera, which has narrow lateral fringes on toes. By the presence of rudimentary webbing on toes, Boulenophrys fengshunensis sp. nov. differs from B. daweimontis, B. fansipanensis, B. frigida, and B. rubrimera, all of which lack webbing on toes. Boulenophrys fengshunensi sp. nov. further differs from the remaining B. dongguanensis and B. nankunensis by having raised tubercles on the surface of posterior abdomen (vs. absence of such tubercles in both B. dongguanensis B. nankunensis); the presence of tubercles bearing spines on their tips on the temporal region including the tympanum (vs. temporal region lacking tubercles or spines in both B. dongguanensis and B. nankunensis). Description of holotype. Adult male. Small body size, SVL 37.4 mm; head width slightly larger than head length, HWD/HDL 1.17; snout pointed in dorsal view, projecting, sloping backward to mouth in profile, protruding well beyond margin of lower jaw; top of head flat; eyes moderate in size, ED 0.37 of HDL, pupil vertical, near diamond-shaped; nostril oblique-ovoid; canthus rostralis well developed; loreal region slightly oblique; internasal distance slightly larger than interorbital distance; tympanum moderate in size with an obvious margin, TD/ED 0.65; large ovoid choanae at base of maxilla; vomerine ridge and vomerine teeth present, maxillary teeth present; margin of tongue rounded, not notched distally; presence of single subgular vocal sac, and pair of slit-like openings at posterior of jaw. Forearm (i.e., radioulna) length 0.21 of SVL and hand 0.25 of SVL; hand without webbing, fingers without lateral fringes, relative finger length I = II Dorsal skin rough, granular, with sparse tubercles; skin of dorsal body and limbs bearing tiny spines; sparse large conical tubercles on flanks; single horn-like prominent tubercle on edge of upper eyelid; obvious supratympanic fold curving posteroventrally from posterior corner of eye to level above insertion of arm; dense tubercles on skin of upper lip, upper eyelid, mandibular articulation, loreal, temporal region including tympanum and surface around cloaca; tip of tubercles on skin of temporal region excluding tympanum bearing tiny spine; single discontinuous “X” shaped ridge and few elongated tubercles arranged in longitudinal rows on two sides at mid-dorsum; sparse tubercles on dorsal shank and thigh; ventral skin of throat, chest and anterior part of belly smooth; ventral skin of thighs and posterior part of belly bearing dense tubercles; surface around cloaca with dense tubercles bearing tiny spines; small pectoral gland closer to axilla; single femoral gland positioned on posterior surface of thigh at midpoint between knee and cloaca.. Coloration of holotype in life. Dorsal surface of body dark brown, with incomplete dark brown triangular marking between eyes. Two wide oblique black bands present on forearm. Dorsal surface of fingers and hindlimbs with dark grey transverse bands. Presence of vertical dark brown band below eye. Tip of tubercles on edge of upper eyelid greyish white. Supratympanic fold orangey brown. Ventral surface dark brown, black longitudinal band on surface of throat, posterior part of belly with irregular greyish white patches. Tubercles on ventral surface of posterior part of belly and thighs greyish white; spines on tips of tubercles on temporal region, ventral surface of thighs and around cloaca dark grey. Digits, inner and outer metacarpal tubercles, and inner metatarsal tubercle dark grey. Pectoral glands beige and femoral glands greyish white. Iris orangish brown. Coloration of holotype in preservative. Dorsal surface of body dark brown. Triangular marking between eyes, vertical dark brown band below eye and transverse bands on dorsal forearms and hind limbs become indistinct. Supratympanic fold greyish white. All bands and patterns on ventral surface no longer apparent. Irregular greyish white patches on posterior part of belly become dark grey. Variation. Mensural data of the type series are listed in Table 6. Most of the paratypes are similar to the holotype in morphology and color pattern, except for the following: dorsal surface and ventral surface dark brown, posterior part of belly with irregular greyish white patches, ventral surface of thighs dark grey, triangular marking between eyes is incomplete in the holotype (vs. dorsal surface beige and ventral surface light orange, posterior part of belly and ventral surface of thighs greyish white, triangular marking between eyes is complete in the female paratype SYS a005221 (Fig. 8); tibio-tarsal articulation reaching forward to middle of tympanum when hind limb stretched along body in the holotype (vs. tibio-tarsal articulation reaching forward to posterior margin of tympanum in the paratype SYS a004725; reaching forward to the region between tympanum and eye in the paratype SYS a004726). Females are distinctly larger than the males. Distribution and natural history. Currently, Boulenophrys fengshunensis sp. nov. is only known from its type locality, Mt. Tongguzhang of Fengshun. It inhabits flowing montane streams and the nearby forest floor and leaf litter at elevations between 800–1500 m. Boulenophrys fengshunensis sp. nov. is found to be sympatric with Pachytriton granulosus Chang, 1933 and Cynops glaucus Yuan, Jiang, Ding, Zhang & Che, 2013. Advertisement calls of males were heard during April and June. Males were found calling under the leaf litters around the flowing seeps. Tadpoles could be found in this period. Female specimens collected during August had immature eggs; males were not heard calling during this period, but sub-adults were observed.

