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Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.

Evidence before this study We did a systematic review of studies that focused on the angiotensin-converting enzyme 2 (ACE2) expression after targeted treatments in patients with primary aldosteronism (PA), along with comparisons to patients with essential hypertension (EH). ACE2 is a component of the counter-regulatory renin–angiotensin system, which has important roles in various cardiovascular events. Major electronic databases (including, but not limited to, PubMed, Embase, medRXIV, and Web of Science, without language restriction) were searched for related articles published by Nov, 2021. This search was complemented by interrogation of grey literature and manual searching of reference lists by abstracts and titles to identify relevant studies. The review was done in accordance with PRISMA guidelines. We identified no prospective or retrospective cohort report that specifically focused on PA patients and changes of their ACE2 levels with treatments as well as cardiovascular events. It was reported that the imbalance of ACE2 can be shed by both metalloprotease 17 (ADAM17) and type II transmembrane serine protease (TMPRSS2). Added value of this study This study provides the first epidemiological analysis of the plasma ACE2 concentrations ([pACE2]) in incident PA patients from a multi-center inception registration, and patients’ blood pressure readings were followed regularly before and after treatments. We found that the PA, together with EH, patients had similarly higher pACE2 levels and cellular TMPRSS2 from peripheral blood mononuclear cells (PBMCs), in comparison to those of normotensive controls. Such higher [pACE2] in PA patients are concordant to the known association of increased [pACE2] and worse cardiovascular disease outcomes and metabolic abnormalities. Additionally, we revealed unprecedentedly that adrenalectomy could attenuate [pACE2] and TMPRSS2 expression in PBMCs among unilateral PA (uPA) patients, regardless of their hypertension remission. We found such attenuation was not observed in those treated with mineralocorticoid receptor antagonist (MRA), in a large combined cohort of uPA and bilateral PA patients. Pre-treated PA, MRA-treated PA and EH patients have higher [pACE2] than those of the PA patients who had complete hypertension-remission and those normotensive controls. Implications of all the available evidence The known association between SARS-CoV-2 and ACE2 implicates a probable link of hypertension in COVID-19 pathogenesis. Increased pACE2 concentrations and expression of TMPRSS2 in PBMCs of PA patients could indicate augmented risks of SARS-CoV-2 infection in PA and hypertensive patients. Our study found that unilateral PA patients had attenuated pACE2 and TMPRSS2 levels after adrenalectomy, regardless of hypertension-remission or not. High pACE2 in PA was associated with all-cause mortality and incident cardiovascular events after targeted treatments. No similar reduction of pACE2 was noticed after MRA treatment, implicating the importance of early PA diagnosis and advising adrenalectomy as an optimal treatment for uPA patients. Elevated [pACE2] (> 23ng/ml) after targeted treatments was associated the risk of mortality and incident cardiovascular events.

Lobellina gladius sp. nov. Figures 2, 4, 6, 10–14, 16, 18, 20, Tables 4–5 Type material. Holotype: male, China, Hunan, Xinning county, Langshan National Geopark. Coordinates: 26.273767N, 110.732951E, alt. 770m, in forest of bamboo, leg. Ji-Gang Jiang, Cheng Jiang, Li-Ping Duan, 29.iv.2018. Paratypes: 5 females and 2 juveniles, about 30 specimens in alcohol, the same data as holotype, collection number as J2018042904. One female, subadult, and 4 juvenile, Guangxi, Ziyuan county, Langshan National Geopark. Coordinates: 26.274416N, 110.732011E, alt. 685m, in forest of bamboo, leg. Ji-Gang Jiang, Cheng Jiang, Li-Ping Duan, 29.iv.2018 (J2018042903). Female and male, Guangxi, Ziyuan county, Langshan National Geopark. Coordinates: 26.276824N, 110.730528E, alt. 510m, nearby the entrance of the Park, leg. Ji-Gang