Search

The development of amplification strategies is one of the central challenges for detection of low-abundance targets. One-to-many (1:M) amplification strategies in which one target lights many signal probes, has improved the detection sensitivity in bulk solution, but with discounted contrast in cell imaging, because the lighted probes are dissociative and dispersible. In this work, a one-to-large (1:L) signaling mechanism, in which the lighted probes were orderly connected to each other, was conceptually proposed to enhance the contrast in cell imaging by avoiding signal dispersion in amplification. Accordingly, target-triggered hairpin-free chain-branching assembly (HFCBA) holds great potential to implement the 1:L mechanism, but using it in cell imaging has yet to be demonstrated. As a proof of concept, a group of probes were first programmed to implement miRNA-21-triggered HFCBA. After transfection of probes, gradually-growing signal flares in cells were monitored along with the growth of DNA dendrimers; and the in situ fluorescence accumulation in HFCBA resulted in highly-enhanced contrast to the surrounding by avoiding signal dispersion in amplification. The contrast-enhanced imaging with signal amplification is significant for biological analysis and molecular medicine. We expect the 1:L mechanism will provide a new thought for high-performance imaging of biomarkers in cells.

NMR experiments can detect in situ structures and dynamic interactions, but the NMR assignment process requires expertise and is time-consuming, thereby limiting its applicability. Deep learning algorithms have been employed to aid in experimental data analysis. In this work, we developed a RASP model which can enhance structure prediction with restraints. Based on the Evoformer and structure module architecture of AlphaFold, this model can predict structure based on sequence and a flexible number of input restraints. Moreover, it can evaluate the consistency between the predicted structure and the imposed restraints. Based on this model, we constructed an iterative NMR NOESY peak assignment pipeline named FAAST, to accelerate assignment process of NOESY restraints and obtaining high quality structure ensemble. The RASP model and FAAST pipeline not only allow for the leveraging of experimental restraints to improve model prediction, but can also facilitate and expedite experimental data analysis with their integrated capabilities.

It is critical to improve the efficiency of cancer therapy with minimized side effects. Chemodynamic therapy (CDT) is a tumor therapeutic strategy designed to generate abundant reactive oxygen spec...

Long-term specific tracing of the fibroblast activation protein (FAP) has been of great importance because it is heavily expressed by stromal fibroblasts of multiple diseases, and several disorders associated with FAP are chronical. Bioluminescence (BL) imaging has its advantages to detect FAP in vivo since no external excitation is required, but the current FAP-responsive BL probe was constructed by covalently masking the firefly luciferase substrate and easily secreted out from the animal, resulting in transient BL imaging of FAP. To circumvent this problem, a peptide-linked amphiphilic block copolymer-based probe (PABC) was developed and applied to the long-lasting BL image of FAP in vivo. For this purpose, an amphiphilic block copolymer containing an FAP-responsive peptide was fabricated to self-assemble into micelles, which act as a depot to load amounts of d-luciferin for constructing the BL probe. Upon reaction with FAP, the micelle would be destroyed to release the internal d-luciferin for BL emission by a luciferase-catalyzed reaction. By virtue of the high loading capability of micelles, the FAP was determined from 0.5 to 10 ng/mL with a detection limit of 0.105 ng/mL, and the high sensitivity makes the PABC capable of distinguishing cancer cells from normal ones. Importantly, compared with free d-luciferin, PABC can be used to persistently image the FAP in living cells and in vivo. This characteristic of long-lasting specific tracing of the FAP makes us envision that this BL probe could be used for screening of FAP inhibitors and diagnosing various FAP-related diseases in future.