Boulenophrys hungtai sp. nov. Wang, Zeng, Lyu, Xiao & Wang Hung-Ta Chang���s Horned Toad (in English) / Jiē Y��ng Ji��o Ch��n (DZffiDzdz in Chinese) Figures 5���6 Holotype. SYS a007578, adult male, collected by Jian Wang, Hong-Hui Chen and Hui-Wen Xiao on 5 January 2019 from Mt. Liwangzhang (23��38'6.42"N, 115��48'51.78"E; ca. 990 m a.s.l.), Jiexi, Jieyang, Guangdong, China. Paratypes (N=12). SYS a007575/ CIB118527, SYS a007576���7577, 7579���7582, 7594���7597, adult males, collected on 5���6 January 2019 from the same stream as the holotype at elevations between 950���1000 m. SYS a008576, adult male, collected by Jian Wang, Hong-Hui Chen, and Shuo Qi on 28 February 2021 from Shuangkeng Forestry Station (23��43'56.25"N, 116��21'26.4"E; ca. 550 m a.s.l.), Jiedong, Jieyang, Guangdong, China. Etymology. The specific epithet ��� hungtai ��� is a patronym in honor of Professor Hung-Ta Chang (=Hong-Da Zhang, �����ffl, 1914���2016), an outstanding botanist who was born in Jiexi. Diagnosis. (1) Small body size, SVL 25.8���33.3 mm (28.2 �� 2.3, N = 12) in adult males; (2) snout pointed in dorsal view; (3) tympanum moderate, TD/ED 0.52���0.61; (4) tympanic region smooth without granules or tubercles; (4) vomerine ridge and vomerine teeth absent; (5) margin of tongue rounded, not notched distally; (6) hindlimbs short, heels not meeting and tibio-tarsal articulation reaching forward to the region between tympanum and posterior corner of eye; (7) a subarticular tubercle present at the base of each fingers; (8) toes without lateral fringes and webbing; (9) distinct enlarged tubercles on the surface of limbs, flanks, chest, belly and around the cloaca; (10) tips of the tubercles on posterior abdomen, ventral thighs and around the cloaca bearing tiny spines; (11) single subgular vocal sac in males; (12) nuptial pads with villiform black nuptial spines on the dorsal surface of the first and second fingers in breeding males. Comparisons. Comparative data of Boulenophrys hungtai sp. nov. and the other recognized members of Boulenophrys are listed in Table 3. Boulenophrys hungtai sp. nov. can be easily distinguished from Boulenophrys puningensis sp. nov. by having a moderately sized tympanum, TD/ED 0.52���0.61 (vs. tympanum large, TD/ED 0.68���0.71); lacking both a vomerine ridge and vomerine teeth (vs. vomerine ridge and vomerine teeth present); lacking webbing on toes (vs. having rudimentary webbing on toes). Boulenophrys hungtai sp. nov. is strongly supported as the sister taxon to B. insularis, which is stated by Wang et al. (2017a) to be an endemic species of an offshore island in Shantou, China. Though the mean p -distance in the 16S gene is only 2.2 %, B. hungtai differs by having a snout pointed in dorsal view (vs. snout obtusely rounded in dorsal view); by the absence of vomerine ridge and vomerine teeth (vs. presence of strong vomerine ridge bearing vomerine teeth); margin of tongue not notched distally (vs. tongue notched distally); absence of webbing on toes (vs. having rudiment of webbing on toes); distinct enlarged tubercles on the surface of limbs, flanks, chest, belly and around the cloaca (vs. ventral surface smooth). Boulenophrys hungtai sp. nov. forms a clade with B. ombrophila (mean p -distance 4.9 % in the 16S gene), B. obesa (mean p -distance 3.9 % in the 16S gene), and B. cheni (mean p -distance 2.5 % in the 16S gene) though there is weak support for these relationships. However, the new species differs from the latter two congeners by having no webbing on toes (vs. having rudiment of webbing on toes in B. obesa); no vomerine ridge (vs. presence of vomerine ridges in B. obesa); a pointed snout in dorsal view (vs. snout rounded in dorsal view in B. ombrophila and B. obesa); distinct enlarged tubercles on the surface of limbs, flanks, chest, belly and around the cloaca (vs. ventral surface smooth in B. ombrophila and B. obesa); margin of tongue not notched distally, the shorter shanks with heels not meeting, absence of lateral fringes on toes (vs. tongue notched, heels meeting, presence of wide lateral fringes on toes in B. cheni). With a smaller body size, SVL 25.8���33.3 mm in adult males, Boulenophrys hungtai sp. nov. differs from the seven congeners whose SVL ��� 50 mm in males, including B. caudoprocta (81.3 mm in a single male), B. jingdongensis (53.0��� 56.5 mm in males), B. liboensis (60.5���67.7 mm in males), B. mirabilis (55.8���61.4 mm in males), B. omeimontis (56.0��� 59.5 