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Yun Lan,* Xizi Deng,* Linghua Li, Weiping Cai, Junbin Li, Xiaoli Cai, Feng Li, Fengyu Hu, Chunliang Lei, Xiaoping Tang Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, 510030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunliang Lei; Xiaoping TangGuangzhou Eighth People’s Hospital, Guangzhou Medical University, 627 Dongfeng East Road, Yuexiu District, Guangzhou, 510030, People’s Republic of ChinaEmail gz8hlcl@126.com; tangxp@gzhmu.edu.cnBackground: Guangdong, located in South China, is one of the areas heavily affected by HIV-1 in China. The transmission of HIV-1 among men who have sex with men (MSM) has gradually been increasing in Guangdong.Objective: To investigate the characteristics of the HIV-1 drug resistance, and genetic transmission networks in MSM with antiretroviral therapy (ART) failure from 2014 to 2019 in Guangdong.Methods: HIV-1 pol gene sequences were amplified. An online subtyping tool was used to determine the genotype, and a maximum likelihood phylogenetic tree was reconstructed to confirm the genotype results. The Stanford University HIV Drug Resistance Database was used to analyse the sequences of drug resistance mutations (DRMs) and drug resistance profiles. A pairwise Tamura-Nei 93 genetic distance-based method was used to analyse the genetic transmission networks.Results: Of 393 sequences isolated from HIV-infected MSM with ART failure, CRF01_AE (47.3%), CRF07_BC (21.4%) and CRF55_01B (21.4%) were the top three strains. 55.2% individuals harboured NRTI DRMs, whereas 67.4% carried NNRTI DRMs. 96.8% cases harboured mutations resistance to NRTIs or NNRTIs at high-level. The most common DRMs were M184I/V (42.2%), followed by V179D/E (37.9%) and K65R (27.2%). Of the subtype B sequences, no sequence fell into a cluster. Of the CRF01_AE, CRF55_01B, and CRF59_01B sequences, 14.5%, 61.9%, and 33.3% fell into clusters, respectively. Of the CRF07_BC

Yun Lan,1,* Linghua Li,2,* Weilie Chen,1,* Xizi Deng,1 Junbin Li,2 Qinghong Fan,1 Xiaoli Cai,1 Weiping Cai,2 Fengyu Hu1 1Institute of Infectious Disease, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Infectious Disease Center, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiping CaiInfectious Disease Center, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, 627 Dongfeng East Road, Yuexiu District, Guangzhou 510030, People’s Republic of ChinaTel +86-20-83710825Email gz8hcwp@126.comFengyu HuInstitute of Infectious Disease, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, 627 Dongfeng East Road, Yuexiu District, Guangzhou 510030, People’s Republic of ChinaTel +86-20-83710851Email gz8hhfy@126.comBackground: Antiretroviral therapy (ART) containing an integrase strand transfer inhibitor (INSTI) plus two nucleoside reverse-transcriptase inhibitors has been recommended as a first-line regimen for ART-naïve HIV-1-infected patients in the latest Chinese Guidelines for Diagnosis and Treatment of HIV/AIDS.Objective: To determine the prevalence of INSTI-related mutations among ART-naïve HIV-1-infected adults in Guangdong, China, in 2018.Methods: The entire integrase gene was amplified from blood plasma. Demographic and epidemiological information was collected. INSTI mutations and antiretroviral susceptibility were interpreted using the Stanford University HIV Drug Resistance Database HIVdb program.Results: Of 927 samples, 827 integrase sequences were successfully obtained. Among them, no major resistance mutations to INSTIs were identified, and four accessory mutations, including T97A (0.12%, 1/827), A128T (0.24%, 2/827), E157Q (0.85%, 7/827), and G1

