mteb/CovidQA huggingface dataset:
attributed to parvovirus B19-induced vasculitis (18) . In our patient, there was no sign of aplasia or any neuroradiological finding of parvovirus B19 infection. Finally, acute encephalitis has been observed in SCD patients in the context of arterial hypoxemia from fat embolism, pulmonary embolism, sudden anemia, or acute chest syndrome due to pneumonia (19) . This was ruled out as the patient did not have clinical or radiological signs of acute chest syndrome or embolism and there was no arterial hypoxemia.
Acute hemorrhagic encephalomyelitis has been described in pediatric patients following ADEM or ADEM-like episodes (20, 21) . AHEM is the most plausible diagnosis in our patients based on the clinical and radiological presentation, the preceding ADEM-like episode, and the exclusion of other etiologies of acute encephalopathy. Other patients with AHEM have been described in the SCD context (7, 19) . Many treatment options have been used to treat AHEM; of these, IV steroids have been associated with survival following aggressive, high-dose corticosteroid therapy (5) (6) (7) (8) (9) (22) (23) (24) (25) .
Autosomal dominant mutations (with incomplete penetrance) in RANBP2 have been associated with susceptibility to infectioninduced necrotizing encephalopathy (26, 27) . Previously healthy patients with pathogenic mutations in RANBP2 can present acutely with encephalopathy and convulsions in the context of an infection, with brain imaging revealing involvement of the brainstem, thalami, putamina, cerebellum and external capsules, and claustrum (10) . Our patient has a similar presentation and imaging features as infection-induced necrotizing encephalopathy, including bilateral thalamic involvement. The rare heterozygous previously unreported variant we identified in RANBP2 affects a very conserved aminoacid and is predicted deleterious using in silico tools (a prediction tool performing a fast bioinformatics analysis which can predict the pathogenicity of a variant based on the change to an amino acid). It is possible that this variant is pathogenic and responsible for the clinical
phenotype. There is an overlap between the diagnostic criteria of AHEM and those of acute hemorrhagic encephalopathy (25, 26) making possible that both entities might be part of the same pathophysiological continuum. RANBP2 is a protein playing an important role in the energy homeostasis of neuronal cells (28) . Hence, RANBP2 dysfunction might make neuronal cells much vulnerable to energy failure and necrosis when exposed to inflammatory or other stresses, such as those implicated in AHEM.
This study was carried out in accordance with the recommendations of our institutional ethic committee. Written informed consent was obtained from all the participants for the publication.

All authors participated in gathering the data, designing the article, and discussing and editing the manuscript.

aCKNoWleDgMeNts We thank Dr. S. Abish, Dr. N. Ahmed, and Mrs. C. Guiraut for their help. We are grateful to the Hoppenheim Fund from the Montreal Children Hospital Foundation.

The first author of this article received a scholarship from the Hoppenheim Fund, Montreal Children Hospital Foundation (2016). This work was supported by grants from Heart and Stroke Foundation of Canada (grant number: G-14-0005756), and Foundation of Stars.
New Isoxazolidine-Conjugates of Quinazolinones—Synthesis, Antiviral and Cytostatic Activity