Sodium-ion storage technologies are promising candidates for large-scale grid systems owing to the abundance and low cost of sodium. However, compared to well-understood lithium-ion storage mechanisms, sodium-ion storage remains relatively unexplored. Herein, we systematically determine the sodium-ion storage properties of anatase titanium dioxide (TiO2(A)). During the initial sodiation process, a thin surface layer (~3 to 5 nm) of crystalline TiO2(A) becomes amorphous but still undergoes Ti4+/Ti3+ redox reactions. A model explaining the role of the amorphous layer and the dependence of the specific capacity on the size of TiO2(A) nanoparticles is proposed. Amorphous nanoparticles of ~10 nm seem to be optimum in terms of achieving high specific capacity, on the order of 200 mAh g-1, at high charge/discharge rates. Kinetic studies of TiO2(A) nanoparticles indicate that sodium-ion storage is due to a surface-redox, capacitor-like reaction mechanism that is not dependent on nanoparticle size in contrast to the lithiation of TiO2(A) which is a diffusion-limited intercalation process. The surface-redox properties of TiO2(A) result in excellent rate capability, cycling stability and low overpotentials. Moreover, the surface-redox mechanism is instrumental in enabling thick electrodes of TiO2(A) retain high rate properties, and represent a promising direction for high-power sodium-ion storage.

Sodium-ion storage technologies are promising candidates for large-scale grid systems due to the abundance and low cost of sodium. However, compared to well-understood lithium-ion storage mechanisms, sodium-ion storage remains relatively unexplored. Herein, we systematically determine the sodium-ion storage properties of anatase titanium dioxide (TiO2(A)). During the initial sodiation process, a thin surface layer (~3 to 5 nm) of crystalline TiO2(A) becomes amorphous but still undergoes Ti4+/Ti3+ redox reactions. A model explaining the role of the amorphous layer and the dependence of the specific capacity on the size of TiO2(A) nanoparticles is proposed. Amorphous nanoparticles of ~10 nm seem to be optimum in terms of achieving high specific capacity, on the order of 200 mAh g−1, at high charge/discharge rates. Kinetic studies of TiO2(A) nanoparticles indicate that sodium-ion storage is due to a surface-redox mechanism that is not dependent on nanoparticle size in contrast to the lithiation of TiO2(A) which is a diffusion-limited intercalation process. The surface-redox properties of TiO2(A) result in excellent rate capability, cycling stability and low overpotentials. Moreover, tailoring the surface-redox mechanism enables thick electrodes of TiO2(A) to retain high rate properties, and represents a promising direction for high-power sodium-ion storage.

Background 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-naive 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-naive 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 G163R (0.24%, 2/827), were found in twelve individuals. Two patient samples contained the G163R mutation conferring low-level resistance to elvitegravir and raltegravir. Conclusion The overall prevalence of INSTI mutations remains low. Drug resistance mutation testing for the detection of INSTI drug resistance mutations in HIV treatment-naive patients should be considered due to the circulation of polymorphisms contributing to INSTI resistance and the expected increasing use of this class of drugs.

In this work, we investigated the effect of 2 MeV proton irradiation on the performance of InAs/GaSb type-II superlattice long-wave infrared detectors by combining ground-based irradiation experiments with Stopping and Range of Ions in Matter (SRIM) computer simulations. We found that irradiation with 2 MeV protons significantly increases the dark current density of the detector by more than two orders of magnitude. At the same time, the quantum efficiency decreases by an order of magnitude. Moreover, proton irradiation degrades the device's performance by raising bulk and surface leakage currents. As the mesa size of the device increases, the proportion of surface leakage current in the total dark current drops. When the mesa size is smaller, the detector irradiation damage is greater. In addition, simulations indicate that the amount of damage produced by 2 MeV proton irradiation rises as irradiation fluences increase. The trends of the irradiation damage produced by the SRIM simulation results and the photocurrent measurements after proton irradiation are consistent, whereas the dark current measurements are identical only at small fluences.

