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The goal of the paper is to study the tonal features of the Quốc Oai variant (former H Ty, H Nội nowaday). By use of instrumental phonetics, phonological description and comparative methods, the study presents the following results: (1) A description of tonal features of Quốc Oai using synchronic data; (2) A comparison of Quốc Oai with Thạch Thất tones and the urban H Nội tones to provide a broader view of H Ty tones; (3) A comparison of Quốc Oai tones with the tones of some neighboring Mường dialects in synchronous and chronological aspects, which help to establish a few details explaining the interesting nature of this dialect; (4) Finally, we also provide some interdisciplinary evidences to support the linguistic data. All kinds of data point to the idea that xứ Đoi, Ba V (including Quốc Oai in the past and present) is a mixed space of Việt-Mường culture. In this mixed space one may find similar features of all elements of culture, including linguistic similarities, especially in tones.

This article investigates the impact of external debt on economic convergence in 201 economies from 1990 to 2020. Panel data collected from the fiscal space database of the World Bank are analyzed using the conditional beta convergence framework. Results show that external debt negatively affects growth and there is no evidence to support the non-linear association. However, external debt influences the convergence speed in an inverted-U-shaped fashion. The economic convergence speeds up as the level of indebtedness increases to a threshold above which the convergence slows down as the level of foreign debts continues to increase. We also disaggregate external debt into its six sub-components and discover the non-linear effects of private debts and debts denominated in domestic currency on the convergence process.

Việt Nam đang dần bước vào giai đoạn già hóa dân số nên vấn đề chất lượng cuộc sống của nhóm tuổi lão hóa là vấn đề cần được quan tâm. Hiện nay đã có nhiều nghiên cứu về chất lượng cuộc sống của người cao tuổi, tuy nhiên lão hóa là một quá trình, bắt đầu ngay từ giai đoạn tuổi trung niên. Chúng tôi tiến hành nghiên cứu nhằm mục đích mô tả thực trạng chất lượng cuộc sống của người dân từ 40 tuổi trở lên tại Hà Nam, và phân tích các yếu tố liên quan đến chất lượng cuộc sống của người dân. Phương pháp nghiên cứu mô tả cắt ngang được thực hiện bằng việc phỏng vấn trực tiếp 847 đối tượng từ 40 tuổi trở lên tại Hà Nam, dựa trên bộ câu hỏi cấu trúc có sẵn. Kết quả cho thấy tỉ lệ người dân đánh giá chất lượng cuộc sống ở mức tốt trở lên đạt 65,5%. Chất lượng cuộc sống có mối tương quan thuận với tiếp cận truyền thông giáo dục sức khỏe từ nhân viên y tế và hỗ trợ xã hội từ bạn bè. Ngược lại, đối tượng mắc bệnh mạn tính, lo âu, stress có chất lượng cuộc sống thấp hơn.

Applying Giles' communication accommodation theory and Trudgills accommodation model through quantitative analysis method, this paper presents the investigative findings of accommodation of the Northern dialect community in Ho Chi Minh City of Vietnam. Communication accommodation is demonstrated by selecting dialect variants of the community in the new settlement. Research shows that the communicative environment has created significant pressure that influences the level of accommodation. It also shows that the accommodation index is compatible with some of social variables such as prestige status of an immigrant dialect, duration of living in a new city, type of communication, and marriage models, in which, prestige status of an immigrant dialect and duration of living in a new city are the most important.

Antibody detection of prior SARS-CoV-2 infection depends on severity, assay, and timing with implications for serosurveillance., Interpretation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveillance studies is limited by poorly defined performance of antibody assays over time in individuals with different clinical presentations. We measured antibody responses in plasma samples from 128 individuals over 160 days using 14 assays. We found a consistent and strong effect of disease severity on antibody magnitude, driven by fever, cough, hospitalization, and oxygen requirement. Responses to spike protein versus nucleocapsid had consistently higher correlation with neutralization. Assays varied substantially in sensitivity during early convalescence and time to seroreversion. Variability was dramatic for individuals with mild infection, who had consistently lower antibody titers, with sensitivities at 6 months ranging from 33 to 98% for commercial assays. Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on infection severity, timing, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.