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273226/

SHA: eefddcf51f8426ecaa9e3ace144dadfb34a74cf5

Authors: Piotrowska, Dorota G.; Andrei, Graciela; Schols, Dominique; Snoeck, Robert; Grabkowska-Drużyc, Magdalena
Date: 2016-07-22
DOI: 10.3390/molecules21070959
License: cc-by
Abstract: A novel series of (3-diethoxyphosphoryl)isoxazolidines substituted at C5 with various quinazolinones have been synthesized by the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N3-substitued 2-vinyl-3H-quinazolin-4-ones. All isoxazolidines were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-11f/cis-11f (90:10), trans-11h and trans-11i/cis-11i (97:3) showed weak activity (EC(50) = 6.84, 15.29 and 9.44 μM) toward VZV (TK(+) strain) which was only one order of magnitude lower than that of acyclovir used as a reference drug. Phosphonates trans-11b/cis-11b (90:10), trans-11c, trans-11e/cis-11e (90:10) and trans-11g appeared slightly active toward cytomegalovirus (EC(50) = 27–45 μM). Compounds containing benzyl substituents at N3 in the quinazolinone skeleton exhibited slight antiproliferative activity towards the tested immortalized cells with IC(50) in the 21–102 μM range.
Text: Nitrogen-containing heterocycles form the core of natural products (e.g., alkaloids) and they are also present in many pharmacophores as well as in numerous marketed drugs. Among them, quinazolines and quinazolinones have drawn special attention due to the broad spectrum of biological activities of their derivatives, including sedative [1] [2] [3] , anticancer [4] [5] [6] [7] , antiviral [8] [9] [10] [11] [12] , antibacterial [13] [14] [15] , antifungal [15, 16] , anti-inflamatory [15, [17] [18] [19] and antifibrotic [20, 21] activities. Several reviews focused on the synthetic strategies and biological activities of these compounds have been published [22] [23] [24] [25] [26] [27] [28] [29] . The significant impact of various functional groups installed into quinazoline/quinazolinone frameworks on pharmacological properties have been proven.
In the last decades several compounds containing the quinazolin-4-one framework, which exhibited promising anticancer as well as antiviral properties, have been obtained ( Figure 1 ). Furthermore, some biologically active substituted quinazolin-4(3H)-ones were isolated from various fungi and bacteria species. For example, 2-(4-hydroxybenzyl)quinazolin-4(3H)-one (1) was found in an entomopathogenic fungus Isaria farinosa and its strong inhibitory properties on the replication of tobacco mosaic virus (TMV) [30] were recognised, whereas its 2-(4-hydroxybenzoyl) analogue 2 present in fungus from Penicillium genus appeared only slightly active toward TMV [30] . Moreover, compound 1 exhibited significant cytotoxicity toward various cancer cell lines [31, 32] . Quinazolinone 3 isolated from Streptomyces sp. appeared cytotoxic against Vero cells [33] . Very recently synthetic pyridine-containing analogue 4 and its 3-substituted derivatives 5 and 6 have been obtained and their slight activity
against influenza A virus was revealed [34] . On the other hand, various 2,3-disubstitued quinazolin-4(3H)-ones, including compounds 7-10, have been found to possess antitumor activity [35] . slight activity against influenza A virus was revealed [34] . On the other hand, various 2,3-disubstitued quinazolin-4(3H)-ones, including compounds 7-10, have been found to possess antitumor activity [35] . In continuation of our studies on antiviral and cytostatic activity of isoxazolidine analogues of C-nucleoside analogues, we designed a new series of compounds of the general formula 11 containing a substituted quinazolinone moiety as a false nucleobase at C5 in the isoxazolidine ring and the diethoxyphosphoryl function attached at C3. Our synthetic strategy to compounds trans-11/cis-11 relies on the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone 12 [36] with 2-vinyl-3H-quinazolin-4-ones 13 substituted at N3 (Scheme 1). Scheme 1. Retrosynthesis of (isoxazolidinyl)
phosphonates trans-11/cis-11.
2-Vinyl-3H-quinazolin-4-ones 13 modified at N3 with substituted benzyl groups were synthesized from commercially available 2-aminobenzamide (14) by acylation with 3-chloropropionyl chloride followed by cyclization and dehydrohalogenation to prepare 2-vinyl-3Hquinazolin-4-one (13a) as a key intermediate [37] and a subsequent reaction with substituted benzyl bromides 13b-i [38] (Scheme 2). Moreover, compounds 13j (R = Me) and 13k (R = Et) were also obtained with intention to determine the influence of the benzyl substituent on biological activity of the designed isoxazolidines trans-11/cis-11. In the 1 H-NMR spectra of compounds 13a-k characteristic signals for vinyl protons were observed in the 6.94-5.59 ppm (three doublets of doublets). In continuation of our studies on antiviral and cytostatic activity of isoxazolidine analogues of C-nucleoside analogues, we designed a new series of compounds of the general formula 11 containing a substituted quinazolinone moiety as a false