mm in males), B. sangzhiensis (54.7 mm in a single male), and B. shuichengensis (102.0��� 118.3 mm in males). In having relatively shorter shanks with heels that do not meet when the flexed hind limbs are held at right angles to the body axis, Boulenophrys hungtai sp. nov. can be easily distinguished from the following 31 congeners, i.e. B. angka, B. anlongensis, B. baishanzuensis, B. baolongensis, B. binchuanensis, B. binlingensis, B. boettgeri, B. congjiangensis, B. chishuiensis, B. jiangi, B. jinggangensis, B. jiulianensis, B. leishanensis, B. lini, B. minor, B. mufumontana, B. nanlingensis, B. palpebralespinosa, B. qianbeiensis, B. sanmingensis, B. shimentaina, B. shunhuangensis, B. spinata, B. tongboensis, B. wuliangshanensis, B. wushanensis, B. xiangnanensis, B. xianjuensis, B. yaoshanensis, B. yangmingensis, B. yingdeensis and B. yunkaiensis, all of which have relatively longer shanks with the heels meeting or overlapping. By the absence of vomerine teeth, Boulenophrys hungtai sp. nov. differs from B. daiyunensis, B. daweimontis, B. dongguanensis, B. fansipanensis, B. frigida, B. hoanglienensis, B. nankunensis, and B. rubrimera, all of which have vomerine teeth. By having a rounded margin of the tongue that is not notched distally, Boulenophrys hungtai sp. nov. differs from B. huangshanensis, B. kuatunensis, and B. lushuiensis, all of which have notched tongues. By the absence of lateral fringes on toes, Boulenophrys hungtai sp. nov. differs from B. acuta, and B. daoji, all of which have lateral fringes on toes. By the absence of webbing on toes, Boulenophrys hungtai sp. nov. differs from B. brachykolos, B. caobangensis, B. tuberogranulatus, and B. wugongensis, all of which have rudimentary webbing on toes. Boulenophrys hungtai sp. nov. further differs from the remaining B. lishuiensis by having raised tubercles bearing spines on their tips on surface of posterior abdomen (vs. surface of belly smooth in B. lishuiensis). Description of holotype. Adult male. Body size small, SVL 28.7 mm. Head width slightly larger than head length, HDW/HDL 1.11; snout pointed in dorsal view, projecting, sloping backward to mouth in profile, protruding well beyond margin of lower jaw; top of head flat; eyes moderate in size, ED 0.34 of HDL, pupil vertical, near diamond-shaped; nostril oblique-ovoid; canthus rostralis well developed; loreal region slightly oblique; internasal distance slightly larger than interorbital distance; tympanum moderate in size with an obvious margin, TD/ED 0.58; large ovoid choanae at base of maxilla; vomerine ridges and vomerine teeth absent, maxillary teeth present; margin of tongue rounded, not notched distally; presence of a single subgular vocal sac, and pair of slit-like openings at posterior of jaw. Forearm (i.e., radioulna) length 0.22 of SVL and hand 0.23 of SVL; hand lacking webbing, fingers lacking lateral fringes, relative finger length I Coloration of holotype in life. Dorsal surface of body maroon, with an incomplete dark brown triangular marking between eyes. Flanks yellowish brown. Two wide oblique black bands present on forearm. Dorsal surface of fingers and hindlimbs with dark grey transverse bands. Presence of vertical dark brown band below eye. Tip of tubercle on the edge of upper eyelid white. Supratympanic fold greyish white with orange mottling. Ventral surface of throat, chest, and sides of belly dark brown with white and orange mottling, black longitudinal band on surface of throat; central and posterior part of belly white, with dark brown patches and orange mottling. Tubercles on ventral surface of chest, belly, and thighs greyish white; spines on tips of tubercles on surface of posterior abdomen, ventral surface of thighs and around cloaca dark grey. Digits, inner and outer metacarpal tubercles, and inner metatarsal tubercle greyish white. Pectoral glands and femoral glands beige. Iris reddish brown. Coloration of holotype in preservative. Maroon fades to dark brown dorsally. Coloration of flanks fades to greyish brown. Triangular marking between eyes and transverse bands on dorsal forearms and hind limbs become indistinct. Orange mottling on the supratympanic fold absent. Color of ventral surface fades; patterns of become indistinct; orange mottling on ventral skin absent. Pectoral glands and femoral glands greyish white. Variation. Mensural data of the type series are listed in Table 5. Most of the paratypes are similar to the holotype in