A detailed understanding of long-term SARS-CoV-2-specific T cell responses and their relationship to humoral immunity and markers of inflammation in diverse groups of individuals representing the spectrum of COVID-19 illness and recovery is urgently needed. Data are also lacking as to whether and how adaptive immune and inflammatory responses differ in individuals that experience persistent symptomatic sequelae months following acute infection compared to those with complete, rapid recovery. We measured SARS-CoV-2-specific T cell responses, soluble markers of inflammation, and antibody levels and neutralization capacity longitudinally up to 9 months following infection in a diverse group of 70 individuals with PCR-confirmed SARS-CoV-2 infection. The participants had varying degrees of initial disease severity and were enrolled in the northern California Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort. Adaptive T cell responses remained remarkably stable in all participants across disease severity during the entire study interval. Whereas the magnitude of the early CD4+ T cell immune response is determined by the severity of initial infection (participants requiring hospitalization or intensive care), pre-existing lung disease was significantly associated with higher long-term SARS-CoV2-specific CD8+ T cell responses, independent of initial disease severity or age. Neutralizing antibody levels were strongly correlated with SARS-CoV-2-specific CD4+ T but not CD8+ T cell responses. Importantly, we did not identify substantial differences in long-term virus-specific T cell or antibody responses between participants with and without COVID-19-related symptoms that persist months after initial infection.

We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses, soluble markers of inflammation, and antibody levels and neutralization capacity longitudinally in 70 individuals with PCR-confirmed SARS-CoV-2 infection. Participants represent a spectrum of illness and recovery, including some with persistent viral shedding in saliva and many experiencing post-acute sequelae of SARS-CoV-2 infection (PASC). T cell responses remain stable for up to 9 months. Whereas the magnitude of early CD4+ T cell immune responses correlates with severity of initial infection, pre-existing lung disease is independently associated with higher long-term SARS-CoV-2-specific CD8+ T cell responses. Among participants with PASC 4 months following coronavirus disease 2019 (COVID-19) symptom onset, we observe a lower frequency of CD8+ T cells expressing CD107a, a marker of degranulation, in response to Nucleocapsid (N) peptide pool stimulation, and a more rapid decline in the frequency of N-specific interferon-γ-producing CD8+ T cells. Neutralizing antibody levels strongly correlate with SARS-CoV-2-specific CD4+ T cell responses., Graphical abstract, CD4+ and CD8+ T cell responses following natural infection with COVID-19 are stable over 8 months. Individuals with PASC demonstrate a lower frequency of CD8+ T cells expressing CD107a, a marker of degranulation, and a more rapid decline in the frequency of N-specific interferon-γ-producing CD8+ T cells.

A 9-week feeding experiment was conducted to evaluate different dietary protein levels in juvenile Nile tilapia reared in either a biofloc (Bio-RAS) or clear water recirculating aquaculture system (CW-RAS). The fish were fed four isoenergetic (19 MJ kg−1) diets with graded levels of a fixed mixture of three protein sources (animal, plant, and microbial origin) and containing 23, 27, 31 or 35% crude protein. Triplicate groups of 20 juvenile tilapia (initial weight: 39.1 ± 2.5 g) were randomly assigned to 24 identical conical 500-L tanks equipped with feed waste traps. Twelve of the tanks were supplied with clear water purified by a mechanical and biological filter, denoted CW-RAS, and on average 15% daily replacement of water. The other 12 tanks were supplied with a biofloc suspension, maintained by a bioreactor system, denoted Bio-RAS, where the mechanical and biological filters were replaced with four serial 10 m3 open bioreactor tanks. In this later system only evaporated water was replaced. The bioreactor tanks were initially inoculated with Bacillus subtilis, and nutrients were supplied to achieve a C: N ratio of 10, supporting heterotrophic bacterial growth. Feed and protein intake, weight gain, specific growth rate, protein efficiency of fish in all treatments, and biomass of micro components in the bioreactor tanks, as well as apparent digestibility of dietary components, were determined at end of the experiment. Growth, feed intake and protein efficiency, especially if retention of the floc was included, was overall higher in the Bio-RAS than in the CW- RAS system. Feed conversion was influenced both by protein level and by the availability of biofloc, with a general lower value in the Bio-RAS and fish given higher protein containing diets. Apparent digestibility of total protein did not vary with the rearing system but was higher with higher dietary levels of crude protein. No significant effect was found for mortality or body index, except for hepato-somatic index and intestinal quotient index, with the latter being significantly higher in the fish given access to biofloc. In all fish given access to biofloc, given all other factors being equal, displayed higher and more feed efficient growth than fish kept in clear water with only access to fabricated diets. Our results tally with other studies using biofloc tank technology and reports from more commercial settings indicating that our data is valid also at a more general level.