nucleobase at C5 in the isoxazolidine ring and the diethoxyphosphoryl function attached at C3. Our synthetic strategy to compounds trans-11/cis-11 relies on the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone 12 [36] with 2-vinyl-3H-quinazolin-4-ones 13 substituted at N3 (Scheme 1). slight activity against influenza A virus was revealed [34] . On the other hand, various 2,3-disubstitued quinazolin-4(3H)-ones, including compounds 7-10, have been found to possess antitumor activity [35] . In continuation of our studies on antiviral and cytostatic activity of isoxazolidine analogues of C-nucleoside analogues, we designed a new series of compounds of the general formula 11 containing a substituted quinazolinone moiety as a false nucleobase at C5 in the isoxazolidine ring and the diethoxyphosphoryl function attached at C3. Our synthetic strategy to compounds trans-11/cis-11 relies on the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone 12 [36] with
2-vinyl-3H-quinazolin-4-ones 13 substituted at N3 (Scheme 1). Scheme 1. Retrosynthesis of (isoxazolidinyl) phosphonates trans-11/cis-11.
2-Vinyl-3H-quinazolin-4-ones 13 modified at N3 with substituted benzyl groups were synthesized from commercially available 2-aminobenzamide (14) by acylation with 3-chloropropionyl chloride followed by cyclization and dehydrohalogenation to prepare 2-vinyl-3Hquinazolin-4-one (13a) as a key intermediate [37] and a subsequent reaction with substituted benzyl bromides 13b-i [38] (Scheme 2). Moreover, compounds 13j (R = Me) and 13k (R = Et) were also obtained with intention to determine the influence of the benzyl substituent on biological activity of the designed isoxazolidines trans-11/cis-11. In the 1 H-NMR spectra of compounds 13a-k characteristic signals for vinyl protons were observed in the 6.94-5.59 ppm (three doublets of doublets). Scheme 1. Retrosynthesis of (isoxazolidinyl) phosphonates trans-11/cis-11.
2-Vinyl-3H-quinazolin-4-ones 13 modified at N3 with substituted benzyl groups were synthesized from commercially available 2-aminobenzamide (14) by acylation with 3-chloro-propionyl chloride followed by cyclization and dehydrohalogenation to prepare 2-vinyl-3H-quinazolin-4-one (13a) as a key intermediate [37] and a subsequent reaction with substituted benzyl bromides 13b-i [38] (Scheme 2). Moreover, compounds 13j (R = Me) and 13k (R = Et) were also obtained with intention to determine the influence of the benzyl substituent on biological activity of the designed isoxazolidines trans-11/cis-11. In the 1 H-NMR spectra of compounds 13a-k characteristic signals for vinyl protons were observed in the 6.94-5.59 ppm (three doublets of doublets). The 1,3-dipolar cycloaddition of a nitrone 12 with 2-vinylquinazolinones 13a-k led to the formation of diastereoisomeric mixtures of 5-substituted (3-diethoxyphosphoryl)isoxazolidines trans-11 and cis-11 with good (80%-88%) diastereoselectivities
(Scheme 3, Table 1 ). Ratios of cis/trans diastereoisomers were calculated from 31 P-NMR spectra of crude reaction mixtures and confirmed by the analysis of 1 H-NMR spectral data. Crude mixtures of isoxazolidine cycloadducts were then subjected to purification on silica gel columns. However, attempts to isolate pure diastereoisomers were fruitful for trans-11a The relative configurations of isoxazolidines trans-11a and cis-11a were established based on our previous studies on stereochemistry of cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone (12) with various vinyl aryls [39, 40] since similar 1 H-NMR spectral patters for the respective series of trans-and cis-isoxazolidines were observed. Since for compound trans-11a all necessary coupling constants were successfully extracted from the 1 H-and 13 C-NMR spectra, detailed conformational analysis was performed based on these data {J(H3-H4α) = 9.3 Hz [41] , J(H3-H4β) = 8. 3 Hz, J(H4α-P) = 9.9 Hz The 1,3-dipolar cycloaddition of a
nitrone 12 with 2-vinylquinazolinones 13a-k led to the formation of diastereoisomeric mixtures of 5-substituted (3-diethoxyphosphoryl)isoxazolidines trans-11 and cis-11 with good (80%-88%) diastereoselectivities (Scheme 3, Table 1 ). Ratios of cis/trans diastereoisomers were calculated from 31 P-NMR spectra of crude reaction mixtures and confirmed by the analysis of 1 H-NMR spectral data. Crude mixtures of isoxazolidine cycloadducts were then subjected to purification on silica gel columns. However, attempts to isolate pure diastereoisomers were fruitful for trans-11a (R = H), trans-11c (R = 2-NO 2 -C 6 H 4 -CH 2 ), trans-11g (R = 3-F-C 6 H 4 -CH 2 ), trans-11h (R = 4-F-C 6 H 4 -CH 2 ) and trans-11j (R = Me) only. Table 1 ). Ratios of cis/trans diastereoisomers were calculated from 31 P-NMR spectra of crude reaction mixtures and confirmed by the analysis of 1 H-NMR spectral data. Crude mixtures of isoxazolidine cycloadducts were then subjected to purification on silica gel columns.