morphology and color pattern, except for the following: coloration of dorsum is light brown and iris is reddish brown in the holotype (vs. dorsum beige and iris greyish white with irregular dark brown and light orange patterns in the paratype SYS a008576 (Fig. 6A���B); central and posterior part of belly white, with dark brown patches and orange mottling in the holotype (vs. ventral skin dark brown, without regular patches in the paratype SYS a008576 (Fig. 6C���D); larger body size in the paratypes SYS a007582 (SVL 32.7 mm) and SYS 008576 (SVL 33.3 mm); tibio-tarsal articulation reaching forward to middle of tympanum when hind limb stretched along body (vs. tibio-tarsal articulation reaching forward to posterior corner of eye in the paratypes SYS a007576, 7582, 7596, 7597, 8576). Distribution and natural history. Currently, Boulenophrys hungtai sp. nov. is known from Mt. Liwangzhang of Jiexi (800���1000 m a.s.l.) and Shuangkeng Forestry Station (500���800 m a.s.l.) of Jiedong, which are ca. 55 km from each other. This toad inhabits flowing montane streams and the nearby forest floor and leaf litter, and is sympatric with Pachytriton brevipes (Sauvage, 1876). Cynops orphicus Risch, 1983 can also be observed in the surrounding area. Advertisement calls of males from Mt. Liwangzhang were heard from November to the following January. A single male (SYS a008576) from Shuangkeng Forestry Station was noticed discontinuously calling on March after the heavy rain. Males were found calling under the leaf litter or in rock crevices in flowing streams., Published as part of Wang, Jian, Zeng, Zhao-Chi, Lyu, Zhi-Tong, Qi, Shuo, Liu, Zu-Yao, Chen, Hong-Hui, Lu, Yu-Hong, Xiao, Hui-Wen, Lin, Can-Rong, Chen, Kai & Wang, Ying-Yong, 2022, Description of three new Boulenophrys species from eastern Guangdong, China, emphasizing the urgency of ecological conservation in this region (Anura, Megophryidae), pp. 91-119 in Zootaxa 5099 (1) on pages 106-110, DOI: 10.11646/zootaxa.5099.1.4, http://zenodo.org/record/6036964, {"references":["Wang, J., Liu, Z. Y., Lyu, Z. T., Zeng, Z. C. & Wang, Y. Y. (2017 a) A new species of the genus Xenophrys (Amphibia: Anura: Megophryidae) from an offshore island in Guangdong Province, southeastern China. Zootaxa, 4324 (3), 541 - 556. https: // doi. org / 10.11646 / zootaxa. 4324.3.8","Sauvage, H. E. (1876) L'Institut. Journal des Academies et Societes Scientifiques de la France et de l'Etrangers, Paris, 4, 274 - 275.","Risch, J. P. (1983) Cynops orphicus, a new salamander from Guangdong Province, South China (Amphibia, Caudata, Salamandridae). Alytes, Paris, 2, 45 - 52."]}

Boulenophrys puningensis sp. nov. Wang, Zeng, Lyu, Xiao & Wang Puning Horned Toad (in English) / Pǔ Níng Jiǎo Chán (DṪDzdz in Chinese) Figures 3–4 Holotype. SYS a005770, adult male, collected by Jian Wang on 24April 2017 from Longkeng Village (23°7'54.07"N, 115°51'5.28"E; ca. 120 m a.s.l.), Daping Town, Puning, Jieyang, Guangdong, China. Paratypes (N=5). Adult male, SYS a006755/ CIB118526, collected by Jian Wang, Can-Rong Lin and Hui-Wen Xiao on 14 February 2018; adult males SYS a007649, 7650 and adult females SYS a007647, 7648, collected by Jian Wang, Can-Rong Lin and Hui-Wen Xiao on 18 March 2019, all from the same stream as the holotype at elevations between 250–300 m. Etymology. The specific epithet “ puningensis ” refers to the type locality of the new species in Puning. Three of the authors of this work (Jian Wang, Hui-Wen Xiao and Can-Rong Lin) chose this nomen in honor of their hometown. Diagnosis. (1) Small body size, SVL 31.7–34.6 mm (33.0 ± 1.3, N = 4) in adult males and SVL 37.8–38.3 mm (N = 2) in adult females; (2) snout rounded in dorsal view; (3) tympanum large, TD/ED 0.68–0.71; (4) tympanic region smooth without granules or tubercles; (5) vomerine ridge and vomerine teeth present; (6) margin of tongue rounded, not notched distally; (7) hindlimbs short, heels not meeting and tibio-tarsal articulation reaching forward to the region between tympanum and eye; (8) a subarticular tubercle present at the base of each fingers; (9) toes without lateral fringes and with rudiment of webbing; (10) distinct enlarged tubercles on the surface of limbs, flanks, chest, belly and around the cloaca; (11) tips of the enlarged tubercles on posterior abdomen, ventral thighs and around the cloaca bearing tiny spines; (12) single subgular vocal sac in males; (13) nuptial pads with villiform black nuptial spines on the dorsal