Jiang, Cheng Jiang, Li-Ping Duan, 29.iv.2018 (J2018042901). One male, Hunan, Xinning county, Shunhuangshang National Nature Reserve, Coordinates: 26.450028N, 111.014716E, alt. 930m, in forest, leg. Ji-Gang Jiang, Cheng Jiang, Li-Ping Duan, 1.v.2018 (J2018050102). Type materials are housed in the Key Laboratory of Zoology, Hunan University of Arts and Science (HUAS), Changde, Hunan Province, China. Diagnosis. Three pigmented eyes on head, mandible with six teeth, cephalic chaeta O present and including in tubercle Fr, cephalic tubercle Di not fused, non-cross type chaetotaxy on posterior area of head, cephalic lateral tubercle Dl, L and So independent respectively, Ant. I with 9 chaetae, Th. I with 4+4 tubercles, VT with 6–8 (usually 7) chaetae. Description. Body length: holotype, male, 4.0 mm. Usually, males: 4.0– 4.4 mm, females: 3.5–4.8 mm, juveniles: 1.5–3.5 mm. Body color. Red while living (Fig. 2) and white in alcohol (Fig. 4). Chaetal morphology (Fig. 6). Dorsal ordinary chaetae of four types: Ml, Mc, Mcc and me. Macrochaetae Ml long, sheathed, smooth and with blunt tip, gladius shaped (Fig. 6j), some Ml not sheathed and with pointed tip, such as F chaetae on head (Fig.6k) and macrochaetae on Abd. VI (Fig. 6l). Macrochaetae Mc similar to Ml morphologically, but shorter (Fig. 6 m–n). Macrochaetae Mcc morphologically similar to Mc and shorter than Mc (Fig. 6o). Mesochaetae similar to ventral chaetae, thin, smooth, and pointed, with various length (Fig. 6 p–r, t). S-chaetae on terga thin, smooth, equal to Mc and longer than Mcc (Fig. 6s). Head (Table 4, Fig. 10). Eyes 3+3, black (Fig. 11). Antenna 4-segmented (Fig. 16). Ant. I with 9 Chaetae. Ant. II with 9–11 Chaetae. Ant. III dorsally fused to Ant. IV. Two guard chaetae sgd and sgv present. Two short rods exposed in separate pit. Ant. IV dorsally with 8 thickened and curved sensilla, apical bulb trilobed. sensory organite (or) present. Ventral chaetotaxy of Ant. IV: ap with 7 bs and 3 miA, ca with 3 bs and 1 miA, cm with 2 bs and 2 miA, cp with 1 miA. On ventral side of Ant. III, Vi, Vc, Ve respectively with 3, 5, 4 chaetae. Buccal cone weakly developed, labrum truncated, chaetal formula as 0/2, 2. Mandible with four apical teeth, one curved middle tooth and one basal tooth (Fig. 12). Maxilla crochet form (Fig. 13). Labium with 11 chaetae and no x (Fig.18). Group Vi with 6+6 chaetae (Fig.18). Groups Vea, Vem and Vep with 5, 2 and 2 chaetae respectively. Dorsal chaetotaxy of head as in Table 4. and Fig. 10. Dorsal central area with 6 separate tubercles: 1 tubercle Cl, 2 An, 1 Fr and 2 Oc. Dorsal posterior area with 4 separate tubercles: 2 Di and 2 De. Line of chaetae Di2–De2 not crosses line Di1– De1 on head (non-cross type, Deharveng, 1983). Dorsal lateral area with 3 separate tubercles: Dl, L and So. Thorax (Table 5 & Fig. 10). Th. I with 4+4 tubercles (Di, De, Dl and L). Th. II and Th. III with 4+4 tubercles respectively. Chaetotaxy of thorax and legs as in Table 2. Unguis with a basal inner tooth, unguiculus absent. Chaeta M present on tibiotarsus. Abdomen (Table 5 & Fig. 10). Abd.I–IV respectively with 4+4 tubercles. Abd. V dorsally with 3+3 tubercles, two tubercles Di separate from each other, tubercle De separate from Dl, tubercle L present, on ventral side. Abd. VI with 1 tubercle on each side. VT with 7+7 chaetae, sometimes 6+6 or 8+8. Furcular remnant with 4 chaetae (Fig. 20). Etymology. The name of the species derives from the “ gladius ” shape of its macrochaetae. Remarks. The new species can be separated from known species by the following characters: Th. I with 4+4 tubercles; tubercle Di with 3 chaetae on Abd. I–III respectively, VT with 6–8 chaetae (usually 7); non-crossed type chaetae on cephalic posterior area. Including the new species, sixteen species of genus Lobellina are known worldwide. Seven of them have O chaeta on cephalic tubercle Fr, of which, 4 with chaeta O free from the tubercle, and three species, i.e. L. nanjingensis, L.fusa and L. gladius sp. nov. with chaeta O included in tubercle Fr. The new species can be easily differentiated from the other two species of the last group by the following key.