However, attempts to isolate pure diastereoisomers were fruitful for trans-11a (R = H), trans-11c (R = 2-NO2-C6H4-CH2), trans-11g (R = 3-F-C6H4-CH2), trans-11h (R = 4-F-C6H4-CH2) and trans-11j (R = Me) only. The relative configurations of isoxazolidines trans-11a and cis-11a were established based on our previous studies on stereochemistry of cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone (12) with various vinyl aryls [39, 40] since similar 1 H-NMR spectral patters for the respective series of trans-and cis-isoxazolidines were observed. Since for compound trans-11a all necessary coupling constants were successfully extracted from the 1 H-and 13 C-NMR spectra, detailed conformational analysis was performed based on these data {J(H3-H4α) = 9.3 Hz [41] , J(H3-H4β) = 8. 3 Hz, J(H4α-P) = 9.9 Hz Scheme 3. Synthesis of Isoxazolidines cis-11a-k and trans-11a-k. Reaction and conditions: a. toluene, 70˝C, 24 h. The relative configurations of isoxazolidines trans-11a and cis-11a were
established based on our previous studies on stereochemistry of cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone (12) with various vinyl aryls [39, 40] since similar 1 H-NMR spectral patters for the respective series of transand cis-isoxazolidines were observed. Since for compound trans-11a all necessary coupling constants were successfully extracted from the 1 H-and 13 C-NMR spectra, detailed conformational analysis was performed based on these data {J (H3-H4α) = 9.3 Hz [41] , J (H3-H4β) = 8. 3 Hz, J (H4α-P) = 9.9 Hz [42, 43] , J (H4β-P) = 16.9 Hz, J (H4α-H5) = 6.2 Hz, J (H4β-H5) = 8. 3 Hz, J (CCCP) = 8.5 Hz [44, 45] } and revealed that isoxazolidine ring in trans-11a adopts a 3 E conformation in which the diethoxyphosphoryl group resides in the equatorial position of the isoxazolidine ring while a quinazolinone substituent is located pseudoequatorially (Figure 2 ). On the other hand, cis configuration of the minor isomer was established from the corresponding couplings [J
(H3-H4α) = 9.0 Hz, J (H3-H4β) = 6.5 Hz, J (H4α-P) = 11.2 Hz, J (H4β-P) = 20.0 Hz, J (H4α-H5) = 9.1 Hz, J (H4β-H5) = 3.9 Hz, J (CCCP) = 7. 3 Hz] indicating the 2 E conformation of the isoxazolidine ring ( Figure 2 ). The additional arguments to support our assignments follow from shielding of the CH 3 CH 2 OP protons observed for the cis isomer (∆δ ca. 0.1 ppm) when compared with the trans-11a. Furthermore, it was found that on a 1 H-NMR spectrum taken on the 83:17 mixture of cisand trans-11a, the H-N proton in the quinazolinone ring of cis-11a was significantly deshielded (∆δ = 0.7 ppm) when compared with the trans isomer, highly likely, as a result of the hydrogen bond formation with the phosphoryl oxygen amide, a phenomenon spatially achievable in the cis isomer only.
Since introduction of various substituents at N3 of quinazolinone moiety has no influence on the stereochemical outcome of the cycloaddition therefore configuration of the all major isoxazolidines 11 were assigned as trans, thereby minor ones as cis. Figure  2 ). The additional arguments to support our assignments follow from shielding of the CH3CH2OP protons observed for the cis isomer (Δδ ca. 0.1 ppm) when compared with the trans-11a. Furthermore, it was found that on a 1 H-NMR spectrum taken on the 83:17 mixture of cis-and trans-11a, the H-N proton in the quinazolinone ring of cis-11a was significantly deshielded (Δδ = 0.7 ppm) when compared with the trans isomer, highly likely, as a result of the hydrogen bond formation with the phosphoryl oxygen amide, a phenomenon spatially achievable in the cis isomer only.
Since introduction of various substituents at N3 of quinazolinone moiety has no influence on the stereochemical outcome of the cycloaddition therefore configuration of the all major isoxazolidines 11 were assigned as trans, thereby minor ones as cis. Ganciclovir, cidofovir, acyclovir, brivudin, zalcitabine, zanamivir, alovudine, amantadine, rimantadine, ribavirin, dextran sulfate (molecular weight 10,000, DS-10000), mycophenolic acid, Hippeastrum hybrid agglutinin (HHA) and Urtica dioica agglutinin (UDA) were used as the reference compounds. The antiviral activity was expressed as the EC50: the compound concentration required to reduce virus plaque formation (VZV) by 50% or to reduce virus-induced cytopathogenicity by 50% (other viruses).
Several isoxazolidines trans-11/cis-11 were able to weakly inhibit the replication of TK + and TK − VZV strains with EC50 values in the range of 6.84-100 μM ( Table 2 ). Among them, phosphonates Ganciclovir, cidofovir, acyclovir, brivudin, zalcitabine, zanamivir, alovudine, amantadine, rimantadine, ribavirin, dextran sulfate (molecular weight 10,000, DS-10000), mycophenolic acid, Hippeastrum hybrid agglutinin (HHA) and Urtica dioica agglutinin (UDA) were used as the reference compounds.