The issue of tourism impacts is one that has plagued the tourism industry. This study develops a quantitative approach using hierarchical variance analysis, which deals with the exploration of the relevant factors and the confirmation of their significant contribution to analyze the residents&rsquo, perception of tourism impacts. Hierarchical variance analysis includes three mathematical procedures: Cronbach&rsquo, s alpha tests, the exploration of relevant factors, and a hierarchical factor confirmation. Data are collected using a structured questionnaire completed by 452 surveyed residents living in Ly Son Island, Vietnam. The significant effects of socio-demographic variables on the overall impact assessment are observed. The bilateral and simultaneous relationships are analyzed using a one-factor ANOVA. A two-factor ANOVA shows the significant contribution of each socio-demographic variable on the economic, socio-cultural, and environmental impacts. Interaction between factors such as &ldquo, Education level&rdquo, &ldquo, Type of work&rdquo, etc. are hierarchically confirmed. The findings allow a better understanding of the residents&rsquo, perception of the effects of tourism on society, the economy, and the environment. This provides a scientific basis to help define problems and promote legal regulations for community participation in tourism planning in a small island destination.

Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i)10 nM for the mTOR kinase and500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.

Durable suppression of HIV-1 replication requires the establishment of antiretroviral drug concentrations that exceed the susceptibility of the virus strain(s) infecting the patient. Minimum plasma drug concentrations ( C trough ) are correlated with response, but determination of target C trough values is hindered by a paucity of in vivo concentration-response data. In the absence of these data, in vitro susceptibility measurements, adjusted for serum protein binding, can provide estimations of suppressive in vivo drug concentrations. We derived serum protein binding correction factors (PBCF) for protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and an integrase inhibitor by measuring the effect of a range of human serum concentrations on in vitro drug susceptibility measured with the PhenoSense HIV assay. PBCFs corresponding to 100% HS were extrapolated using linear regression and ranged from 1.4 for nevirapine to 77 for nelfinavir. Using the mean 95% inhibitory concentration (IC 95 ) for ≥1,200 drug-susceptible viruses, we calculated protein-bound IC 95 (PBIC 95 ) values. PBIC 95 values were concordant with the minimum effective C trough values that were established in well-designed pharmacodynamic studies (e.g., indinavir, saquinavir, and amprenavir). In other cases, the PBIC 95 values were notably lower (e.g., darunavir, efavirenz, and nevirapine) or higher (nelfinavir and etravirine) than existing target recommendations. The establishment of PBIC 95 values as described here provides a convenient and standardized approach for estimation of the minimum drug exposure that is required to maintain viral suppression and prevent the emergence of drug-resistant variants, particularly when in vivo concentration-response relationships are lacking.

A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K(i)1.0 nM and were highly (100×) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK-PD relationship in a mouse model of cancer.

An efficient synthesis of pyranonaphthoquinones is achieved by ethylenediamine diacetate-catalyzed reactions of 4-hydroxy-2-quinolones with a variety of α,β-unsaturated aldehydes in moderate yields. This method provides arapid entry into biologically interesting α-lapachone derivatives with a variety of substituents on the pyran ring.

Benzothiophene-anthranilamide 1 (3-chloro- N -[2-[[(4-fluorophenyl)amino]carbonyl]-4-methylphenyl]benzo[ b ]thiophene-2-carboxamide) was discovered by high throughput screening to be a highly potent and selective non-amidine inhibitor of human factor Xa with a K i of 15±4 nM. Compound 1 is a selective inhibitor of human factor Xa as suggested by the K i (app) determined for nine other human serine proteases and bovine trypsin. The activity of reconstituted human prothrombinase complex was inhibited by compound 1 when assayed in physiological concentrations of the substrate prothrombin. However, 27-fold higher inhibitor concentrations were needed to achieve the same level of inhibition than were required for the inhibition of free factor Xa, due in part to non-specific binding of the inhibitor to phospholipid under the assay conditions. Failure to demonstrate enzymatic cleavage of compound 1 suggests that compound 1 is solely an inhibitor rather than a substrate for factor Xa. The inhibition of factor Xa by compound 1 was reversible upon dilution of the enzyme/inhibitor mixture. Analyses of the inhibition mechanism with Dixon, Cornish–Bowden, and Lineweaver–Burk plots showed that compound 1 is a linear mixed-type inhibitor with 5-fold higher affinity for free factor Xa than the factor Xa/substrate complex. The linear mixed-type inhibition suggests that compound 1 binds to the active site region of factor Xa, but its binding cannot be fully displaced by the substrate S2222 (1:1 mixture of N -benzoyl-Ile-Glu-Gly-Arg- p -nitroanilide and N -benzoyl-Ile-Glu(γ-OMe)-Gly-Arg- p -nitroanilide hydrochloride). Thus, the inhibition mechanism for compound 1 is novel compared to most serine protease inhibitors including amidine-containing factor Xa inhibitors, which rely on binding to the S1 pocket of the enzyme active site. Compound 1 represents an attractive, novel structural template for further development of efficacious, safe, and potentially orally active human factor Xa inhibitors.