Objectives To comprehensively analyse the prevalence of drug resistance and the transmission characteristics of CRF59_01B strains in infected patients in Guangdong, China. Methods CRF59_01B-infected individuals were recruited, and the HIV-1 pol region was amplified. Drug resistance-associated mutations (DRMs) and antiretroviral susceptibility were examined using the Stanford University HIV Drug Resistance Database to analyse pretreatment drug resistance (PDR) and acquired drug resistance (ADR). Genetic transmission networks were extracted from the maximum likelihood phylogenetic tree with Cluster Picker and visualized with Cytoscape. Results Two hundred and twenty-five CRF59_01B-infected individuals, comprising 35 ART-experienced and 190 ART-naive individuals, were recruited. No patients harboured PI DRMs, 5.33% (12/225) of the patients harboured NRTI DRMs and 11.11% (25/225) of the patients harboured NNRTI DRMs. The overall prevalence of strains with ADR was 51.43% (18/35), while the prevalence of strains with PDR was 2.63% (5/190). A total of 20 transmission networks, involving 25.78% (58/225) database-derived sequences, were identified. The networks ranged in size from 2 to 10 individuals, of which most (55.00%, 11/20) were made up of two individuals. Among the 225 study subjects, 9.78% (22/225) had 1 link and 16.00% (36/225) had ≥2 links. Conclusions The overall prevalence of CRF59_01B strains with ADR among the ART-experienced patients was high. Although the overall prevalence of CRF59_01B strains with PDR among the ART-naive patients was low, it is necessary to remain vigilant regarding some important DRMs.

Photodetectors are receiving increasing attention because of their widely important applications. Therefore, developing broadband high-performance photodetectors using new materials that can function at room temperature has become increasingly important. As a functional material, tin telluride (SnTe), has been widely studied as a thermoelectric material. Furthermore, because of its narrow bandgap, it can be used as a novel infrared photodetector material. In this study, a large-area SnTe nanofilm with controllable thickness was deposited onto a quartz substrate using magnetron sputtering and was used to fabricate a photodetector. The device exhibited a photoelectric response over a broad spectral range of 400-1050 nm. In the near-infrared band of 940 nm, the detectivity (D*) and responsivity (R) of the photodetector were 3.46×1011 cmHz1/2w-1 and 1.71 A/W, respectively, at an optical power density of 0.2 mWcm-2. As the thickness of the SnTe nanofilm increased, a transition from semiconducting to metallic properties was experimentally observed for the first time. The large-area (2.5cm × 2.5cm) high-performance nanofilms show important potential for application in infrared focal plane array (FPA) detectors.

Background Transmitted drug resistance (TDR) that affects the effectiveness of the first-line antiretroviral therapy (ART) regimen is becoming prevalent worldwide. However, its prevalence and transmission among HIV-1 treatment-naïve patients in Guangdong, China are rarely reported. We aimed to comprehensively analyze the prevalence of TDR and the transmission clusters of HIV-1 infected persons before ART in Guangdong. Methods The HIV-1 treatment-naïve patients were recruited between January 2018 and December 2018. The HIV-1 pol region was amplified by reverse transcriptional PCR and sequenced by sanger sequencing. Genotypes, surveillance drug resistance mutations (SDRMs) and TDR were analyzed. Genetic transmission clusters among patients were identified by pairwise Tamura-Nei 93 genetic distance, with a threshold of 0.015. Results A total of 2368 (97.17%) HIV-1 pol sequences were successfully amplified and sequenced from the enrolled 2437 patients. CRF07_BC (35.90%, 850/2368), CRF01_AE (35.56%, 842/2368) and CRF55_01B (10.30%, 244/2368) were the main HIV-1 genotypes circulating in Guangdong. Twenty-one SDRMs were identified among fifty-two drug-resistant sequences. The overall prevalence of TDR was 2.20% (52/2368). Among the 2368 patients who underwent sequencing, 8 (0.34%) had TDR to protease inhibitors (PIs), 22 (0.93%) to nucleoside reverse transcriptase inhibitors (NRTIs), and 23 (0.97%) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Two (0.08%) sequences showed dual-class resistance to both NRTIs and NNRTIs, and no sequences showed triple-class resistance. A total of 1066 (45.02%) sequences were segregated into 194 clusters, ranging from 2 to 414 sequences. In total, 15 (28.85%) of patients with TDR were included in 9 clusters; one cluster contained two TDR sequences with the K103N mutation was observed. Conclusions There is high HIV-1 genetic heterogeneity among patients in Guangdong. Although the overall prevalence of TDR is low, it is still necessary to remain vigilant regarding some important SDRMs.