Crossodonthina langshanensis sp. nov. Figures 1, 3, 5, 7–9, 15, 17, 19, Tables 1–3 Type material. Holotype: female, China, Hunan, Xinning county, Langshan National Geopark. Coordinates: 26.277054N, 110.730618E, alt. 520m, in forest, leg. Ji-Gang Jiang, Cheng Jiang, Li-Ping Duan, 30.iv.2018 (J2018043002). Paratypes: 2 females, China, Hunan, Xinning county, Langshan National Geopark. Coordinates: 26.276580N, 110.729240E, alt. 470m, in forest, leg. Ji-Gang Jiang, Cheng Jiang, Li-Ping Duan, 30.iv.2018 (J2018043003); 3 juvenile, Guangxi, Ziyuan county, Langshan National Geopark, Coordinates: 26.276824N, 110.730528E, alt. 510m, nearby the entrance of the Park, leg. Ji-Gang Jiang, Cheng Jiang, Li-Ping Duan, 29.iv.2018 (J2018042901). Type materials are housed in the Key Laboratory of Zoology, Hunan University of Arts and Science (HUAS), Changde, Hunan Province, China. Othermaterial. 2females, China, Hunan, Xinningcounty,LangshanNationalGeopark. Coordinates: 26.276986N, 110.736902E, alt. 527m, in forest, leg. Ji-Gang Jiang, Ya-Hui Hu, Wei Hu, 25.vii.2019 (J2019072502). Diagnosis. 2+2 black eyes on head; labral chaetotaxy as 2/4, 2; cephalic chaeta O present; tubercle Dl on Th. II with 3 chaetae (2+s); mandible with 2 prominent basal teeth and 2 fringed rami of quite different sizes; maxilla with marginal filaments on outer lamella; tubercle Di on Abd. V separated; Description. Body length: holotype 2.4 mm, two paratypes 2.3–2.4 mm, three juveniles 1.0– 1.1mm. Color. Red while living (Fig. 1) and white in alcohol (Fig. 3). Chaetal morphology (Fig. 5). Dorsal ordinary chaetae of five types: Ml (Fig. 5 a–b), Mc (Fig. 5c), Mcc (Fig. 5d), me (Fig. 5 e–f) and mi (Fig. 5h). S-chaetae on terga thin, smooth, shorter than Ml and longer than Mc (Fig. 5g). Head. Eyes 2+2, black. Antenna 4-segmented (Fig. 15). Ant. I with 9 chaetae. Ant. II with 11 chaetae. Ant. III and IV dorsally fused. Dorsal sensory guard chaeta (sgd) on Ant. III not migrated distally, two rods exposed in separate pit. Ant. IV dorsally with 8 slightly thickened and blunt sensilla, apical bulb trilobed. sensory organite (or) present. Ventral chaetotaxy of Ant. IV: ap with 8 bs and 3 miA, ca with 2 bs and 3 miA, cm with 3 bs and 1 miA, cp without miA. On ventral side of Ant. III, Vi, Vc, Ve with 3, 4, 4 chaetae respectively. Buccal cone moderately developed. Labrum truncated, chaetal formula as 2/4, 2 (adult) or 4/4, 2 (juvenile). Labium with 11 chaetae and 2 x (Fig. 17). Mandible complicated (Fig. 8), consisting of 2 rami, 2 definite teeth and some spine-like chaetae. Small ramus consisting of one spine-like chaeta and 7–8 slender chaetae, large ramus developed, with 2 rows of marginal chaetae, 4 strong and spine-like chaetae, marginal chaetae on ramus simple, bifurcated or tri-furcated, about 9-12 spine-like chaetae present on the central area of basal part of the large ramus. The longer ramus about 10 times as long as the small one. Maxilla consisting of two lamellae, the inner lamella much shorter than the outer one, with two minute apical teeth, the outer one with marginal filaments on inner side (Fig. 9). On ventral side of head, group Vi with 6+6 chaetae, groups Vea, Vem and Vep with 4, 3 and 2 chaetae respectively. Dorsal tubercles and chaetotaxy of head as in Tab. 1. and Fig. 7. Dorsal central area with 6 separate tubercles; one tubercle Cl, 2 An, one Fr and 2 Oc, chaeta O absent. Dorsal posterior area with 4 separate tubercles: 2 Di and 2 De. Line of chaetae Di2–De2 crosses line Di1– De1 on head (cross-type, Deharveng 