The antiviral activity was expressed as the EC 50 : the compound concentration required to reduce virus plaque formation (VZV) by 50% or to reduce virus-induced cytopathogenicity by 50% (other viruses).
Several isoxazolidines trans-11/cis-11 were able to weakly inhibit the replication of TK + and TKV ZV strains with EC 50 values in the range of 6.84-100 µM ( Table 2) . Among them, phosphonates trans-11f/cis-11f (90:10) (R = 2-F-C 6 H 4 -CH 2 ) (EC 50 = 6.84 µM), trans-11h (R = 4-F-C 6 H 4 -CH 2 ) (EC 50 = 15.29 µM), trans-11i/cis-11i (97:3) (R = 2,4-diF-C 6 H 3 -CH 2 ) (EC 50 = 9.44 µM) were the most active toward TK + VZV Oka strain, while exhibiting no activity toward TK´VZV strain. The activity of these isoxazolidines trans-11/cis-11 against TK + VZV Oka strain was 8-to 22-folds lower than that of the reference drug acyclovir. On the other hand, the EC 50 values for the TK´VZV 07-1 strain (which is an acyclovir resistant strain) of the phosphonates trans-11e/cis-11e (90:10) (R = 4-NO 2 -C 6 H 4 -CH 2 ) (EC 50 = 42.87 µM) and trans-11k/cis-11k (97:3) (R = Et) (EC 50 = 41.57 µM) were comparable to that of acyclovir (EC 50 = 39.69 µM). These derivatives showed similar EC 50 's for TK
+ and TK´VZV strains and therefore their potency against TK + VZV was approximately 50-fold lower compared to acyclovir.
Furthermore, compounds trans-11b/cis-11b (90:10) (R = C 6 H 5 -CH 2 ), trans-11c (R = 2-NO 2 -C 6 H 4 -CH 2 ), trans-11e/cis-11e (90:10) (R = 4-NO 2 -C 6 H 4 -CH 2 ) and trans-11g (R = 3-F-C 6 H 4 -CH 2 ) showed some activity against human cytomegalovirus (EC 50 = 27-45 µM), although they were less active than ganciclovir and cidofovir used as the reference compounds ( Table 3) . None of the phosphonate derivatives here described showed activity against the other tested DNA and RNA viruses.
The 50% cytostatic inhibitory concentration (IC 50 ) causing a 50% decrease in cell proliferation was determined against murine leukemia L1210, human lymphocyte CEM, human cervix carcinoma HeLa and immortalized human dermal microvacsular endothelial cells (HMEC-1). Isoxazolidines trans-11a (R = H) and trans-11j (R = Me) did not inhibit cell proliferation at the highest tested concentration (i.e., 250 µM), whereas trans-11k/cis-11k (97:3) (R = Et) appeared slightly cytostatic towards the tested cell lines (IC 50 = 85-101 µM). On the other hand (Table 4 , entries b to i), compounds having benzyl substituents at N3 in the quinazolinone moiety showed lower IC 50 values (IC 50 = 21-102 µM) thereby indicating that installation of functionalized benzyl groups was profitable for inhibitory properties. Table 4 . Inhibitory effect of the tested compounds against the proliferation of murine leukemia (L1210), human T-lymphocyte (CEM), human cervix carcinoma (HeLa) and immortalized human dermal
microvascular endothelial cells (HMEC-1).
To the solution of 2-vinyl-3H-quinazolin-4-one (13a, 1.00 mmol) in acetonitrile (15 mL) potassium carbonate (3.00 mmol) was added. After 15 min the respective benzyl bromide (1.10 mmol) was added and the reaction mixture was stirred under reflux for 4 h. A solvent was removed and the residue was extracted with water (3ˆ10 mL). An organic layer was dried (MgSO 4 ), concentrated and the crude product was purified on a silica gel column with a methylene chloride: hexane mixture (7:3, v/v) followed by crystallisation (chloroform-petroleum ether) to give pure quinazolinones 13b-e and 13g-i. 133.57, 128.60, 128.28, 128.25, 127.67, 126.60, 123.81, 123.61, 115.59, 68.32 (s, N-CH 2 ) . Anal. Calcd. for C 17 To the solution of 2-vinyl-3H-quinazolin-4-one (13a, 1.00 mmol) in acetonitrile (15 mL) potassium carbonate (3.00 mmol) was added. After 15 min. iodomethane (2.00 mmol) or iodoethane (1.10 mmol) was added and the reaction mixture was stirred at 60˝C for 5 h. The solvent was removed and a
residue was extracted with water (3ˆ10 mL). Organic layer was dried (MgSO 4 ), concentrated and the crude product was purified on a silica gel column with methylene chloride:hexane mixture (7:3, v/v) followed by crystallization (chloroform : petroleum ether) to give pure quinazolinones 13j [35] or 13k.
3-Methyl-2-vinylquinazolin-4(3H)-one (13j). Amorphous solid, m.p. = 122˝C-124˝C (reference [35] m.p. = 123˝C-125˝C). 