In Drosophila, the Bicoid protein servers as paradigm as the first identified morphogen, whose concentration gradient provides the initial positional information in the anterior half of the embryo. There, it differentially activates segmentation genes, in particular the gap genes. Insofar, there are two mainly prevailing models to explain how the Bicoid protein concentration gradient forms: 1) the SDD (Synthesis, Diffusion and Degradation) model proposing that the bicoid mRNA is located at the anterior pole of the embryo at all times. The mRNA then serves as a source for translation of the Bicoid protein, followed by diffusion of the protein to the posterior, combined with uniform degradation. 2) the ARTS (Active RNA Transport and Synthesis) model proposing that the mRNA is transported at the cortex along microtubules to form the mRNA gradient, which serves as template for the production of Bicoid. Hence, there are clear differences between the SDD and the ARTS model.To corroborate the ARTS model, we used several approaches: 1) we investigated on the transport mechanism of bicoid mRNA. To this end, we detected a cortical microtubular network that was present in the anterior half of the early Drosophila embryos, which was only active during metaphase and early anaphase. We found that αTubulin67C is crucial for establishing the cortical microtubular network and that cortical bicoid mRNA transport is compromised in αTubulin67C mutants. We defined a motor protein, nonclaret disjunctional (ncd) to be a critical motor for bicoid mRNA transport and demonstrated that ncd interacts genetically with αTubulin67C. This data suggested that ncd required αTubulin67C for cortical bicoid mRNA transport, also demonstrated by colocalization of αTubulin67C with Ncd. 2) we chose one special fly stock that expresses 3 times more Bicoid and treated the embryos with hypoxia to challenge the validity of the SDD model. Our data showed that under hypoxic conditions, the Bicoid protein did not

Background: micro RNAs (miRNAs) are important regulators of many biological pathways. A plethora of steps are required to form, from a precursor, the mature miRNA that eventually acts on its target RNA to repress its expression or to inhibit translation. Recently, Drosophila nibbler (nbr) has been shown to be an important player in the maturation process of miRNA and piRNA. Nbr is an exoribonuclease which helps to shape the 3' end of miRNAs by trimming the 3' overhang to a final length. Results: In contrast to previous reports on the localization of Nbr, we report that 1) Nbr is expressed only during a short time of oogenesis and appears ubiquitously localized within oocytes, and that 2) Nbr was is not enriched in the nuage where it was shown to be involved in piwi-mediated mechanisms. To date, there is little information available on the function of nbr for cellular and developmental processes. Due to the fact that nbr mutants are viable with minor deleterious effects, we used the GAL4/UAS over-expression system to define novel functions of nbr. We disclose hitherto unknown functions of nbr 1) as a tumor suppressor and 2) as a suppressor of RNAi. Finally, we confirm that nbr is a suppressor of transposon activity. Conclusions: Our data suggest that nbr exerts much more widespread functions than previously reported from trimming 3' ends of miRNAs only.

Background: micro RNAs (miRNAs) are important regulators of many biological pathways. A plethora of steps are required to form, from a precursor, the mature miRNA that eventually acts on its target RNA to repress its expression or to inhibit translation. Recently, Drosophila nibbler (nbr) has been shown to be an important player in the maturation process of miRNA and piRNA. Nbr is an exoribonuclease which helps to shape the 3' end of miRNAs by trimming the 3' overhang to a final length. Results: In contrast to previous reports on the localization of Nbr, we report that 1) Nbr is expressed only during a short time of oogenesis and appears ubiquitously localized within oocytes, and that 2) Nbr was is not enriched in the nuage where it was shown to be involved in piwi-mediated mechanisms. To date, there is little information available on the function of nbr for cellular and developmental processes. Due to the fact that nbr mutants are viable with minor deleterious effects, we used the GAL4/UAS over-expression system to define novel functions of nbr. We disclose hitherto unknown functions of nbr 1) as a tumor suppressor and 2) as a suppressor of RNAi. Finally, we confirm that nbr is a suppressor of transposon activity. Conclusions: Our data suggest that nbr exerts much more widespread functions than previously reported from trimming 3' ends of miRNAs only.

Background: micro RNAs (miRNAs) are important regulators of many biological pathways. A plethora of steps are required to form, from a precursor, the mature miRNA that eventually acts on its target RNA to repress its expression or to inhibit translation. Recently, Drosophila nibbler (nbr) has been shown to be an important player in the maturation process of miRNA and piRNA. Nbr is an exoribonuclease which helps to shape the 3' end of miRNAs by trimming the 3' overhang to a final length. Results: In contrast to previous reports on the localization of Nbr, we report that 1) Nbr is expressed only during a short time of oogenesis and appears ubiquitously localized within oocytes, and that 2) Nbr was is not enriched in the nuage where it was shown to be involved in piwi-mediated mechanisms. To date, there is little information available on the function of nbr for cellular and developmental processes. Due to the fact that nbr mutants are viable with minor deleterious effects, we used the GAL4/UAS over-expression system to define novel functions of nbr. We disclose hitherto unknown functions of nbr 1) as a tumor suppressor and 2) as a suppressor of RNAi. Finally, we confirm that nbr is a suppressor of transposon activity. Conclusions: Our data suggest that nbr exerts much more widespread functions than previously reported from trimming 3' ends of miRNAs only.