surface of the first and second fingers in breeding males. Comparisons. Comparative data of Boulenophrys puningensis sp. nov. and the other recognized members of Boulenophrys are listed in Table 3. With a smaller body size, SVL 31.7–34.6 mm in adult males and SVL 37.8–38.3 mm in adult females, Boulenophrys puningensis sp. nov. differs from the eight congeners whose SVL ≥ 50 mm in adult males or females, including B. caudoprocta (81.3 mm in a single male), B. jingdongensis (53.0– 56.5 mm in males and 63.5 mm in a single female), B. liboensis (60.5–67.7 mm in males and 60.8–70.6 in females), B. mirabilis (55.8–61.4 mm in males and 68.5–74.8 mm in females), B. omeimontis (56.0– 59.5 mm in males and 68.0– 72.5 mm in females), B. sangzhiensis (54.7 mm in a single male), B. shuichengensis (102.0– 118.3 mm in males and 99.8–115.6 mm in females), and B. spinata (54.0–55.0 mm in females). Boulenophrys puningensis sp. nov. shows the least genetic divergence from B. kuatunensis (mean p -distances 5.3 % in the 16S gene) and B. daiyunensis (mean p -distances 6.2 % in the 16S gene). However, the new species distinctively differs from these species by having relatively shorter shanks with the heels not meeting when the flexed hindlimbs are held at right angles to the body axis (vs. heels meeting or overlapping in B. daiyunensis); having rudiment of webbing and no lateral fringes on toes (vs. lateral fringes narrow in B. daiyunensis; webbing absent in B. kuatunensis); having raised and enlarged tubercles with spines on their tips on surface of posterior abdomen, ventral thighs and around the cloaca (vs. such tubercles not enlarged and without spines in B. daiyunensis; ventral surface smooth in B. kuatunensis). Boulenophrys puningensis sp. nov. is morphologically most similar to B. brachykolos, which is restricted to Hong Kong and Shenzhen, China (Liu et al. 2018). The new species differs from B. brachykolos by having vomerine teeth (vs. absent in B. brachykolos); lacking spines on the surface of the tympanic region (vs. having dense tiny spines on the surface of the tympanic region in B. brachykolos); and having different relative finger length formula (I = II Banophrys puningensis sp. nov. vs. II B. brachykolos). In having relatively shorter shanks with heels that do not meet when the flexed hind limbs are held at right angles to the body axis, Boulenophrys puningensis sp. nov. can be easily distinguished from the following 32 congeners, i.e. B. angka, B. anlongensis, B. baishanzuensis, B. baolongensis, B. binchuanensis, B. binlingensis, B. boettgeri, B. congjiangensis, B. cheni, B. chishuiensis, B. jiangi, B. jinggangensis, B. jiulianensis, B. leishanensis, B. lini, B. minor, B. mufumontana, B. nanlingensis, B. palpebralespinosa, B. qianbeiensis, B. sanmingensis, B. shimentaina, B. shunhuangensis, B. tongboensis, B. wuliangshanensis, B. wushanensis, B. xiangnanensis, B. xianjuensis, B. yaoshanensis, B. yangmingensis, B. yingdeensis and B. yunkaiensis, all of which have relatively longer shanks with the heels meeting or overlapping. By the presence of vomerine teeth, Boulenophrys puningensis sp. nov. differs from B. acuta, B. caobangensis, B. daoji, B. huangshanensis, B. lishuiensis, B. lushuiensis, B. obesa, B. ombrophila, B. tuberogranulatus, and B. wugongensis, all of which lack vomerine teeth. By having a rounded tongue margin that is not notched distally, Boulenophrys puningensis sp. nov. differs from B. hoanglienensis, and B. insularis, all of which have notched tongues. By the absence of lateral fringes on toes, Boulenophrys puningensis sp. nov. differs from B. rubrimera, which has narrow lateral fringes on toes. By the presence of rudimentary webbing on the toes, Boulenophrys puningensis sp. nov. differs from B. daweimontis, B. fansipanensis, and B. frigida, all of which lack webbing on the toes. Boulenophrys puningensis sp. nov. further differs from the remaining B. dongguanensis and B. nankunensis by having raised tubercles bearing spines on the surface of the posterior abdomen, ventral thighs, and around the cloaca (vs. absence of such tubercles and spines in B. dongguanensis and B. nankunensis). Description of holotype. Adult male. Body size small, SVL 34.6 mm. Head width slightly larger than head length, HWD/HDL 1.03; snout rounded in dorsal view, projecting, sloping backward to mouth in profile, protruding well beyond margin of lower jaw; top of head flat; eyes moderate in size, ED 