A solution of the nitrone 12 (1.0 mmol) and the respective vinyl quinazolinone (1.0 mmol) in toluene (2 mL) was stirred at 70˝C until the disappearance (TLC) of the starting nitrone. All volatiles were removed in vacuo and crude products were subjected to chromatography on silica gel columns with a chloroform/methanol (100:1, 50:1, 20:1, v/v) mixtures as eluents.
Diethyl trans-(2-methyl-5-(4-oxo-3,4-dihydroquinazolin-2-yl)isoxazolidin-3-yl)phosphonate (trans-11a). Yellowish oil; IR (film, cm´1) ν max : 3085, 2980, 2929, 2782, 1687, 1610, 1469, 1331, 1132, 1098, 1052 , 13 Diethyl trans-(2-methyl-5-(3-(3-nitrobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl)isoxazolidin-3-yl)-phosphonate (trans-11d). Data noted below correspond to a 92:8 mixture of trans-11d and cis-11d. A yellowish oil; IR (film, cm´1) ν max : 3070, 2982, 2930, 2910, 1620, 1574, 1531, 1497, 1415, 1298, 1103, 1025, 774
Epidemiology of HBoV1 infection and relationship with meteorological conditions in hospitalized pediatric patients with acute respiratory illness: a 7-year study in a subtropical region

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048719/

SHA: f2f78c95ab378a31bd35dc1de84e0ec75eb7ce1b

Authors: Liu, Wen-Kuan; Liu, Qian; Chen, De-Hui; Tan, Wei-Ping; Cai, Yong; Qiu, Shu-Yan; Xu, Duo; Li, Chi; Li, Xiao; Lin, Zheng-Shi; Zhou, Rong
Date: 2018-07-16
DOI: 10.1186/s12879-018-3225-3
License: cc-by