1983). Dorsal lateral area with 1 fused tubercle (Dl+L+So). Thorax (Table 2 & Fig. 7). Th. I with 3+3 tubercles (Di, De, Dl). Th. II and Th. III with 4+4 tubercles respectively, ms on tubercle Dl of Th. II present (its form as in Fig. 5i). Chaetotaxy of thorax and legs as in Table 2. Unguis with a basal inner tooth, unguiculus absent. Chaeta M present on tibiotarsus. Abdomen (Table 2 & Fig. 7). Abd. I–IV respectively with 4+4 tubercles. Abd. V dorsally with 2+2 tubercles, two tubercles Di close to each other, but not fused together, tubercle De fused to Dl, tubercle L present on ventral side. Abd. VI with 1 tubercle on each side, no cryptopygy. VT with 4+4 chaetae. Furcular remnant with 3-4 chaetae (Fig. 19). Etymology. The name of the species derives from the locality where it was collected. Ecology. Among decayed leaves in forest. Remarks. So far, 12 species of genus Crossodonthina were reported worldwide, 11 species were from Asia and only one from Oceania, seven species were reported from China (Jiang & Zhang, 2012). In genus Crossodonthina, three species have 2+2 eyes, they are C. bidentata, C. hainana and C. montana, the new species is the fourth one with 2+2 eyes. In general appearance, Crossodonthina langshanensis sp. nov. strongly resembles Chinese species C. bidentata (Luo & Chen, 2009) in the number of mandible basal teeth, the arrangement of body tubercles, the presence of chaeta O of tubercle Fr, the number of chaetae on VT, and the presence of inner tooth on claw. However, these species can be distinguished by the following features: structure of mandible (in C. langshanensis with two fringed rami, in C. bidentata with three fringed rami), structure of maxilla (in C. langshanensis outer lamella fringed, in C. bidentate outer lamella not fringed), whether the tubercle Di fused on Abd. V or not (in C. langshanensis not fused, in C. bidentate fused), the labral chaeta formula (in C. langshanensis 2/4, 2, in C. bidentata 2/5, 2), number of chaetae (besides of ms) on tubercles Dl of Th. II (in C. langshanensis 3, in C. bidentata 4). The new species is also similar to the 2+2-eyed Chinese species C. montana (Lee & Kim, 1990) and C. hainana (Xiong et al., 2005) in the arrangement of body tubercles, the presence of chaeta O of tubercle Fr, the separate tubercle Di of Abd. V and the presence of 4+4 chaetae on VT. The new species can be separated from the above species by the characters listed in Table 3., Published as part of Hu, Ya-Hui, Jiang, Cheng & Jiang, Ji-Gang, 2019, Two new species of Lobellini from Central-South China (Collembola Neanuridae), pp. 77-89 in Zootaxa 4712 (1) on pages 78-82, DOI: 10.11646/zootaxa.4712.1.5, http://zenodo.org/record/3586860, {"references":["Deharveng, L. (1983) Morphologie evolutive des Collemboles Neanurinae en particulier de la lignee Neanurinae. Travaux de Laboratoire d'Ecobiologie des Arthropodes Edaphiques, Toulouse, 4, 1 - 63.","Luo, Y. Z. & Chen, J. X. (2009) A new species of the genus Crossodonthina (Collembola: Neanuridae: Lobellini) from China. Zootaxa, 2121 (1), 57 - 63. https: // doi. org / 10.11646 / zootaxa. 2121.1.6","Lee, B. H. & Kim, J. T. (1990) Systematic studies on Chinese Collembola (Insecta) II. Five new species and two new records from Taiwan in the family Neanuridae. The Korean Journal of Systematic Zoology, 6 (2), 235 - 250.","Xiong, Y., Chen, L. Q. & Yin, W. Y. (2005) Two new species of the genus Crossodonthina (Collembola, Neanuridae) from China. Acta Zootaxonomica Sinica, 30 (3), 545 - 548."]}