0.36 of HDL, pupil vertical, near diamond-shaped; nostril oblique-ovoid; canthus rostralis well developed; loreal region slightly oblique; internasal distance slightly larger than interorbital distance; tympanum large with an obvious margin, TD/ED 0.70; large ovoid choanae at base of maxilla; vomerine ridge and vomerine teeth present, maxillary teeth present; margin of tongue rounded, not notched distally; presence of single subgular vocal sac, and pair of slit-like openings at posterior of jaw. Forearm (i.e., radioulna) length 0.21 of SVL and hand 0.23 of SVL; hand without webbing, fingers without lateral fringes, relative finger length I = II Dorsal skin rough and granular, with raised conical tubercles; sparse large tubercles on flanks; single horn-like prominent tubercle on edge of upper eyelid; obvious supratympanic fold curving posteroventrally from posterior corner of eye to level above insertion of arm; tympanic region smooth without granules or tubercles; dense tubercles on skin of upper lip, upper eyelid, mandibular articulation, loreal, temporal region excluding tympanum and surface around cloaca; a single discontinuous “V” shaped ridge present on occipital region; dense tubercles on shanks and thighs; ventral surface with dense raised tubercles; tubercles on surface of posterior abdomen, ventral surface of thighs and around cloaca bearing tiny spines on their tips; small pectoral gland closer to axilla; single femoral gland positioned on posterior surface of thigh at midpoint between knee and cloaca. Coloration of holotype in life. Dorsal surface of body yellowish brown, with incomplete dark brown triangular marking between eyes. Two wide oblique black bands present on forearm. Dorsal surface of fingers and hindlimbs with dark grey transverse bands. Presence of vertical dark brown band below eye. Tubercles on edge of upper eyelid beige. Supratympanic fold light brown. Ventral surface dark grey, with black longitudinal band on surface of throat; surface of throat and chest mottled with orange patches. Tubercles on ventral surface of chest, belly, and thighs greyish white; spines on tips of tubercles on surface of posterior abdomen; ventral surface of thighs and around cloaca dark grey. Digits, inner and outer metacarpal tubercles and inner metatarsal tubercle greyish white. Pectoral glands and femoral glands beige, mottled with orange patches. Iris yellowish brown, with greyish white patches on upper and lower margin. Coloration of holotype in preservative. Yellowish brown fades to greyish brown dorsally. Color of the triangular marking between eyes, oblique bands on forearms, patterns on ventral surface faded. Orange patches on surface of throat, chest; color of pectoral glands and femoral glands faded. Variation. Mensural data of the type series are listed in Table 4. Most of the paratypes are similar to the holotype in morphology and color pattern, except for the following: dorsal surface of body yellowish brown in the holotype (vs. dorsal surface of body light brown in the paratypes SYS a007647 (Fig. 4C) and SYS a007648 (Fig. 4E); ventral surface dark grey with orange patches (vs. ventral surface lacking bright patches in the paratypes SYS a007649 (Fig. 4B), SYS a007647 (Fig. 4D) and SYS a007648 (Fig. 4F); iris yellowish brown, with greyish white patches on its upper and lower margin in the holotype (vs. iris grey with beige and dark mottling in the paratype SYS a007649 (Fig. 4A); tubercles on posterior part of abdomen of the paratype SYS a007648 (Fig. 4F) are weakly developed. Females are distinctly larger than the males. Distribution and natural history. Currently, Boulenophrys puningensis sp. nov. is only known from its type locality, Longkeng Village of Puning. It inhabits flowing montane streams and the nearby forest floor and leaf litter at elevations between 120– 300 m. Advertisement calls of males were heard from February until April. Males were found calling in rock crevices in the flowing streams. Tadpoles could be found in this period.

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N6-methyladenosine (m6A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m6A modifications in NPM1-mutated AML. In this study, the decreased m6A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m6A suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its m6A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m6A demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.