Background: micro RNAs (miRNAs) are important regulators of many biological pathways. A plethora of steps are required to form, from a precursor, the mature miRNA that eventually acts on its target RNA to repress its expression or to inhibit translation. Recently, Drosophila nibbler (nbr) has been shown to be an important player in the maturation process of miRNA and piRNA. Nbr is an exoribonuclease which helps to shape the 3' end of miRNAs by trimming the 3' overhang to a final length. Results: In contrast to previous reports on the localization of Nbr, we report that 1) Nbr is expressed only during a short time of oogenesis and appears ubiquitously localized within oocytes, and that 2) Nbr was is not enriched in the nuage where it was shown to be involved in piwi-mediated mechanisms. To date, there is little information available on the function of nbr for cellular and developmental processes. Due to the fact that nbr mutants are viable with minor deleterious effects, we used the GAL4/UAS over-expression system to define novel functions of nbr. We disclose hitherto unknown functions of nbr 1) as a tumor suppressor and 2) as a suppressor of RNAi. Finally, we confirm that nbr is a suppressor of transposon activity. Conclusions: Our data suggest that nbr exerts much more widespread functions than previously reported from trimming 3' ends of miRNAs only.

Background: micro RNAs (miRNAs) are important regulators of many biological pathways. A plethora of steps are required to form, from a precursor, the mature miRNA that eventually acts on its target RNA to repress its expression or to inhibit translation. Recently, Drosophila nibbler (nbr) has been shown to be an important player in the maturation process of miRNA and piRNA. Nbr is an exoribonuclease which helps to shape the 3' end of miRNAs by trimming the 3' overhang to a final length. Results: In contrast to previous reports on the localization of Nbr, we report that 1) Nbr is expressed only during a short time of oogenesis and appears ubiquitously localized within oocytes, and that 2) Nbr was is not enriched in the nuage where it was shown to be involved in piwi-mediated mechanisms. To date, there is little information available on the function of nbr for cellular and developmental processes. Due to the fact that nbr mutants are viable with minor deleterious effects, we used the GAL4/UAS over-expression system to define novel functions of nbr. We disclose hitherto unknown functions of nbr 1) as a tumor suppressor and 2) as a suppressor of RNAi. Finally, we confirm that nbr is a suppressor of transposon activity. Conclusions: Our data suggest that nbr exerts much more widespread functions than previously reported from trimming 3' ends of miRNAs only.

The Bicoid (Bcd) protein gradient in Drosophila serves as a paradigm for gradient formation in textbooks. To explain the generation of the gradient, the ARTS model, which is based on the observation of a bcd mRNA gradient, proposes that the bcd mRNA, localized at the anterior pole at fertilization, migrates along microtubules (MTs) at the cortex to the posterior to form a bcd mRNA gradient which is translated to form a protein gradient. To fulfil the criteria of the ARTS model, an early cortical MT network is thus a prerequisite. We report hitherto undiscovered MT activities in the early embryo important for bcd mRNA transport: (i) an early and omnidirectional MT network exclusively at the anterior cortex of early nuclear cycle embryos showing activity during metaphase and anaphase only, (ii) long MTs up to 50 µm extending into the yolk at blastoderm stage to enable basal-apical transport. The cortical MT network is not anchored to the actin cytoskeleton. The posterior transport of the mRNA via the cortical MT network critically depends on maternally-expressed αTubulin67C and the minus-end motor Ncd. In either mutant, cortical transport of the bcd mRNA does not take place and the mRNA migrates along another yet undisclosed interior MT network, instead. Our data strongly corroborate the ARTS model and explain the occurrence of the bcd mRNA gradient.