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 sequences, 39.3% fell into clusters. The majority of MSM in transmission networks were concentrated at age below 35 years old, with multiple links. Moreover, approximately 54.8% of MSM had more than 2 potential transmission partners.Conclusion: Drug resistance mutations more frequently occurred in NNRTIs among MSM with ART failure in Guangdong Province. Transmission network analysis revealed a complex transmission pattern, and more attention should be given to younger HIV-1-infected MSM with multiple links.Keywords: HIV-1, drug resistance, genetic transmission networks, MSM

The composition of anodic sulfidization layers of GaSb and InAs, prepared by electrochemistry anodic sulfidization, are investigated by X-ray photoelectron spectroscopy (XPS). The result of composition profile of GaSb anodic sulfidization samples, studied by XPS and Ar + etching, indicates that the anodic sulfidization layers contains not only sulfide, but also oxides and oxysulfide. The oxide/oxysulfide is sandwiched by sulfide layer and GaSb. While for the InAs anodic sulfidization sample, the whole anodic sulfidization layer of InAs is composed of oxysulfide and oxide. The oxide is sandwiched by oxysulfide layer and InAs. Moreover, long-wave InAs/GaSb superlattice IR detectors are fabricated to confirm the effect of anodic sulfidization layer on reduction the leakage current. The current–voltage (I-V) result indicates that the dark current of detector with anodic sulfidization layer is more than three orders of magnitude lower than that of without anodic sulfidization layer.

Strains of the HIV-1 circulating recombinant forms (CRFs) 06_cpx and 56_cpx were identified for the first time in Guangzhou, China. The nearly full-length genome (NFLG) sequence was amplified, and the PCR products were sequenced by the Sanger method. The CRF06_cpx and CRF56_cpx strains were identified using the Basic Local Alignment Search Tool (BLAST) and confirmed by neighbour-joining (NJ) phylogenetic analysis. Additionally, these strains were found to contain transmitted drug resistance mutations that have little effect on first-line efavirenz (EFV)-based treatment. Genetic analysis of the detailed sequence data will provide more information on the HIV-1 epidemic in China.

The wide variety of new HIV-1 recombinant variants are a predominant challenge for understanding the molecular epidemiology and preventing the spread of the HIV-1 epidemic. In this study, we confirmed a novel HIV-1 unique B/C recombinant (ZLQ01186) isolated from a male patient infected with HIV-1 through injection drug use in Foshan city, Guangdong Province. The near full-length genome was amplified, and then the polymerase chain reaction products were sequenced by Sanger sequencing. The genomic sequence of the strain, with two subtype B segments inserted into the subtype C backbone, was 8,953 bp in length, extending from 647 to 9,599 bp according to the HXB2 genome. In addition, this B/C recombinant strain contained the non-nucleoside reverse transcriptase inhibitor resistance mutation K103N and the integrase strand transfer inhibitor other resistance mutation L74I according to the Stanford University HIV Drug Resistance Database program. The drug resistance profile indicates high-level resistance against efavirenz and rilpivirine. This study identified a recombinant between the main circulating strains, indicating a more complicated trend of the HIV-1 epidemic in Guangdong, China.