Background: Hyaluronan mediated motility receptor (also known as RHAMM) is another one of few defined hyaluronan receptors, play pivotal roles in cell growth. However, the functionof HMMR in lung adenocarcinoma remain unclear.Methods: HMMR expression was analyzed emoloyed the public databases, the prognosis of HMMR was analysis by prognoscan, KMplot and GEPIA databases. The GO and KEGG pathway was analysis by the DAVID and GSEA software. The correlation between the HMMR expression was analysis by the TIMER databases, the gene and protein networks was analysis by Genemania and STRING databases, the DNA methylation was analysis by the MethSurv and UALCAN databases. The expression of HMMR was analysis by IHC and qPCR, the function of HMMR on cell proliferation and migration was examine by the cell growth curve, clone information, transwell and wound healing assay.Results: in this study, we find that HMMR was elevated in LUAD and it’s highly expression associated with the poor prognosis and lymph node metastasis. Furthermore, the expression of HMMR was induced by hypoxia in LUAD. HMMR expression level not only positively correlation with the different immune cells, but also positively correlation with the expression of immune checkpoints related gene. Finally, depletion of HMMR significantly represses the cell growth and migration of NSCLC. We also found that the HOXB7/TMPO-AS1/Let-7b-5p axis mediated high expression of HMMR in NSCLC, depletion of TMPO-AS1 and over-expression the Let-7b-5p would result in decreased the expression of HMMR in NSCLC cells, the TMPO-AS1 was positively with the HMMR and negatively related to the Let-7b-5p in NSCLC. Overall, this study emphasized the significance of HOXB7/TMPO-AS1/Let-7b-5p axis mediated high expression of HMMR in cancer progression and Immune infiltration of LUAD.Conclusions: we demonstrated HMMR was elevated in LUAD and positively relation to poor prognosis. We find the hypoxia microenvironment and DNA hypomethylation able to up-regulation of the HMMR expression. Additionally, HMMR expression was positive with the diverse immune cell and immune regulator related gene in LUAD. Finally, we found that depletion of HMMR was inhibits the cell proliferation and migration ability of NSCLC cells. These findings suggest that HMMR could be served as a biomarker for prognosis and immune infiltration in LUAD.

BackgroundHyaluronan mediated motility receptor (also known as RHAMM) is another one of few defined hyaluronan receptors, play pivotal roles in cell growth. However, the relationships between HMMR and prognosis and tumor-infiltrating lymphocytes in lung adenocarcinoma remain unclear.MethodsHMMR expression was analyzed emoloyed the TIMER, GEPIA, UALCAN, CCLE databases, the prognosis of HMMR was analysis by prognoscan, KMplot and GEPIA databases. The GO and KEGG pathway was analysis by the DAVID and GSEA software. The correlation between the HMMR expression was analysis by the TIMER databases, the gene and protein networks was analysis by Genemania and STRING databases, the DNA methylation was analysis by the MethSurv and UALCAN databases, the gene mutation of HMMR was analysis by the cBioportal and COSMIC databases. The expression of HMMR was analysis by IHC and qPCR, the function of HMMR on cell proliferation and migration was examine by the cell growth curve, clone information, transwell and wound healing assay.ResultsIn this study, we find that HMMR was elevated in LUAD and it’s highly expression associated with the poor prognosis and lymph node metastasis. Furthermore, the expression of HMMR was induced by hypoxia in LUAD. HMMR expression level not only positively correlation with the different immune cells, but also positively correlation with the expression of immune checkpoints related gene, for instance, CD279, CD274, CTLA4, LAG3, PDCD1LG2, TIGIT and HAVCR2. Finally, depletion of HMMR significantly represses the cell growth and migration of NSCLC. Overall, this study emphasized the significance of HMMR in cancer progression and Immune infiltration of LUAD.ConclusionsWe demonstrated HMMR was elevated in LUAD and positively relation to poor prognosis. We find the hypoxia microenvironment and DNA hypomethylation able to up-regulation of the HMMR expression. Additionally, HMMR expression was positive with the diverse immune cell and immune regulator related gene in LUAD. Finally, we found that depletion of HMMR was inhibits the cell proliferation and migration ability of NSCLC cells. These findings suggest that HMMR could be served as a biomarker for prognosis and immune infiltration in LUAD.

Rui-huan Gan,1,* Li-song Lin,2,* Jing Xie,3–5,* Li Huang,2,4 Lin-can Ding,2 Bo-hua Su,2 Xian-e Peng,1,5 Da-li Zheng,4,5 You-guang Lu1,3 1Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, Fuzhou 350005, People’s Republic of China; 3Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350000, People’s Republic of China; 4Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350004, People’s Republic of China; 5Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350122, People’s Republic of China*These authors contributed equally to this workCorrespondence: You-guang LuDepartment of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, People’s Republic of ChinaTel +86 591 8373 6429Fax +86 591 8372 0599Email fjlyg63@fjmu.edu.cnXian-e PengDepartment of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou 350122, People’s Republic of ChinaTel +86 138 0951 6580Fax +86 591 8372 0599Email fmuxe@163.comPurpose: The Notch signaling pathway plays an oncogenic role in tongue squamous cell carcinoma. The aim of this study was to inhibit the proliferation and self-renewal of tongue cancer cells by applying Notch signaling pathway inhibitor FLI-06 (Selleck, USA) and to lay a foundation for the clinically targeted treatment of tongue cancer for the future.Methods: The mRNA expression level of Notch1 and the overall survival rate of patients with tongue cancer were examined by analyzing the