Phase diagram of the ground states of DNA in a bad solvent is studied for a semi-flexible polymer model with a generalized local elastic bending potential characterized by a nonlinearity parameter $x$ and effective self-attraction promoting compaction. $x=1$ corresponds to the worm-like chain model. Surprisingly, the phase diagram as well as the transition lines between the ground states are found to be a function of $x$. The model provides a simple explanation for the results of prior experimental and computational studies and makes predictions for the specific geometries of the ground states. The results underscore the impact of the form of the microscopic bending energy at macroscopic observable scales., Comment: 5 pages, 5 figures, to appear in PRE Rapid Communication

A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.

A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K I against factor Xa of 0.12 nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d , which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.

Inhibitors based on the benzimidazole scaffold showed subnanomolar potency against Factor Xa with 500–1000-fold selectivity against thrombin and 50–100-fold selectivity against trypsin. The 2-substituent on the benzimidazole ring had a strong impact on the FXa inhibitory activity. Crystallography studies suggest that the 2-substituent may have a conformational effect favoring the extended binding conformation.

A series of indole and carbazole based inhibitors of factor Xa (FXa) has been investigated. The most potent compound inhibits FXa with a Ki of 0.2 nM and has 900- and 750-fold selectivity over thrombin and trypsin, respectively.

An arylamidine linker has been employed for the solid-phase synthesis of N-substituted amidinoaryloxypyridine analogs 2 via nucleophilic substitution on a fluoropydyl template. Two novel N-substituted amidinoaryloxypyridine derivatives 2a and 2b were discovered via this approach.

A high-throughput, nonradioactive telomerase assay using a europium-labeled oligonucleotide probe and time-resolved fluorescence has been developed to detect PCR-amplified telomerase products. The use of a thermally activated TAQ polymerase, rather than a wax barrier, to implement a PCR hot-start facilitated the use of laboratory automation equipment. Results obtained with this high-throughput protocol correlate well with those obtained with the TRAP protocol. Screening a set of 125,000 compounds from the Berlex library, we identified a set of isothiazolone-containing telomerase inhibitors. The most potent of these inhibitors have submicromolar IC 50 values and may be reacting with a telomerase thiol. These compounds may be useful tools to evaluate the effects of telomerase in cancer cells.

We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.

A matrix-based compound pooling and deconvolution method has been developed that significantly increased the efficiency of a high-capacity screening program. This method is based on screening pools of 10 compounds. The matrix used to assemble the pools resulted in each compound being assayed twice—each time with a completely different set of pooled compounds. The active compound in an active pool was accurately predicted by determining which compound was present in an active pool both times that a pool containing that compound was tested. This has eliminated the need to re-assay each individual member of active pools. This approach has been tested with a set of 6,680 compounds in three different assays: inhibition of Factor Xa, inhibition of gastrin-releasing peptide receptor binding, and inhibition of nitric oxide synthase (isoform II). Thus significant time is saved not only by pooling the compounds for the initial assay but also by avoiding the need to re-assay all compounds in active pools. Moreover, no false negatives occurred in these assays—an important consideration from a drug discovery perspective. © 1996 Wiley-Liss, Inc.

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

The synthesis of amidinoaryloxy 9-benzyl-8-methyl-9H-purine, 7,8-dihydropteridine-6(5H)-one and 5,7-dihydropyrimido[4,5-b][1,4]oxazine-6-one inhibitors of Factor Xa is described. These compounds show nanomolar potency against FXa and maintain high selectivity over thrombin and trypsin.