Guangzhou city is the political, economic, and cultural center of the Guangdong Province, China. The molecular epidemiological characteristics of HIV-1 in Guangzhou are not widely known. The aim of this study was to explore the characteristics of HIV-1 genotypes among treatment naive HIV/AIDS patients living in Guangzhou. HIV-1 RNA was extracted from serum specimens. The partial pol gene of the HIV-1 genome was amplified and sequenced. The genotypes were screened using the subtyping tool COMET and further confirmed by phylogenetic analysis, with the exception of the URFs that were analyzed by jpHMM and RIP. The distributions of HIV genotypes in different risk populations were analyzed. Subsequently, pol sequences were used to construct transmission networks and analyze drug resistance. Twelve HIV-1 genotypes including 3 subtypes and 9 CRFs, with several URFs were identified from 1388 HIV-1 sequences, which were derived from 1490 patients. The main genotypes circulating in Guangzhou were CRF07_BC (38.3%), CRF01_AE (32.3%), and CRF55_01B (10.7%). CRF01_AE was the secondary dominant strain and multiple lineages of CRF01_AE had been identified in Guangzhou. The 01B recombinant forms, including CRF55_01B, CRF59_01B and CRF68_01B, have circulated widely in Guangzhou. 42.22% (586/1388) of the study sequences fell into 143 transmission networks, and the three main clusters revealed that sequences from MSM and HET populations were intermixed. 5.40% (75/1388) of patients had pre-treatment drug resistance. The HIV-1 strains that were present in Guangzhou have demonstrated complex genotypes. Particular attention should be given on these genotypes for the further strategy of prevention and intervention of HIV transmission.

Hyaluronidase 1 (Hyal-1) is an important enzyme involved in intracellular hyaluronic acid (HA) catabolism for performing various physiological functions, and its aberrant level is closely associated with many malignant diseases. Bioluminescence imaging is advantageous for monitoring Hyal-1 activity in vivo, but it remains challenging to design an available probe for differentiating Hyal-1 from other isoforms by a traditional strategy that covalently masks the firefly luciferase substrate. Herein, we, for the first time, present a noncovalently caging approach to construct a Hyal-1-specific bioluminogenic nanosensor by entrapping d-luciferin (d-Luc) inside the cholesterylamine-modified HA (CHA) nanoassembly to inhibit the bioluminescence production. When encountered with intracellular Hyal-1, CHA could be fully dissembled to liberate multiple copies of the loaded d-Luc, thereby emitting light by the luciferase-catalyzed bioluminescence reaction. Because of its cascade signal amplification feature, d-Luc@CHA displayed a remarkable "turn-on" response (248-fold) to 5 μg/mL Hyal-1 with a detection limit of 0.07 ng/mL. Importantly, bioluminescence imaging results validated that d-Luc@CHA could be competent for dynamically visualizing endogenous Hyal-1 changes in living cells and animals and possessed the capability of discriminating between normal and cancer cells, thus offering a promising toolbox to evaluate Hyal-1 roles in biological processes as well as to diagnose Hyal-1-related diseases.

We fabricated a high-performance InAs/GaSb type-II superlattice infrared detector. The tolerance of various sizes of detector irradiated with 1-MeV electrons was characterized. X-Ray Diffraction (XRD) and Atomic Force Microscope (AFM) measurements demonstrated the high quality of the materials. The response spectrum had a 50% cutoff wavelength of 8.85 μm. Irradiation with 1-MeV electrons caused a significant increase in the dark current density from 2.54 × 10−3 to 2.58 × 10−1 A/cm2 at Vb = –0.03 V. The 1-MeV electron irradiation mainly caused displacements in the device, which had a significant impact on the generation-recombination dark current and surface leakage current.

In this paper, we construct a class of collapsing spacetimes in vacuum without any symmetries. The spacetime contains a black hole region which is bounded from the past by the future event horizon. It possesses a Cauchy hypersurface with trivial topology which is located outside the black hole region. Based on existing techniques in the literature, the spacetime can in principle be constructed to be past geodesically complete and asymptotic to Minkowski space. The construction is based on a semi-global existence result of the vacuum Einstein equations built on a modified version of the a priori estimates that were originally established by Christodoulou in his work on the formation of trapped surface, and a gluing construction carried out inside the black hole. In particular, the full detail of the a priori estimates needed for the existence is provided, which can be regarded as a simplification of Christodoulou's original argument., Comment: 47 pages, 10 figures, accepted version