TCGA database. Tongue cancer cells were treated with FLI-06. Cell proliferation, apoptosis, and stem cell self-renewal ability were tested in appropriate ways. A xenograft mouse model was established to observe tumor growth.Results: From the TCGA data, we demonstrated that patients with high expression of Notch1 had a poor prognosis. We observed that the Notch signaling pathway inhibitor FLI-06 can restrain the activation of the Notch signaling pathway, decrease cell proliferation and induce cell apoptosis in vitro. The xenograft experiment indicated that intraperitoneal injection of FLI-06 inhibited tumor growth and increased cell apoptosis. FLI-06 suppressed both the mRNA and protein expression of Notch receptor and Notch targeted genes. We also observed that FLI-06 suppressed the proliferation of tongue cancer stem cells.Conclusion: FLI-06 can block the proliferation and self-renewal of tongue cancer cells. It is inferred that this compound, which inhibits the Notch signaling pathway, may serve as a potential targeted drug for the treatment of tongue cancer in the clinic.Keywords: tongue cancer, Notch signaling pathway, Notch inhibitor, cancer stem cells

Purpose The Notch signaling pathway plays an oncogenic role in tongue squamous cell carcinoma. The aim of this study was to inhibit the proliferation and self-renewal of tongue cancer cells by applying Notch signaling pathway inhibitor FLI-06 (Selleck, USA) and to lay a foundation for the clinically targeted treatment of tongue cancer for the future. Methods The mRNA expression level of Notch1 and the overall survival rate of patients with tongue cancer were examined by analyzing the TCGA database. Tongue cancer cells were treated with FLI-06. Cell proliferation, apoptosis, and stem cell self-renewal ability were tested in appropriate ways. A xenograft mouse model was established to observe tumor growth. Results From the TCGA data, we demonstrated that patients with high expression of Notch1 had a poor prognosis. We observed that the Notch signaling pathway inhibitor FLI-06 can restrain the activation of the Notch signaling pathway, decrease cell proliferation and induce cell apoptosis in vitro. The xenograft experiment indicated that intraperitoneal injection of FLI-06 inhibited tumor growth and increased cell apoptosis. FLI-06 suppressed both the mRNA and protein expression of Notch receptor and Notch targeted genes. We also observed that FLI-06 suppressed the proliferation of tongue cancer stem cells. Conclusion FLI-06 can block the proliferation and self-renewal of tongue cancer cells. It is inferred that this compound, which inhibits the Notch signaling pathway, may serve as a potential targeted drug for the treatment of tongue cancer in the clinic.

El estudio expuso que los obreros municipales inicialmente eran considerados como parte de la carrera administrativa a consecuencia del Caso Huatuco, siendo esto solucionado por el TC a través de una sentencia aclaratoria para pasar a pertenecer al D.L. N°728. Sin embargo, pese a los beneficios que otorga tal decreto a favor del obrero, la Municipalidad aún los sigue contratando bajo la locación de servicios. Propuso como objetivo determinar cómo el contrato por locación de servicios vulnera los derechos fundamentales de los obreros de la Municipalidad Provincial de San Martín, 2018-2020. La investigación tuvo un enfoque mixto de tipo aplicada, nivel descriptivo y diseño correlacional - no experimental, la población se ha conformado por todos los contratos del periodo 2018-2020 y especialistas en materia laboral; la muestra por 33 contratos y 5 especialistas, utilizando como técnicas el análisis documental y entrevista, y como instrumentos la guía de análisis documental y guía de entrevista. Resultados: El contrato de locación de servicios fue desnaturalizado en los años 2018-2019, el derecho fundamental vulnerado en mayor medida fue seguridad social y existe relación entre el contrato por locación con la vulneración de los derechos fundamentales pues la significancia fue 035. Conclusión: El contrato de locación de servicios vulnera los derechos fundamentales al afectarles la seguridad social y estabilidad laboral. Recomendación: Al intendente regional de SUNAFIL-San Martín, programar y ejecutar actividades o talleres orientados a informar a las entidades e instituciones públicas de diferentes niveles de gobierno sobre el respeto de los derechos fundamentales. The study exposed that the municipal workers were initially considered as part of the administrative career as a result of the Huatuco Case, being this solved by the Constitutional Court through a clarifying sentence to become part of the D.L. N°728. However, in spite of the benefits granted by such decree in favor of the worker, the Municipality still continues to hire them under a service contract. It proposed as an objective to determine how the service contract violates the fundamental rights of the workers of the Provincial Municipality of San Martin, 2018-2020. The research had a mixed approach of applied type, descriptive level and correlational - non-experimental design, the population was made up of all the contracts of the period 2018-2020 and specialists in labor matters; the sample consisted of 33 contracts and 5 specialists, using as techniques the documentary analysis and interview, and as instruments the documentary analysis guide and interview guide. Results: The service contract was denaturalized in 2018-2019, the most violated fundamental right was social security and there is a relationship between the service contract and the violation of fundamental rights since the significance was 035. Conclusion: The service contract violates fundamental rights by affecting their social security and work stability. Recommendation: To the regional intendant of SUNAFIL-San Martín, program and implement activities or workshops aimed at informing public entities and institutions at different levels of government about respect for fundamental rights.